MD Anderson Medical Oncology 4th Edition 2022

The MD Anderson Manual
of Medical Oncology
Notice
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The MD Anderson
Manual of
Medical Oncology
Fourth Edition
Editors
Hagop M. Katarjia, MD
Proessor o Medicine
Chair, Department o Leukemia
The University o Texas MD Anderson Cancer Center
Houston, Texas
Robrt A. Wolff, MD
Department o Gastrointestinal Medical Oncology
Houston, Texas
Alyssa G. Ribr, MD
Department o General Oncology
Houston, Texas
New York Chicago San Francisco Athens London Madrid Mexico City
Milan New Delhi Singapore Sydney Toronto
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Dedication
Emil J Freireich, MD
March 16,1927 – February 1, 2021
Dedication of the fourth Edition of “The MD Anderson Manual of Medical Oncology” to Emil J
Freireich, a Legendary Trailblazer in Cancer and Leukemia Research and Therapy
Emil J Freireich was a ounding ather o modern cancer research, and leader o the world’s rst generation o
cancer research pioneers.
Following his medical training at the University o Illinois College o Medicine at Chicago, and internal medi-
cine training at Cook County Hospital and Presbyterian Hospital, he moved to the National Cancer Institute
(1955-1965), where he made his rst seminal discoveries: the benet o platelet transusions in reducing bleeding;
the design o the rst-ever continuous-fow blood cell separator that extracted platelets rom whole blood; the
development o multidrug regimens that paved the way or the cure o childhood acute lymphoblastic leukemia
(ALL).
In 1965, Freireich moved to Houston and spent the next 55 years at MD Anderson, his real home. He was a
ounding member o the institution, which owed much o its early success and reputation to his work and that
o his mentees. Freireich’s name became synonymous with that o MD Anderson. He created a department o
Developmental Therapeutics (DT), dedicated to medical cancer research and to developing novel cancer strate-
gies. Over the next 15 years, he attracted hundreds o cancer researchers rom all over the world who, like him,
were convinced that cancer was curable and were determined to accomplish this. Many o the early chemo-
therapy drugs (cytarabine, Adriamycin, cisplatin, others) were developed during this period, and became building
blocks or curative combinations. Together with Dr Gerald Bodey, Freireich discovered the association between
neutropenia and increased risk o inections and developed the concept o empiric antibiotic therapy to prevent
and treat ever and inections in patients with cancer. This, along with platelet transusions, made cancer care
saer and opened the research venues or intensive chemotherapy and stem cell transplantation in hematologic
and solid tumors. The pheresis machines he helped to create were later used to collect stem cells or the purpose
o transplantation.
In DT, and later as a senior leader at MD Anderson, Freireich trained and mentored hundreds o oncologists, many
o whom later created their own legacies and helped hundreds o thousands o patients with cancer. He also cre-
ated in 1966 the rst training ellowship program in cancer and established clinical-translational research and care
as a new critical discipline in oncology.
To the hundreds o us who trained under Freireich, he and his stories and education are indelibly cemented in our
memories. In recognition o his massive contributions to education in cancer research and care, we dedicate this
ourth edition to Emil J Freireich.
v
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Contents
Contributors xi 9. aggrssv B-Cll Lyphos 191

A Brie History o MD Anderson Cancer Center xxv Raphael Steiner, Jason R. Westin, Sergej N. Konoplev, Luis
E. Fayad, L. Jefrey Medeiros
Foreword xxix
10. mntl Cll Lypho 227
Preace xxxi Preetesh Jain, Michael Wang
11. Nodl Prphrl T-Cll Lypho 253
I Leukemia Ranjit Nair, Francisco Vega, Swaminathan P. Iyer
Section Editor: William G. Wierda 12. Ctnos Lyphos 269
1. act Lyphoblstc L 3 Auris Huen
Hind Raei, Sergej N. Konoplev, Sa A. Wang, 13. Hodgn Lypho 291
Nicholas J. Short, Hagop M. Kantarjian, Elias J. Jabbour Collin K. Chin, L. Jefrey Medeiros, Fredrick B.
2. adlt act mylod L 23 Hagemeister, Hun J. Lee
apan M. Kadia, Joseph D. Khoury, Farhad Ravandi 14. Systc inoglobln Lght Chn
aylodoss 323
3. Chronc Lyphocytc L
nd assoctd Dsordrs 49 Gregory P. Kauman, Muzafar H. Qazilbash, Krina Patel,
Sheeba Tomas, Robert Z. Orlowski, Hans C. Lee
Nitin Jain, Philip Tompson, Carlos Bueso-Ramos,
Susan M. O’Brien, William G. Wierda 15. Wldnströ mcroglobln 333
4. Chronc mylod L 67 Melody Becnel, Gregory P. Kauman,
Elisabet E. Manasanch, Krina Patel, Hans C. Lee,
Koji Sasaki, Elias Jabbour, Jorge Cortes, Robert Z. Orlowski, Sheeba Tomas
Hagop Kantarjian
16. mltpl mylo 341
5. mylodysplstc Syndros: Th mD andrson
Paul Lin, Gregory P. Kauman, Hans C. Lee,
Cncr Cntr approch 91
Elisabet E. Manasanch, Melody Becnel, Sheeba Tomas,
Kelly Chien, Carlos Bueso-Ramos, Donna Weber, Robert Z. Orlowski, Krina Patel
Guillermo Garcia-Manero
17. Clllr Thrpy for Lypho 363
6. Phldlph Chrooso-Ngtv
Sairah Ahmed, Simrit Parmar, Sattva Neelapu
myloprolfrtv Noplss 119
Prithviraj Bose, Lucia Masarova, Hesham M. Amin,
Srdan Verstovsek III STem CeLL TRaNSPLaNTaTiON
Section Editor: Elizabeth J. Shpall
II LYmPHOma aND mYeLOma 18. atologos Htopotc Progntor-Cll
Section Editor: Nathan H. Fowler Trnsplntton 383
Neeraj Saini, Yago Nieto
7. Follclr Lypho 165
Paolo Strati, Jillian R Gunther, L. Jefrey Medeiros, Loretta 19. allognc Trnsplntton 397
J. Nastoupil Rohtesh S. Mehta, Chitra Hosing
8. mrgnl Zon nd Othr Sll Cll 20. altrntv Donor Trnsplnts: Cord Blood
Lyphos 183 Trnsplnt 427
Melody Becnel, Felipe Samaniego Hind Raei, Amanda Olson, Rohtesh S. Mehta, Betul Oran,
Katayoun Rezvani, Elizabeth J. Shpall
vii
v Cotts
21. altrntv Donor Trnsplnts: 31. Sll Bowl Cncr nd appndcl
Hplodntcl Htopotc Tors 707
St Cll Trnsplntton 447 Pat Gulhati, John Paul Shen, Kanwal P. Raghav,
Samer A. Srour, Richard E. Champlin, Michael J. Overman
Stean O. Ciurea
32. Colorctl Cncr 733
22. Clllr Thrpy n allognc Htopotc Arvind Dasari, Benny Johnson, Christine Parseghian,
Cll Trnsplntton 457 Kanwal P. Raghav, Scott Kopetz
Amanda Olson, Jeremy Ramdial, Uri Greenbaum, Paul
33. anl Cncr 765
Lin, Katayoun Rezvani, Partow Kebriaei
Emma Holliday, Van Morris, Craig A. Messick
34. Nrondocrn Tors 781
iV LuNG CaNCeR Jessica E. Maxwell, James C. Yao, Daniel M. Halperin
Section Editor: Bonnie S. Glisson
23. Sll Cll Crcno o th Lng 475 Vii BReaST CaNCeR
Jeremy A. Ross, Lauren A. Byers, Carl M. Gay Section Editor: Gabriel N. Hortobagyi
24. Non–Sll Cll Lng Cncr: Gnrl
Prncpls, mngnt o Loclzd Dss, 35. erly-Stg nd Loclly advncd Brst
nd Trtnt o mtsttc Dss wthot Cncr 803
Oncogn Drvrs 495 Demetria Smith-Graziani, Mariana Chavez-MacGregor
Mehmet Altan, Joshua M Gulvin, George Simon, 36. mtsttc Brst Cncr 829
Bonnie Glisson Haven R. Garber, Meghan S. Karuturi,
25. Trgtd Thrps n Non–Sll Cll Lng Gabriel N. Hortobagyi
Cncr 535 37. mngnt o Loclly advncd Brst
Yasir Y. Elamin, Don L. Gibbons, Marcelo V. Negrao Cncr, incldng intory Brst
Cncr 863
Bora Lim, Gabriel N. Hortobagyi
V HeAD AnD neCK CAnCeR
Section Editor: Bonnie S. Glisson 38. Spcl Sttons n Brst Cncr 875
Rachel M. Layman
26. Hd nd Nck Cncr 555
Ruth Sacks, David Boyce-Fappiano, Amy Moreno,
Frank Mott Viii GYNeCOLOGiC maLiGNaNCieS
Section Editor: Karen H. Lu
Vi GaSTROiNTeSTiNaL 39. Ovrn Cncr 897

CaNCeR Roni Nitecki, Lauren P. Cobb, Amir A. Jazaeri,
J. Alejandro Rauh-Hain
Section Editor: Robert A. Wol
40. Tors o th utrn Corps 931
27. Gstrc, Gstrosophgl Jncton, nd Michaela A. Onstad, Shannon N. Westin, Karen H. Lu
esophgl Cncrs 579
Mariela Blum Murphy, Elena Elimova, 41. Tors o th utrn Crvx 955
Ahmed Abdelhakeem, Jaer Ajani Gloria Salvo, Mila P. Salcedo, Sol Basabe, Pedro . Ramirez
28. Pncrtc Cncr 619 42. Gsttonl Trophoblstc Dss 983
Jonathan D. Mizrahi, Anirban Maitra, Han . Cun, Aaron Shaer
Robert A. Wol
29. Blry Trct Cncr 647 ix GeNiTOuRiNaRY

Shalini Makawita, Sunyoung Lee, Yun Shin Chun, maLiGNaNCieS
Millicent A. Roach, Eugene J. Koay, Milind Javle
Section Editor: Nizar M. annir
30. Hptoclllr Crcno 677
Sunyoung S. Lee, Hao Chi Zhang, Hop S. ran Cao, 43. Rnl Cll Crcno 1005
Sudha Kodali, Joshua D. Kuban, Eugene J. Koay, Andrew W. Hahn, Jose A. Karam, Christopher G. Wood,
Rony Avritscher, Ahmed O. Kaseb Nizar M. annir
Cotts 
44. Blddr Cncr 1027 55. Cncr Gnocs 1283

Alexander Y. Andreev-Drakhlin, Ashish M. Kamat, Jason A. Willis, Jennier B. Goldstein, Zhijing Zhang,
Arlene O. Sieer-Radtke Andy Futreal
45. Prostt Cncr 1049 56. ino-oncology 1297

Patrick Pilié, Paul Viscuse, Christopher J. Logothetis, Bilal A. Siddiqui, Sangeeta Goswami, James P. Allison,
Paul G. Corn Padmanee Sharma
46. Pnl Cncr 1071 57. Trgtd Thrpy n Cncr 1323

Jad Chahoud, Curtis A. Pettaway Rabih Said, Apostolia-Maria simberidou
47. Gr Cll Tors 1081 58. Vrl inctons n Ptnts
Joseph A. Moore, Shi-Ming u wth Cncr 1345
Fareed Khawaja, Roy F. Chemaly
NeuROLOGiC TumORS 59. Fngl inctons n Ptnts wth

x Cncr 1363
Section Editor: John de Groot
Bruno P. Granwehr, Dimitrios P. Kontoyiannis
48. Tors o th Cntrl Nrvos 60. endocrn nd mtbolc Coplctons
Syst 1105 o Cncr Thrpy 1381
Shiao-Pei Weathers, Barbara O’Brien, Ashley Aaroe, Rachael Hosein, Sara Bedrose, Rebecca Jeun,
Debra Yeboa, Sujit Prabhu, John de Groot Jeena M. Varghese, Sonali N. Tosani
61. Oncologc ergncs 1407

xi maLiGNaNT meLaNOma Sai-Ching Jim Yeung, Ellen F. Manzullo,
Section Editor: Michael A. Davies Patrick Chafari
62. Oncocrdology 1435

49. mlno 1133
Elie Mouhayar, Danielle El-Haddad,
Houssein Saa, Jane Mattei, Andrew J. Bishop, Peter Kim, Kara Tompson, Cezar Iliescu,
Emily Z. Keung, Sirisha Yadugiri, Michael A. Davies, Abdulrazzak Zaria
Isabella C. Glitza Oliva
63. Plonry Coplctons o Cncr
Thrpy 1461
xii SaRCOmaS Audra J. Schwalk, Saadia A. Faiz, Horiana B. Grosu,
Section Editor: Shreyaskumar Patel Lara Bashora, Vickie R. Shannon
50. Sot Tss nd Bon Srcos 1159 64. Cncr-assoctd Throboss 1493
Kelly A. Casteel, Michael H. Kroll
J. Andrew Livingston, Anthony P. Conley, Ravin Ratan,
Vinod Ravi, Shreyaskumar Patel
xiV SuPPORTiVe aND PaLLiaTiVe

xiii OTHeR TumORS aND CaNCeR CaRe
TOPiCS OF iNTeReST Section Editor: Eduardo Bruera
Section Editor: Alyssa G. Rieber
65. inptnt Spportv nd Plltv
51. endocrn mlgnncs 1189 Cr 1509
Ha Nguyen, Mouhammed Amir Habra Ahsan Azhar, Ali Haider, Eduardo Bruera
52. Th acqrd inodfcncy 66. intgrtd Otptnt

Syndro–Rltd Cncrs 1223 Spportv Cr 1519
Adan Rios, Fredrick B. Hagemeister Akhila Reddy, David Hui, Eduardo Bruera
53. Crcno o unknown Prry 1253 67. Rhbltton 1529

Gauri R. Varadhachary, Kanwal P. Raghav, Ryan W. Huey Brian Fricke, An Ngo-Huang, Ekta Gupta
54. Pdtrc Cncrs 1271 68. Pn mngnt nd Sypto

Branko Cuglievan, Wak Zaky, Richard Gorlick, Control 1553
Douglas Harrison Kaoswi K. Shih, Rony Dev, Shalini Dalal
 Contents
70. Bg D nd Mhne Lernng

xV Biostatistics n onlgy 1593
Section Editor: Xuelin Huang Peng Wei, Hai Shu
69 . sl Degn fr onlgy clnl 71. Vlue-Bed onlgy 1603

trl 1579 Casey J. Allen, Aileen Chen, Ryan W. Huey,
Ya-Chen Tina Shih
Xuelin Huang, Wei Qiao, Fang Xia, E Lin, Liang Zhu,
Jing Ning Index 1619
The fourth edition of The MD Anderson Manual of Medical Oncology is also available online as part of the excellent
accesshemonc.com website, with direct links to a comprehensive drug therapy database and to other important
medical texts that include Hematology-Oncology Therapy. The online edition of The MD Anderson Manual of Medical
Oncology also includes PubMed links to journal articles cited in the references.
New in this edition is the online-only presentation of clinical cases, The MD Anderson Manual of Medical Oncology
Cases, for readers to explore, with each case linked to the relevant chapter.
Contributors
Hind Raei, MD Joseph D. Khoury, MD

Instructor Assistant Proessor
Department o Stem Cell Transplantation and Cellular Therapy The University o Texas MD Anderson Cancer Center
Fellow, Hematology and Oncology Houston, Texas
Division o Cancer Medicine
The University o Texas MD Anderson Cancer Center Farhad Ravandi, MD
Houston, Texas Proessor
Department o Leukemia
Sergej N. Konoplev, MD, PhD The University o Texas MD Anderson Cancer Center
Associate Proessor Houston, Texas
Department o Hematopathology
The University o Texas MD Anderson Cancer Center Nitin Jain, MD
Houston, Texas Associate Proessor
Sa A. Wang, MD The University o Texas MD Anderson Cancer Center
Proessor Houston, Texas
Department o Hematopathology
Division o Pathology/Lab Medicine Philip Thompson, MD
The University o Texas MD Anderson Cancer Center Associate Proessor
Houston, Texas Department o Leukemia
The University o Texas MD Anderson Cancer Center
Nicholas J. Short, MD Houston, Texas
Assistant Proessor
Department o Leukemia Carlos Bueso-Ramos, MD, PhD
Division o Cancer Medicine Proessor
The University o Texas MD Anderson Cancer Center Department o Hematopathology
Houston, Texas The University o Texas MD Anderson Cancer Center
Houston, Texas
Hagop M. Kantarjian, MD
Proessor and Chairman Susan M. O’Brien, MD
Department o Leukemia Associate Director or Clinical Science
Samsung Distinguished University Chair in Cancer Medicine Chao Family Comprehensive Cancer Center
The University o Texas MD Anderson Cancer Center University o Caliornia Irvine
Houston, Texas Irvine, Caliornia
Elias J. Jabbour, MD William G. Wierda, MD, PhD

Department o Leukemia Proessor
Division o Cancer Medicine Department o Leukemia
The University o Texas MD Anderson Cancer Center The University o Texas MD Anderson Cancer Center
Houston, Texas Houston, Texas
Tapan M. Kadia Koji Sasaki, MD, PhD

Department o Leukemia Department o Leukemia
Division o Cancer Medicine The University o Texas MD Anderson Cancer Center
The University o Texas MD Anderson Cancer Center Houston, Texas
Houston, Texas
xi
xii Contributors
Elias Jabbour, MD Srdan Verstovsek, MD, PhD

Proessor Proessor
Department o Leukemia United Energy Resources, Inc.
The University o Texas MD Anderson Cancer Center Department o Leukemia
Houston, Texas Director, Hanns A. Pielenz Clinical Research Center or
Myeloprolierative Neoplasms (MPN)
Jorge Cortes, MD The University o Texas MD Anderson Cancer Center
Director Houston, Texas
Georgia Cancer Center at Augusta University
Medical College o Georgia Paolo Strati, MD
Augusta, Georgia Assistant Proessor
Department o Lymphoma and Myeloma
Hagop Kantarjian, MD The University o Texas MD Anderson Cancer Center
Proessor and Chairman Houston, Texas
Samsung Distinguished University Chair in Cancer Medicine Jillian R. Gunther, MD, PhD
The University o Texas MD Anderson Cancer Center Assistant Proessor
Houston, Texas Department o Radiation Oncology
Kelly Chien, MD Houston, Texas
Department o Leukemia L. Jerey Medeiros, MD
The University o Texas MD Anderson Cancer Center Proessor
Houston, Texas Department o Hemato-Pathology
Carlos Bueso-Ramos, MD, PhD Houston, Texas
Proessor
Department o Hematopathology Loretta J. Nastoupil, MD
The University o Texas MD Anderson Cancer Center Associate Proessor
Houston, Texas Department o Lymphoma and Myeloma
Guillermo Garcia-Manero, MD Houston, Texas
Proessor
Chie, Section o Myelodysplastic Syndromes Felipe Samaniego, MD
Department o Leukemia Department o Lymphoma and Myeloma
Prithviraj Bose, MD Raphael Steiner, MD

Associate Proessor Assistant Proessor
Lucia Masarova, MD Jason R. Westin, MD

Assistant Proessor Associate Proessor
Hesham M. Amin, MD, MSc Sergej N. Konoplev, MD, PhD

Proessor Associate Proessor
Department o Hematopathology Department o Hematopathology
Contributors xiii
Luis E. Fayad, MD Gregory P. Kauman, MD

Proessor Assistant Proessor
Department o Lymphoma and Myeloma Department o Lymphoma and Myeloma
Preetesh Jain, MBBS, MD, DM, PhD Muzaar H. Qazilbash, MD

Assistant Proessor Proessor
Department o Lymphoma and Myeloma Department o Stem Cell Transplantation and Cellular Therapy
Mantle Cell Lymphoma Program o Excellence The University o Texas MD Anderson Cancer Center
Houston, Texas
Krina Patel, MD
Michael Wang, MD Associate Proessor
Proessor Department o Lymphoma and Myeloma
Department o Lymphoma/Myeloma The University o Texas MD Anderson Cancer Center
Houston, Texas
Sheeba Thomas, MD
Ranjit Nair, MD Proessor
Assistant Proessor Department o Lymphoma and Myeloma
Department o Lymphoma and Myeloma The University o Texas MD Anderson Cancer Center
Houston, Texas
Robert Z. Orlowski, MD, PhD
Francisco Vega, MD, PhD Proessor
Department o Hematopathology The University o Texas MD Anderson Cancer Center
Houston, Texas
Elisabet E. Manasanch, MD, MHSc
Swaminathan P. Iyer, MD Associate Proessor
Department o Lymphoma and Myeloma The University o Texas MD Anderson Cancer Center
Houston, Texas
Paul Lin
Auris Huen, PharmD, MD Assistant Proessor
Associate Proessor Department o Stem Cell Transplantation and Cellular Therapy
Department o Dermatology The University o Texas MD Anderson Cancer Center
Houston, Texas
Hans C. Lee, MD
Collin K. Chin, MBBS Assistant Proessor
Bloodwise Clinic Department o Lymphoma and Myeloma
Perth, Australia The University o Texas MD Anderson Cancer Center
Houston, Texas
Fredrick B. Hagemeister
Department o Lymphoma and Myeloma Melody Becnel, MD
Hun J. Lee Houston, Texas
The University o Texas MD Anderson Cancer Center Donna Weber
Houston, Texas
xiv Contributors
Sairah Ahmed Samer A. Srour, MB ChB, MS

Department o Lymphoma and Myeloma Assistant Proessor
The University o Texas MD Anderson Cancer Center Department o Stem Cell Transplantation and Cellular Therapy
Houson, Texas
Simrit Parmar
Department o Lymphoma and Myeloma Richard E. Champlin, MD
The University o Texas MD Anderson Cancer Center Chairman
Houston, Texas Department o Stem Cell Transplantation and Cellular Therapy
Sattva Neelapu Houston, Texas
The University o Texas MD Anderson Cancer Center Stean O. Ciurea, MD
Department o Stem Cell Transplantation and Cellular Therapy
Neeraj Saini, MD The University o Texas MD Anderson Cancer Center
Assistant Proessor Houston, Texas;
Department o SCT and Cellular Therapy Proessor, Director o the Hematopoietic Stem Cell
Department o Lymphoma and Myeloma Transpalntation and Cellualr Therapy Program
The University o Texas MD Anderson Cancer Center University o Caliornia, Irvine, Caliornia
Houston, Texas
Amanda Olson, MD
Yago Nieto, MD Associate Proessor
Proessor Department o Stem Cell Transplantation and Cellular Therapy
Department o SCT and Cellular Therapy The University o Texas MD Anderson Cancer Center
Houston, Texas
Jeremy Ramdial
Rohtesh S. Mehta, MD, MPH, MS Assistant Proessor
Assistant Proessor Department o Stem Cell Transplantation and Cellular Therapy
Department o Stem Cell Transplantation and Cellular Therapy The University o Texas MD Anderson Cancer Center
Division o Cancer Medicine Houston, Texas
Houston, Texas Uri Greenbaum
Chitra Hosing, MD The University o Texas MD Anderson Cancer Center
Proessor Houston, Texas
Houston, Texas Partow Kebriaei
Proessor
Betul Oran, MD Department o Stem Cell Transplantation and Cellular Therapy
Associate Proessor The University o Texas MD Anderson Cancer Center
Department o Stem Cell Transplantation and Cellular Therapy Houston, Texas
The University o Texas MD Anderson Cancer Center Jeremy A. Ross, MD
Houston, Texas Medical Oncologist
Center or Cancer and Blood Disorders
Katayoun Rezvani, MD, PhD Fort Worth, Texas
Proessor
Department o Stem Cell Transplantation and Cellular Therapy Lauren A. Byers, MD
Division o Cancer Medicine Proessor
The University o Texas MD Anderson Cancer Center Department o Thoracic/Head and Neck Medical Oncology
Houston, Texas Division o Cancer Medicine
Elizabeth J. Shpall, MD Houston, Texas
Proessor
Houston, Texas
Contributors xv
Carl M. Gay, MD, PhD Amy Moreno, MD

Assistant Proessor Assistant Proessor
Department o Thoracic/Head and Neck Medical Oncology Department o Radiation Oncology, Head and Neck Service
Division o Cancer Medicine The University o MD Anderson Cancer Center
Houston, Texas
Frank Mott, MD, FACP
Mehmet Altan Proessor
Department o Thoracic/Head and Neck Medical Oncology Department o Thoracic/Head and Neck Medical Oncology
Division o Cancer Medicine The University o MD Anderson Cancer Center
Houston, Texas
Mariela Blum Murphy
Joshua M. Gulvin, MD Department o Gastrointestinal Medical Oncology
Hematology/Oncology The University o Texas MD Anderson Cancer Center
St. Charles Health System Houston, Texas
Redmond, OR
Elena Elimova, MD
George Simon, MD Medical Oncologist
Executive Director, Clinical Research Unit Princess Margaret Cancer Centre
Mott Cancer Center-Advent Health Toronto, ON
Celebration, FL
Ahmed Abdelhakeem, MD
Bonnie Glisson Internal Medicine Resident
Department o Thoracic/Head and Neck Medical Oncology Department o Medicine
The University o Texas MD Anderson Cancer Center Jaer Ajani
Houston, Texas Department o Gastrointestinal Medical Oncology
Yasir Y. Elamin Houston, Texas
Department o Thoracic / Head and Neck Medical Oncology Jonathan D. Mizrahi, MD
Houston, Texas Department o Hematology and Oncology
The Oschner Clinic
Don L. Gibbons
Proessor Anirban Maitra, MBBS
Department o Thoracic / Head and Neck Medical Oncology; Proessor
Department o Molecular and Cellular Oncology Department o Anatomical Pathology
Marcelo V. Negrao Robert A. Wol, MD

Department o Thoracic / Head and Neck Medical Oncology Department o GI Medical Oncology
Ruth Sacks, MD Shalini Makawita, MD

Assistant Proessor Medical Oncologist
Department o Hematology and Medical Oncology Baylor College o Medicine
Winship Cancer Center o Emory University Houston, Texas
Atlanta, Georgia
Sunyoung Lee, MD, PhD
David Boyce-Fappiano, MD Assistant Proessor
Resident Physician Department o Gastrointestinal Medical Oncology
Department o Radiation Oncology Division o Cancer Medicine
The University o MD Anderson Cancer Center The University o Texas MD Anderson Cancer Center
xvi Contributors
Yun Shin Chun, MD, FACS Rony Avritscher

Associate Proessor Proessor
Department o Surgical Oncology Department o Interventional Radiology
Division o Surgery The University o Texas MD Anderson Cancer Center
Houston, Texas
Ahmed O. Kaseb
Millicent A. Roach, BS Proessor
Assistant Clinical Research Coordinator Department o Gastrointestinal Medical Oncology
Department o Radiation Oncology The University o Texas MD Anderson Cancer Center
Division o Radiation Oncology Houston, Texas
Houston, Texas Pat Gulhati, MD, PhD
Eugene J. Koay, MD, PhD Cancer Institute o New Jersey
Associate Proessor Rutgers University
Department o Radiation Oncology
Division o Radiation Oncology John Paul Shen
The University o Texas MD Anderson Cancer Center Department o Gastrointestinal Medical Oncology
Houston, Texas
Milind Javle, MD
Proessor Michael J. Overman
Department o Gastrointestinal Medical Oncology Department o Gastrointestinal Medical Oncology
Houston, Texas
Arvind Dasari, MD, MS
Sunyoung S. Lee Associate Proessor
Proessor Department o Gastrointestinal Medical Oncology
Department o Gastrointestinal Medical Oncology The University o Texas MD Anderson Cancer Center
Houston, Texas
Benny Johnson, DO
Hao Chi Zhang Assistant Proessor
Assistant Proessor Department o Gastrointestinal Medical Oncology
Department o Gastroenterology, Hepatology, and Nutrition, The University o Texas MD Anderson Cancer Center
Houston, Texas
Christine Parseghian, MD
Hop S. Tran Cao Assistant Proessor
Associate Proessor Department o Gastrointestinal Medical Oncology
Department o Surgical Oncology The University o Texas MD Anderson Cancer Center
Houston, Texas
Kanwal P. Raghav, MD
Sudha Kodali Associate Proessor
Transplant Hepatology, Houston Methodist Hospital Department o Gastrointestinal Medical Oncology
Houston, Texas
Joshua D. Kuban
Associate Proessor Scott Kopetz, MD, PhD
Department o Interventional Radiology Proessor and Deputy Chair
The University o Texas MD Anderson Cancer Center Department o Gastrointestinal Medical Oncology
Houston, Texas
Eugene J. Koay
Associate Proessor Emma Holliday, MD
Department o Radiation Oncology Department o Radiation Oncology
Contributors xvii
Van Morris, MD Bora Lim, MD

Department o Medical Oncology Associate Proessor
The University o Texas MD Anderson Cancer Center Department o Medicine-Oncology
Houston, Texas Baylor College o Medicine
Houston, Texas
Craig A. Messick, MD, FACS, FASCRS
Associate Proessor Gabriel N. Hortobagyi, MD, FACP
Department o Colon and Rectal Surgery; Proessor
Department o Surgical Oncology Department o Breast Medical Oncology
Jessica E. Maxwell, MD, MBA Rachel M. Layman, MD

Department o Surgical Oncology The University o Texas MD Anderson Cancer Center
Houston, Texas
Roni Nitecki, MD, MPH
James C. Yao, MD Clinical Fellow
Proessor and Chair Department o Gynecologic Oncology and Reproductive
Department o Gastrointestinal Medical Oncology Medicine
Daniel M. Halperin, MD Lauren P. Cobb, MD

Department o Gastrointestinal Medical Oncology Department o Gynecologic Oncology and Reproductive
The University o Texas MD Anderson Cancer Center Medicine
Houston, Texas
Demetria Smith-Graziani, MD
Fellow, Hematology and Medical Oncology J. Alejandro Rauh-Hain, MD, MPH
The University o Texas MD Anderson Cancer Center; Instructor Assistant Proessor
Department o Medicine, Section o Hematology and Oncology, Gynecologic Oncology and Reproductive Medicine
Baylor College o Medicine The University o Texas MD Anderson Cancer Center
Mariana Chavez-MacGregor, MD Amir A. Jazaeri, MD

Associate Proessor Proessor
Department o Health Services Research Department o Gynecologic Oncology
Haven R. Garber, MD, PhD Michaela A. Onstad, MD, MPH

Department o Breast Medical Oncology Gynecologic Oncology and Reproductive Medicine
Meghan S. Karuturi, MD Shannon N. Westin, MD, MPH

Associate Proessor Associate Proessor
Department o Breast Medical Oncology Department o Gynecologic Oncology and Reproductive
The University o Texas MD Anderson Cancer Center Medicine
Houston, Texas
Gabriel N. Hortobagyi, MD, FACP
Proessor
Department o Breast Medical Oncology
Houston, Texas
xviii Contributors
Karen H. Lu, MD Jose A. Karam, MD, FACS

Chair and Proessor Associate Proessor
Department o Gynecologic Oncology and Reproductive Department o Urology
Medicine Division o Surgery and Department o Translational Molecular
The University o Texas MD Anderson Cancer Center Pathology
Houston, Texas Division o Pathology and Laboratory Medicine
Gloria Salvo, MD Houston, Texas
Clinical Research
Department o Gynecologic Oncology and Reproductive Christopher G. Wood, MD, FACS
Medicine Proessor
The University o Texas MD Anderson Cancer Center Deputy Chairman, Department o Urology
Houston Texas The University o Texas MD Anderson Cancer Center
Houston, Texas
Mila P. Salcedo, MD
Visiting Scientist Nizar M. Tannir, MD, FACP
Department o Gynecologic Oncology and Reproductive Proessor
Medicine Department o Genitourinary Medical Oncology
The University o Texas MD Anderson Cancer Center, Houston, Division o Cancer Medicine
Texas; Associate Proessor, Chair o Gynecology The University o Texas MD Anderson Cancer Center
The Obstetrics and Gynecology Department, Federal University Houston, Texas
o Health Sciences o Porto Alegre/Santa Casa de Misericordia
o Porto Alegre Hospital, Brazil Alexander Y. Andreev-Drakhlin, MD, PhD
Genentech, San Francisco, Caliornia
Sol Basabe, MD
Postdoctoral Fellow Arlene O. Sieker-Radtke, MD
Medicine, Department o Genitourinary Medical Oncology
Pedro T. Ramirez, MD Ashish M. Kamat, MD

Proessor, Editor-in-Chie Proessor
International Journal o Gynecological Cancer, David M. Department o Urology
Gershenson Distinguished Proessor in Ovarian Cancer The University o Texas MD Anderson Cancer Center
Research, Director o Minimally Invasive Surgical Research Houston, Texas
and Education, Department o Gynecologic Oncology and
Reproductive Medicine Patrick Pilié, MD
Houston, Texas Department o GU Medical Oncology
Han T. Cun, MD Houston, Texas
Clinical Fellow
Department o Gynecologic Oncology and Reproductive Paul Viscuse, MD
Medicine Clinical Fellow
The University o Texas MD Anderson Cancer Center Division o Cancer Medicine
Houston, Texas
Aaron Shaer, MD
Associate Proessor Christopher J. Logothetis, MD
Medicine Department o GU Medical Oncology
Andrew W. Hahn, MD Paul G. Corn, MD

Medical Oncology Fellow Proessor
Division o Cancer Medicine Department o GU Medical Oncology
Contributors xix
Jad Chahoud, MD, MPH Houssein Saa, MD

GU Department, Mott Cancer Center, Tampa, Florida Internal Medicine Resident
Montefore Health System
Curtis A. Pettaway, MD Bronx, New York
Urology Department
The University o Texas MD Anderson Cancer Center Jane Mattei
Houston, Texas Clinical Fellow
Department o Melanoma Medical Oncology
Joseph A. Moore, MD The University o Texas MD Anderson Cancer Center
Sta Oncologist Houston, Texas
Cancer Center o Kansas
Wichita, Kansas Andrew J. Bishop, MD, AM
Shi-Ming Tu, MD Department o Surgical Oncology
Proessor The University o Texas MD Anderson Cancer Center
Department o GU Medical Oncology Houston, Texas
Houston, Texas Emily Z. Keung, MD
Shiao-Pei Weathers, MD Department o Surgical Oncology
Assistant Proessor The University o Texas MD Anderson Cancer Center
Department o Neuro-Oncology Houston, Texas
Division o Cancer Medicine; Clinical Medical Director, Brain and
Spine Center Sirisha Yadugiri, PhD, MHA
The University o Texas MD Anderson Cancer Center Sr. Technical Writer, Department o Melanoma Medical Oncology
Houston, Texas
Barbara O’Brien, MD
Assistant Proessor Michael A. Davies, MD, PhD
Department o Neuro-Oncology Proessor and Chair
Division o Cancer Medicine Department o Melanoma Medical Oncology
The University o Texas MD Anderson Cancer Center Proessor, Translational Molecular Pathology, Genomic Medicine,
Houston, Texas Systems Biology, Anne and John Mendelsohn Chair in Cancer
Research
Ashley Aaroe, MD The University o Texas MD Anderson Cancer Center
Clinical Fellow, Department o Neuro-Oncology Houston, Texas
The University o Texas MD Anderson Cancer Center Isabella C. Glitza Oliva
Houston, Texas Department o Melanoma Medical Oncology
Debra Yeboa, MD Houston, Texas
Department o Radiation Oncology J. Andrew Livingston, MD
Division o Radiation Oncology Assistant Proessor
The University o Texas MD Anderson Cancer Center Department o Sarcoma Medical Oncology
Houston, Texas
Sujit Prabhu, MD, FRCS (Ed)
Proessor Anthony P. Conley
Department o Neurosurgery Associate Proessor
Division o Surgery Department o Sarcoma Medical Oncology
John de Groot, MD Ravin Ratan, MD

Department Chair ad interim, Department o Neuro-Oncology Department o Sarcoma Medical Oncology
Houston, Texas
xx Contributors
Vinod Ravi, MD Jason A. Willis, MD

Associate Proessor Assistant Proessor
Department o Sarcoma Medical Oncology Department o GI Medical Oncology (or Gastrointestinal Medical
The University o Texas MD Anderson Cancer Center Oncology)
Houston, Texas
Shreyaskumar Patel, MD
Proessor Jennier B. Goldstein, MD, PhD
Department o Sarcoma Medical Oncology Medical Oncologist
The University o Texas MD Anderson Cancer Center University o Caliornia-Irvine
Houston, Texas Irvine, Caliornia
Ha Nguyen, MD Zhijing Zhang

Assistant Proessor College Student
Department o Medicine Department o Genomic Medicine
Baylor College o Medicine The University o Texas MD Anderson Cancer Center
Mouhammed Amir Habra, MD Andy Futreal

Proessor Department o Genomic Medicine
Department o Endocrine Neoplasia The University o Texas MD Anderson Cancer Center
Houston, Texas
Bilal A. Siddiqui, MD
Adan Rios, MD Assistant Proessor
Associate Proessor Department o Genitourinary Medical Oncology
Division o Medical Oncology The University o Texas MD Anderson Cancer Center
The University o Texas Health Science Center-Houston Houston, Texas
Houston, Texas
Sangeeta Goswami, MD, PhD
Gauri R. Varadhachary, MD† Assistant Proessor
Proessor Departments o Genitourinary Medical Oncology and
Department o GI Medical Oncology Immunology
Branko Cuglievan, MD James P. Allison, PhD

Assistant Proessor Chair and Regental Proessor, Department o Immunology, MD
Section Chie ad Interim, Pediatric Leukemia, and Lymphoma Anderson Cancer Center
Wafk Zaky, MD Padmanee Sharma, MD, PhD

Associate Proessor Proessor, Departments o Genitourinary Medical Oncology and
Department o Pediatrics Immunology
Richard Gorlick, MD Rabih Said, MD, MPH

Proessor Associate Proessor, Oncology Division, St George Hospital
Division Head and Department Chair, University Medical Center, University o Balamand, Beirut,
Department Chair ad interim, Sarcoma Medical Oncology Lebanon
Houston, Texas Apostolia-Maria Tsimberidou, MD, PhD
Proessor
Douglas Harrison, MD, MS Department o Investigational Cancer Therapeutics
Associate Proessor The University o Texas MD Anderson Cancer Center
Center Medical Director Houston, Texas
Houston, Texas
Contributors xxi
Fareed Khawaja, MD Sai-Ching Jim Yeung

Department o Inectious Diseases Department o Emergency Medicine
Roy F. Chemaly, MD Ellen F. Manzullo, MD, FACP

Department o Inectious Diseases Deputy Division Head (Clinical) Internal Medicine
Bruno P. Granwehr, MD, MS, FACP, CMQ Patrick Chatari, MD, MBA, FACP
Department o Inectious Diseases Department o Emergency Medicine
The University o Texas MD Anderson Cancer Center Clinical Medical Director, Clinical Decision Unit (CDU)
Houston, Texas
Dimitrios P. Kontoyiannis, MD, ScD, PhD(Hon.), FACP,
FIDSA, FECMM, FAAM, FAAAS Elie Mouhayar, MD, FACC, FSVM
Department o Inectious Diseases, Texas 4000, Distinguished Department o Cardiology.
Endowed Proessor or Cancer Research, Deputy Head The University o Texas M. D. Anderson Cancer Center
Division o Internal Medicine Houston, Texas
Houston, Texas Danielle El-Haddad, MD
Clinical research resident, Department o Cardiology.
Rachael Hosein, MD The University o Texas M. D. Anderson Cancer Center
Aurora Health Care, 2414 Kohler Memorial Dr, Sheboygan, Houston, Texas
Wisconsin; Division o Endocrinology, Diabetes, and
Metabolism, McGovern Medical School Peter Kim, MD
The University o Texas Health Science Center Associate Proessor
Houston, Texas Department o Cardiology.
The University o Texas M. D. Anderson Cancer Center
Sara Bedrose, MD Houston, Texas
Department o Endocrinology, Diabetes and Metabolism, Baylor
College o Medicine Kara Thompson, MD
Department o Cardiology.
Rebecca Jeun, MD The University o Texas M. D. Anderson Cancer Center
Department o Endocrinology, Diabetes and Metabolism, Baylor Houston, Texas
College o Medicine
Houston, Texas Cezar Iliescu, MD
Proessor
Sonali N. Thosani, MD Department o Cardiology.
Associate Proessor The University o Texas M. D. Anderson Cancer Center
Department o Endocrine Neoplasia and Hormonal Disorders Houston, Texas
Section Chie, Diabetes and Metabolic Disorders
Certifed in Medical Quality (CMQ) Kaoswi K. Shih, MD
Division o Internal Medicine Quality Council, Chair Assistant Proessor
Patient Saety and Quality Ocer, Endocrine Department Palliative Care Medicine
The University o Texas MD Anderson Cancer Center University o Texas MD Anderson Cancer Center
Jeena M. Varghese, MD Rony Dev, MD

Endocrine Neoplasia and Hormonal Disorders Palliative Care Medicine
The University o Texas MD Anderson Cancer Center University o Texas MD Anderson Cancer Center
xxii Contributors
Shalini Dalal, MD Ahsan Azhar, MD

Palliative Care Medicine Palliative, Rehabilitation and Integrative Medicine Department
University o Texas MD Anderson Cancer Center The University o Texas MD Anderson Cancer Center
Abdulrazzak Zaria, MD Eduardo Bruera, MD

Department o Cardiology. Proessor and Chair, Palliative, Rehabilitation and Integrative
The University o Texas M. D. Anderson Cancer Center Medicine Department
Houston, Texas
Audra J. Schwalk, MD
Assistant Proessor Akhila Reddy, MD
Department o Internal Medicine-Pulmonary and Critical Care Associate Proessor
Medicine Department o Palliative, rehabilitation, and Integrative Medicine
University o Southwestern Medicine Center The University o Texas MD Anderson Cancer Center
Dallas, Texas Houston, Texas
Saadia A. Faiz, MD David Hui, MD

Department o Pulmonary Medicine Department o Palliative, Rehabilitation, and Integrative Medicine
Horiana B. Grosu, MD Brian Fricke, MD

Associate Proessor Fellow, Department o Palliative, Rehabilitation, and Integrative
Department o Pulmonary Medicine Medicine
Lara Bashora, MD An Ngo-Huang, DO

Vickie R. Shannon, MD Ekta Gupta, MD

Kelly A. Casteel Xuelin Huang, PhD

Department o Benign Hematology Deputy Chair, Department o Biostatistics
Michael H. Kroll, MD Wei Qiao, PhD

Proessor Senior Biostatistician, Department o Biostatistics
Department o Benign Hematology The University o Texas MD Anderson Cancer Center
Houston, Texas
Fang Xia, PhD
Ali Haider, MD Biostatistics Manager, Gilead Sciences, Foster City, Caliornia
Department o Palliative, Rehabilitation and Integrative Medicine E Lin, MD, PhD
Department Associate Director o Biostatistics, PTC Therapeutics, Inc., South
The University o Texas MD Anderson Cancer Center Plainfeld, New Jersey
Houston, Texas
Contributors xxiii
Liang Zhu, PhD Aileen Chen, MD, MPP

Associate Proessor, Department o Internal Medicine Associate Proessor
The University o Texas Health Science Center at Houston Department o Radiation Oncology and Department o Health
Houston, Texas Services Research
Jing Ning, PhD Houston, Texas
Associate Proessor
Department o Biostatistics Ryan W. Huey, MD
Houston, Texas Department o Gastrointestinal Medical Oncology
Peng Wei, PhD The University o Texas MD Anderson Cancer Center
Department o Biostatistics Houston, Texas
Houston, Texas Ya-Chen Tina Shih, PhD
Proessor
Hai Shu, PhD Department o Health Services Research, Chie, Section o Cancer
Department o Biostatistics, School o Global Public Health, New Economics and Policy
York University, New York, New York Division o Cancer Prevention and Population Sciences
Casey J. Allen, MD Houston, Texas
Fellow, Department o Surgical Oncology
Division o Surgery
Houston, Texas
A Brief History
of MD Anderson
Cancer Center
Houston’s evolution into the ourth largest city in the The charter o the Anderson
United States was propelled by our seminal events. Foundation did not speciy
First was the Great Galveston Hurricane o 1900, how the money should be
which destroyed the city port o Galveston and led to used, but Mr. Anderson’s
the realization that Houston could become a viable and trustees and close riends—
saer deep-water port; this led to the widening o the Colonel William Bates,
Ship Channel to oer direct access to Houston. Second John Freeman and Horace
was the discovery o oil at Spindletop in Beaumont, Williams—leaned strongly
Texas in 1901. This prompted the development o the in avor o health care. Soon
oil industry in Texas and transormed Houston rom ater taking possession o the
a small town into a large city. Third was (o course) estate rom its executors, the
the commercialization o air conditioning in 1950’s, FiGURe 2. trustees turned to Dr. Ernest
which made Houston (and many Southern cities o the Bertner (Fig. 2) or advice. Dr.
United States) more livable. And lastly, the allocation Bertner was a prominent Houston surgeon and gyne-
o land or the Texas Medical Center created the larg- cologist who was well known to the trustees because
est medical center in the world with one o the high- o his care or cancer patients, despite inadequate
est densities o clinical acilities or patient care, basic acilities and treatment options (he was later called the
science, and translational research. The Texas Medical “ather o the Texas Medical Center”).
Center is a major contributor to Houston’s economy The trustees and Dr. Bertner noted that the 1941
and growth. Texas legislature authorized the University o Texas
Several additional actors contributed to the cre- to create a hospital or cancer research and treat-
ation o The University o Texas MD Anderson Cancer ment, allocating $500,000 or the purpose. Today,
Center in Houston and its that gure would be approximately $8 million. The
development into one o the Anderson trustees, with Dr. Bertner’s guidance,
most important cancer cen- seized the opportunity and oered to match the
ters in the world. First was $500,000 legislative appropriation, i the hospital
the generous philanthropy was to be named or Monroe Dunaway Anderson
o visionary Texans such as and located in Houston. The legislature accepted
Monroe Dunaway Anderson their oer. The trustees then purchased 134 acres o
(Fig. 1) (his nephew died o mosquito-inested land to create the Texas Medical
leukemia in 1936) and his Center, stating that the new cancer hospital would
partner Will Clayton, who be located there. They made it known that the new
ounded the charitable MD state hospital should be an academic institution. In
Anderson Foundation, which act, MD Anderson was the rst comprehensive can-
FiGURe 1. helped create the Texas cer hospital to be associated with a major university
Medical Center in 1945. as an independent ree-standing unit.
v
v A Brif History of MD Adrso Cacr Ctr
In 1942, The University o Texas Board o Regents carriage house became the oce and stables were the
appointed Dr. Bertner as the director o the new hospi- research laboratories. Twelve surplus army barracks
tal. A 6-acre property near downtown was purchased were procured or patient clinics (Figs. 3A-C). With
rom the estate o Captain James A. Baker, granda- the addition o 22 leased beds at Hermann Hospital,
ther o ormer Secretary o State James Baker III, and the dream became realityA small aculty o physi-
became the rst campus o the hospital. An empty cians and scientists was recruited rom the University
FiGURe 3A.
FiGURe 3B.
A Brif History of MD Adrso Cacr Ctr v
FiGURe 3c.
o Texas Medical Branch in Galveston, and cancer In 1946, Dr. Bertner persuaded Dr. Randolph Lee
patients nally had a home. The name proposed in Clark, a native Texan, to become president o what
1941 was the “Texas State Cancer Hospital and the was to become The University o Texas MD Anderson
Division o Cancer Research”, which was changed to Cancer Center. Dr. Clark, a widely recognized surgeon,
“M.D. Anderson Hospital or Cancer Research o The concentrated on recruiting an excellent surgical aculty
University o Texas” (to acknowledge the donation o and then set upon acquiring all the basic and clinical
M.D. Anderson). The name was again changed in 1955 scientists and clinicians. From the outset, all eorts,
to “The University o Texas M.D. Anderson Hospital whether administrative, clinical or research, were
and Tumor Institute at Houston” ( to avoid the word ocused on developing excellence in research-driven
“cancer” which elicited ear and avoidance). In 1988 cancer care. Forty-six patients were receiving treat-
the name was nally changed to its current “The ment in these early quarters when the hospital moved
University o Texas MD Anderson Cancer Center”. to its current site in March 1954 (Figs. 4A and B).
FiGURe 4A. FiGURe 4B.

v A Brif History of MD Adrso Cacr Ctr
FiGURe 5.
Additional resources to the No. 1 hospital or cancer

expand the MD Anderson care by the U.S. News and
inra-structure (Fig. 5) and World Report in 11 o the past
research capacities came 14 years. The MD Anderson
rom several venues: (1) gen- Cancer Center research has
erous donations rom the resulted in numerous discov-
oil industry; (2) the vision- eries that became standards o
ary research and administra- care across many types o can-
tive leadership under its ve cers, and that have saved the
presidents, Drs. Randolph lives and/or improved surviv-
Lee Clark (1946–1978) (Fig. als and outcomes o millions
FiGURe 6A. FiGURe 6D.
6A), Charles A. LeMaistre o patients with cancer around
(1978–1996) (Fig. 6B), John the world.
Mendelsohn (1996–2011) (Fig. One component o MD
6C), Ronald DePinho (2011– Anderson’s mission is to
2017) (Fig. 6D), and Peter WT spread its knowledge about
Pisters (2017-present) (Fig. 6E); cancer research and discover-
(3) the recruitment o world- ies across the globe. This edu-
renowned cancer research cational mission is urthered
pioneers (some o the early by the hematology/oncol-
legends included Drs. Emil J. ogy ellowship that currently
Freireich, Emil Frei, Gilbert trains more than 40 medical
Fletcher, James Butler, Felix hematology-oncology cancer
FiGURe 6B. Rutledge, Gerald Dodd, and FiGURe 6e. specialists on its premises.
Sidney Wallace); and (4) the The MD Anderson Manual of
relentless research eorts o Medical Oncology, created as part o our educational
the cancer experts on the MD mission, is oten written by our ellows as rst authors
Anderson’s aculty. ( many o whom later join the MD Anderson aculty)
Today, MD Anderson is and supported in depth by senior tumor specialty ac-
one o the largest cancer cen- ulty as co-authors. We envision this ourth edition
ters in the world, with more expanding into a continuously updated electronic ver-
than 21,000 employees and sion that educates and spreads knowledge and discov-
1800 aculty; serving more eries in cancer research and therapy rapidly and widely.
than 150,000 patients with
cancer in Houston every year; Hagop M. Kantarjian, MD
operating a 700-bed cancer Robert A. Wolff, MD
FiGURe 6c.
hospital; and being ranked as Alyssa G. Reiber, MD
Foreword
The MD Anderson Manual of Medical Oncology, ourth extraordinary wealth o inormation brought about
edition, articulates the personalized, multidisciplinary by big data analytics and its application to infuence
approach to cancer management pioneered by The value-based oncology care. Supportive and Palliative
University o Texas MD Anderson Cancer Center. Care content refects current approaches in advanced
Our unique perspective has evolved rom decades o symptom management concurrent with a patient’s
clinical practice and research with more than 1.6 mil- entire cancer journey, starting at diagnosis.
lion patients turning to MD Anderson or care. We are Every chapter includes abundant tables and dia-
expanding our reach, making it easier or the patients grams, including algorithms and decision trees devel-
and communities we serve to access our expertise. oped at MD Anderson or specic cancers or disease
We are enabling high-impact discovery and introduc- subtypes; promising novel therapy targets and the lat-
ing novel therapies through a leading clinical trials est clinical trial phase o drugs targeting them; and new
network. And we are setting new standards or high- molecular therapies recommended to overcome resis-
touch, high-value cancer care. tance to previously eective therapies.
This book is designed to bring a pragmatic approach Emphasis on saety is even more relevant now than
to cancer management that may serve as a guide or in prior editions o this book. MD Anderson’s core
oncologists around the world. The text refects how value o Saety drives our colleagues each day, and
MD Anderson currently operates, including many this was especially highlighted during the COVID-
patient care practices that would not have been rec- 19 pandemic when we came together with diligence,
ognized by practitioners just a decade ago. Since the determination and evidence-based protocols to ensure
rst edition, MD Anderson’s experts have improved the saest possible environment or our immuno-
our ability to identiy biomarkers that are predictive compromised patients. Additionally, we remain laser
or survival, a major triumph in medical oncology that ocused on survivorship, as advances in cancer care
is demonstrated throughout the text. have increased the number o people who are cancer
Refecting new advances in our research and our ree or who are living with cancer as a chronic con-
approach to cancer management, the ourth edition o dition rather than a atal one. We remain dedicated
The MD Anderson Manual of Medical Oncology eatures to our bold aspiration o maximizing our impact on
a wealth o new material. The sections on Lymphoma humanity through research-driven patient care, educa-
and Myeloma and Gastrointestinal Cancer contain tion, prevention and science that contribute to Making
additional chapters ocused on recently dened sub- Cancer History®.
sets o disease and their treatment modalities. New
targeted therapies are described in Lung Cancer. Peter WT Pisters, MD, MHCM
Additional Cancer Topics o Interest chapters detail President, The University o Texas MD Anderson
updated knowledge in viral and ungal inections, or Cancer Center
example, as well as oncocardiology and thrombosis. Houston, Texas
Biostatistics now has its own section, underscoring the January, 2022

Preface
When we rst envisioned The MD Anderson Manual The new edition o The MD Anderson Manual
of Medical Oncology, we hoped that it would ll an of Medical Oncology contains new chapters on cord
important void in oncology reerence material by serv- blood transplant, haploidentical stem cell transplan-
ing as a hands-on resource or the practicing oncolo- tation, cellular therapy in allogeneic hematopoietic
gist. The rst edition, published in 2006, was written cell transplantation, pediatric cancers, molecular
exclusively by our aculty and ellows with the idea o biomarkers and cancer, immuno-oncology, targeted
giving a bird’s-eye view o how multidisciplinary care therapies in cancer, applied biostatistics, oncocardi-
was practiced at our institution. We were proud o that ology, pulmonary complications o cancer therapy,
initial eort and pleased that the book received posi- and cancer-associated thrombosis. In addition, there
tive reviews rom several high-impact journals, includ- is expanded coverage o the rapidly growing areas o
ing JAMA, The Lancet, and The New England Journal of biological and immune therapies o cancer, with one
Medicine. chapter co-authored by our very own Nobel Laureate,
The second edition, published in 2011, moved closer Jim Allison.
to the aims o providing more illustrations, gures, The new edition o The MD Anderson Manual of
tables, and algorithms. In addition, the second edition Medical Oncology will also be a continually updated
included new chapters on myelodysplastic syndromes, version o the book, online, with the latest science and
Philadelphia chromosome-negative myeloprolierative clinical recommendations rom the world-renowned
neoplasms, T-cell lymphomas, small bowel cancer and clinical investigators at MD Anderson.
appendiceal tumors, infammatory breast cancer, and We hope that this edition serves to help oncologists
penile cancer. everywhere provide high-quality, state-o-the-art can-
In the third edition, we have continued the tradition cer care to their patients.
o including evidence-based management algorithms
in the orm o fowcharts and diagrams, shaped by the Hagop M. Kantarjian, MD
clinical experience o our world-class aculty at MD Robert A. Wol, MD
Anderson. Readers are also provided with a practical Alyssa G. Reiber, MD
guide to the diagnostic and therapeutic strategies used
at MD Anderson.

Section I Leukemia
Section Editor: William G. Wierda
1 Acute Lymphoblastic Leukemia
2 Adult Acute Myeloid Leukemia
3 Chronic Lymphocytic Leukemia and Associated Disorders
4 Chronic Myeloid Leukemia
5 Myelodysplastic Syndromes: The MD Anderson Cancer Center

Approach
6 Philadelphia Chromosome–Negative Myeloproliferative

Neoplasms
1 Acute Lymphoblastic Leukemia
Hind Rafei
Sergej N. Konoplev
Sa A. Wang
Nicholas J. Short
Hagop M. Kantarjian
Elias J. Jabbour
KEY CONCEPTS
 Acute lymphoblastic leukemia (ALL) is classied into B-cell methotrexate and cytarabine) or allogeneic hematopoi-
ALL, T-cell ALL, and natural killer cell ALL. Cytogenetics are etic stem cell transplant. Maintenance consists o POMP
key in the diagnosis o ALL because they hold a predictive (Purinethol, Oncovin, methotrexate, and prednisone) or
and prognostic value. A Philadelphia chromosome–like DOMP (Dexamethasone, Purinethol, Oncovin, and metho-
signature that lacks the expression o BCR-ABL1 usion pro- trexate) chemotherapy or 2 to 3 years. Clinical trials are
tein but does have a gene expression prole similar to BCR- evaluating the use o novel agents, such as antibody–
ABL1+ ALL has been recently dened. drug conjugates and bispecic antibodies, in the rontline
 Measurement o measurable residual disease (MRD) using setting.
multiparameter fow cytometry, quantitative polymerase  The combination o chemoimmunotherapy is the main-
chain reaction, and next-generation sequencing is stan- stay o treatment o patients with ALL and is a eld o
dard o care in the treatment o patients with ALL, and it ongoing research to identiy the best combinations as well
holds prognostic as well as predictive signicance. Treat- as timing o their use.
ment o patients with MRD-positive disease ater achieve-  In adolescents and young adults, pediatric regimens and
ment o response consists o the use o immunotherapy, the hyper-CVAD regimen showed similar complete remis-
such as blinatumomab or combinatorial agents. sion rates, remission duration, and survival outcomes.
 The rontline therapy o patients with ALL consists o our  The role o allogeneic hematopoietic stem cell transplan-
major components: induction o remission, consolidation, tation (AHSCT) in rst remission remains currently valid
maintenance, and central nervous system prophylaxis. in certain high-risk circumstances, such as (1) KMT2A-
Intensive induction chemotherapy regimens are modeled rearranged ALL, (2) early T-cell precursor ALL, and (3) ALL
ater either the pediatric-inspired roadmap regimens or with complex cytogenetics and hypodiploidy.
the hyper-CVAD (hyperractionated cyclophosphamide,
 In the salvage setting, a number o novel agents have been
vincristine, doxorubicin, and dexamethasone) regimen.
approved, including monoclonal antibodies, bispecic
Consolidation depends on the risk category and consists
antibodies, and chimeric antigen receptor T-cell therapies.
o either consolidation chemotherapy (e.g., high-dose
EPIDEMIOLOGY AND ETIOLOGY 6150 individuals would be diagnosed with ALL in the
United States that year, and 1520 patients would suc-
Acute lymphoblastic leukemia (ALL) is characterized cumb to the disease.1 ALL is projected to represent
by the proliferation and accumulation of lymphoid 20% of adult leukemias and 46% of leukemias in
progenitor cells in the blood, bone marrow, and other teenagers (15–19 years old) and will be the most com-
tissues. It has a bimodal distribution. The overall age- mon childhood acute leukemia in children 14 years old
adjusted incidence is 1.7 per 100,000 persons, with and younger, representing approximately 75% in this
a peak in early childhood and then a smaller peak in patient population.1
older adults. Approximately 60% of cases are diag- The cause of ALL is unknown in most cases.2–6 Chro-
nosed in patients who are 20 years old or younger. mosomal translocations occurring in utero during fetal
In 2020, the American Cancer Society estimated that hematopoiesis have suggested genetic factors as the
3
4 Section I Leukemia
primary cause o pediatric ALL and postnatal genetic WHO classication states that the diagnosis o ALL
events as secondary contributors. Monozygotic and “should be avoided when there are <20% blasts” but
dizygotic twins o patients with ALL and individuals at the same time does recognize that cases o ALL with
with genetic disorders, such as Klineelter (XXY and blasts o less than 20% do exist.9
ChAPTER 1
variants) and Down (trisomy 21) syndromes, or inher- Morphologically, ALL is characterized by the pres-
ited diseases with excessive chromosomal ragility, such ence o a large number o lymphoblasts. Blasts may
as Bloom syndrome, Fanconi anemia, and ataxia telan- show signicant variation in cell size, nuclear shape,
giectasia, have all been ound to have higher incidence visibility o nucleoli, amount o cytoplasm, and cyto-
o ALL, implicating a possible genetic predisposition. plasmic basophilia or vacuolization. Auer rods are
Additional studies have postulated inectious causes.3 consistently absent. In the past, the French-American-
British (FAB) Cooperative Group recommended the
separation o ALL cases into three subtypes (L1, L2,
CLINICAL PRESENTATION AND and L3) based on cytologic characteristics;11 this cyto-
LABORATORY ABNORMALITIES logic classication is no longer used. In act, Burkitt
lymphoma/leukemia, which was a part o B-ALL in
The presenting symptoms can be nonspecic, particu- the FAB classication scheme under the L3 subtype,
larly in children. They largely refect bone marrow has been moved to the mature B-cell lymphoma cat-
ailure and include malaise, atigue, bleeding or bruis- egory.9 Table 1–2 summarizes lineage assignment.
ing, and secondary inections. The B symptoms, such The initial diagnosis o ALL is largely based on fow
as ever, night sweats, and weight loss, are requent. cytometric immunophenotyping (FCI). FCI success-
White blood cell (WBC) count at presentation var- ully assigns lineage in more than 95% o cases. True
ies widely, and circulating blasts are generally noted. mixed-phenotype acute leukemia is rare.12 Aberrant
Symptoms related to hyperleukocytosis are rare in myeloid antigen expression o markers is reported in
ALL, given the lymphoblast morphology, even when 15% to 50% o adult and 5% to 35% o pediatric ALL
WBC counts are high. cases.13–15 ALL blasts are negative or myeloperoxidase
Leukemic involvement o the central nervous sys- (MPO), although a low-level MPO positivity (<3%)
tem (CNS), ranging rom cranial neuropathies to may occur in rare cases that otherwise are typical or
meningeal inltration, occurs in ewer than 10% o ALL.16 The diagnosis o ALL requires the detection o
patients at presentation. It is more common in mature
B-cell acute lymphoblastic leukemia (B-ALL) or Burkitt
Table 1–1 Classifcation o Acute Lympoblastic
leukemia.7 A history or ndings o abdominal masses,
Leukemia
signicant spontaneous tumor lysis syndrome, and
chin numbness (mental nerve) indicating cranial nerve
I. B-lymphoblastic leukemia/lymphoma (B-ALL)
involvement are also more common in this subtype 1. B-ALL, not otherwise specied
o ALL.8 Lymphadenopathy and hepatosplenomegaly, 2. B-ALL with recurrent genetic abnormalities
although rarely symptomatic, are observed in approxi- B-ALL with t(9;22)(q34.1;q11.2); BCR-ABL1
mately 20% o patients.8 B-ALL with t(v;11q23.3); KMT2A rearranged
B-ALL with t(12;21)(p13.2;q22.1); ETV6-RUNX1
B-ALL with hyperdiploidy
DIAGNOSIS B-ALL with hypodiploidy
B-ALL with t(5;14)(q31.1;q32.3); IL3-IGH
The revised World Health Organization (WHO) clas- B-ALL with t(1;19)(q23;p13.3); TCF3-PBX1
sication recognizes three types o ALL: B-ALL, T-cell B-ALL, BCR-ABL1–likea
acute lymphoblastic leukemia (T-ALL), and natural B-ALL with iAMP21a
II. T-lymphoblastic leukemia/lymphoma (T-ALL)
killer cell acute lymphoblastic leukemia (NK-ALL)9
Early T-cell precursor lymphoblastic leukemia (ETP-
(Table 1–1). ALL can involve predominantly bone mar-
ALL)a
row or predominantly extramedullary sites. In patients Near ETP (“close to” ETP) ALLb
with extramedullary lymphoblastic lymphoma, an III. Natural killer (NK) cell lymphoblastic leukemia/
arbitrary cut-o o 25% blasts in bone marrow was lymphomaa
applied to distinguish lymphoblastic leukemia rom
a
Provisional entities in the current World Health Organization (WHO)
lymphoma in the past.10 Currently, this distinction has classication.
been practically abandoned, and the current WHO b
This entity is not recognized in the current WHO classication but is widely
used.
classication uses a combined term “lymphoblastic Data rom Swerdlow SH. WHO Classifcation o Tumours o Haematopoietic and
leukemia/lymphoma.” In contrast to acute myeloid Lymphoid Tissues. International Agency or Research on Cancer; 2017 and Jain
N, Lamb AV, O’Brien S, et al. Early T-cell precursor acute lymphoblastic leukemia/
leukemia, there is no agreed-upon minimal blast per- lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood.
centage required or a diagnosis o ALL. The current 2016 Apr 14;127(15):1863-1869.
Capter 1 Acute Lymphoblastic Leukemia 5
Table 1–2 Diagnosis o Acute Lympoblastic Leukemia by Immunopenotype
Lineage-Dening Frequent Positive Important Negative

Markers Markers Markers Diagnosis Requirement
ChAPTER 1
B-ALL CD19, CD22, cytoplasmic CD10, HLADR, TDT, CD34 Cytoplasmic CD3, CD19, i strong and uniorm, one
CD79a, cytoplasmic MPO, and monocytic o B markers or CD10; i CD19
IgM,a PAX5 markers weak and partial, two more B
markers or CD10
T-ALL Cytoplasmic CD3 CD7 (bright), variable MPO and monocytic Cytoplasmic CD3 and negative
CD1a, CD2, CD4, CD5, markers;. B-lineage or other lineage markers
CD8, TDT markersa
NK-ALL CD56, CD94, CD161 CD7, CD2, TDT May MPO, and monocytic CD56+, CD94, CD161, TCR gene
express cytoplasmic markers; TCR gene rearrangement germline
CD3b,c rearrangement
a
PAX5 is an excellent B-lineage marker, but it is perormed by immunohistochemistry.
b
May express partial or dim CD19, CD56, or CD79a but oten negative or PAX5. Overall, not sufcient to assign B lineage.
c
Depending on the clone o CD3 with reactivity to cytoplasmic CD3 epsilon chain.
B-ALL, B-cell acute lymphoblastic leukemia; MPO, myeloperoxidase; NK-ALL, natural killer cell acute lymphoblastic leukemia; T-ALL, T-cell acute lymphoblastic leukemia;
TCR, T-cell receptor.
immature markers, such as CD34 or terminal deoxy- ETP-ALL in adolescent and adult patient populations.19
nucleotidyl transerase (TdT), as well as lineage-specic Immunophenotypically, ETP-ALL is dened by the lack
markers. For B-ALL, it requires a combination o strong o CD8 and CD1a, negative or dim expression o CD5
CD19 and at least one additional B-cell marker, such (as dened by CD5 expression in <75% lymphoblasts
as CD22 and cytoplasmic CD79a or CD10; i CD19 is or 1 log scale dimmer than normal T-cells), and expres-
weak, it requires at least two additional markers. Cyto- sion o at least one myeloid or stem cell marker (e.g.,
plasmic CD3 is the lineage-dening marker or T-ALL. CD13, CD33, CD34, CD65, CD117, or HLA-DR).18
In addition, T-ALL is oten bright positive or CD7, Although the original description o ETP-ALL
with variable expression o other markers. CD19 can phenotype stresses the absent or weak CD5 expres-
be aberrantly expressed in 10% to 20% o T-ALL blasts. sion on lymphoblasts, an original study described
The immunophenotypic classication o ALL is three patients with an immunophenotype similar to
summarized in Table 1–2. The original classication ETP except or no decrease in CD5 but showing a
proposed by the European Group or the Immunologi- gene expression prole o ETP-ALL.19 These ndings
cal Characterization o Leukemias in 1995 separated were conrmed in subsequent studies,20 which led to
B-ALL cases into our categories according to the stages the introduction o the term o “near ETP-ALL” (also
o maturation: pro-B-ALL, early pre-B-ALL, pre-B-ALL, known as “close to ETP-ALL”) to describe T-ALL with
and mature B-ALL.17 The mature B-ALL group was a phenotype typical or ETP-ALL with an exception o
subsequently removed rom B-ALL categories. This normal or bright CD5.
immunophenotypic classication o B-ALL is still used NK-ALL has been recently added to the WHO clas-
in some practice, but with the advances in genetic and sication as a provisional entity.9 The entity remains
molecular characterization o B-ALL, its clinical impor- ill-dened and extremely challenging to diagnose,9 in
tance became obsolete. part because o the limited knowledge about early
In contrast to B-ALL, the immunophenotypic clas- stages o NK cell development. The inormation mostly
sication o T-ALL has acquired a critical clinical comes rom ex vivo analyses o normal CD34-positive
importance since the concept o early T-cell precursor progenitor populations;21 the inormation regarding its
lymphoblastic leukemia (ETP-ALL) was introduced.18 malignant counterpart is sparse. The true requency
As with B-ALL, the European Group or the Immu- o NK-ALL remains unknown. The neoplastic cells
nological Characterization o Leukemias separated are reported to express CD56, CD94, and CD161 and
T-ALL cases according to the stages o maturation in cytoplasmic CD3-epsilon. CD2, CD7, and even CD5
our categories: pro-T, pre-T, cortical T, and medullary could be positive, but CD16 is usually absent.9 T-cell
T.17 In 2009, gene expression proling studies in pedi- receptor (TCR) gene rearrangement is germline.
atric patients identied a unique subgroup within the
pro-T category, which was associated with high risk o
induction ailure and relapse and thereater designated
Cytogenetic and Molecular Profling
as ETP-ALL.18 The study conducted at our institution Frequent cytogenetic and molecular abnormali-
conrmed a poor clinical outcome o patients with ties associated with adult ALL oer insight into
leukemogenesis and leukemic progression (Table PTEN mutations are associated with a poor prognosis
1–3).22 They are o both prognostic and predictive sig- in T-ALL.24 Next-generation sequencing (NGS), expres-
nicance and have varying requencies in children and sion proteomics, and oligonucleotide microarrays have
adults, which explains some o the dierences in out- transormed our understanding o the genomic land-
ChAPTER 1
comes in these two groups. This is particularly true in scape o ALL, yielding new molecular subgroups with
the case o B-ALL harboring Philadelphia chromosome actionable targets.25–27
[t(9;22)] (Ph) or other chromosomal changes with prog- Recently, a Ph-like signature has been dened using
nostic relevance, such as t(4;11)/mixed lineage leuke- genome-wide gene expression arrays, which is ound
mia (KMT2A)-AF4. Cytogenetic alterations provide an in 10% o children with standard-risk ALL and as
important basis or B-ALL subclassication. In T-ALL, many as 25% to 30% o young adults with ALL. This
an abnormal karyotype is ound in about 50% to 70% subgroup lacks the expression o BCR-ABL1 usion
o cases, commonly involving TCR loci, 14q11.2/ protein but does have a gene expression prole simi-
TCR alpha/delta, 7p14-15/TCR gamma, or 7q35/TCR lar to BCR-ABL1+ ALL.28–30 The vast majority o these
beta. The partner genes involve 10q24/HOX11,5q35/ patients have deletions in genes encoding key transcrip-
HOX11L2,1q32/TAL1,11p15/LMO1, or 8q24/MYC. tion actors involved in B-cell signaling, such as IKZF1,
del(9p) with the loss o CDKN2A is also common. Acti- TCF3, EBF1, PAX5, and VPREB1, as well as kinase-
vating mutations in NOTCH1 are detected in around activating alterations involving ABL1, ABL2, CRLF2,
50% and FBXW7 in about 30% o cases o T-ALL. CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP,
The presence o NOTCH1/FBXW7 mutations in the or TYK2 and sequence mutations involving FLT3, IL7R,
absence o KRAS/NRAS or PTEN abnormalities is or SH2B3. The most common alterations (~60% in
associated with a good outcome.23 On the other hand, adults) are rearrangements o CRLF2, which activate
the absence o NOTCH1/FBXW7 mutations, the pres- downstream signaling through Janus kinases (JAKs),
ence o KRAS/NRAS mutations, and the presence o and approximately hal o CRLF2-rearranged cases
Table 1–3 Cytogenetic and Molecular Abnormalities in Acute Lympoblastic Leukemia
Category Cytogenetics Involved Genes Adult Frequency (%) Children Frequency (%)
Hyperdiploid 2–15 10–26
Hypodiploid 5–10 5–10
Pseudodiploid t(9;22)(q34;q11) BCR-ABL1 15–25 2–6
del(9)(q21-22) p15, p16 6–30 20
t(4;11);t(9;11); KMT2A 5–10 <5
t(11;19); t(3;11)
del(11)(q22-23) ATM 25–30a 15a
t(12;21)(p12;q22) TEL-AML1 <1b 20–25b
t(1;19) E2A-PBX1 <5 <5
t(17;19) E2A-HLF <5 <5
t(1;14)(p32;q11) TAL1 10–15 5–10
t(7;9)(q34;q32) TAL2 <1 <1
t(10;14)(q24;q11) HOX11 5–10 <5
t(5;14)(q35;q32) HOX11L2 1 2–3
ac
t(1;14)(p32;q11) TCR 20–25 20–25c
del(13)(q14) miR15/miR16 <5 <5
t(8;14); t(8;22); t(2;8) C-MYC 5 2–5
+8 ? 10–12 2
del(7p) ? 5–10 <5
del(5q) ? <2 <2
del(6q); t(6;12) ? 5 <5
a
As determined by loss o heterozygosity.
b
As determined by polymerase chain reaction.
c
In T-cell acute lymphoblastic leukemia, overall incidence <10%.
BCR-ABL1 positive?
Yes No
ChAPTER 1
Positive for CRLF2
STOP by flow cytometry?
Yes
No
FISH for CRLF2 Sending out Run targeted FISH

MDL for JAK2 for kinase based on chromosomal
mutation study fusion testing abnormalities
STOP
FIGURE 1-1 Philadelphia chromosome–like acute lymphoblastic leukemia molecular lesions and associated molecular usions
or mutations. FISH, fuorescence in situ hybridization.
have activating mutations in JAK1 or JAK2 (Fig. 1–1). and the ETV6-NTRK3 usion is sensitive to ALL kinase
CRLF2 expression can be rapidly detected by fow inhibitors (e.g., crizotinib).29 The identication o
cytometry, and a positive CRLF2 expression correlates kinase alterations expands therapeutic options in this
100% with CRLF2 rearrangement by fuorescence in subgroup o ALL with a poor outcome (Table 1–4).
situ hybridization (FISH).31 Importantly, Ph-like ALL At our institution, we use the ollowing algorithm to
with ABL1, ABL2, CSF1R, and PDGFRB expression stratiy B-ALL cases (see Fig. 1–1). For every new patient
usions (the ABL class) has been shown sensitive to with B-ALL, we perorm FISH or BCR/ABL1 and test or
tyrosine kinase inhibitors (TKIs; e.g., dasatinib) both CRLF2 expression by FCI. I FCI detects CRLF2 expres-
by in vitro and in vivo human xenograt models. On sion, FISH studies are ordered to conrm CRLF2 rear-
the other hand, rearrangements in EPOR, IL-7R, and rangement, and molecular studies are ordered to check
JAK2 are sensitive to JAK inhibitors (e.g., ruxolitinib); or JAK2 (or JAK1, JAK3) mutations. In the absence o
Table 1–4 Genetic Determinants in Acute Lympoblastic Leukemia by Lineage
ALL Lineage Cytogenetic Aberration Involved Genes Protein

B-cell BCR/ABL+ (Ph+) IKZF1 Ikaros
CRLF2 + the Ig heavy chain locus or an interstitial PAR1 deletion CRLF2
BCR/ABL-like IKZF1 deletions; rearrangements/mutations in CRLF2, IGH-
CRLF2, and NUP214-ABL1; in-rame usions o EBF1-PDGFRB,
BCR-JAK2, or STRN3-JAK2; cryptic IGH-EPOR rearrangements
Near hypodiploid NRAS, KRAS, FLT3, and NF1
Low hypodiploid IKZF2, and by TP53 disruptions, CDKN2A/B locus deletion
Hyperdiploid CREBBP
NT5C2 mutations NT5C2
TP53 mutations
T-cell PICALM-MLLT10, NUP214-ABL1 usion, EML-ABL1, SET-NUP214
usion, MLL, NOTCH1, FBW7, BCL11B, JAK1, PTPN2, IL7R, PHF6,
RAS/PTEN
ALL, acute lymphoblastic leukemia; Ig, immunoglobulin; mTOR, mammalian target o rapamycin; TKI, tyrosine kinase inhibitor.
BCR/ABL1 rearrangement and CRLF2 expression, the study rom our institution analyzed 215 patients with
sample is sent out or additional molecular testing. newly diagnosed Ph-negative B-ALL who received
intensive chemotherapy and had available MRD
assessment by MFC at CR and around 12 weeks. Early
Measurable Residual Disease
ChAPTER 1
responders dened as MRD negativity at CR had bet-

Measurable residual disease (MRD), or minimal residual ter outcome, with 3-year EFS rates o 65% vs 42% in
disease, is dened as residual leukemic blasts detected late responders (P <.001) and 3-year OS rates o 76% vs
ater cytoreductive chemotherapy despite apparent 58% (P = .001). On multivariate analysis, the KMT2A
morphologic remission (<5% blasts in the bone mar- rearrangement and MRD positivity at CR were the
row). Assessment o MRD has become a standard-o- only actors that correlated with worse OS.40
care practice in the management o patients with ALL
because o its powerul prognostic value as a predic-
tor o relapse and survival.32 The signicant prognostic FRONTLINE ThERAPY
value o MRD spans across all subtypes o ALL and
supersedes that o historical parameters, such as age, The treatment o patients with ALL consists o our
WBC count, and cytogenetics.24 A meta-analysis o major components: induction o remission, consolida-
13,637 pediatric and adult ALL patients showed that tion, maintenance, and CNS prophylaxis.41 The goal o
across all subgroups and covariates, MRD negativity induction is to induce remission by eradicating leukemic
has a hazard ratio (HR) o 0.23 in pediatric patients and cells rom the bone marrow. Intensive induction che-
0.28 in adults or event-ree survival (EFS) and an HR motherapy regimens are modeled ater either the pedi-
o 0.28 in both children and adults or overall survival atric-inspired roadmap regimens or the hyper-CVAD
(OS).33 In adult patients, this translated to 10-year OS (hyperractionated cyclophosphamide, vincristine,
rates o 60% and 15% or patients who were MRD doxorubicin, and dexamethasone) regimen developed
negative and MRD positive, respectively. at MD Anderson Cancer Center (MDACC). Pediatric-
There are dierent methods to assess MRD ater inspired regimens have previously been studied in
treatment, including multiparameter fow cytometry patients o all ages, but their use in patients older than
(MFC), quantitative polymerase chain reaction (PCR), 40 years has largely allen out o avor because o higher
and NGS. Ideally, MRD should be tested on a bone rates o toxicity and treatment-related mortality rates in
marrow sample because it can be 1 to 3 logs higher this patient population, and they are generally reserved
in MRD levels than that in the peripheral blood.34–36 or use in the adolescent and young adult (AYA) popula-
MRD assessment is recommended to perorm on bone tion.42 Ater achieving CR, the consolidation phase aims
marrow with morphologic remission ater induction, to eradicate any residual leukemia cells remaining ater
at approximately 3 months, and every 3 to 6 months induction and, depending on the risk category, consists
thereater. MRD inormation is currently used to guide o either consolidation chemotherapy (e.g., high-dose
postinduction therapy. Bassan et al.37 assigned patients methotrexate and cytarabine) or AHSCT. Consolidation
who achieved complete remission (CR) ater inten- is ollowed by maintenance therapy to prevent relapse
sive chemotherapy to either maintenance or alloge- and prolong remission. Maintenance consists o daily
neic hematopoietic stem cell transplantation (AHSCT) 6-mercaptopurine, weekly methotrexate, and monthly
based on their MRD status and ound a 75% OS rate pulses o vincristine and prednisone or dexamethasone,
or patients who achieved MRD negativity and did not given over 2 to 3 years (POMP [Purinethol, Oncovin,
undergo AHSCT, regardless o their cytogenetic or clin- methotrexate, and prednisone] or DOMP (Dexametha-
ical risk stratication at diagnosis. Another example o sone, Purinethol, Oncovin, and methotrexate), depend-
the use o MRD to guide therapies is the use o blinatu- ing on corticosteroid used).43 Maintenance is omitted
momab in patients with poor MRD clearance. In a mul- in mature B-ALL because o high cure rates, and BCR-
ticenter single-arm phase II study o blinatumomab in ABL1 TKIs are included in all phases or patients with
MRD-positive (≥10-3) B-ALL in morphologic CR, MRD Ph-positive ALL.
negativity was achieved in 88 o 113 (78%) patients. One extensively studied regimen used in treatment
Complete MRD responders had longer relapse-ree sur- o adult ALL is the hyper-CVAD regimen, in which
vival (RFS) (23.6 vs 5.7 months; P = .002) and OS (38.9 vs patients receive hyper-CVAD alternating with high-
12.5 months; P = .002) compared with patients whose dose methotrexate and cytarabine or a total o eight
MRD did not clear ater blinatumomab. The 4-year OS alternating cycles approximately every 3 to 4 weeks.42
rate was 52% among MRD responders.38 These nd- This is ollowed by 2.5 years o POMP maintenance
ings were urther conrmed using propensity score therapy interspersed with intensication courses dur-
matching by comparing them with historical data.39 ing months 6, 7, 18, and 19.
The time to achieve MRD negativity is also a strong The advances made in the eld o immunotherapy
prognostic actor, particularly in Ph-negative ALL. A and the remarkable results achieved in the salvage
setting o ALL led to the investigation o chemoim- cycles, we have changed practice during the metho-
munotherapy in the rontline setting. To improve trexate and cytarabine (even) courses, reversing the
outcomes o younger patients with newly diagnosed sequence o IT therapy to avoid increased risk o neu-
B-ALL, an ongoing phase II trial is investigating the rotoxicity. Thereore, IT cytarabine is administered on
sequential use o hyper-CVAD and blinatumomab day 2 and methotrexate on day 8.48
ChAPTER 1
with promising saety and ecacy. The regimen con- CNS disease is diagnosed by the presence o more
sists o our cycles o hyper-CVAD ollowed by our than ve lymphoblasts per microliter in the cerebro-
cycles o blinatumomab. Blinatumomab is started ater spinal fuid (CSF). Patients with CNS involvement are
two cycles o chemotherapy or patients at high risk treated with triple IT therapy (hydrocortisone 50 mg,
or relapse, including those with Ph-like ALL, complex cytarabine 40 mg, and methotrexate 12 mg) twice per
karyotype, t(4;11), low-hypodiploidy, or near triploidy week until the CSF is negative or malignant cells on
or who are MRD positive. Four cycles o blinatu- two occasions, then weekly IT or our to eight doses
momab are also incorporated in the POMP mainte- ollowed by every other week or our doses, and then
nance (three cycles o POMP ollowed by one cycle o the normal prophylaxis schedule is resumed with the
blinatumomab) or a total o 16 cycles (i.e., 18 months) remaining chemotherapy treatment. Ater this, consol-
o maintenance therapy. Among 27 patients treated, idative craniospinal irradiation is considered in select
the median age was 27 years (range, 18–57 years). The patients with a curative intent, particularly beore
CR rate was 100%, and MRD negativity was achieved AHSCT.
in 96%. There were no induction deaths. One-third o
patients underwent AHSCT because o the presence Philadelphia Chromosome–Positive Acute
o high-risk disease eatures. With a median ollow-up
period o 17 months, 93% o patients were still alive;
Lymphoblastic Leukemia
one patient died ater o AHSCT-related complica- The combination o cytotoxic chemotherapy with
tion, and one died o sepsis during reinduction ater TKIs has been the mainstay o the rontline treatment
relapse. The 1-year RFS and OS rates were 76% and o patients with Ph-positive ALL, with the early intro-
89%, respectively. This trial is currently ongoing at our duction and continuous administration o TKIs lead-
institution (NCT02877303).44 ing to best results.49–52 Imatinib, a rst-generation TKI,
combined with intensive and nonintensive chemo-
Central Nervous System Prophylaxis and therapy, results in CR rates greater than 90% and OS
rates ranging rom 33% to 50%.53,54 The best results
Treatment are achieved when imatinib is administered in a con-
Regularly scheduled lumbar punctures with intrathe- tinuous ashion. Despite the improved outcomes with
cal (IT) chemotherapy are a mainstay o ALL therapy the addition o imatinib to chemotherapy, imatinib
to prevent or treat CNS disease and are implemented resistance is common and leads to a high incidence o
throughout the eight courses o the hyper-CVAD regi- relapse, which led to the evaluation o more potent
men in a risk-adapted manner. In Ph-negative B-ALL TKIs or the rontline treatment o patients with Ph-
and T-ALL, a total o eight IT treatments (two per positive ALL.
course or the rst our courses) are given, which has The second-generation TKI dasatinib has bet-
decreased the rate o isolated CNS relapse to approxi- ter potency and selectivity than the rst-generation
mately 6%.42,45 Because outcomes or patients with TKIs.55 It was rst developed or chronic myeloid
Ph-positive B-ALL improved with the addition o leukemia in patients who could not tolerate or devel-
BCR-ABL TKIs to the hyper-CVAD regimen, leading oped resistance to imatinib. Dasatinib is also reported
to better survival, a higher percentage o CNS relapse to cross the blood–brain barrier.56 A single-institution
is observed with only eight IT courses (~10%).46 The study conducted at MDACC o 72 patients with Ph-
addition o our more IT courses (12 IT in total) in Ph- positive ALL treated with hyper-CVAD and dasatinib
positive B-ALL reduced the CNS relapse rate to 0% in the rontline setting led to 96% CR rate, 83% com-
and hence is our current practice.47 In patients with plete cytogenetic response (CCyR) rate ater the rst
Burkitt leukemia or mature B-ALL, prophylaxis is ur- course, and 65% complete molecular response (CMR)
ther intensied to include 16 IT doses, a dosing strat- rate. The 5-year OS rate was 46%.55 These results
egy that has successully reduced the risk o isolated were conrmed by a multicenter SWOG study o 94
CNS relapse in this patient population.45 patients with newly diagnosed Ph-positive ALL. At a
During hyper-CVAD courses, IT chemotherapy median ollow-up period o 26 months, the CR rate
alternating methotrexate and cytarabine is given on was 88%, and the 3-year OS rate was 71%.57 Dasatinib
days 2 and 8, respectively. However, to avoid the in combination with low-intensity chemotherapy was
simultaneous administration o IT methotrexate and also evaluated. The the European Working Group on
systemic high-dose methotrexate during the even Adult ALL (EWALL) study number 01 or Ph(+) ALL
(EWALL-PH-01) study investigated the combination o days –14 to 29 during course 1). Complete hematologic
dasatinib with low-intensity chemotherapy in patients response occurred in 95% o patients at 6 weeks and
55 years o age or older with newly diagnosed Ph-posi- 91% at 24 weeks. The CMR rate at 24 weeks was 46%.
tive ALL, showing a 96% CR rate, 28% 5-year RFS, and The estimated 24-month OS rate was 60%.64
ChAPTER 1
36% 5-year OS rate.58 The majority (75%) o patients It is worth noting that although none o the TKIs
who relapsed had the T315I mutation, which coners has been compared head to head in Ph-positive ALL,
resistance to all rst- and second-generation TKIs.58 one meta-analysis showed that ponatinib is more
Nilotinib is another second-generation TKI with ecacious than earlier-generation TKIs in the ront-
activity against most imatinib-resistant mutants o line setting, with a higher percentage o patients
ABL1.59 The EWALL international trial investigated achieving CMR with ponatinib-based therapy than
the combination o low-intensity chemotherapy with with earlier-generation TKI-based therapies (79% vs
nilotinib in older adult patients (median age, 65 years) 34%) and a higher OS with ponatinib (2-year, 83%
with Ph-positive ALL. The regimen was well-toler- vs 58%; 3-year, 79% vs 50%),65 and one propensity-
ated. The CR rate was 94%, the 4-year EFS rate was score analysis showed that ponatinib is superior to
42%, and the OS rate was 47%. Thirty-two percent o dasatinib: 3-month CMR rates were 82% versus 65%
patients underwent AHSCT, and the 4-year OS rate or (P = .03); 3-year EFS and OS rates were 69% vs 46%
transplanted patients was 61%.60 (P = .04) and 83% versus 56% (P = .03), respectively.66
Because the emergence o T315I mutation is a driv- The sequential combination o ponatinib combined
ing orce o relapse and the achievement o CMR is with low-intensity chemotherapy ollowed by blina-
associated with better survival, an improvement o tumomab and ponatinib in patients with newly diag-
outcome relies on more potent TKIs that can suppress nosed Ph-positive ALL is currently being investigated
the emergence o T315I mutation. Ponatinib is a third- in a clinical trial (NCT03147612).
generation TKI that is active against the T315I muta- The combination o blinatumomab with TKIs
tion. In a phase II single-arm trial, patients with newly (mainly ponatinib) has been shown to be sae and
diagnosed Ph-positive ALL were treated with ponatinib eective in a small case series o 15 patients rom
and hyper-CVAD.61 Ponatinib was given orally at 45 MDACC with 50% CR rate and 75% CMR rate.67 The
mg/day or the rst 14 days o cycle 1 and then con- GIMEMA group has recently presented early results
tinuously at 45 mg/day or the subsequent cycles. Ater rom D-ALBA, the rst trial investigating the sequen-
treating 37 patients, the protocol was amended ater the tial use o TKIs–steroid (in induction) and blinatu-
occurrence o two atal myocardial events to reduce the momab (in consolidation). Sixty-three patients were
dose o ponatinib to 30 mg/day at cycle 2, with urther treated with this regimen o prednisone, dasatinib, and
reduction to 15 mg when a CMR (dened as absence o blinatumomab. The CR rate was 98%, and the 1-year
quantiable BCR-ABL1 transcripts) was achieved. Ater disease-ree survival (DFS) rate was 88%. Deep molec-
the protocol amendment, no urther vascular events ular response increased throughout therapy (29% ater
occurred. A recent update was reported o 86 patients induction, 60% ater two cycles o blinatumomab,
treated with hyper-CVAD and ponatinib with a median and 80% ater our cycles). Notably, T315I muta-
ollow-up period o 43 months. The 3-month CMR rate tion was noted in 6 o 15 patients with rising MRD
was 74%, and the cumulative CMR rate was 84%. Only in the induction phase, all o which was cleared ater
18 patients (21%) underwent AHSCT in rst CR (CR1). blinatumomab.68 However, T315I resistance muta-
With a median ollow-up period o 44 months, 71% tion and patients harboring IKZF1 and/or PAX5 and/
o patients remain alive in remission, and only three or CDKN2A/B deletions remain a therapeutic chal-
relapses were observed in patients while still taking lenge. Several similar trials are evaluating the combina-
ponatinib. The 5-year CR duration and OS rates were tion o blinatumomab with dasatinib (NCT02143414,
68% and 74%, respectively. A landmark analysis per- NCT04329325) and ponatinib (NCT03263572) in both
ormed at 6 months showed a trend toward better OS rontline and relapsed or reractory settings. At our
in patients who did not undergo AHSCT in rst remis- institution, we are evaluating the combination o pona-
sion (5-year OS rate o 66% or patients who under- tinib with blinatumomab with promising early results.
went AHSCT compared with 83% or patients who
did not [P = .07]).62 The grade 3/4 toxicities included
Philadelphia Chromosome–Like Acute
inections, liver unction test abnormalities, thrombotic
events, myocardial inarction, pancreatitis, and rash.61–63
The Gruppo Italiano Malattie Ematologiche The treatment o patients with Ph-like ALL remains
Ddell’Adulto (GIMEMA) 1811 phase II trial included challenging because o the poor prognosis that this sub-
42 patients with newly diagnosed Ph-positive ALL who type coners. In a retrospective study rom MDACC
were treated with ponatinib at 45 mg/day (or eight con- investigating the outcomes o patients with Ph-like
secutive courses o 6 weeks) and steroids (prednisone ALL treated with standard intensive chemotherapy,
148 patients with untreated Ph-like ALL received 90% to 100%, respectively. O note, the majority o
hyper-CVAD or the pediatric-inspired augmented patients (90%) had low- and intermediate-risk disease:
Berlin-Frankurt-Münster (aBFM) regimen. O the 148 only 13% had marrow involvement, and 3% had CNS
patients, 56 patients (median age, 34 years) had Ph-like involvement, both being known adverse actors.75
ALL, 37 o whom (61%) had CRLF2 overexpression. One concern with the DA-EPOCH-R (dose-adjusted
ChAPTER 1
The majority o patients with CRLF2 rearrangements etoposide phosphate, prednisone, Oncovin, cyclo-
(84%) had concurrent IKZF1 deletion. Patients with Ph- phosphamide, hydroxydaunorubicin, and rituximab)
like ALL had lower rates o MRD negativity at CR and regimen is the lack o highly CNS-penetrating chemo-
a worse 5-year survival rate (23% vs 59%; P = .006).69 therapy agents, such as high-dose methotrexate and
Recently, the outcomes o 24 patients with B-ALL cytarabine, which are essential components o high-
harboring ABL-class usions and treated with a com- intensity chemotherapy or Burkitt leukemia. A recent
bination o TKIs and chemotherapy were reported in report showed signicantly higher 3-year rates o CNS
both rontline (n = 19) and relapse (n = 5) settings. The relapse in patients with Burkitt leukemia treated with
median age was 24 years (range, 5–72 years). Eleven DA-EPOCH compared with regimens that incorporate
patients (46%) harbored IKZF1 deletions. Ater induc- agents with good CNS penetration, such as hyper-
tion therapy, only 16 o 24 patients (67%) achieved CVAD and CODO-M/IVAC (cyclophosphamide, Onc-
CR, all with detectable MRD, including 7 with MRD ovin, doxorubicin, high-dose methotrexate/iosamide,
o 10-2 or greater. In 14 o 18 patients (78%), an MRD etoposide, and high-dose cytarabine) (12% compared
level below 10-4 was achieved within a median time o with 3%–4%), despite the use o IT CNS prophylaxis
2.5 months (range, 1.4–14.8 months) ater TKI initia- with DA-EPOCH.76 A phase III clinical trial comparing
tion. The median remission duration and OS were not R-CODOX-M/R-IVAC (cyclophosphamide, doxorubi-
reached ater a median ollow-up period o 36 months. cin, vincristine, methotrexate/iosamide, etoposide,
The 3-year EFS and OS rates were 55% and 77%, high-dose cytarabine) with DA-EPOCH-R in patients
respectively.70 Given that patients are more likely to with newly diagnosed high risk mature B-ALL is
remain MRD positive ater induction therapy, the use underway (EudraCT Number: 2013-004394-27).
o blinatumomab as rontline or or MRD in CR1 may
improve outcomes.
CD20-Positive Precursor B-Cell Acute
Our current treatment strategies in patients with
Ph-like ALL include the use o TKIs in patients with
ABL-class usions and blinatumomab and inotuzumab Expression o cell surace marker CD20 in adult ALL
ozogamicin combinations mainly among patients with ranges rom 35% to ubiquitous, depending on the
CRLF2 and JAK activations. subtype, and has been associated with an inerior
prognosis.77 The addition o two doses o monoclo-
Mature B-Cell and Burkitt Acute nal CD20 antibody (rituximab) administered with the
rst our cycles o chemotherapy and during mainte-
Lymphoblastic Leukemia nance intensication at months 6 and 18 resulted in
The addition o rituximab to short intensive che- improved OS in younger patients compared with simi-
motherapy has improved outcomes in adults with lar chemotherapy historical control participants (75%
Burkitt and Burkitt-type lymphoma or ALL. 71–73 Its vs 47% at 3 years; P = .003).45 Similar results were
addition to hyper-CVAD resulted in a 3-year survival reported by the German Multicenter Study Group or
rate o 89% compared with 53% with chemotherapy ALL (GMALL).78 The addition o rituximab to che-
alone. This was conrmed in a randomized, open- motherapy in the GRAAL-R 2005 randomized study
label, phase III trial, in which 260 patients with newly improved the 2-year EFS and OS rates rom 52% to
diagnosed Burkitt lymphoma/leukemia received 65% (P = .038) and 64% to 71% (P = .095; censoring
intensive chemotherapy with or without rituximab. or AHSCT, P = .018), respectively.79
The addition o rituximab improved EFS (3-year rate, Oatumumab is a second-generation anti-CD20
75% vs 62%; P = .024) and OS (3-year rate, 83% vs monoclonal antibody that has a dierent binding site
70%; P =.011).74 than rituximab, targeting a membrane proximal small-
To urther reduce early morbidity and mortality, a loop epitope on the CD20 molecule.80 Oatumumab in
pilot study investigated dose-adjusted EPOCH (eto- combination with hyper-CVAD was ound to be highly
poside phosphate, prednisone, Oncovin, cyclophos- eective in a phase II study o 69 patients with newly
phamide, and hydroxydaunorubicin) in combination diagnosed Ph-negative CD20-positive B-ALL. All but
with rituximab in 30 patients (median age, 33 years; one patient (98%) achieved CR, and the MRD negativ-
age older than 40 years, 40%) diagnosed with Burkitt ity rate was 93% overall. At a median ollow-up period
lymphoma. The treatment was sae and highly eec- o 44 months, the median RFS was 52 months, and the
tive. The PFS and OS rates were 95% to 100% and median OS was not reached. The 4-year RFS and OS
rates were 60% and 68%, respectively. For AYAs, the tailoring ALL therapy to the dierent treated popu-
4-year OS rate was 74%. Overall, the combination o lations. Such dierences include (1) a higher T-cell
hyper-CVAD plus oatumumab was highly eective. phenotype in patients aged 10 to 40 years old; (2) a
Oatumumab is our preerred anti-CD20 monoclonal near absence o the two avorable subgroups o ALL
ChAPTER 1
antibody in ALL, particularly or patients with CD20 (hyperdiploidy and t(12;21)/ETV6-RUNX1) during the
expression less than 20%.81 second decade o lie compared with a 60% preva-
lence in children; and (3) an increasing prevalence o
T-Cell Acute Lymphoblastic Leukemia high-risk Ph-positive ALL with age, rom 3% in chil-
dren to almost 50% in older adults.89 In the US inter-
Treatment o adults with T-ALL and T-cell lympho- group trial C10403 o 295 AYA patients (17–39 years
blastic lymphoma (T-LL) results in long-term survival o age) treated with a pediatric regimen, the 3-year
rates o 40% to 60%; the outcome is strongly asso- OS rate was 73%.90 At MDACC, a nonrandomized
ciated with the T-cell phenotype.18,82 Nelarabine, a study including AYA patients showed no dierence
T-cell-specic purine nucleoside analog, is approved or between the pediatric asparaginase-containing aBFM
the treatment o patients with relapsed and reractory regimen and the non-asparaginase-containing hyper-
T-ALL, leading to CR rates o 31% to 36% in phase II CVAD regimen. The 5-year CR duration rate was 53%
trials,83,84 allowing some patients to undergo AHSCT with hyper-CVAD, compared with 55% with aBFM.
with long-term survival. In the pediatric experience, The 5-year OS rates were 60% in both groups. The
the addition o nelarabine to rontline aBFM chemo- aBFM regimen had a higher incidence o asparaginase
therapy in patients with T-ALL up to 31 years o age adverse eects, such as hepatotoxicity (41%), pancre-
improved the 4-year DFS rate rom 83% with aBFM atitis (11%), and thrombosis (19%), and myelosup-
alone to 89% (P = .0332).85 However, these results have pression-related complications were more common
not yet been replicated in adult patients. A single-arm with hyper-CVAD.91 More recently, the hyper-CVAD
phase II study rom MDACC o nelarabine combined and oatumumab combination reported a 4-year OS
with rontline hyper-CVAD regimen in 67 patients rate o 74% in the AYA population.81
ailed to improve CR duration or OS rates compared In summary, pediatric regimens and the hyper-
with historical control participants treated with hyper- CVAD regimen showed similar CR, remission duration,
CVAD alone.86 This study has now been amended to and survival outcomes. In the absence o a randomized
include the incorporation o nelarabine, peg-asparagi- study comparing both regimens in the AYA popula-
nase, and venetoclax into the hyper-CVAD regimen. tion, our practice is to use the hyper-CVAD regimen
Recent insights into the biology o ETP-ALL have as a backbone or clinical trial development because
revealed BCL-2 dependence, which perhaps explains this regimen has less organ-specic toxicity than aspar-
the sensitivity to BCL-2 antagonism.87 The addition o aginase-based regimens and is thus more conducive to
venetoclax to lower-intensity chemotherapy in older combination with investigational agents.
adults with newly diagnosed ALL has yielded encourag-
ing early results in interim reports o 10 patients treated
(three with T-ALL, including two with ETP-ALL), with
Acute Lymphoblastic Leukemia in Older
90% CR/CR with incomplete hematologic recovery
Patients
(CRi) rate and 90% MRD negativity.88 The combination In older patients with ALL (generally dened as those
o venetoclax and navitoclax may also be particularly older than 55–60 years), intensive chemotherapy
promising in this subgroup. Clinical trials evaluating results in CR rates o 80% but with unacceptable
the ecacy and saety o venetoclax with navitoclax toxicities.92 One-third o patients achieving CR may
(NCT03181126) and in combination with chemother- die o myelosuppression-associated complications.
apy (NCT03808610; NCT03504644; NCT03576547; The historical long-term cure rate is 15% to 20%.93
NCT03319901) in patients with relapsed and rerac- Among 727 older adult patients (older than 65 years;
tory ALL are currently ongoing. Studies evaluating the 2007–2012) treated under Medicare, the majority o
biology o near ETP-ALL are ongoing at our institution patients did not receive chemotherapy; in those who
to better tailor the treatment and thus improve the out- received chemotherapy, the median OS period was
come o this poor-risk subgroup. only 10 months.94 In the National Cancer Institute
Surveillance, Epidemiology, and End Results database,
Adolescent and Young Adult Acute among 1675 adults (age 60 years or older) with ALL
(1980–2011), the median survival time was 4 months,
Lymphoblastic Leukemia and the 3-year survival rate was 12.8%.95
The AYA population consists o patients 15 to 39 years Strategies to de-intensiy treatment regimens have
o age. The biology o ALL diers between children, been thus investigated in this population. Inotuzumab
AYAs, and older adults, which is the rationale behind ozogamicin with mini hyper-CVD (i.e., a lower
intensity version o the hyper-CVAD regimen with- as blinatumomab, are potent in eradicating MRD, as
out anthracycline), with or without blinatumomab, was proved by the BLAST trial, which showed no di-
is one such strategy and appears to be promising in erence in OS or RFS between patients who received
the older adult population. Among 64 patients treated AHSCT during CR1 and those who did not.99 Hence,
with this regimen, the median age was 68 years (range, the role o AHSCT in the era o new therapeutics is
ChAPTER 1
60–81 years), and 42% o patients were 70 years o becoming increasingly questionable.
age or older. The CR rate was 98%, and 95% achieved Similarly, in the era o potent TKIs, the role o
MRD negativity. The 3-year CR duration and OS AHSCT in patients with Ph-positive ALL is also
rates were 76% and 54%, respectively. A propensity- becoming controversial, even though it has been his-
matched analysis showed that this regimen signi- torically shown that AHSCT does improve outcomes
cantly improved survival compared with a historical in these patients. Although a study showed that
3-year OS rate o 32% with hyper-CVAD in this older AHSCT improved RFS and OS in patients with Ph-
population (P = .007). No early deaths occurred dur- positive ALL treated with hyper-CVAD and dasatinib,
ing induction. However, the rates o death in remis- a subgroup analysis according to molecular responses
sion were 33% overall and were signicantly higher was not perormed.57 On the other hand, achievement
in those 70 years o age or older compared with those o a 3-month CMR predicted a very good prognosis in
ages 60 to 69 years (50% vs 22%, respectively; P = patients who received chemotherapy plus TKIs, sug-
.02). For the population o patients 70 years o age or gesting that these patients might not need AHSCT.100,101
older, the protocol has now been amended to decrease An analysis perormed on patients treated with hyper-
the number o mini hyper-CVD and inotuzumab ozo- CVAD and ponatinib with censoring at time o trans-
gamicin cycles rom our to two and to replace POMP plant showed that the long-term probability o survival
maintenance with blinatumomab monotherapy to is the same, suggesting that most o these patients may
mitigate toxicity in this population.96 be cured without AHSCT.61,63
The role o AHSCT in CR1 remains currently valid
in certain high-risk circumstances, such as (1) KMT2A-
Role o Allogeneic Hematopoietic Stem rearranged ALL, (2) ETP-ALL, and (3) ALL with com-
Cell Transplantation plex cytogenetics and hypodiploidy. Patients with
AHSCT has traditionally been reserved or patients Ph-like ALL with negative MRD and those in CR1
with high-risk eatures, including B lineage with WBC who achieve MRD negativity ater blinatumomab
30 × 109/L or greater; T-lineage with WBC 100 × 109/L may not need AHSCT. Patients with Ph-positive ALL
o greater; hypodiploid; Ph-positive; or KMT2A trans- with 3-month CMR should not be reerred to AHSCT;
location ALL [e.g., t(4;11)]. However, there has been in contrast, patients with positive MRD should be
some debate regarding who should be reerred or considered or blinatumomab or other MRD-targeted
AHSCT in CR1 because o the emergence o newer therapy and eventually AHSCT, particularly in patients
promising therapies that have improved outcomes who remain positive or MRD. Patients with ALL in
in this disease. As an alternative, many centers have CR2 should be reerred or AHSCT (Fig. 1–2).
incorporated MRD via Flow cytometry (FCM) or
reverse transcription PCR ater induction or consoli-
dation to stratiy patients based on their response to SALVAGE ThERAPY
chemotherapy.97 In one study, MRD status at various
time points ater CR was used to guide treatment The prognosis o adult patients with relapsed ALL
in adult patients with ALL.37 Patients who remained was historically associated with a dismal prognosis,
MRD positive at the end o consolidation were with a cure rate o less than 10%102,103 and CR rates
deemed to be higher risk and underwent AHSCT o 30% to 40% in rst relapse and 20% to 25% in
instead o receiving prolonged maintenance therapy. second relapse with standard chemotherapy regi-
Patients who achieved MRD-negative status had a mens, with an AHSCT rate o only 10% to 30% in
signicantly improved 5-year OS (75% vs 33%; P = adult patients.102,103 The recent advent o monoclonal
.001). Ph-like ALL and ETP-ALL coner a poor prog- antibodies, bispecic antibodies, and chimeric antigen
nosis, and AHSCT should be considered regardless o receptor T-cell (CAR T) therapies has revolutionized
MRD status.19,98 The GRAALL (Group or Research the treatment o ALL and resulted in a number o Food
in Adult Acute Lymphoblastic Leukemia)-2003/2005 and Drug Administration approvals or the treatment
trials showed that postinduction MRD positivity, o ALL in the salvage setting, such as blinatumomab in
the presence o IKZF1 mutations in B-ALL, and the 2014 and inotuzumab ozogamicin and tisagenlecleucel
absence o NOTCH1 or FBXW7 mutations in T-ALL in 2017.104–106 These agents are currently the subject o
are the main actors predicting benets o AHSCT investigation in dierent schemas and combinations
in CR1.23,69 It is noteworthy that newer agents, such (Table 1–5).
Ph-negative ALL Ph-positive ALL
CMR within 3 No CMR within 3

MRD negative MRD positive
ChAPTER 1
months months
Poor-risk Others B-cell T-cell Continue Blinatumomab +

cytohenetics chemotherapy/blinat TKI or inotuzumab
or genomics* umomab + TKI + TKI (clinical trial)
AHSCT Continue Blinatumomab MRD-directed Consider AHSCT

Maintenance
consolidation or inotuzumab clinical trial based on MRD
TKI +/-
or maintenance (clinical trial) (preferable) response and
blinatumomab
chemotherapy AHSCT risk
+/- blinatumomab
Consider AHSCT AHSCT Maintenance
based on MRD TKI
response and
AHSCT risk
FIGURE 1-2 MD Anderson Cancer Center algorithm or reerring or allogeneic hematopoietic stem cell transplant (AHSCT) in
acute lymphoblastic leukemia (ALL). Asterisk indicates Philadelphia chromosome (Ph)–like, 11q23 rearrangement, early T-cell
precursor ALL, low hypodiploidy or near triploidy, or complex cytogenics. CMR, complete molecular response; MRD, measur-
able residual disease; TKI, tyrosine kinase inhibitor.
Table 1–5 Seminal Trials or Treatment o Relapsed or Reractory BCell Acute Lympoblastic
Leukemia
Median Overall MRD

Survival Time Negativity
Clinical Trial Disease Setting Patients (n) Response (months) (%)a
Blinatumomab
TOWER103 R/R Ph- ALL 271 ORR: 44% 7.7 76
CR: 34%
ALCANTARA109 R/R Ph+ ALL 45 ORR: 36% 7.1 88b
CR: 31%
Inotuzumab Ozogamicin
INO-VATE105 R/R ALL 109 ORR: 81% 7.7 78
CR: 35.8%
mini-hyper-CVD + inotuzumab R/R ALL 84 ORR: 80% S1: 25 82
ozogamicin ± blinatumomab115 CR: 58% S2: 6
S3: 7
CAR T-Cell Therapy
ELIANA105,123 R/R ALL (age younger 79 ORR: 82% NR 98
than 26 years) CR/CRi: 62%
Anti-CD19 CAR T cells124 R/R ALL (adults) 53 CR: 83% 12.9 67
a
Measured by ow cytometry.
b
Within two cycles.
ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CR, complete remission; CRi, complete response with incomplete hematologic recovery; CVD,
cyclophosphamide, vincristine, and dexamethasone; MRD, measurable residual disease; NR, not reported; ORR, objective response rate; Ph, Philadelphia; R/R, relapse or
reractory; S1, salvage 1; S2, salvage 2; S3, salvage 3.
Blinatumomab technology.107 It consists o a recombinant monoclo-

Blinatumomab is an anti-CD19-directed CD3 bispe- nal antibody composed o an anti-CD19 ragment
cic T-cell engager constructed using BiTE antibody antigen-binding (Fab) region joined by a short linker to
an anti-CD3 Fab region.107 In the conrmatory phase o 9.5 months. Weekly administration o inotuzumab
II study o 189 patients with Ph-negative ALL, blina- ozogamicin resulted in ewer adverse events, includ-
tumomab was associated with an objective response ing lower rates o veno-occlusive disease (VOD).113
rate (ORR) o 43%. The median response duration was In a separate, multicenter phase II trial in heavily pre-
9 months, and the median OS period was 6 months.108 treated patients with relapsed or reractory ALL, ino-
ChAPTER 1
Following these results, a phase III trial (TOWER tuzumab ozogamicin therapy resulted in a remission
study) was conducted in more than 400 patients rate o 66%, with 78% o patients who achieved CR
with relapsed or reractory Ph-negative ALL ran- becoming MRD negative. The median survival period
domized (2:1) to blinatumomab (n = 271) or stan- was 7.4 months.114
dard o care (n = 134). The rate o CR with ull, These results led to a randomized trial compar-
partial, or incomplete hematologic recovery was ing inotuzumab ozogamicin with physician’s choice
signicantly higher in the blinatumomab group than o chemotherapy in patients with relapsed ALL. The
in the chemotherapy group (44% and 25%, respec- CR rates were 81% with inotuzumab ozogamicin
tively; P <.001). Molecular remission rates among and 29% with standard o care (P <.0001). Among
responders, dened as MRD less than 10 -4 in the rst responders, the MRD negativity rates were 78% and
12 weeks, were 76% and 48%, respectively. Blina- 28% (P <.0001), respectively. The median survival
tumomab prolonged survival, the primary study period was 7.7 versus 6.7 months (P = 0.02; HR, 0.77).
endpoint; the median OS was 7.7 months versus 4.0 The 2-year survival rates were 23% and 10%, respec-
months (P = .01). A total o 24% o the patients in tively. Serious toxicities included VOD ater AHSCT,
each group underwent AHSCT. 104 mainly in patients who received double alkylators in
A recent report rom a phase III study with 1:1 ran- pretransplant conditioning. Age was also a risk actor
domization o 208 children and AYAs in rst salvage or VOD.105
to blinatumomab or standard o care showed that Recently, inotuzumab ozogamicin was assessed in
blinatumomab induced a higher rate o MRD negativ- 48 children and AYAs (median age, 9 years).1–21 The
ity (79% with blinatumomab compared to 21% with ORR and MRD negativity rates were 62% and 65%,
standard o care; P <.001) and a better 2-year OS rate respectively. The 12-month OS rate was 40%.115
(79% with blinatumomab compared with 59% with
standard o care; P = .005).109
In patients with relapsed or reractory Ph-positive
Combination Immunotherapies
ALL, blinatumomab also demonstrated a positive Given the encouraging results achieved with these
eect. In the phase II ALCANTARA trial, 45 patients novel antibody constructs in ALL, they were urther
with relapsed or reractory Ph-positive ALL were evaluated in combination with lower-intensity chemo-
treated. Thirty-six percent achieved a response. The therapy backbone with the goal o urther improving
median RFS and OS periods were 6.7 months and outcomes.
7.1 months, respectively; 44% o patients received Inotuzumab ozogamicin was evaluated with
AHSCT.110 mini hyper-CVD in relapsed or reractory B-cell Ph-
negative ALL (details described earlier). Among the
initial 59 patients with relapsed or reractory ALL
Inotuzumab Ozogamicin treated, the response rate was 78%, with 82% o
Inotuzumab ozogamicin is a novel anti-CD22 mono- responders achieving MRD negativity. The 1-year RFS
clonal antibody conjugated to the toxin calicheami- and OS rates were 46% and 41%, respectively. The
cin.111 In a single-institution phase II study in patients median OS and RFS were 11 months and 8 months,
with relapsed or reractory ALL, inotuzumab ozogami- respectively. Almost hal o the patients were able to
cin was administered at a starting dose o 1.3 to 1.8 receive subsequent AHSCT, with an estimated 1-year
mg/m2 intravenously (IV) every 3 to 4 weeks. Forty- survival rate o 63% among these patients. The rate
nine patients were treated. The ORR was 57%, and o VOD was 15%, mainly in patients with prior or
the median survival period was 5.1 months. Nearly subsequent AHSCT (23%). When compared with a
hal o the patients treated with inotuzumab ozogami- historical cohort o patients treated with inotuzumab
cin proceeded to AHSCT.112 To minimize toxicities ozogamicin monotherapy in the salvage setting, the
and based on pharmacokinetic and pharmacodynamic results o the combination were signicantly better
data, inotuzumab ozogamicin was administered on a (median survival 9.3 months vs 5.6 months, P = .02).
weekly basis at 0.8 mg/m2 IV on day 1 ollowed by To urther improve these outcomes, the study was
0.5 mg/m2 IV on days 8 and 15 every 3 to 4 weeks amended to investigate the addition o our cycles o
in 40 patients. The study yielded a similar response blinatumomab ollowing our cycles o the combina-
rate as inotuzumab ozogamicin given every 3 to 4 tion o weekly lower doses o inotuzumab ozogami-
weeks (59% vs 57%), with a median survival period cin and mini hyper-CVD. The hypothesis is that the
addition o blinatumomab may allow or the use o ORR was 56%, and the 6-month duration o response
less chemotherapy and lower doses o weekly ino- rate was 43%.121
tuzumab ozogamicin, the eradication o MRD, and
the distancing o AHSCT rom the last dose o inotu- Chimeric Antigen Receptor T-Cell
ChAPTER 1
zumab ozogamicin, thereby leading to less treatment- Therapies

related morbidity, less VOD, and less mortality. In
act, the incidence o VOD was signicantly reduced CAR T cells are autologous T cells that are genetically
(rom 15% to 5%) by using lower and ractionated engineered to express a chimeric antigen receptor that
doses o inotuzumab ozogamicin (rst dose o 0.6 mg/ is composed o dierent structural parts, including a
m2; then 0.3 mg/m 2 or each subsequent dose) and by binding site o a specic antibody and a signal trans-
spacing out the last dose o inotuzumab ozogamicin duction part with or without additional costimulatory
rom AHSCT by 3 to 6 months. In the overall cohort domains.122 CAR T cells are powerul therapeutic inno-
o patients treated with mini hyper-CVD with inotu- vations that combine the antigen specicity o anti-
zumab ozogamicin (n = 59) alone and those treated bodies and the cytotoxic activity o T-cells and hence
with sequential combination with blinatumomab harness the power o targeted therapy and immuno-
(n = 30), the 2-year survival rate was 39%, and the therapy. Although rst-generation CAR T cells express-
median survival period was 14 months. In 62 patients ing anti-CD20 or -CD19 CAR T cells ailed to expand
treated in rst salvage with mini hyper-CVD and ino- in vivo and produce signicant antitumor eects,122
tuzumab ozogamicin with or without blinatumomab, second- and third-generation CAR T cells, incorporat-
the CR/CRi rate was 92%, the MRD negativity rate ing one or more co-stimulatory domains, respectively,
was 86%, the median survival time was 25 months, demonstrated strong expansion and persistence in vivo
and the 3-year OS rate was 42%. The 60-day mortal- and powerul antitumor activity. In ourth-generation
ity rate was 3%.116 These results compare avorably CAR T cells, cytokines are added to urther increase
with the results obtained with single-agent inotu- the expansion and survival o CAR T cells.
zumab ozogamicin and blinatumomab and historical A multicenter phase I/II study was conducted in 25
salvage chemotherapy with median survival period o centers around the world and treated 79 children and
only 6 to 12 months. Longer ollow-up is needed to young adults (median age, 11 years) with relapsed or
assess the relative contribution o blinatumomab to reractory CD19-positive B-ALL with a single inusion
the regimen. o tisagenlecleucel, anti-CD19 CAR T cells produced
The SWOG 1312 study is a phase I trial o inotu- by Novartis. Among the 65 patients with CR/CRi,
zumab ozogamicin and CVP (cyclophosphamide, vin- 64 (98%) were MRD negative within 3 months. The
cristine, and prednisone) or relapsed or reractory ALL. median duration o response was not reached. The
Fity patients (median age, 43 years) were enrolled, estimated 18-month RFS rate was 66%. Median OS
among whom ve patients were identied as having was not reached, and the estimated 18-month OS rate
a Ph-like signature. The CR/CRi rate was 61% in the was 70%.106,123 Tisagenlecleucel is now approved or
23 evaluable patients treated at the maximal tolerated patients up to age 25 years with B-ALL that is rerac-
dose (MTD), and 60% (three o ve) in patients with tory to rontline therapy or with two or more relapses.
the Ph-like signature. The median OS periods were 7.7 Anti-CD19 CAR-T cells were also studied in 53
months or all patients and 10.9 months or patients adult patients at Memorial Sloan Kettering Can-
treated at the MTD.117 cer Center and showed a CR rate o 83%. The
median EFS and OS were 6.1 months and 12.9
months, respectively. The median EFS in patients
BH3 Mimetics with low (<5% bone marrow blasts) and high disease
The BH3 mimetics venetoclax and navitoclax have burden (≥5% bone marrow blasts or extramedullary
demonstrated promising preclinical activity in cell disease) were 10.6 months and 5.3 months, respec-
lines o B-TALL and T-ALL.118–120 Navitoclax is a BH3 tively. The median OS periods were 20.1 and 12.4
mimetic that inhibits BCL-2, BCL-xL, and BCL-W with months, respectively. Patients with a higher burden
encouraging antileukemic activity in ALL cells.120 A o disease had a greater incidence o cytokine release
particularly strong activity was seen in KMT2A-rear- syndrome (CRS) and neurotoxic events as well.124
ranged B-ALL, and both single-agent activity as well as ZUMA-3 is a phase I trial that investigated the autolo-
synergistic killing in combination with chemotherapy gous anti-CD19 KTE-X19 in adults with relapsed or
were observed because o the upregulation o BCL-2 reractory ALL and successully rened the dosing and
in these cell lines.118,119 In a phase I trial, 36 patients the saety o the product,125 leading to a pivotal phase
with relapsed or reractory ALL (median age, 27 years; II trial that is currently ongoing (NCT02614066).
range, 6–72 years) were treated with venetoclax and There are two main saety concerns with CAR T-cell
navitoclax in combination with chemotherapy. The therapy: CRS and neurotoxicity, occurring in 77% to
Table 1–6 Ongoing Trials at MD Anderson Cancer Center Available or Patients wit Acute
Lympoblastic Leukemia (Frontline and Salvage Settings)
Trial Characteristics
ChAPTER 1
ALL Subgroup Frontline Setting Salvage Setting
Pre-B-cell ALL 1. Hyper-CVAD + inotuzumab ozogamicin + 1. Hyper-CVD + inotuzumab ozogamicin +
blinatumomab blinatumomab
2. Hyper-CVD + inotuzumab ozogamicin + 2. Hyper-CVD + venetoclax
blinatumomab 3. ADCT-602
4. CAR T cells (UCART19, UCART22, KTE-C19)
5. CAR-NK cells
Pre-B-cell ALL, MRD+ 1. Blinatumomab
2. Inotuzumab ozogamicin
T-cell ALL 1. Hyper-CVAD + nelarabine + peg asparaginase + 1. Hyper-CVD + venetoclax
venetoclax
2. Hyper-CVD + venetoclax
Ph-positive ALL 1. Hyper-CVD + ponatinib + blinatumomab 1. Blinatumomab + ponatinib
2. Blinatumomab + ponatinib 2. Venetoclax + ponatinib
ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone; CVD, cyclophosphamide,
vincristine, and dexamethasone; MRD, measurable residual disease; NK, natural killer; Ph, Philadelphia chromosome.
83% and 40% to 43% o patients, respectively, and EMERGING ThERAPIES:

being more common in patients with a higher disease MD ANDERSON APPROACh
burden at baseline.126 Grade 3 or greater CRS, including
one death, was observed in 26% o patients and grade A number o innovative therapies or various stages o
3 or greater neurotoxicity in 42% o patients, and most disease, tailored to risk-adapted strategies, are trans-
o them required treatment with the anti–interleukin-6 orming the treatment o adult ALL and resulting in
monoclonal antibody tocilizumab.124 signicant improvements in long-term outcomes.
Strategies to improve the saety o CAR T cells while Several ongoing trials are available or patients with
preserving their ecacy are an active area o basic and ALL at our institution and elsewhere in the rontline
translational research. A novel anti-CD19 CAR T cell and salvage settings (Table 1–6).
product with a lower anity to CD19 and ast-o rate Our preerred approach to newly diagnosed Ph-neg-
has been evaluated and showed improved in vitro pro- ative B-ALL is the addition o blinatumomab to hyper-
lieration and cytotoxic activity and enhanced proli- CVAD in the rontline setting. In this ongoing protocol,
eration and in vivo antitumor eect.127 To circumvent only our cycles o chemotherapy are given instead o
CD19 antigen escape as a mechanism o resistance, the standard eight cycles ollowed by our cycles o
CD22-targeted CAR T cells and dual CD19 and CD22 blinatumomab incorporated into an 18-month main-
CAR T cells have also been developed. tenance regimen (hal the duration o standard POMP
Tremendous eorts have also been made to develop maintenance). With the addition o blinatumomab,
new platorms o “o-the-shel” CAR-based therapies the goal is to both decrease the amount o intensive
to decrease the high cost and manuacturing complex- chemotherapy received and deepen responses. This
ity and delay associated with currently approved CAR protocol was recently amended to add the CD22
T cells. Allogeneic CAR T cells manuactured rom antibody–drug conjugate inotuzumab ozogamicin,
healthy donors have been investigated. For example, thereby incorporating all o the most active agents in
UCART19 is an allogeneic, genetically modied sec- B-ALL into our rontline regimen.
ond-generation CAR T cell product manuactured Because older adult patients oten cannot tolerate
rom healthy donor T-cells, in which TRAC and CD52 intensive chemotherapy, our preerred regimen con-
genes have been knocked out to allow its adminis- sists o low-intensity chemotherapy (hyper-CVD)
tration to non–human leukocyte antigen–matched combined with both inotuzumab ozogamicin (given at
patients without increasing the risk o grat-versus- a lower ractionated dose to decrease the rate o VOD)
host disease. “O-the-shel” NK cells derived rom and blinatumomab to deepen the level o response. We
umbilical cord blood and modied to express CAR also use this regimen in the relapsed or reractory set-
(CAR-NK cells) are being developed at our institution ting at any age. We also have protocols or low-inten-
with promising results in B-lymphoid malignancies.128 sity chemotherapy with venetoclax in older patients
with Ph-negative ALL and or patients with relapsed Finally, or relapsed or reractory Ph-positive ALL,
or reractory ALL (mainly T-ALL). besides the chemotherapy-ree combination o pona-
In patients with Ph-positive ALL, there is a ratio- tinib and blinatumomab being investigated, we have
nale to combine ponatinib with a less intensive an ongoing phase I/II trial o the oral, chemotherapy-
ChAPTER 1
chemotherapy backbone (mini hyper-CVD). Given ree regimen, consisting o the combination o veneto-
its activity in patients with Ph-positive ALL, blina- clax and ponatinib, or patients o all ages with relapsed
tumomab is also added to this regimen. The goal is or reractory Ph-positive ALL. There is a signicant
that by reducing toxicity rom intensive chemother- preclinical rationale or the combination o venetoclax
apy and incorporating the most active agents in Ph- and ponatinib, showing synergistic activity. Ponatinib
positive ALL (blinatumomab and ponatinib), we will may also help to prevent venetoclax resistance by pre-
reduce treatment-related morbidity and mortality and venting upregulation o Mcl-1, an established resis-
urther increase the cure rate. This regimen is open tance mechanism o venetoclax-based regimens.
to patients o all ages with newly diagnosed Ph-pos-
itive ALL. In older patients (60 years and older) with
newly diagnosed Ph-positive ALL or younger patients CONCLUSION
who are unt or intensive chemotherapy, we are also
evaluating a chemotherapy-ree combination o pona- Therapeutic capabilities in adult ALL have rapidly
tinib and blinatumomab, which is also available or reached new heights over the past decade with the
patients with relapsed or reractory Ph-positive ALL introduction o highly promising monoclonal anti-
at any age. bodies, immune conjugates, CAR T cells, and new-
In the salvage setting, we designed a phase I/II generation TKIs. Genomic proling has identied
study o the combination o hyper-CVD plus veneto- new prognostic markers (e.g., IKZF1) as well as new
clax or patients with relapsed or reractory ALL. This therapeutic targets (e.g., ABL, JAK1/2, ETV6-NTRK3)
regimen is particularly promising or patients with to improve the adverse prognosis o some ALL sub-
T-ALL. Another phase I/II trial available at our institu- sets, such as Ph-like ALL. As many o the newer agents
tion is investigating ADCT-602, which is an antibody advance through the nal stages o development, we
drug conjugate composed o a humanized monoclo- will seek to determine the optimal combination and
nal antibody directed against CD22, conjugated to the order o delivery and the role o cytotoxic chemother-
cross-linking cytotoxic agent tesirine (SG3249). The apy in the saest achievement o durable cure rates.
hope is that this agent will be a potent anti-CD22 ther- Moreover, the rontline introduction o these eec-
apy, without the hepatic toxicity associated with ino- tive therapies can be expected to increase the rate o
tuzumab ozogamicin. Moreover, we have a number MRD negativity, optimize responses, and close the
o CAR-based therapies being investigated in clinical outcome gap separating pediatric rom adult ALL. Har-
trials, including those targeting both CD19 and CD22 nessing the ull potential o the immune system with
as well as both autologous (KTE-C19) and allogeneic the durable presence o autologous or allogeneic T-cell
approaches (UCART19, UCART22, and CAR NK-cell constructs may ultimately lead to obviation o AHSCT
therapies). in search o better cure rates in adult ALL.
MD ANDERSON PRACTICE TIPS

J There are several ongoing clinical trials at MDACC J In patients with Ph-positive ALL, we combine pona-
or patients with ALL. The treatment ollows a tinib with a less intensive chemotherapy backbone
risk-tailored strategy. Our preerred approach to (mini hyper-CVD). Given its activity in Ph-positive
patients with newly diagnosed Ph-negative B-ALL is ALL, blinatumomab is also added to this regimen. In
the addition o blinatumomab to hyper-CVAD in the older patients (60 years or older) with newly diag-
rontline setting. nosed Ph-positive ALL or younger patients who are
J Our preerred regimen in older adult patients con- unt or intensive chemotherapy, we are also evalu-
sists o low-intensity chemotherapy (hyper-CVD) ating a chemotherapy-ree combination o pona-
combined with both inotuzumab ozogamicin (given tinib and blinatumomab, which is also available or
at a lower ractionated dose to decrease the rate o patients with relapsed or reractory Ph-positive ALL
VOD) and blinatumomab to deepen the level o at any age.
response. We also use this regimen in the relapsed or J In the salvage setting, we have a number o tri-
reractory setting at any age. We also have protocols als including the combination o hyper-CVD with
or low-intensity chemotherapy with venetoclax in venetoclax and antibody drug conjugates as well
older patients with Ph-negative ALL and or patients as CAR-based therapies with T-cells as well as NK
with relapsed or reractory ALL (mainly T-ALL). cells.
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nation o inotuzumab ozogamicin (InO) with low-intensity
2 Adult Acute Myeloid Leukemia
Tapan M. Kadia
Joseph D. Khoury
Farhad Ravandi
KEY CONCEPTS
 Newer techniques and wider applicability o genomic  Chemotherapy combined with an FLT3 inhibitor such
sequencing have identied numerous recurrent somatic as midostaurin or others on clinical trial are now part o
mutations and patterns o mutation that reveal the exten- the standard o care or patients with newly diagnosed
sive heterogeneity o acute myeloid leukemia (AML). Better FLT3-mutated AML.
understanding o the biology behind the genomic aber-  The BCL2 inhibitor venetoclax has signicantly improved
rations has led to more accurate disease prognostication outcomes or older and unt patients with newly diag-
as well as development o specic therapies or genomi- nosed AML, having demonstrated a signicant survival
cally dened subgroups. The most recent European Leu- benet in combination with hypomethylating agents
kemiaNet (ELN) 2017 classication system incorporates (HMAs) compared with HMAs alone.
several o these mutations or risk classication. Thereore,
 Monitoring o minimal residual disease (MRD) by multi-
pretreatment assessment o these mutations (FLT3, NPM1,
parameter ow cytometry or molecular methods at the
CEBPA, TP53, RUNX1, ASXL1) along with conventional karyo-
time o remission ater induction and ater consolidation
typing is becoming a part o standard practice.
is a powerul tool to help predict the risk o relapse and
 Since 2017 and as o 2020, several new therapies have guide risk stratication, including postremission strategies
been approved or reintroduced or the treatment o such as stem cell transplant (SCT). Complete remission
patients with AML. These include the FLT3 (ms-like tyro- with or without MRD positivity is being incorporated into
sine kinase 3) inhibitors midostaurin and gilteritinib, the response criteria.
IDH1 inhibitor ivosidenib, the IDH2 inhibitor enasidenib,
 Maintenance therapy with oral azacytidine (CC486) has
the BCL2 inhibitor venetoclax, the hedgehog inhibitor
become the standard o care or patients not eligible or
glasdegib, the CD33 antibody–drug conjugate gemtu-
postremission SCT ater demonstrating improvement in
zumab ozogamicin (GO), the liposomal ormulation CPX-
survival compared with placebo. Maintenance strategies
351, and oral azacytidine.
with targeted therapies ater achieving remission and
 The CD33 antibody–drug conjugate GO has been shown even ater SCT are being investigated.
to provide signicant survival benet in patients with
 Repeat molecular testing or mutations at the time o
avorable or intermediate-risk disease and should be
relapse should be strongly considered to allow incorpo-
incorporated into the rontline treatment o core-binding
ration o specic targeted therapies that are indicated
actor AML when appropriate. GO also has an important
in genomically dened subgroups (eg, enasidenib, ivo-
role in the treatment o patients with acute promyelo-
sidenib, gilteritinib).
cytic leukemia.
Acute myeloid leukemia (AML) consists o a hetero- advances in our understanding o the molecular biol-
geneous group o hematologic neoplasms character- ogy o AML, its treatment remains challenging, and
ized by clonal prolieration o myeloid blasts involving outcomes vary greatly depending on a constellation o
peripheral blood and bone marrow, with occasional cytogenetic and molecular eatures as well as age and
tumor ormation in extramedullary tissues. Despite comorbidities.
23
24 Scion I Leukemia
AML is thought to be the culmination o genetic an enrichment o TP53 mutations among patients with
mutations and chromosomal aberrations within therapy-related AML.6,7 Exposure to agents that inhibit
myeloid precursors resulting in disrupted dierentia- the DNA repair enzyme topoisomerase II (eg, etopo-
tion, excessive prolieration, and suppressed apoptosis side) is also associated with secondary AML with a
Chapter 2
o neoplastic cells reerred to as blasts. typically shorter latency period, usually 1 to 3 years.8
Over the past several decades, improvements in Benzene, smoking, dyes, herbicides, and pesticides
chemotherapeutic regimens, supportive care, and have been implicated as potential risk actors or devel-
improved understanding o underlying biology have opment o AML.9
resulted in signicant progress in treating patients with AML may also be secondary to transormation o
AML. Knowledge o the biological underpinnings and an antecedent myeloid disorder, such as MDS, myelo-
heterogeneity o AML has resulted in the identica- prolierative neoplasm (MPN), or MDS/MPN, or other
tion o new therapeutic targets and rationally designed bone marrow disorders, such as aplastic anemia.
inhibitors or a number o these targets. Despite these
advances, the majority o patients with AML have an
incurable disease and succumb rom relapses or com- CLINICAL PRESENTATION
plications o their disease. With better denition o
molecular abnormalities and elucidation o the patho- Fatigue, bruising or bleeding, ever, and inection,
genic events in various AML subtypes and with the refecting a state o bone marrow ailure, are common
development o novel targeted agents, a better out- in patients with AML. Only 10% o patients present
come or patients with AML may be achievable in the with white blood cell (WBC) count greater than 100 ×
near uture. 109/L1; these patients are at higher risk o tumor lysis
syndrome, central nervous system involvement, and
leukostasis. Leukostasis may maniest as dyspnea,
EPIDEMIOLOGY, ETIOLOGY, AND chest pain, headaches, altered mental status, cranial
RISK FACTORS nerve palsies, or priapism. Leukostasis and tumor
lysis syndrome are oncologic emergencies and require
Approximately 19,000 individuals are diagnosed with prompt recognition and management.
leukemia annually in the United States. The incidence Physical ndings other than bleeding and inection
o AML is 4.3 per 100,000. The median age at pre- may include organomegaly, lymphadenopathy, ster-
sentation is 68 years. The incidence o AML, as well nal tenderness, retinal hemorrhages, and inltration o
as myelodysplastic syndrome (MDS), rises with age, gingivae, skin, sot tissues, lungs, or meninges (more
with the majority o AML patients being older than 60 common in AML with monocytic dierentiation).
years old.1 The incidence o AML is slightly higher in Disseminated intravascular coagulopathy (DIC) with
males and in populations o European descent. Acute bleeding diathesis is a common presentation in APL.
promyelocytic leukemia (APL), a distinct subtype o
AML, has been reported to be more common among
populations o Hispanic background.2 DIAGNOSIS AND CLASSIFICATION
An increased incidence o AML is seen in patients
with disorders associated with increased chromatin The diagnosis o AML is typically dened as the pres-
ragility such as Bloom syndrome, Fanconi anemia, ence o 20% or more myeloid blasts in the bone mar-
Kostmann syndrome, Wiskott-Aldrich syndrome, row or peripheral blood in accordance with World
and ataxia-telangiectasia. Other syndromes, such as Health Organization (WHO) classication criteria
Down (trisomy o chromosome 21), Klineelter (XXY (Table 2–1).10 AML subtypes in the WHO classica-
and variants), and Patau (trisomy o chromosome 13) tion are dened on the basis o morphology, immu-
syndromes, have also been associated with a higher nophenotype, and molecular or genetic eatures. In
incidence o AML.3 some patients, AML presents as a mass in extramed-
Exposure to cytotoxic therapies increases AML risk. ullary tissues (myeloid sarcoma). Patients who have
Two categories o therapy-related AML have been the “AML-dening” cytogenetic abnormalities t(8;21)
described. Patients exposed to alkylating agents (eg, (q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), and
cyclophosphamide, melphalan, nitrogen mustard) or t(15;17)(q22;q12) are diagnosed with AML regardless
radiation therapy can develop AML ater a latency o the blast percentage.
period o 4 to 8 years, which is oten associated with Bone marrow sampling is essential or the initial
abnormalities o chromosomes 5 and/or 7 and/or com- workup o a patient with suspected acute leukemia.
plex karyotype but may also present without charac- Sampling should include a core (trephine) biopsy as
teristic chromosome abnormalities.4,5 Recent analysis well as aspiration material. The core biopsy is used to
o next-generation sequencing (NGS) data also suggests perorm touch preparations, which are invaluable in
C 2 Adult Acute Myeloid Leukemia 25
tbl 21 acu Myloid Lukmi nd rld pcuso Nolsms nd acu Lukmis o
ambiguous Ling
Myeloproliferative neoplasms (MPN) AML, NOS

Chronic myeloid leukemia (CML), BCR-ABL11 AML with minimal diferentiation
Chapter 2
Chronic neutrophilic leukemia (CNL) AML without maturation
Polycythemia vera (PV) AML with maturation
Primary myelobrosis (PMF) Acute myelomonocytic leukemia
PMF, prebrotic/early stage Acute monoblastic/monocytic leukemia
PMF, overt brotic stage Pure erythroid leukemia
Essential thrombocythemia (ET) Acute megakaryoblastic leukemia
Chronic eosinophilic leukemia, not otherwise specied (NOS) Acute basophilic leukemia
MPN, unclassiable Acute panmyelosis with myelobrosis
Mastocytosis Myeloid sarcoma
Myeloid/lymphoid neoplasms with eosinophilia and Myeloid proliferations related to Down syndrome
rearrangement of Transient abnormal myelopoiesis (TAM)
PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2 Myeloid leukemia associated with Down syndrome
Myeloid/lymphoid neoplasms with PDGFRA rearrangement Blastic plasmacytoid dendritic cell neoplasm
Myeloid/lymphoid neoplasms with PDGFRB rearrangement Acute leukemias of ambiguous lineage
Myeloid/lymphoid neoplasms with FGFR1 rearrangement Acute undiferentiated leukemia
Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2 Mixed phenotype acute leukemia (MPAL) with t(9;22)
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (q34.1;q11.2); BCR-ABL1
Chronic myelomonocytic leukemia (CMML) MPAL with t(v;11q23.3); KMT2A rearranged
Atypical chronic myeloid leukemia (aCML), BCR-ABL12 MPAL, B/myeloid, NOS
Juvenile myelomonocytic leukemia (JMML) MPAL, T/myeloid, NOS
MDS/MPN with ring sideroblasts and thrombocytosis (MDS/ Blymphoblastic leukemia/lymphoma
MPN-RS-T) B-lymphoblastic leukemia/lymphoma, NOS
MDS/MPN, unclassiable B-lymphoblastic leukemia/lymphoma with recurrent
Myelodysplastic syndromes (MDS) genetic abnormalities
MDS with single lineage dysplasia B-lymphoblastic leukemia/lymphoma with t(9;22)
MDS with ring sideroblasts (MDS-RS) (q34.1;q11.2);BCR-ABL1
MDS-RS and single lineage dysplasia B-lymphoblastic leukemia/lymphoma with
MDS-RS and multilineage dysplasia t(v;11q23.3);KMT2A rearranged
MDS with multilineage dysplasia B-lymphoblastic leukemia/lymphoma with t(12;21)
MDS with excess blasts (p13.2;q22.1); ETV6-RUNX1
MDS with isolated del(5q) B-lymphoblastic leukemia/lymphoma with
MDS, unclassiable hyperdiploidy
Provisional entity: Reractory cytopenia o childhood B-lymphoblastic leukemia/lymphoma with
Myeloid neoplasms with germ line predisposition hypodiploidy
Acute myeloid leukemia (AML) and related neoplasms B-lymphoblastic leukemia/lymphoma with t(5;14)
AML with recurrent genetic abnormalities (q31.1;q32.3) IL3-IGH
AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1 B-lymphoblastic leukemia/lymphoma with t(1;19)
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11 (q23;p13.3);TCF3-PBX1
APL with PML-RARA Provisional entity: B-lymphoblastic leukemia/
AML with t(9;11)(p21.3;q23.3);MLLT3-KMT2A lymphoma, BCR-ABL1–like
AML with t(6;9)(p23;q34.1);DEK-NUP214 Provisional entity: B-lymphoblastic leukemia/
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, lymphoma with iAMP21
MECOM Tlymphoblastic leukemia/lymphoma
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1 Provisional entity: Early T cell precursor
Provisional entity: AML with BCR-ABL1 lymphoblastic leukemia
AML with mutated NPM1 Provisional entity: NK cell lymphoblastic leukemia/
AML with biallelic mutations o CEBPA lymphoma
Provisional entity: AML with mutated RUNX1
AML with myelodysplasiarelated changes
Therapyrelated myeloid neoplasms
NK, natural killer.

Reproduced with permission rom Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the World Health Organization classication o myeloid neoplasms and
acute leukemia, Blood 2016 May 19;127(20):2391-2405.
taBLe 22 Immunonoyic Mks o hmooiic Ling Diniion Commonly Usd in

rouin Flow Cyomy anlysis
Myeloid Lymphoid
Chapter 2
Granulocytic Monocytic Erythroid Megakaryocytic B Cell T Cell

MPO CD4 CD36 CD41 CD19 CD2
CD13 CD14 CD71 CD42b CD20 cCD3
CD15 CD64 CD235a CD61 CD22 CD5
CD33 cCD79a CD7
CD117 cIgM
taBLe 23 Nx-Gnion SquncingBsd Muion anlysis pnl o Myloid Nolsms
Cunly Usd o Fonlin assssmn   MD andson Cnc Cn
ANKRD26 CBLB EED GFI1 JAK1 NF1 PTEN SH283 SUZ12

ASXL1 CBLC ELANE GNAS JAK2 NOTCH1 PTPN11 SMC1A TERC
ASXL2 CEBPA ETNK1 HNRNPK JAK3 NPM1 RAD21 SMC3 TERT
BCOR CREBBP ETV6 HRAS KDM6A NRAS RARA SRSF2 TET2
BCORL1 CRLF2 EZH2 IDH1 KIT PAX5 RUNX1 STAG1 TP53
BRAF CSF3R FBXW7 IDH2 KMT2A PHF6 SETBP1 STAG2 U2AF1
BRINP3 CUX1 FLT3 IKZF1 KRAS PIGA SF1 STAT3 U2AF2
CALR DDX41 GATA1 IL2RG MAP2K1 PML SF3A1 STAT5A WT1
CBL DNMT3A GATA2 IL7R MPL PRPF40B SF3B1 STAT5B ZRSR2
case o a dry tap. The aspiration material is typically Molecular diagnostics play a critical role in the labo-
used to prepare a clot and aspirate smears, in addition ratory workup o AML. Whereas the scope o known
to having portions submitted or fow cytometry, cyto- molecular alterations in AML was limited until a ew
genetics, and molecular diagnostics. Wright-Giemsa– years ago, the advent o NGS has dramatically increased
stained aspirate smears or touch preparations are our understanding o the molecular landscape o AML.
evaluated, and the percentage o blasts is determined As a result, the limited number o polymerase chain
through a 500-cell manual dierential count. reaction (PCR)–based assays that used to be perormed
Conrmation o myeloid lineage is commonly accom- during AML workup have now been largely replaced
plished using fow cytometry immunophenotyping. In by NGS-based panels that simultaneously assess the
most AML cases, blasts express one or more markers mutation status o tens to hundreds o genes. The cur-
o immature hematopoietic precursors such as CD34, rent NGS mutation panel or new and relapsed myeloid
CD117, and HLA-DR, in addition to dim CD45 (com- malignancies used at our institution assesses the coding
mon leukocyte antigen). Myeloid lineage is predicated on sequences o the 81 genes listed in Table 2–3.
the expression o antigens associated with granulocytic,
monocytic, erythroid, and/or megakaryocytic dierentia-
tion by blasts (Table 2–2). Expression o myeloperoxidase RISK STRATIFICATION OF ACUTE
(MPO) is considered specic or myeloid dierentia- MYELOID LEUKEMIA
tion, although AML blasts may lack MPO expression.
Although aberrant expression o lymphoid antigens is Ater a diagnosis o AML has been made, risk strati-
commonly seen in some cases with a bona de AML cation is the critical next step to determine therapy,
phenotype, such expression is generally limited to one or prognosis, and longer-term management. Several vari-
a ew lymphoid antigens. Acute leukemia with ambigu- ables are predictive o outcome, including patient-
ous lineage is beyond the scope o this discussion; briefy, related variables, such age and perormance status, as
it reers to acute leukemia with overlapping expression o well as disease-related predictors, such as cytogenetic
myeloid and lymphoid antigens or lack o both. and molecular characteristics.
taBLe 24 risk Sifcion o acu Myloid Lukmi euon LukmiN Cii, 2017
ELN Genetic Abnormality

Favorable t(8;21)(q22;q22), inv(16)/t(16;16)(p13;q22),
Chapter 2
NPM1-mutated and FLT3-ITD-wild type (normal karyotype) or FLT3-ITD mutated (low allelic ratio),
mutated CEBPα (normal karyotype)
Intermediate NPM1-mutated and FLT3-ITD mutated (high allelic ratioa)
NPM1-wild type and FLT3-ITD mutated (low allelic ratio)
NPM1-wild type and FLT3-ITD wild type
Cytogenetics that are neither avorable nor adverse
t(9;11)(p21.3;q23.3); MLLT3-KMT2A
Adverse inv(3)/t(3;3)(q21;q26);
t(6;9)(p23,q34); t(v;11q23.3), KMT2A rearranged; t(9;22) BCR-ABL; -5 or del(5q); -7; abnl(17p); complex
karyotype; monosomal karyotype; NPM1-wildtype and FLT3-ITD (high allelic ratio); RUNX1, ASXL1,
TP53 mutations
a
Low allelic ratio is <0.5; high allelic ratio is ≥0.5.
Abn, abnormal; ELN, European LeukemiaNet; inv, inversion
The karyotype remains one o the best predic- analysis showed that the TP53 mutation was com-
tors o outcome in patients with AML. The European monly associated with older patients and a monosomal
LeukemiaNet (ELN) guidelines have proposed a risk- karyotype and correlated with a low complete remis-
stratication system based on cytogenetics and molecu- sion (CR) rate and shorter relapse-ree survival (RFS),
lar analysis.1 As listed in Table 2–4, patients are classied event-ree survival (EFS), and overall survival (OS). On
as having avorable-, intermediate-, or unavorable-risk multivariate analysis, TP53 mutations were associated
disease. A limitation o the current ELN classication with the worst prognosis.14 We recently reported the
system is that it takes into account only a ew o the importance o TP53 variant allelic requency in deter-
commonly mutated genes or prognostication. As more mining outcome to various intensities o therapy.15
validated data on other mutations and co-mutations Several novel molecular aberrations, including
become available, a more expansive prognostication mutations o the DNMT3A, TET2, MLL, and PHF6
system may help rene risk stratication. For example, genes, have been described, particularly in patients
it is known that the avorable prognosis attributed to with a normal karyotype.16 However, their utility in
mutant CEBPA is true in cases o biallelic CEBPA muta- current clinical practice remains limited, and they have
tion rather than the monoallelic mutation.11 In patients limited value in determining best treatment strategies
with FLT3-wild-type/NPM1-mutated AML, DNMT3A or patients. However, the presence o other mutations
assessment is o importance. Loghavi et al12 showed such as RUNX1 and ASXL1 has been recognized to
that in patients with karyotypically normal AML with have an adverse prognostic impact as reported in the
NPM1 mutations, the presence o concurrent DNMT3A revised version o ELN classication.
mutation has an adverse eect on outcomes, with the
eect being more detrimental than either FLT3-ITD or
FLT3-TKD mutations. This analysis demonstrated that TREATMENT OF ACUTE MYELOID
in patients with de novo karyotypically normal AML, LEUKEMIA
particularly those younger than 60 years old, patients
with AMLDNMT3A/FLT3/NPM1 (sometimes reerred to as tri- In the 1960s, Freireich et al17 demonstrated the signi-
ple-positive) seem to have the worst clinical outcomes cance o achieving a CR to improve survival. Since then,
ollowed by those with AMLFLT3/DNMT3A and then those the objective o therapy has been to produce and main-
with AMLNPM1/DNMT3A.12 Currently, normal karyotype tain CR, the only currently accepted approach to AML
AML patients with NPM1-mutated/FLT3-wild-type cure. Criteria or CR have been dened by the Inter-
disease are considered avorable risk according to the national Working Group and are ollowed in the clinic
ELN guidelines. and in clinical trials or response assessment.1,18 Ater 3
The presence o TP53 mutations is associated with years in CR, the probability o AML recurrence declines
a poor outcome.13 A recent report by German and sharply to less than 10%,19 and patients in continuous
Austrian investigators indicated that the outcome o CR or 3 or more years can be considered “potentially
patients with TP53 mutations is worse than that o cured.” However, the denition o CR is an arbitrary one,
patients with the monosomal karyotype known to signaling control o the disease burden and recovery o
be an adverse prognostic indicator.14 In this study, the spontaneous hematopoiesis; with improved technology,
the precision or detection o residual disease ater the 5 days (IA). An alternative used by many cooperative
initial therapy has increased prompting the addition o groups and in the community is the “3 + 7 regimen,”
minimal residual disease (MRD) status to the denition in which the anthracycline (ie, IDA or daunorubicin
o CR (ie, CR with or without detectable MRD). The [DNR]) is usually given daily or 3 days and ara-C is
Chapter 2
persistence o MRD ater remission induction and con- given at a lower dosage o 100 to 200 mg/m2 daily or
solidation has important implications on risk o relapse 7 days by continuous inusion. Based on evidence o
as well as indications or and success o allogeneic stem synergy, a second nucleoside analogue such as fudara-
cell transplant (allo-SCT).20 Whether the improved detec- bine, cloarabine, or cladribine has been added to the
tion and application o novel strategies to eradicate the IA backbone (discussed in detail later).
residual leukemia will translate to improved cure rates is In clinical practice, a bone marrow aspirate is usu-
the subject o ongoing and uture trials. ally obtained 2 to 3 weeks ater beginning therapy. A
Ater AML is diagnosed, the need or emergency biopsy is needed only i the quality o the aspirate does
therapy must be assessed. Emergency treatment is not permit determination o cellularity. I the day 21
required (1) in cases o APL, (2) in cases o circulating marrow is hypoplastic, therapy is usually delayed until
blast count greater than 50 to 100 × 109/L or rapid rate count recovery (in the case o remission) or until it is
o prolieration, and (3) in the presence o DIC or organ clear that there is persistence o leukemia, at which
dysunction (especially pulmonary) attributed to leu- time the second course begins. A second repeated
kemic inltration (mostly seen in patients with >10 × course o induction therapy can produce remissions in
109/L circulating blasts and/or M4 or M5 French-Ameri- a subset o patients, but these are usually o shorter
can-British [FAB] morphology). In the latter situation, it duration than remissions produced ater one course o
is important to initiate immediate chemotherapy. Leu- therapy. The timing o a second course with persis-
kapheresis or severe leukocytosis and/or leukostasis tent AML is controversial. Several cooperative groups
should also be considered,21 although a number o stud- advocate starting a second course i there is persistent
ies have suggested that this has limited value on long- AML on days 10 to 15 o chemotherapy. With high-
term outcome. In patients presenting with low WBC dose ara-C (HDAC), a delay o a second course with
counts, several studies have demonstrated that initia- persistent disease on days 21 to 28 may be indicated
tion o therapy can be delayed or several days until i the blasts are decreasing because most (90%) CRs
all the necessary diagnostic inormation is available,22 are obtained ater the rst course and response to a
however, this delay should be as short as possible. second course is poor. It is important to recognize that
At the University o Texas MD Anderson Cancer the initial marrow obtained ater a period o hypopla-
Center (MDACC), most patients are enrolled in clini- sia may occasionally demonstrate a higher percent-
cal trials, i eligible. Urgent cytoreductive therapy is age o blasts, sometimes as high as 30% to 40%, as
given when needed, with clinical trials designed to a refection o the regeneration o normal, not “leuke-
accommodate and expressly allow emergent chemo- mic,” marrow elements while peripheral blood counts
therapy beore enrollment. The therapy is tailored are recovering. In this circumstance, ollow-up (eg, at
to the individual patients’ characteristics, including 1- to 2-week intervals) marrows may show sequential
their pretreatment cytogenetic and molecular proles. reduction in blast percentages concomitant with a rise
We discuss here the therapies or the various patient in neutrophils and platelets.23 Detection o persistent
groups with AML. cytogenetic or pretreatment clonal abnormalities in
the blasts can help distinguish disease-related versus
healthy regenerating blasts. Such a distinction can also
INDUCTION THERAPY IN ACUTE be achieved using fow cytometry immunophenotyp-
MYELOID LEUKEMIA ing in specialized centers.
Typically, when in remission ater treatment with
Conventional treatment or AML with intensive che- the induction course, patients receive postremission
motherapy, divided into remission induction and postconsolidation therapy, with the same drugs admin-
remission therapy, has been with combinations o istered at approximately monthly intervals or 4 to 6
anthracyclines and cytarabine (ara-C). months. Ater sucient consolidation therapy, patients
may be reerred or allo-SCT or be oered long-term
maintenance therapy.
Anthracyclines and Cytarabine
At MDACC, young patients (younger than 60 years
old) with AML are treated with a core backbone o
Choice of Anthracyclines
idarubicin (IDA) plus cytarabine-based regimens. The Randomized trials have attempted to identiy the
dosage o IDA is 10 to 12 mg/m2 or 3 days, and ara-C superior anthracycline (eg, IDA, DNR, mitoxantrone
is given at a dosage ranging rom 1 to 2 g/m2 or 4 to [MTZ], aclarubicin).24 In a three-arm randomized
study comparing DNR, IDA, and MTZ as part o the overall response rate (ORR) o 66.7% (vs 57.6%; P =
induction regimen or older patients, there was no .06). Improvements in the median OS (14.7 months vs
advantage or any one arm.25 In contrast, in a three- 12.9 months) and EFS (6.5 months vs 2 months) were
arm randomized trial conducted by the European noted in the CPX-351 cohort.32 Based on these data
Organization or Research and Treatment o Cancer and a signicant signal o ecacy in secondary AML,
Chapter 2
(EORTC) and Italian Group or Hematological Dis- a randomized phase 3 trial was conducted in patients
eases in Adults (GIMEMA) comparing the same three with newly diagnosed secondary AML. Among 309
agents, the 5-year disease-ree survival (DFS) and OS patients randomized to CPX-351 versus the 3 + 7
were signicantly better or patients receiving IDA and regimen, CPX-351 was associated with a signicantly
MTZ (P = .03 and .02, respectively). The recovery time improved OS compared with the 7 + 3 regimen(9.56
was longer with IDA and MTZ (P <.0001).26 A study vs 5.95 months; hazard ratio [HR], 0.69;P = .005). The
by Pautas and colleagues27 randomized 468 patients CR rate was 38% with CPX-351 versus 26% with
to either DNR 80 mg/m2 daily or 3 days versus IDA the 3 + 7 regimen(P = .035), and the CR + complete
12 mg/m2 daily or 3 or 4 days combined with stan- response with incomplete hematologic recovery (CRi)
dard-dose cytarabine. Three days o IDA resulted in rate was 48% versus 33% (P = .016). 33 CPX-351 was
a higher CR rate (83% vs 70%; P = .007) and a trend well tolerated and associated with lower induction
or better 4-year EFS (21% vs 12%) and survival (32% morality but was associated with more prolonged
vs 23%) rates, with no additional benet seen with 4 myelosuppression compared with the 7 + 3 regimen.
days o IDA. Gardin et al28 analyzed pooled data rom More o the patients achieving CR ater CPX-351
trials conducted in patients with AML who were age were able to undergo later allo-SCT (20% vs 12%);
50 years o age or older. These trials compared the e- their survival was also longer ater SCT. This pivotal
cacy o IDA versus DNR in induction and consolida- study was the basis or Food and Drug Administration
tion. They assessed the outcomes o these patients and (FDA) approval o CPX-351 as rontline therapy or
showed that IDA resulted in a higher CR rate o 69% patients with secondary AML. Combinations using
(vs 61% with DNR; P = .02) but did not lead to supe- CPX-351 as a new backbone or AML therapy, includ-
rior OS (median OS, 14.2 months; P = .13).28 ing gemtuzumab, venetoclax, IDH inhibitors, and
Dierent doses o DNR have been evaluated in sev- FLT3 (ms-like tyrosine kinase 3) inhibitors are being
eral trials, combined with standard-dose ara-C (SDAC; investigated.
100 or 200 mg/m2 daily or 7 days). Two studies showed
that using DNR 90 mg/m2 had better outcomes than
DNR 45 mg/m2 regardless o age. Both studies showed
High-Dose Cytarabine
higher CR rates and OS in patients receiving a higher Several randomized trials have assessed the ecacy
dose o DNR, without any additional toxicity. The o HDAC (1–3 g/m2) versus SDAC (100–200 mg/
benecial eect was mostly seen in patients younger m2) or induction therapy. The Cancer and Leuke-
than 50 years old and with more avorable cytogenet- mia Group B (CALGB) and the Eastern Cooperative
ics.29,30 More recently, a French group also showed that Oncology Group (ECOG) restricted their analysis to
DNR 60 mg/m2 had similar relapse rate, RFS, and OS patients in CR, whereas the SWOG compared HDAC
compared with DNR 90 mg/m2.31 with SDAC during induction and randomized SDAC
Although there is not a clear survival advantage patients to SDAC or HDAC when the patients were
with IDA over DNR, CR rates and RFS avor the use in CR.34 Finally, the Australian Leukemia Study Group
o IDA, with a trend or OS advantage. Based on these (ALSG) randomized patients to HDAC or SDAC
data, at MDACC, IDA is the preerred anthracycline o during induction only (Table 2–5).35 These trials con-
or intensive induction therapy. cluded that (1) the toxicity o HDAC (eg, cerebellar)
outweighs the anti-AML eect in patients older than
65 years; (2) patients older than 60 years benet rom
CPX-351 HDAC given during induction (SWOG, ALSG), in CR
CPX-351 is a liposomal ormulation or delivery o (CALGB, ECOG), and perhaps both (SWOG); and (3)
ara-C and DNR preerentially to leukemic cells. In this HDAC potentially increases the cure rates to 70% to
ormulation, ara-C and DNR are encapsulated in a 5:1 80% in patients with inversion 16 or t(8;21) and to
xed molar ratio that was ound to be consistently 30% to 40% in patients with normal karyotype, but
synergistic in vitro. A multicenter, open-label, phase II little, i at all, in patients with adverse karyotypes. In a
study was conducted across 18 centers in the United meta-analysis o three trials in 1691 patients, induction
States in the rst-line setting. Patients older than 60 with HDAC was compared with SDAC. Although
years old with de novo AML were randomized to there was no dierence in CR rates, the 4-year RFS
receive the CPX-351 versus the 7 + 3 regimen. Higher (P = .03), 4-year OS (P <= .0005), and 5-year EFS (P
response rates were noted with CPX-351, with an <.0001) were better with HDAC.36
taBLe 25 Sndd vsus hig-Dos Cybin (hDaC) in pins wi Nwly Dignosd acu
Myloid Lukmi
Study HDAC During: Patients (n) Benecial Efect o HDAC

Chapter 2
ALSG Induction 279 CR duration

SWOG Induction, consolidation, or both 723 EFS
ECOG Consolidation 170 I age younger than 60 years
CALGB Consolidation 596 I age younger than 60 years
ALSG, Australian Leukemia Study Group; CALGB, Cancer and Leukemia Group B; CR, complete response; EFS, event-ree survival; ECOG, Eastern Cooperative Oncology
Group.
A group o more recent randomized studies, in the era concerns. However, in a trial by the French Leukemia
o modern supportive care, looked to reexamine the util- Association, patients aged 50 to 70 years with previ-
ity o higher dose cytarabine during AML induction and ously untreated de novo AML were randomized to
reported some nuanced results. Lowenberg et al37 ran- receive standard chemotherapy with the 7 + 3 regimen
domized 858 patients with a median age o 49 years to (DNR, ara-C) with or without GO. Gemtuzumab was
induction therapy with IDA combined with either high- administered in ractionated doses. The ORR was 81%.
dose cytarabine 1g/m2 every 12 hours or 10 versus stan- The OS (34 months vs 19 months; P = .036), EFS (15.6
dard-dose cytarabine given at 200 mg/m2 daily or 7 days. months vs 9.7 months; P = .0003), and RFS (28 months
The study ound no dierence in rate CR, EFS, or OS vs 11 months; P = .0003) were signicantly better in the
between the two arms. Further examination o the treat- GO group.40 Another study by the Medical Research
ment plan design reveals that all patients in both arms Council (MRC) in the United Kingdom showed a benet
received high-dose cytarabine during cycle 2 o therapy, or the addition o GO to ara-C and anthracycline-based
conounding the results and ailing to have a clear com- induction regimen.41 A recent meta-analysis examined
parison between higher or standard-dose cytarabine. The ve randomized trials in untreated patients with AML
EORTC-GIMEMA cooperative group compared HDAC demonstrated that the addition o GO to rontline ther-
with standard-dose cytarabine in a backbone combin- apy o AML led to a signicantly reduced risk o relapse
ing DNR and etoposide.38 Among 1942 patients aged 60 and improved 5-year OS.42 This was most evident in
years or younger, they ound signicantly higher rates patients with avorable- and intermediate-risk cytoge-
o CR (82% vs 76%), rates o 6-year EFS (44% vs 35%), netics but not in those with adverse karyotype. These
and OS (52% vs 43%) in patients receiving HDAC-based data suggest utility o GO in patients with AML, sup-
induction. These benets were seen primarily and signi- porting the recent re-approval o GO by the FDA.
cantly in patients younger than 46 years o age, but there
was only a trend or OS improvement in those aged 46 to
60 years.38 Finally, Bassan et al39 randomized 574 patients TREATMENT OF YOUNGER PATIENTS
with a median age o 52 years to IDA + etoposide + stan- WITH ACUTE MYELOID LEUKEMIA
dard-dose cytarabine or IDA plus sequential high-dose
cytarabine. The sequential high-dose cytarabine arm
was associated a higher CR rate ater one course (81% vs
Purine Analogues
69%; P = .0007) and a signicantly improved the 5-year The addition o the purine analogues cloarabine,
survival rate (49vs versus 39%; P = .045). Our current cladribine, and fudarabine to cytarabine and anthracy-
approach at MDACC, thereore, is the incorporation o clines has been associated with improved outcomes in
higher dose cytarabine during induction and consolida- a number o studies. Based on work by Plunkett and
tion or intensive regimens. Gandhi,43–48 the addition o a second nucleoside ana-
logue such as fudarabine, cladribine, or cloarabine
unctioned as a potent inhibitor o ribonucleotide reduc-
Gemtuzumab Ozogamicin tase, increased intracellular cytarabine concentration,
Gemtuzumab ozogamicin (GO) is a CD33-targeted and led to synergistic activity against leukemic blasts.
immunoconjugate linking an anti-CD33 antibody to Our rontline intensive induction therapy has evolved
calicheamicin. It received an accelerated approval by to incorporate a second nucleoside analogue (fudara-
the FDA or use in older adults with relapsed or rerac- bine, cloarabine, or cladribine) along with a lower dose
tory AML but was withdrawn voluntarily by the man- o cytarabine (1–2 g/m2) to optimize the balance o syn-
uacturer rom the market in 2010 because o toxicity ergy and reduced extramedullary toxicity.49
Fludarabine, Idarubicin, and Cytarabine DA plus fudarabine (DAF). The consolidation regimen
was the same or all arms and included two consecu-
The rst translation o this preclinical work into the tive courses o ara-C (1.5 g/m2 intravenously [IV] days
clinic was the combination o fudarabine, high-dose 1–3) plus MTZ (10 mg/m2 IV days 3–5) and HDAC (2
cytarabine, and IDA (FLAG-IDA or FIA), developed at g/m2 IV twice a day on days 1, 3, and5). The overall
Chapter 2
MDACC or patients with AML.43,50 The regimen has CR rate was 61%, with 56% achieving a CR ater one
since been used internationally and orms a standard cycle o induction and 5% ater two cycles. The CR
backbone or patients with newly diagnosed as well rate was higher in the DAC arm compared with the
as relapsed AML. The MRC o the United Kingdom DA arm (62% vs 51%; P = .02). The CR rates were
has published several analyses o the AML 15 random- similar in the DA and DAF arms. The median OS was
ized trial studying FLAG-IDA in younger patients with signicantly higher in the DAC arm (24 months) com-
AML compared with 3 + 7 regimens without or with pared with the DA arm (14 months; P = .02). There was
etoposide.41,51,52 The FLAG-IDA regimen (cytarabine 2 no signicant dierence in the median OS between the
g/m2 on days 1–5, fudarabine 30 mg/m2 on days 1–5, DAF and DA arms.55
and IDA 8–10 mg/m2 on days 1–5), among patients Based on these data, we designed a higher-dose
who were able to receive our courses, was associated cytarabine-based combination o cladribine (5 mg/m2
with an improved 8-year survival rate o 66% com- IV on days 1–5), IDA (10 mg/m2 IV on days 1–3), and
pared with 47% in the standard arm. cytarabine (1 g/m2 IV on days 1–5) (CLIA) or patients
with AML. In a recent update o our data with CLIA
Clofarabine, Idarubicin, and Cytarabine in 73 t patients with newly diagnosed AML, we
observed a CR/CRi rate o 76% with 58% o patients
Cloarabine is a second-generation nucleoside analogue having undetectable MRD at the time o response.56
that has activity in adult patients with AML. A phase The median OS and DFS were 21.9 months and none
I trial o cloarabine conducted at MDACC, in com- reached, respectively. Based on these promising results
bination with IDA alone versus IDA and ara-C (CIA) and tolerability, CLIA currently orms our rontline
in patients with relapsed, reractory AML showed a backbone or younger and t patients with AML.
CR rate o 13% versus 48%, respectively. The median
duration o remission was also longer with the CIA
combination (15 months) compared with cloarabine TREATMENT OF PATIENTS 60 YEARS
and IDA (4.5 months).53 This was ollowed by a phase OF AGE OR OLDER
II trial that investigated the CIA regimen in patients
60 years old or younger with newly diagnosed AML. AML in older adults (60 years or older) is considered
Patients who achieved a response (CR or CRp) went a biologically and clinically distinct entity. The out-
on to receive up to six cycles o consolidation therapy. comes o older AML patients are poor with the stan-
The cycles were administered every 4 to 6 weeks. All dard anti-AML therapies. The analysis o the Swedish
patients received prophylactic antibiotics, antiungals, Acute Leukemia Registry (1976–2005) showed that the
and antivirals. The median age o the patients was 48 early death rates in all patients with AML, regardless
years (range, 19–60 years), 66% had intermediate-risk o age, were lower with intensive therapy compared
cytogenetics, and 36% had diploid and 34% adverse with palliative therapy.57 However, most older patients
karyotype. The ORR was 79%, with 74% CR and 3% may not be ideal candidates or intensive chemother-
CRp. Eighteen percent o patients received two induc- apy because o disease- and patient-related actors.
tion cycles to achieve a CR or CRp, and 42% went Newer, lower intensity therapies with less toxicity and
on to receive an allo-SCT in rst CR. The median OS preserved ecacy are being developed to help address
and RFS were not reached, whereas the median EFS this challenging subset.
was 13.5 months. A subset analysis showed better OS AML in older adults has adverse biologic eatures
(P = .04) and EFS (P = .04) in patients 40 years old or such as higher requency o stem cell–like phenotype
younger compared with those older than 40 years.54 o leukemic blasts, higher requency o multilineage
involvement with dysplastic eatures, higher requency
Cladribine o antecedent hematologic disorders, and higher re-
quency o MDR-1 gene expression, which leads to
Holowiecki et al55 conducted a randomized phase III higher potential or cytotoxic drug extrusion by the
trial evaluating the addition o cladribine or fudara- leukemic blasts, causing resistance to chemotherapeu-
bine to DNR/ara-C in younger patients with untreated tic agents.58 AML in older patients is more requently
AML. A total o 652 patients, with a median age o 47 associated with poor-risk cytogenetics (≤50% vs 10%–
years (range, 17–60 years), were randomized to receive 15% in younger patients).59 Given the poor outcomes
DNR plus ara-C (DA), DA plus cladribine (DAC), and associated with standard therapy in these high-risk
subgroups, most older patients with newly diagnosed III trial comparing DAC 20 mg/m2 or 10 days with
AML should be considered or investigational clinical physician’s choice in 485 patients. This study showed
trials. Other actors contributing to worse outcomes in that DAC improved CR/CRp rates compared with
older patients include poor perormance status, organ physician’s choice (18% vs 8%; P = .001). DAC was
Chapter 2
dysunction, and a higher incidence o an antecedent well tolerated with a good saety prole. The primary
hematologic disorders. In general, patients with three analysis showed a nonsignicant improvement in the
or more o these actors have expected CR rates o less OS, but an unplanned analysis 2 years later demon-
than 20%, 8-week mortality rates greater than 50%, strated an improvement in the OS AML who are older
and 1-year survival rates o less than 10% using con- than 65 years old have an ORR o 47% (CR rate, 42%)
ventional regimens. These patients constitute 25% to with intensive chemotherapy and an ORR o 29% (CR
30% o older adult patients with AML. Approximately rate, 28%) with epigenetic therapy (azacitidine, DAC)
20% o older adult patients have none or one o these (P ≤.001).40 The median OS was similar in both the
adverse actors and have a reasonable outcome with groups (0.5 months; P = .413).66 These studies show
expected CR rates above 60%, 8-week mortality rates that hypomethylating agents have similar survival
o 10%, and 1-year survival rates o 50% or greater.60 outcomes in older patients with AML compared with
Several groups have proposed predictive models or intensive chemotherapy.
geriatrics assessment beore determining what ther- In the AML-AZA 001 trial, patients 65 years o age
apy to assign older patients.61,62 These models look or older with newly diagnosed de novo or second-
at several prognostic actors, including unctional sta- ary AML who were deemed ineligible or transplant
tus, cytogenetics, age, and molecular status, to predict and with intermediate- or poor-risk cytogenetics were
mortality and survival with therapy. This suggests that enrolled. Patients were randomized to receive either
a careul assessment o the patient and disease char- azacitidine or a conventional care regimen. Azaciti-
acteristics is needed beore assigning therapy to older dine was administered at 75 mg/m2/day or 7 days
patients. subcutaneously. A prolongation in the median OS
was observed in the azacitidine arm (6.4 months vs
3.2 months; P = .0185). The conventional care regi-
Low-Dose Cytarabine men included best supportive care in 18%, LDAC in
Low-dose ara-C (LDAC) was superior to hydroxyurea 64%, and intensive chemotherapy in 18%.67 Several
in a randomized trial enrolling 204 older adult patients groups have consistently shown a CR rate o 31% to
with AML considered unt or chemotherapy.63 The 47% with DAC 20 mg/m2 administered daily or 10
CR rates were 15% with LDAC and 1% with hydroxy- days, with a median OS o 9 to 12 months. However,
urea (P = .0003); the 1-year survival rates were 27% the associated increased myelosuppression leads to
versus 3% (P = .0004). Although the responses were increased rates o hospitalization or inections.68
modest and not widely used in clinical practice as a
single-agent, this trial conrmed the benet o treating
older patients with newly diagnosed AML rather than
Venetoclax
considering only supportive care. One o the most important advances in the treatment
o AML in older and unt patients has been the devel-
opment o the BCL-2 inhibitor venetoclax in this dis-
Clofarabine ease. Based on the observation o modest single-agent
A randomized phase II study compared cloarabine activity in AML,69 venetoclax was studied in combina-
(30 mg/m2 IV × 5 days) versus cloarabine and ara-C tion with lower intensity (HMA or LDAC) in older and
(20 mg/m2 subcutaneously daily × 14 days) in 70 older unt patients with newly diagnosed AML. Single-arm
adult patients with AML.64 Combination therapy phase Ib/II studies o venetoclax in combination with
achieved a better CR (63% vs 31%; P = .025) and bet- either HMA or LDAC demonstrated ORRs o 54% to
ter EFS (7.1 months vs 1.7 months; P = .04) but did not 68% and median OS ranging rom 10.1 to 17.5 months,
improve OS (11.4 months vs 5.8 months; P = .1). leading to the accelerated FDA approval o these com-
binations in November 2018. The recently reported
phase III randomized VIALE-A study conrmed the
Hypomethylating Agents OS benet o the combination o AZA + venetoclax
Building on their activity in myelodysplastic syndrome, in older or unt patients with newly diagnosed AML,
hypomethylating agents (HMAs) such as decitabine establishing it as standard rontline therapy in this
(DAC) and 5-azacitidine (5-AZA) have been studied population. Among 431 patients with a median age o
in and become the de acto lower intensity therapy 76 years, AZA + venetoclax demonstrated a signicant
or older and unt patients with newly diagnosed improvement in OS o 14.7 months versus 9.6 months
AML. Kantarjian et al65 conducted a randomized phase (HR, 0.66; P <.001) compared with AZA alone.70
Ongoing studies in this population o patients contin- o patients with FLT3-ITD develop mutations in the
ues to build on the backbone o HMA + venetoclax to kinase domain as a mechanism o resistance.
optimize ecacy among subsets. Incorporation o FLT3 inhibitors into the treatment
o AML is now the standard o care. Stone and col-
leagues conducted a randomized phase III RATIFY trial
Chapter 2
Cladribine + Low-Dose Cytarabine (CALGB 10603) in 717 patients younger than 60 years
Although HMAs have been sae and well tolerated o age with newly diagnosed FLT3-mutated AML
in older patients with newly diagnosed AML, newer (FLT3-ITD and/or FLT3-TKD; median age, 48 years;
backbones and combinations may be developed to range, 18–60 years) with the 7 + 3 regimen with or
maintain saety and tolerability while augmenting e- without the FLT3 inhibitor midostaurin.73 The addition
cacy. Based on the synergy o cladribine and cytarabine, o midostaurin improved the CR rate (59% vs 54%,
we developed a lower intensity regimen combining P = .045) and survival (median survival, 74.7 vs 25.6
cladribine (5 mg/m2 IV on days 1–5) with LDAC (20 mg months; P = .009). At MDACC, we have incorporated
subcutaneously twice a day on days 1–10) alternating FLT3 inhibitors as our standard on clinical trials. In a
with two cycles o DAC (20 mg/m2 IV on days 1–5). matched-cohort analysis we similarly showed the ben-
Among 118 patients with a median age o 69 years, we et o adding the multikinase FLT3 inhibitor soraenib
observed a CR/CRi rate o 68%, including a CR rate o to an IDA cytarabine backbone in FLT3-mutated
58%. The 4- and 8-week mortality rates were 1% and AML.74 More recently, our analysis with CLIA + FLT3
7% , respectively.71 With a median ollow-up period inhibitor (soraenib–midostaurin) demonstrated a CR
o 37 months, the median OS was 13.8 months with a rate o 86% and a 1-year OS o 70%.56 The second-
median DFS o 10.8 months. Although these data com- generation FLT3 inhibitor gilteritinib has also been
pare avorably with single-agent HMAs in this popula- FDA approved or use in patients with relapsed or
tion, it is very similar to outcomes seen with HMA + reractory FLT3-mutated AML. In the ADMIRAL
venetoclax. Ongoing studies are evaluating the saety study, patients with relapsed or reractory AML were
and ecacy o venetoclax and other targeted therapies randomized to either gilteritinib or one o our salvage
added to the cladribine–LDAC backbone. chemotherapy regimens chosen by their doctor. Gil-
teritinib was associated with a higher CR rate (21.1%
vs 10.5%) and a signicant improvement in OS (9.3 vs
Targeted Therapy in Acute Myeloid 5.6 months; P = .007).75 Studies in the rontline setting
Leukemia with gilteritinib and other FLT3 inhibitors in combi-
The wider application o newer techniques in DNA nation with intensive and lower intensity therapy are
NGS and a better understanding AML biology have ongoing. Several new FLT3 inhibitors currently under
demonstrated deep heterogeneity in AML and led to a development.
surge in targeted therapy development or genomically
dened subsets. Early detection o recurrent genetic IDHMutated Acute Myeloid Leukemia
abnormalities in newly diagnosed AML now not only
help delineate prognosis but also provide opportuni- Isocitrate dehydrogenase enzymes (IDH1, IDH2) play a
ties or targeted therapy. Specic inhibitors have been critical role in cellular metabolism and are ubiquitously
developed and FDA approved or patients with AML. expressed. Recurrent point mutations in the IDH1 and
IDH2 genes each occur in about 10% to 12% o AML
cases, resulting in neomorphic enzyme activity and the
FLT3Mutated Acute Myeloid Leukemia aberrant production o the onco-metabolite 2-hydrox-
FLT3 is a member o the class III receptor tyrosine yglutarate (2-HG). The 2-HG competitively inhibits
kinase amily that plays an important role in the sur- α-ketoglutarate and leads to dysregulated epigenetic
vival, prolieration, and dierentiation o hematopoi- unction, a hypermethylated phenotype, and a block
etic progenitor cells. FLT3 is overexpressed in most in maturation, contributing to AML leukemogenesis.
patients with AML, and activating mutations o FLT3 Enasidenib is an orally bioavailable small molecule
are among the most prevalent molecular abnormali- inhibitor o mutant IDH2 that is FDA approved or
ties in AML, with internal tandem duplication (ITD) the treatment o relapsed or reractory IDH2-mutated
occurring in 25% to 35% o patients with normal AML. A phase I/II trial o patients with relapsed or
karyotypes.72 In addition, 5% to 7% o patients may reractory IDH2-mutated AML treated with ena-
have point mutations within the activation loop o sidenib demonstrated an ORR o 39%, a CR/CRh rate
the kinase domain or in the juxtamembrane domain. o 23%, a median response duration o 8.2 months,
Patients with FLT3 activating mutations have an ine- and a median survival period o 8.8 months.76 Ivo-
rior outcome with a shorter RFS and OS. In addition, sidenib is a selective small molecule inhibitor o IDH1
ater exposure to FLT3 inhibitors, nearly one quarter that is FDA approved or the treatment o relapsed or
reractory IDH2-mutated AML and recently was also The CBF-MYH11– and RUNX1-RUNXT1–related
approved in the rontline or patients ineligible or leukemias represent CBF-AML. These leukemias are
intensive therapy. A phase I/II clinical trial evaluating chemo-sensitive to intensive induction and consolida-
179 patients with relapsed or reractory IDH1 mutated tion and are characterized by high rates o CR. About
Chapter 2
reported an ORR o 42%, a CR/CRh o 30%, a CR o 10% o unselected newly diagnosed patients (typi-
22%, and a median survival period o 12 months.77 In cally younger patients) have CBF-AML. At MDACC,
a phase 1 dose escalation or expansion study among all newly diagnosed patients with CBF-AML are
older patients with newly diagnosed IDH1-mutated treated with fudarabine (30 mg/m2/day on days 1–5)
AML with a median age o 76.5 years, treatment with and HDAC (2 g/m2/day on days 1–5) regimens with
ivosidenib produced a CR rate o 30% and an ORR or without the addition o granulocyte colony-stim-
o 55%, allowing expansion o the indication to older, ulating actor (G-CSF). This is ollowed by up to six
unt patients with untreated disease.78 Combinations courses o an HDAC-containing consolidation regi-
o IDH inhibitors in the rontline and relapsed or men. A CR rate o 93% and an EFS o 20 months in
reractory settings with chemotherapy and other tar- 114 newly diagnosed patients with CBF-AML were
geted therapies are ongoing. previously reported52. A rontline regimen o fudara-
bine, ara-C, and G-CSF (FLAG)-GO was evaluated at
TP53Mutated Acute Myeloid Leukemia MDACC and showed a remission rate o 95% and a
3-year OS and RFS o 78% and 85%, respectively.81
Mutations in TP53 are present in 15% to 20% o In the UK MRC-AML15 trial, 1113 patients with AML
patients with AML, particularly enriched among were randomized to receive or not receive a small dose
patients with therapy-related AML and complex o GO (3 mg/m2) with their induction therapy. A ben-
karyotypes, and have been associated with an excep- et o adding GO to the induction regimen was seen
tionally adverse prognosis and poor response to inten- in patients with CBF-AML.28 In a meta-analysis o ve
sive chemotherapy.13 Lower intensity approaches with clinical trials in which addition o GO to induction
HMAs and other backbones have produced similar chemotherapy was evaluated, a signicant improve-
outcomes to intensive chemotherapy, with less toxic- ment in OS was noted in patients with avorable- and
ity and lower rates o early mortality.79,80 Recent data intermediate-risk cytogenetics (P = .01). The improve-
suggest that the quantied variant allelic requency ment in survival was attributed to reduced relapse (P =
(VAF) o mutated TP53, refecting its clonal dominance .00006).42 All o these studies strongly support the use
within a bulk AML sample, may help predict whether o FLAG-based regimens or CBF-AML and advocate
intensive chemotherapy may benet a subset o TP53- the addition o GO to the induction to improve sur-
mutated patients. A TP53 VAF o less than 40%, or vival and RFS in these patients.
example, was associated with better outcomes when Approximately 25% o patients with CBF-AML
using intensive chemotherapy compared with those carry a gain-o-unction mutation in the KIT gene,
with a higher VAF.15 This latter subgroup represents which results in a constitutively activated tyrosine
a challenging subset, in which there is a strong need kinase and an inerior outcome when using standard
or newer, more eective therapy. Our approach and 7 + 3–based chemotherapy. Hence, the CALGB 10801
recommendation or this subset o patients has been alliance and a group in Germany are evaluating the
enrollment in clinical trials. addition o a KIT inhibitor, dasatinib, to the standard
induction therapy. The initial results showed a 92%
CR rate and 1-year DFS and OS rates o 90% and 87%,
TREATMENT OF CORE-BINDING respectively.82 Further analysis o this data and conr-
FACTOR ACUTE MYELOID LEUKEMIA matory studies will help to better dene the role o
inhibiting KIT in CBF-AML.
Core-binding actor (CBF) AML is a distinct entity.
It is considered a avorable karyotype. It includes
patients with a pericentric inversion o chromosome MAINTENANCE THERAPY IN ACUTE
16 (inversion 16; associated with FAB subtype M4EO) MYELOID LEUKEMIA
and translocation (16;16) or a translocation between
chromosomes 8 and 21 (t[8;21]; associated with FAB Although dose intensication, novel drug combina-
subtype M2). Each o these abnormalities disrupts tions, and improvements in support care or have led to
the unction o a transcription actor, regulating the high response rates in newly diagnosed AML, disease
expression o genes important in hematopoietic di- relapse remains a major cause o treatment ailure and
erentiation: inv(16) and t(16;16) lead to the orma- mortality. Post remission consolidation with allo-SCT
tion o the CBF-MYH11 usion gene, and t8;21 leads to has been shown to improve remission duration and
the ormation o the RUNX1-RUNXT1 usion gene. survival in patients with higher risk disease, but this is
not available to many patients, particularly or the older placebo-controlled trial investigating the use o post-
and unt patients that make a up a large proportion o transplant soraenib in patients with FLT3-mutated
patients. Postconsolidation maintenance strategies in AML.85 Among 83 patients randomized, with a median
patients with AML have been investigated or decades, age o 54 years, soraenib was associated with a sig-
with no consistent evidence o survival benet. Most nicant improvement in 2-year PFS and OS in avor
Chapter 2
o those strategies involved using the same or similar o soraenib, eectively establishing this as a standard
agents in maintenance that were used during induction o care in the post-SCT setting in this subgroup. Simi-
and consolidation. With the discovery o new thera- larly, the phase III ADMIRAL trial o the type I FLT3
pies with newer schedules o delivery, there has been inhibitor gilteritinib evaluated post-SCT maintenance
a renewed ocus to develop maintenance therapies in in a nonrandomized observational manner. Among 35
AML. The availability o low-dose and well-tolerated patients who received post-SCT gilteritinib, there was
HMAs such as DAC or AZA has prompted investigation an observed improvement in median OS o 16.2 ver-
o these agents or maintenance in AML. The HOVON sus 8.4 compared with patients who did not receive
group conducted a randomized phase III study com- gilteritinib (HR, 0.39 [0.16–0.92]; P = .024).75 Studies
paring maintenance with 5-AZA at a dosage o 50 mg/ are ongoing evaluating FLT3 inhibitors, including gil-
m2 IV or subcutaneous on days 1 to 5 every 4 weeks teritinib, in the postconsolidation maintenance setting
with placebo among patients 60 years o age or older or FLT3-mutated AML. IDH inhibitors, including ena-
with AML in remission ater two cycles o intensive sidenib (IDH2) and ivosidenib (IDH1), are currently
chemotherapy. Among 116 patients, maintenance ther- approved as single agents in patients with relapsed
apy with parenteral 5-AZA demonstrated a signicant AML with IDH2 or IDH1 mutated AML, respectively.
improvement in 12-month DFS compared with pla- As part o the approved treatment label, these patients
cebo (64% vs 42%; P = .04), but there was no OS ben- are treated indenitely with single-agent IDH inhibi-
et.83 In the ECOG-ACRIN E2906 randomized study tor as part o the initial “induction” as well as ongo-
evaluating consolidation with cloarabine or high-dose ing, indenite therapy to maintain response. They have
cytarabine, a second randomization studied the utility thus demonstrated easibility and excellent long-term
o postconsolidation maintenance with IV DAC given tolerability in this setting. At MDACC, our approach
at a dosage o 20 mg/m2 IV on days 1 to 3 o a 4-week is to design appropriate risk-adapted and genomically
cycle. A total o 120 AML patients with a median individualized postremission maintenance strategies
age o 69 years who had received induction and two or patients, including post-SCT–based maintenance in
cycles o consolidation were randomized 1:1 to DAC patients at high risk or relapse.
or placebo. DAC maintenance was associated with an The treatment or newly diagnosed AML is sum-
improved median OS o 25.8 versus 19.5 months (HR, marized in Figures 2–1 and 2–2.
0.69 [0.43–1.09]; P = .06). Recently, an oral ormulation
o AZA, CC-486, demonstrated an OS benet, leading
to its FDA approval as maintenance therapy in AML. RELAPSED OR REFRACTORY ACUTE
The international, multicenter QUAZAR AML-001 MYELOID LEUKEMIA
trial randomized 472 patients55 years o age or older
in rst CR ater intensive chemotherapy, with or with- Although the outcome o patients with AML has
out consolidation to receive either CC-486 or placebo improved, relapse remains requent and constitutes
on days 1 to 14 o a 28-day cycle. CC-486 was asso- the leading cause o death. Relapsed AML remains a
ciated with a signicant improvement on median OS major challenge with ew therapies providing meaning-
compared with placebo (24.7 months vs 14.8 months; ul durable responses or cures. Breems et al86 dened a
P <.001), with 1- and 2-year OS rates o 73% and 51%, prognostic score or patients with AML in rst relapse
respectively.84 Similarly, CC-486 was associated with based on the ollowing variables: (1) relapse-ree inter-
an improvement in median RFS compared with pla- val rom rst CR, (2) cytogenetics at diagnosis, (3) age
cebo (10.2 vs 4.8 months; P <.001). Recent advances in at rst relapse, and (4) SCT beore rst relapse. In an
the development o targeted drugs in AML has created analysis o 818 patients who underwent one or more
the possibility o long-term remission maintenance lines o salvage therapy at MDACC between 2002 and
with chronic dosing o small molecule targeted drugs 2016, rates o CR decreased rom 14% ater rst salvage
in specic genetically determined subgroups. Demon- to 9% and 3% ater second and third salvage, respec-
stration o their long-term saety and tolerability has tively.87 The median OS periods were 6.3, 4.07, and 2.98
made these drugs ideal candidates or long-term ambu- months ater rst, second, and third salvage therapies,
latory maintenance strategies. For example, the multi- respectively.87 In an updated analysis, we specically
kinase inhibitor soraenib has been used successully as patients treated at MDACC in the second salvage set-
an FLT3 inhibitor in patients with FLT3-mutated AML. ting rom 2000 to 2018 to determine actors predicting
The SORMAIN trial was a randomized double-blind actors associated with OS and nonresponse to salvage
Acute myeloid leukemia
Younger and fit Older or unt

(eg, age younger (eg, age 60 years Refer to Fig. 2–2 NPM1+/ NPM1–/
than 60 years) and older) FLT3– FLT3+
Chapter 2
Karyotype CBF ELN favorable ELN intermediate FLT3-mutated AML Poor risk APL
Molecular
studies
Induction Fludarabine + Idarubicin and Idarubicin and

Chemotherapy + FLT3 Idarubicin and ara-C– If TP53 mutated
therapy HDAC + ara-C–based regimen; ara-C–based regimen;
inhibitor; IA-based based regimen; consider with VAF ≥40%,
G-CSF + consider double consider double
backbone + midostaurin double nucleoside consider lower
OG nucleoside analogue nucleoside analogue
(standard of care) or analogue as backbone intensity HMA- ATRA +
as backbone as backbone
clinical trial with FLT3 (ie, cladribine or based therapy to As2O3
(ie, cladribine or (ie, cladribine or
inhibitor fludarabine + ara-C) best response ± GO
udarabine + ara-C) udarabine + ara-C)
Standard consolidation Consolidation

with same backbone chemotherapy + FLT3
regimen inhibitor
If high risk
and patient ATRA +
First Standard consolidation is If eligible; consider patient Allo-SCT As2O3
HDAC-based Evaluate MRD to help
complete with same backbone candidate, for allogenic SCT;
regimen risk stratify
remission regimen consider otherwise; maintenance
SCT therapy with FLT3 inhibitor
Maintenance therapy
with PO AZA or trial
FIGUre 2–1 A proposed approach to the management o patients with newly diagnosed adult acute myeloid leukemia. allo-
SCT, allogeneic stem cell transplantation; APL, acute promyelocytic leukemia; As2O3, arsenic trioxide; ATRA, all-trans-retinoic
acid; CBF, core-binding actor leukemias (including inv[16], t[8;21]); FLT3, ms-like tyrosine kinase 3; G-CSF, granulocyte colony-
stimulating actor; GO, gemtuzumab ozogamicin; HDAC, high-dose cytarabine; IA, idarubicin and cytarabine; MRD, minimal
residual disease; NPM1, nucleophosmin; PO, oral.
Acute myeloid leukemia
Older or unfit
(eg, 60 years or older and
not candidate for intensive
chemotherapy)
Karyotype APL or CBF FLT3 mutated Other IDH1 or IDH2 mutated

and unable to receive
chemotherapy
Performance Please refer Consider clinical trial with HMA + Clinical Cladribine + Consider clinical trial
status to Fig. 2–1 FLT3 inhibitor or lower venetoclax trial LDAC with IDH inhibitor or
intensity therapy + FLT3 alternating single agent IDH inhibitor
inhibitor with decitabine as standard of care
Induction
therapy
Indefinite therapy with FLT For patients not

inhibitor as maintenance For patients deemed considered candidates
First
eligible with available for SCT, consider
complete
donor, consider RIC maintenance therapy
remission
stem cell transplant with oral azacitidine
or clinical trial
FIGUre 2–2 A proposed approach to the management o newly diagnosed adult acute myeloid leukemia in patients 60 years
o age or older. APL, acute promyelocytic leukemia; CBF, core-binding actor leukemias (including inv[16], t[8;21]); PS, peror-
mance status according to the Eastern Cooperative Oncology Group; RIC transplant, reduced-intensity conditioning transplant.
therapy. By multivariate analysis, independent actors SteM CeLL traNSpLaNtatION

associated with worse survival were age 60 years or
older, platelets less than 50, peripheral blasts 20% or High-dose chemotherapy with or without radiation
greater, albumin 3 g/dL or less, and complex karyotype ollowed by SCT is increasingly used as therapy or
(three or more abnormalities). Independent actors asso-
Chapter 2
AML patients in rst CR. In prospective, nonrandom-
ciated with nonresponse (CR-CRp) in the second salvage ized trials in Europe and the United States, patients
setting were platelets less than 50, complex karyotype, younger than age 55 years in rst CR with a human leu-
treatment with regimens that did not include cytarabine kocyte antigen (HLA)–matched sibling were assigned
or HMAs, and no prior CR or 12 months or longer (Fig. to allogeneic transplantation or, i no donor, to autolo-
2–3).88 Recent identication and approval o targeted gous transplantation or one urther course o HDAC
therapies such as FLT3 inhibitors and IDH inhibitors or (with DNR in the European study) (Table 2–6).89–92
specic populations in the relapsed setting have started In a meta-analysis o 24 prospective clinical trials
to provide the ramework or a path o how we may involving more than 6000 patients with AML in rst
divide and overcome the enormous challenge o treat- CR, Koreth et al93 showed that allo-SCT has signicant
ing patients with relapsed disease.
Relapsed or
primary refractory
AML
Evaluate mutations
(ie, FLT3, IDH1, IDH2)
and offer directed therapy
CR1 CR1
duration >1 FLT3 mutated: IDH1 mutated: IDH2 mutated: duration <1
year gilteritinib-based ivosidenib-based enasidenib-based year
therapy therapy therapy
HDAC-based
Clinical trial
regimen
Allogeneic transplant
feasible
No Yes
Clinical Allogeneic
trial transplant
FIGUre 2–3 A proposed algorithm or management o relapsed or reractory acute myeloid leukemia (AML). CR1, rst com-
plete remission; HDAC, high-dose cytarabine.
survival benet in patients with intermediate- and poor- and cytogenetics at the time o SCT.99 Further details on
risk AML but not with good-risk AML. This nding this subject are beyond the scope o this chapter.
contrasts with the retrospective review o 999 patients
by Ferrant et al94 that observed similar benet with allo-
SUPPORTIVE CARE
Chapter 2
geneic and autologous transplantation or patients with

poor-risk karyotype and a benet with allo-SCT only in
patients with good- and intermediate-risk cytogenetics. Adequate and close supportive care is extremely
However, urther stratication o risk groups based on important in the care o patients with acute leukemia.
molecular markers within individual karyotypes sug- Both G-CSF and granulocyte-macrophage colony-
gests that only specic subsets o patients may benet stimulating actor have reduced the median time to
rom allo-SCT . Schlenk et al95 demonstrated superior neutrophil recovery by an average o 5 to 7 days.100
OS with allo-SCT compared with intensive chemo- Antileukemic therapeutic ecacy is not compromised
therapy in only the ollowing groups o patients with by these agents. Therapy o acute leukemia oten
normal-karyotype de novo AML: (1) FLT3-ITD positive results in rapid reduction o elevated WBC counts.
and (2) NPM1/CEBPA/FLT3-ITD negative. Patients with This is oten associated with the development o
inversion 16 or t(8;21) do better with chemotherapy.96 tumor lysis, characterized by hyperuricemia, hyper-
Patients with AML who are younger than 20 years old kalemia, hyperphosphatemia, hypocalcemia, acidosis,
have a relatively low transplant-related mortality rate and renal ailure. Prevention o tumor lysis syndrome
and may do better with allo-SCT. requires administration o IV fuids and allopurinol
New concepts in both transplantation and chemo- (or rasburicase) i the blast count is above 10 × 109/L.
therapy have emerged. These include the use o periph- Saline or steroid eye drops daily should be given to
eral blood rather than marrow as the source o SCT,97 patients undergoing HDAC therapy until 24 hours
the use o nonmyeloablative regimens to allow engrat- ater completion o chemotherapy. In these patients,
ment and take advantage o the grat-versus-leukemia neurologic assessments or cerebellar neurotoxicity
eect, and the use o IV busulan to overcome the should be perormed beore each dose o HDAC.
erratic pharmacology o the oral orm.98 In particular, Acute pulmonary ailure during induction therapy
nonmyeloablative regimens (reduced-intensity con- or AML is a serious complication. Predictive actors
ditioning or “mini-transplant”) have gained particular identied at diagnosis include male sex, diagnosis o
traction in older adult patients, who have traditionally APL, poor ECOG perormance status, lung inltrates
experienced high treatment-related mortality rates with at diagnosis, and an increased serum creatinine. Fluid
conventional myeloablative regimens. The principles restriction, high-dose steroids, and continuous veno-
o this approach include reduction o regimen-related venous hemoltration have been shown to be eective
toxicities and shiting the burden o tumor cell kill rom strategies in treating acute pulmonary ailure.
high-dose cytotoxic therapy to grat-versus-leukemia Inectious complications are a major cause o mor-
eects. A number o recent studies have reported 2- to bidity and death. Prophylactic administration o anti-
5-year survival rates o 25% to 64% ater nonmyeloab- biotics in the absence o ever is usually oered. The
lative allo-SCT or older patients with high-risk MDS development o ever (>101°F), unrelated to administra-
and AML. Survival was similar or recipients o related tion o chemotherapy, calls or administration o broad-
and unrelated HLA-matched grats. The nonrelapse spectrum antibiotics, such as carbapenem or a third- (eg,
mortality rate was 16% to 39%, resulting mainly rom cetazidime) or ourth-generation cephalosporin (eg,
complications o grat-versus-host disease and comor- ceepime). Antibiotic selection should be prompt, indi-
bidities preceding SCT. Relapse rates ranged rom 16% vidualized, and in accordance with the updated antibi-
to 53% and were infuenced both by disease burden otic susceptibility prole o each institution. I inection
taBLe 26 allognic Sm Cll tnslnion (allo-SCt) vsus Cmoy in pins wi
acu Myloid Lukmi in Fis Coml rmission (Cr)
Study Patients (n) Match % Allo-SCT in CR (%) Signicant Diference Favoring Allo-SCT
89
Archimbaud et al 58 74 34 No
92
Zittoun et al 294 63 23 LFS
Cassileth et al91 238 88 23 No
90
Burnett et al 656 58 23 No
LFS, leukemia-ree survival.
persists, G-CSF should be started, and i indicated, acid (ATRA) and arsenic trioxide (ATO) is dierent
granulocyte transusions, using G-CSF to increase the than or other types o AML and is curative in most
donors’ granulocyte counts, should be given. Close fuid patients.104 A stratication system has been developed
balance is critical because fuid retention is common, can that distinguishes newly diagnosed patients with APL
radiologically mimic pneumonia, and may increase the as low, intermediate, or high risk. Low-risk patients
Chapter 2
risk o diuse alveolar hemorrhage during induction. present with WBC count less than 10 × 109/L and
Another controversial area is whether adherence to platelet count above 40 × 109/L; a WBC count above
a neutropenic diet (avoidance o resh ruits and vegeta- 10 × 109/L identies high-risk patients. Others are at
bles) during induction chemotherapy decreases the risk intermediate risk. At MDACC, we only use the WBC
o inection. A total o 153 patients with AML diagnosed cut-o o 10 × 109/L to distinguish low- or high-risk
at MDACC were admitted to a high-eciency particu- patients. Anticipated cure rates are close to 100%,
late air-ltered room or induction chemotherapy.101 90%, and 70% in low-, intermediate-, and high-risk
They were randomized to receive a diet containing no patients, respectively (Table 2–9).105
raw ruits or vegetables (cooked diet) or to a diet con- Several ndings have contributed recently to the
taining resh ruits and vegetables (raw diet). Twenty- increased cure rates in APL. Anthracyclines were
nine percent o patients in the cooked group and 35% historically the rst eective treatment, inducing a
o patients in the raw group developed a major inection cure rate o 30% to 40% in patients with APL. The
(P = .60). Time to major inection and survival time were role o ara-C is questionable and probably bene-
similar in the two groups, suggesting that a neutropenic cial only in the setting o suboptimal anthracycline
diet did not prevent major inection or death. therapy. Addition o ATRA 45 mg/m2 twice daily to
chemotherapy (eg, IDA 12 mg/m2 on days 2, 4, 6,
and 8) increases the CR rate and, more dramatically,
ACUTE PROMYELOCYTIC LEUKEMIA increases the cure rate rom 40% to 70%. The major
toxicity o ATRA is a potentially atal APL dieren-
APL is a distinct subtype o AML, accounting or 5% to tiation syndrome characterized by ever and leakage
15% o cases, with unique clinical, morphologic, and o fuid into the extravascular space producing fuid
cytogenetic eatures. It results rom a translocation retention, eusions, dyspnea, and hypotension; it
between the retinoic acid receptor α (RARα) locus on is eectively treated with dexamethasone (10 mg
chromosome 17 and the promyelocytic leukemia pro- IV twice a day or 35 days, with a rapid taper).106 A
tein (PML) locus located on chromosome 15.102 This molecular test (PML-RARAα usion transcript by PCR)
PML-RARα usion is demonstrable in 95% to 100% o that detects molecular evidence o the t(15;17) pro-
cases. Independent risk actors or a diagnosis o APL vides a relatively sensitive and highly specic means
in a patient with AML are younger age, Hispanic eth- to document MRD negativity and detect impending
nicity, and obesity.2 The main clinical presentation is relapse. 107
bleeding diathesis resulting both rom plasmin-depen- When a diagnosis o APL is suspected, it is impera-
dent primary brinolysis and DIC.103 Cytogenetic anal- tive that the patient be given ATRA, even beore the
ysis detects the distinctive t(15;17). In the rare case in diagnosis is conrmed. ATRA is given at a dosage o
which such analysis does not show the t(15;17) but the 45 mg/m2/day in divided doses. It serves to prevent
clinical or morphologic picture is suggestive, molecular coagulopathy and start induction therapy.108
test or PML-RARα can be conrmatory. The POD test, ATO plus ATRA was shown to be at least nonine-
an immunohistochemical test that can be perormed rior, and possibly superior, to ATRA and chemotherapy
in ew hours, can detect the characteristic disruption in low- and intermediate-risk APL. In the Italian-German
o PML in virtually all cases and is a rapid and reli- APL 0406 trial, Lo-Coco et al109 showed that the CR rate
able quick test or APL. Recognition o APL is crucial was 100% in the ATRA + ATO arm versus 95% in the
because appropriate treatment with all-trans-retinoic ATRA plus chemotherapy (IDA) arm, with a superior
taBLe 27 risk Sifcion o acu pomylocyic Lukmi
Risk Group WBC Count (109/L) Platelet Count ( 109/L) RFS (%)
Low ≤10 >40 98
Intermediate ≤10 ≤40 89
High >10 70
RFS, relapse-ree survival; WBC, white blood cell.
OS o 98.7% versus 91.1% (P = .02). This regimen is MINIMAL OR MEASURABLE

now considered the best option or patients with stan- RESIDUAL DISEASE
dard-risk APL. Patients with high-risk disease require the
addition o either GO or chemotherapy such as IDA. Minimal or measurable residual disease (MRD) is
Chapter 2
The regimens generally used or treatment o dened as any measurable disease detectable above a
patients with APL, according to risk category, are sum- certain level o detection, depending on the methodol-
marized in Tables 2–8 to 2–10. ogy applied. In AML, this usually reers to the detec-
Ravandi et al110 evaluated outcomes o newly diag- tion o disease that cannot be discerned by morphologic
nosed APL patients treated with ATRA and ATO with examination alone. MRD evaluation may be done using
or without GO without traditional cytotoxic chemo- fow cytometry immunophenotyping assays aimed at
therapy. The regimen is summarized in Table 2–13. identiying leukemic cells with at a sensitivity level o
They reported CR rates o 95% and 81%, respectively, 0.01%. MRD assessment using molecular techniques
or low- and high-risk patients. The estimated 3-year can oten attain deeper sensitivity levels.
survival rate was 85%. MRD predicts a ailure to maintain CR, and its
Hence, in the modern era o APL treatment, it is detection is critical to assess the quality o response
possible to have long-term cure or APL without the ater induction therapy and to outline postremis-
use o conventional chemotherapy, which is a tremen- sion therapy based on the individual risk o relapse.
dous achievement or modern-day oncology. As mentioned in the section on APL, the detection o
taBLe 28 tmn o pins wi hig-risk acu pomylocyic Lukmi (apL)
APL INDUCTION THERAPY APL CONSOLIDATION THERAPY

Preerred Regimens
ATRA 45 mg/m2 (days 1–36, divided) + age-adjusted ATRA 45 mg/m2 or 28 days + ATO 0.15 mg/kg/day or 28 days or
idarubicin 6–12 mg/m2 on days 2, 4, 6, and 8 + ATO 0.15 one cycle; then ATRA 45 mg/m2 or 7 days every 2 weeks × 3 +
mg/kg (days 9–36 as 2-hour IV inusion) ATO 0.15 mg/kg/day or 5 days or 5 weeks or one cycle
ATRA 45 mg/m2 in divided doses + ATO 0.15 mg/kg/day IV + ATO 0.15 mg/kg daily 5 days/wk or 4 weeks every 8 weeks
a single dose o GO 9 mg/m2 may be given on day 1, day 2, or a total o our cycles + ATRA 45 mg/m2 or 2 weeks
day 3, or day 4 every 4 weeks or a total o seven cycles; i ATRA or ATO is
discontinued because o toxicity, a single dose o GO 9 mg/m2
may be given once every 4–5 weeks until 28 weeks rom CR
ATRA 45 mg/m2 in divided doses + ATO 0.3 mg/kg IV on days ATRA 45 mg/m2 or 2 weeks every 4 weeks (or or 2 weeks on
1–5 o week 1 and 0.25 mg/kg twice weekly on weeks 2–8 and 2 weeks of ) in consolidation courses 1–4 + ATO 0.3
(category 1) + a single dose o GO 6 mg/m2 may be given mg/kg on days 1–5 o week 1 in consolidation courses 1–4
on day 1, day 2, day 3, or day 4 and 0.25 mg/kg twice weekly in weeks 2–4 in consolidation
courses 1–4 (category 1); i ATRA or ATO is discontinued
because o toxicity, a single dose o GO 9 mg/m2 may given
once every 4–5 weeks until 28 weeks rom CR
Other Recommended Regimens
ATRA 45 mg/m2 in divided doses + daunorubicin 50 mg/m2 ATO 0.15 mg/kg/day or 5 days or 5 weeks every 7 weeks
or 4 days (IV days 3–6) + cytarabine 200 mg/m2 or 7 days or a total o two cycles; then ATRA 45 mg/m2 × 7 days +
(IV days 3–9) daunorubicin 50 mg/m2 or 3 days or two cycles
ATRA 45 mg/m2 in divided doses + daunorubicin 60 mg/m2 Daunorubicin 60 mg/m2 or 3 days + cytarabine 200 mg/
or 3 days + cytarabine 200 mg/m2 or 7 days m2 or 7 days or one cycle; then cytarabine 2 g/m2 (age
younger than 50 years) or 1.5 g/m2 (age 50–60 years) every
12 hours or 5 days + daunorubicin 45 mg/m2 or 3 days or
one cycle + ve doses o IT chemotherapy
ATRA 45 mg/m2 in divided doses + idarubicin 12 mg/m2 on ATRA 45 mg/m2 or 15 days + idarubicin 5 mg/m2 and
days 2, 4, 6, and 8 cytarabine 1 g/m2 or 4 days or 1 cycle; then ATRA × 15
days + mitoxantrone 10 mg/m2/day × 5 days or one cycle;
then ATRA or 15 days + idarubicin 12 mg/m2 or 1 day +
cytarabine 150 mg/m2/8 hours or 4 days or one cycle
ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete remission; GO, gemtuzumab ozogamicin; IT, intrathecal; IV, intravenous.
Data rom NCCN Guidelines 2021.
taBLe 29 tmn o pins wi Low-risk acu pomylocyic Lukmi (apL)
APL INDUCTION THERAPY APL CONSOLIDATION THERAPY

Preerred Regimens
Chapter 2
ATRA 45 mg/m2 in divided doses daily + ATO 0.15 mg/kg ATO 0.15 mg/kg/day IV 5 day/wk or 4 weeks every 8 weeks or a
IV daily (category 1) total o 4 cycles and ATRA 45 mg/m2/day or 2 weeks every 4
weeks or a total o seven cycles (category 1)
ATRA 45 mg/m2 in divided doses daily + ATO 0.3 mg/kg First three consolidation cycles = 56-day cycles:
IV on days 1–5 o week 1 and 0.25 mg/kg twice weekly ATRA 45 mg/m2/day PO divided into two daily doses on days
during weeks 2–8 (category 1) 1–14 and 29–42 (2 weeks on ollowed by 2 weeks of ) + ATO
0.3 mg/kg on days 1–5 o week 1 ollowed by 0.25 mg/kg twice
during weeks 2–4
Fourth consolidation cycle = 28-day cycle: ATRA 45 mg/m2/
day PO divided into 2 daily doses on days 1–14 (2 weeks on
ollowed by 2 weeks of ) + ATO 0.3 mg/kg on days 1–5 o week
1 ollowed by 0.25 mg/kg twice weekly during weeks 2–4
Useul in Certain Circumstances (i arsenic not available or contraindicated)
ATRA 45 mg/m2 in divided doses daily + idarubicin 12 ATRA 45 mg/m2 or 15 days + idarubicin 5 mg/m2 or 4 days × 1
mg/m2 on days 2, 4, 6, and 8 cycle; then ATRA or 15 days + mitoxantrone 10 mg/m2/day or
3 days or one cycle; then ATRA or 15 days + idarubicin 12 mg/
m2 or 1 day or one cycle (category 1)
ATRA 45 mg/m2 in two divided doses daily + a single dose ATRA 45 mg/m2 in divided doses daily during weeks 1–2, 5–6,
o GO 9 mg/m2 on day 5 9–10, 13–14, 17–18, 21–22, and 25–26; a single dose o GO 9
mg/m2 may be given monthly until 28 weeks rom CR
ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete response; GO, gemtuzumab ozogamicin; IV, intravenous.
Data rom NCCN Guidelines 2021.
taBLe 210 tmn o pins wi acu pomylocyic Lukmi wi all-Trans-rinoic acid
(atra) + asnic tioxid (atO) + Gmuzumb Ozogmicin (GO)
A Bone marrow
complete Complete
Day 1 Day 10 remission remission
WBC
<10 × 109/L
WBC
≥10 × 109/L
B Bone marrow
complete Complete
Day 1 remission remission
WBC
<10 × 109/L
ATRA
WBC ATO
≥10 × 109/L GO
Complete 4 8 12 16 20 24 28
remission
PCRa PCRa ATRA
Time after CR (weeks) ATO
(Continued)
taBLe 210 tmn o pins wi acu pomylocyic Lukmi wi all-Trans-rinoic acid
(atra) + asnic tioxid (atO) + Gmuzumb Ozogmicin (GO) (Continued)
ATRA + ATO + GO110 Low Risk High Risk

Chapter 2
2
Induction ATRA 45 mg/m PO every day until CR + ATO ATRA 45 mg/m2 PO every day until CR +
0.15 mg/kg/day IV rom day 10 until there ATO 0.15 mg/kg/day IV rom day 10 +
are <5% blasts and no promyelocytes in GO 9 mg/m2 on day 1 until there are
the bone marrow <5% blasts and no promyelocytes in the
bone marrow
Consolidation or maintenance ATO 0.15 mg/kg/day IV × 5 days/wk × 4 wk or ATO 0.15 mg/kg/day IV × 5 days/wk × 4 wk
our cycles + ATRA 45 mg/m2 PO every day × 4 cycles + ATRA 45 mg/m2 PO every
× 2 wk every 4 wk or seven cycles day × 2 wk every 4 wk or seven cycles
ATO, arsenic trioxide; ATRA, all-trans-retinoic acid; CR, complete remission; D, day; GO, gemtuzumab ozogamicin; IV, intravenous; PCR, polymerase chain reaction; PO,
oral; WBC, white blood cell.
taBLe 211 Monioing o acu pomylocyic normal cytogenetic CR (NCCR). Patients with ACCR
Lukmi ty had a shorted RFS and OS compared with patients
with NCCR (6 months vs 21 months; P <.001; and 11
• Document MR at end o consolidation months vs 46 months; P <.001, respectively). The RFS
• Monitor PCR (BM or PB) every 3 months or 2 years and OS or patients with unavorable cytogenetics at
• High risk diagnosis who were NCCR were similar to those in
• Age older than 60 years patients with avorable or intermediate risk at diagno-
• Long treatment delays during consolidation sis who were ACCR. The ACCR patients who under-
• I PCR becomes positive rom negative, conrm! went an allo-SCT had a signicantly longer 3-year RFS
• I conrmed, intervene. (33% vs 9%; P = .04) and a 3-year OS (33% vs 8%; P
= .06) than the patients who did not undergo an SCT.
• Try to use the same laboratory or PCR.
Interestingly, the RFS and OS achieved by patients
BM, bone marrow; MR, molecular response; PB, peripheral blood; PCR, with ACCR, who underwent an allo-SCT, were simi-
polymerase chain reaction.
lar to the NCCR patients who did not undergo an SCT.
This suggests a role or individualizing AML therapy
based on cytogenetic MRD status.
PML-RARAα usion transcript ater achieving CR and Another method o quantitative detection o MRD
its subsequent monitoring to detect early relapse has in AML is real-time PCR (RT-PCR) (Table 2–14).
become the standard o care or patients with APL. RT-PCR rapidly quanties PCR products by reverse
Detection o MRD in non-APL AML is an upcoming transcriptase fuorescent signals during exponential
eld in which guidelines and standard o care need amplication. The sensitivity o molecular detection
to be dened. Several methods are being assessed to o usion transcripts ranges rom 1 leukemic cell in
determine the best method or detection o MRD in 1000 to 100,000 normal cells, that is, 0.1% to 0.001%
patients with AML. There are several issues with the The usion transcripts most extensively used to
detection o MRD, including lack o a standardized monitor MRD in AML (in addition to PML-RARα or
methodology to measure MRD, inconsistency in MRD APL) are AML1-ETO, CBFβ-MYH11, and MLL-AF9,
thresholds, and uncertainty o the ideal time or evalu- which are present in approximately one third o non-
ation o MRD. APL AML cases.113 Various mutations, such as FLT3,
Konopleva et al111 reported that in patients with NPM1, and c-KIT, can also be assessed by RT-PCR
newly diagnosed AML who have abnormal cytogenet- to determine the residual disease status. PCR analy-
ics at presentation, determination o cytogenetics in sis o NPM1 mutations ater therapy is prognostic
the marrow at day 21 o induction chemotherapy pre- and can be used to predict relapse. NPM1 mutations
dicts RFS independent o the number o blasts. Chen are present in 30% o all patients with AML and in
et al112 rom MDACC demonstrated that persistence o 50% o patients with normal-karyotype AML. Chou
cytogenetic abnormalities at the time o morphologic et al 114 looked at the role o MRD analysis o NPM1
CR portends a worse outcome. They looked at patients mutations by PCR and the impact on outcomes. A
with abnormal cytogenetics at the time o diagno- total o 194 samples rom 38 patients with de novo
sis who achieved a morphologic CR ater induction. AML and NPM1 mutations were analyzed over 10
Twenty-eight percent o patients in CR had abnor- years. The samples were taken 1 month ater induc-
mal karyotype (ACCR), and the remaining 72% had tion and 3 months ater consolidation. Any rise in the
taBLe 212 advngs nd Disdvngs advantages and disadvantages with this technique
o rl-tim rvs tnscis polyms (Table 2–15).
Cin rcion Rubnitz et al116 reported outcomes with MRD-
directed therapy in childhood AML. In this study,
Advantages Disadvantages patients were randomized to receive HDAC-based
Chapter 2
Very sensitive Applicable to a limited number o induction versus LDAC-based induction. MRD levels,
reactions molecular targets on day 22 ater induction, were used to allocate GO to
• PML-RARα determine the timing o the second induction. MRD was
• CBF leukemias determined, and GO was given to patients with poor
• NPM1 early response; high-risk patients were allocated to allo-
Mutations and CBF-AML may have persistence o SCT. This study showed that MRD was no dierent
translocations qualitative assay positivity or years with high-dose chemotherapy versus low-dose chemo-
are commonly therapy at day 22 o induction 1. MRD greater than 1%
ound in AML on day 22 was a signicant prognostic actor infuencing
Can miss therapy-related AML OS and EFS in the high-risk patients but not in the stan-
Expensive dard- or avorable-risk patients. Patients with low-level
MRD (0.1% to <1%) did as well as the MRD-negative
Longer turnaround time
cohort. An Italian group analyzed the outcomes o adult
AML, acute myeloid leukemia; CBF, core-binding actor. AML patients based on MRD levels ater induction and
consolidation and reported that the MRD status at the
end o consolidation was the most important predictor
mutant signals during ollow-up was associated with o prognosis. In the MRD-positive group, patients who
a 3.2 times increased risk o relapse. O the relapsed underwent an allo-SCT had improved outcomes.117
patients, the rise in the mutation levels predicted In general, a lack o standardization among dier-
a relapse at a median o 4.9 months (range, 1–12.3 ent laboratories, identication o thresholds, and time
months) beore a clinical relapse being seen. This points during ollow-up represent the major subjects
analysis also showed that the degree o reduction in o controversy or the routine implementation o MRD
mutation levels aects outcomes and that there is a detection in non-APL AML at this time.
co-relation between MRD ater consolidation and OS
and RFS (but not ater induction). The Wilms tumor CONCLUSION
1 gene (WT1) is highly expressed in most acute leu-
kemias, and its detection in bone marrow has been Ater a period o paucity in discoveries and approv-
associated with the presence, persistence, or relapse als, new strategies are nally evolving, and since 2017,
o leukemia. Recently, investigators rom Turin, Italy,
systematically applied their best-perorming WT1
RT-PCR assay on 620 patient samples and demon-
strated that application o a standardized WT1 assay
taBLe 213 advngs nd Disdvngs o
can indeed provide independent prognostic inorma-
Flow Cyomy o Miniml rsidul Diss
tion in patients with AML.115 Studies are ongoing to
assssmn
urther elucidate the role o the WT1 gene assay to
risk stratiy patients who might benet rom intensi- Advantages Disadvantages
cation o therapy to improve outcomes. Widely Interpretation oten challenging;
Leukemic cells express abnormal patterns o cel- applicable requires experience
lular markers, and these aberrant immunophenotypes (90%–95% o Can be expensive
can be identied by multiparameter fow cytometry. cases) Lack o standardization
Relatively rapid LAIPs may not cover all leukemic
To yield a sensitivity o 0.01% (10–4), at least 200,000
turnaround blasts; partial overlap with normal
cells are needed per tube (at least 200,000 events are
time Antigen shit resulting rom selection
required to detect 20 aberrant blasts), and three to or emergence o subclones: a
our tubes are run per patient; 0.1% is the commonly complete change in LAIPs in ~20%
used threshold in most studies in the literature. An o AML cases, with 80% having at
advantage o fow cytometry–based studies o MRD least one LAIP similar to the original
is that they can accurately quantiy residual leukemic Posttherapy sample is hypocellular;
cells and can also distinguish aberrant blasts rom not enough cells or events
normal myeloid precursors. An immunophenotypic Use o a comprehensive panel o
ngerprint o the AML can be established or MRD antibodies to establish baseline
analysis or ollow-up. However, there are several AML, acute myeloid leukemia; LAIP, leukemia-associated immunophenotype.
new drugs have been approved to improve outcomes targeted therapies, as is the case o gemtuzumab and
in patients with AML. The biology o the disease is CBF-AML. Patients with APL have beneted rom
now better understood, and development o targeted newer treatment with ATRA and arsenical derivatives
therapy is now catching up with the science. Individu- while avoiding classic chemotherapy. Combinations
Chapter 2
alized therapy or patients with FLT3, IDH1, and IDH2 o these newer drugs are being investigated to opti-
mutated AML is now available and part o the stan- mize uture treatment. Better denition o the complex
dard o care. Sae and highly eective therapy is now process initiating and sustaining the leukemic process
available or newly diagnosed older and unt patients will lead to a better denition o targets or therapeu-
with AML with the discovery o venetoclax. Careul tic intervention that may translate into improved cure
genomic annotation o patients at diagnosis ollowed rates. Specic attention must be given to prognostic
by subgroup analyses in large cohorts have identied actors that identiy subsets o AML in which specic
subgroups that may benet more or less rom selected tailored therapies will be helpul.

J In patients with newly diagnosed CBF-AML, at induction cycle o chemotherapy. We routinely use
MDACC, we use the combination o FLAG + GO, antibacterial, antiungal, and antiviral prophylaxis
achieving high rates o CR and long-term survival in all o our patients with AML when appropriate.
rates o 70% to 80%. Dose modications to the FLAG J Our rontline approach to newly diagnosed, older,
backbone are implemented to ofer these patients and unit patients with AML includes lower inten-
the potential or cure. Close monitoring o RT-PCR sity therapy on clinical trials in combination with
or the CBF transcript is critical or risk stratication, targeted therapy (ie, FLT3 inhibitor, IDH inhibi-
with the goal to achieve at least 3-log reduction tor) when appropriate. Lower intensity regimens
rom baseline at the end o consolidation. include a newer backbone on clinical trial, involv-
J Our rontline approach to newly diagnosed, young, ing cladribine + low-dose cytarabine + venetoclax
t patients with newly diagnosed AML is to ofer or HMA + venetoclax. When in remission, dose
double-nucleoside intensive chemotherapy with and schedule modiications are implemented to
either cladribine or udarabine combined with a minimize toxicity and prolonged myelosuppres-
higher dose o cytarabine (1–2 g/m2) combined sion that can be observed ater repeated cycles.
with IDA as the preerred anthracycline. All patients J Postremission therapy is recommend based
have baseline genomic sequencing and karyotyp- on age, tness, and risk assessment at base-
ing. Patients with targetable mutations receive FLT3 line and during therapy (ie, MRD monitoring).
inhibitors, IDH inhibitors, or venetoclax in combina- Maintenance therapy with oral azacytidine or
tion with these backbones on clinical trials. Patients targeted therapy combinations on clinical trials
with TP53 mutations with high allelic requency and are recommended or most higher risk patients
complex karyotype may be ofered less intensive who are not candidates or SCT. Studies o post-
clinical trials in the rontline setting. transplant maintenance therapy are also being
J We recommend close, oten inpatient monitoring conducted.
or patients with newly diagnosed AML during the
standardization o response criteria, treatment outcomes, and

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Chapter 2
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Chapter 2
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2009;27(4):504-510. 2008;26(30):4944-4951.
3 Chronic Lymphocytic Leukemia
and Associated Disorders
Nitin Jain
Philip Thompson
Carlos Bueso-Ramos
Susan M. O’Brien
William G. Wierda
KEY CONCEPTS
 Chronic lymphocytic leukemia (CLL) is the most common obinutuzumab. Ibrutinib and acalabrutinib are intended
leukemia in the United States and has a median age o to be given daily continuously. Venetoclax and obinu-
diagnosis o 70 years. tuzumab is a time-limited treatment approach o 1-year
 The diagnosis o CLL can be established by peripheral duration.
blood ow cytometry in the majority o the patients.  In relapsed CLL, the combination o venetoclax + rituximab
 Treatment o patients with CLL has evolved rom che- has shown improved PFS and OS compared with benda-
moimmunotherapy (CIT) to targeted therapies. Most mustine and rituximab. Additional approved therapies or
patients are currently treated with oral targeted therapies. relapsed CLL include ibrutinib and acalabrutinib. The PI3K
Oral targeted therapies include Bruton tyrosine kinase inhibitors idelalisib and duvelisib are also approved or
inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, and phos- patients with relapsed CLL.
phoinositide 3-kinase (PI3K) inhibitors. Randomized stud-  Richter transormation remains an unmet medical
ies have shown improved progression-ree survival (PFS) need. Outcomes with CIT remains dismal with median
and overall survival (OS) with oral targeted therapies com- survival o less than 1 year. There are emerging data
pared with CIT in CLL. with checkpoint inhibition, use o venetoclax-based
 Targeted therapies approved or frst-line CLL include ibru- combination therapies, and chimeric antigen receptor
tinib, acalabrutinib +/- obinutuzumab, and venetoclax + T-cell therapy
Chronic lymphocytic leukemia (CLL) is a clonal hema- persons older than 80 years. Population studies have
topoietic disorder involving expansion o CD5-posi- not identifed specifc occupational or environmental
tive B cells. Chemoimmunotherapy (CIT) has been the risk actors or developing CLL.2 The risk o CLL is
standard frst-line treatment or patients with CLL.1 In not increased in Asians settled in Western countries,
the past several years, novel oral small-molecule ther- indicating that genetic actors play a part in CLL risk.3
apies have become available, and these have signif- Up to 15% to 20% o patients with CLL have a am-
cantly improved the outcomes o patients with CLL. ily member with CLL or a related lymphoprolierative
disorder.4 Genome-wide association studies identifed
several single nucleotide polymorphisms associated
EPIDEMIOLOGY with an increased risk o CLL.5,6
CLL is the most common leukemia in the Western

Hemisphere, accounting or about 25% o all leuke- BIOLOGY
mias in the United States. The estimated number
o new CLL cases or 2020 was 21,040, with 4060
Surface Antigen Phenotype
deaths. CLL is uncommon in the Asian population and
accounts or only 2.5% o all leukemias in Japan. The CLL is a clonal B-cell lymphoid leukemia. CLL cells
incidence is age related, with an increase rom 5.2 per morphologically resemble small mature lympho-
100,000 persons older than 50 years to 30.4 per 100,000 cytes arrested in an intermediate stage o the B-cell
49
dierentiation pathway. The hallmark o CLL cells is situ hybridization (FISH) perormed on interphase cells
that they are monoclonal and express CD5, an antigen using genomic DNA probes greatly enhanced the abil-
commonly ound on T cells. CD5-positive B cells can ity to detect molecular abnormalities in malignant cells.
be ound in the mantle zone o lymphoid ollicles, but FISH demonstrated that molecular abnormalities occur
ChAPTER 3
they constitute a minor raction o the B-cell population. in over 80% o CLL cases. Del(13q) is the most common
CD19, CD20, and CD23 are B-cell markers expressed genetic aberration ound in CLL by FISH (55%) ollowed
on CLL cells. Surace immunoglobulin (Ig), FMC7, by del(11q) (18%), trisomy 12 (16%), and del(17p) (7%).14
CD22, CD11c, and CD79b are either weakly expressed When divided into ve prognostic categories—del(17p),
or negative in CLL. Based on the antigen expression pro- del(11q), trisomy 12, no observed abnormalities, and
le, CLL appears to arise rom an “activated” B cell. del(13q) (as the sole abnormality)—the survival times
were 32, 79, 114, 111, and 133 months, respectively.
Somatic Hypermutation o Patients with del(11q) tend to have more prominent
Immunoglobulin Heavy-Chain lymphadenopathy. Patients with del(17p) and del(11q)
tend to have more advanced disease and respond poorly
Variable Gene to chemotherapy-based regimens.9 Clonal evolution can
Normal B-cell development involves an antigen-indepen- occur over time and with treatment; thereore, FISH
dent phase and an antigen-dependent phase. During the assessment should be repeated whenever a therapeutic
antigen-independent phase, B cells undergo rearrange- intervention is being considered.
ment o the variable (V), diversity (D), and joining (J) genes Whole-exome sequencing o CLL cases has iden-
in the bone marrow. Somatic mutation o the heavy- and tied genes that are recurrently mutated and may
light-chain variable gene occurs ater encounter with contribute to the pathogenesis o the disease.15,16
antigen in the germinal center. Assessment or somatic Recurrently mutated genes include TP53, NOTCH1,
hypermutation o immunoglobulin heavy-chain variable SF3B1, MYD88, XPO1, and ATM. TP53 mutations are
gene (IGHV) denes two subsets o CLL. Approximately typically associated with del(17p). ATM and SF3B1
50% o patients with CLL have somatic hypermutation mutations are typically associated with del(11q).
(>2% deviation rom germline sequence) o the IGHV
gene and thus appear to arise rom postgerminal B cells,
whereas the subset o CLL lacking IGHV gene hypermu- CLINICAL FEATURES
tation (≤2% deviation rom germline sequence) appears
to arise rom naïve B cells.7,8 The mutation status o CLL At diagnosis, most patients are older than 60 years, with
cells is xed, and mutational status is not gained or lost more than 90% being older than 50 years. The diag-
throughout the course o disease. With the use o CIT, nosis o CLL is oten incidental; a routine blood count
patients with unmutated IGHV have worse clinical out- may reveal an elevated absolute lymphocyte count
comes than those with mutated IGHV.9–11 (ALC). In symptomatic patients, atigue and inections
Because historically, sequencing o the IGHV gene to may be presenting eatures. B symptoms (ever, weight
identiy the mutational status was labor intensive and loss, night sweat) can also occur but are uncommon at
not universally available, Damle et al7 studied the corre- initial diagnosis. Exaggerated skin reactions to insect
lation o IGHV mutation status with CD38 expression bites (Wells syndrome) are requent in those with CLL.
as a surrogate prognostic marker or IGHV mutation Leptomeningeal involvement is rare. Some patients
status. A signicant association between CD38 expres- may present with autoimmune hemolytic anemia or
sion and unmutated IGHV status was noted. Gene immune thrombocytopenia. Physical examination may
expression proling o mutated versus unmutated reveal cervical, axillary, or inguinal lymphadenopathy.
IGHV CLL cases showed zeta-associated protein 70 Splenomegaly and hepatomegaly are not uncommon.
(ZAP-70) to be the most dierentially expressed gene
with higher expression in unmutated IGHV cases, pro-
viding another surrogate or IGHV mutation status.12,13 LABORATORY FEATURES
Laboratory ndings invariably show lymphocytosis.
Genomic Alterations CLL cells resemble mature lymphocytes; they have
Using conventional chromosome banding techniques, dense chromatin as well as scant cytoplasm and lack
cytogenetic abnormalities can be detected in up to 50% nucleoli (Fig. 3–1). Preparation o the blood smear
o CLL cases. These techniques are hampered by the may damage these ragile lymphocytes and pro-
low mitotic activity o CLL cells; B-cell mitogens may duce “smudge” cells. The bone marrow is typically
be used to enhance this activity. In addition, metaphases hypercellular or age, and inltration varies in terms
obtained or karyotyping may also arise rom normal T o the percentage o marrow involved as well as in
cells in the sample, as indicated by sequential immuno- the pattern o involvement, which may be nodular,
typing ollowed by karyotypic analysis. Fluorescent in interstitial, or diuse (Fig. 3–2). Erythroid, myeloid,
Capter 3 Chronic Lymphocytic Leukemia and Associated Disorders 51
ChAPTER 3
FIGURE 3–1 Chronic lymphocytic leukemia. Peripheral FIGURE 3–3 Immune hemolytic anemia. Presence o micro
blood smear showing matureappearing lymphocytes. Note spherocytes (arrows) and nucleated red cells indicates
dense chromatin, scant cytoplasm, absence o nucleoli, and immune destruction o red cells. Diagnosis is conrmed by
smudge cells. demonstrating the presence o immunoglobulin G (IgG) or
complement on red cells.
and megakaryocytic precursors may be normal or

A
decreased. Anemia or thrombocytopenia may result
rom marrow inltration or rom immune destruction.
Findings o microspherocytes in the peripheral blood
smear (Fig. 3–3), reticulocytosis, and demonstration o
Ig G or complement on red cells support the diagnosis
o immune hemolytic anemia. Pure red cell aplasia has
been described in 1% to 6% o cases. Patients oten
develop hypogammaglobulinemia, which can progress
in severity with advancing disease. Monoclonal gam-
mopathy may also develop. Other laboratory abnor-
malities include elevated serum beta-2-microglobulin
(B2M); lactate dehydrogenase (LDH) is rarely elevated.
Up to 5% o otherwise normal individuals older
than the age 40 years may harbor a population o
monoclonal CD5+/CD19+/CD23+ B cells. These indi-
viduals are asymptomatic (absence o cytopenia and
lymphadenopathy or organomegaly); when the abso-
B
lute monoclonal lymphocyte count is less than 5000/
μL and there is no palpable enlarged lymph node, they
are characterized as having monoclonal B lymphocy-
tosis (MBL).17 It is estimated that the rate o progres-
sion rom MBL to CLL is 1% to 2% per year.
DIAGNOSIS
In 2018, the International Workshop on Chronic Lym-
phocytic Leukemia (IWCLL) updated the recommen-
dations on diagnosis and treatment o patients with
CLL.18 The diagnosis o CLL requires 5 × 109 or greater
FIGURE 3–2 A and B. Chronic lymphocytic leukemia. Bone clonal B lymphocytes/L in the peripheral blood, with
marrow biopsies showing nodular, diuse, and interstitial less than 55% o the cells being prolymphocytes.
patterns o involvement. A monoclonal B-cell count 5 × 109/L or greater was
ChAPTER 3
FIGURE 3–4 Zetaassociated protein 70 (ZAP70) expression FIGURE 3–6 Large granular lymphocytes with cytoplasmic
in chronic lymphocytic leukemia cells indicates poor progno azurophilic granules.
sis. Immunohistochemistry (above) or fow cytometry can be
used to detect ZAP70 expression.
specied to distinguish CLL rom small lymphocytic

A lymphoma in patients with palpable lymph nodes or
splenomegaly. B-lymphocyte clonality should be dem-
onstrated by using fow cytometry, which should also
conrm expression o B-cell surace antigens (CD19,
CD20, CD23), low-density surace Ig (M or D), CD200,
and CD5. ZAP-70 (Fig. 3–4) expression in CLL cells
has prognostic implication. Distinguishing CLL rom
mantle cell lymphoma (MCL); Figs. 3–5A and B) (see
“Dierential Diagnosis”) and large granular leukemia
(Fig. 3–6) is o utmost importance.
The presence o more than 55% o prolymphocytes
avors a diagnosis o prolymphocytic leukemia (PLL).
Prolymphocytes (<55%) can be seen in peripheral
blood or bone marrow o patients with CLL (Fig. 3–7).
B
DIFFERENTIAL DIAGNOSIS
Clinical, morphologic, immunophenotypic, and cyto-
genetic help to distinguish between CLL and other
diseases such as MCL, ollicular lymphoma, T-cell
PLL (T-PLL), hairy cell leukemia (HCL), marginal
zone lymphoma, and Waldenström macroglobulin-
emia. Table 3–1 summarizes the immunophenotypic
eatures o these disorders. Distinguishing CLL rom
MCL is important because both can express CD5
(see Fig. 3–5A). Unlike CLL, MCL cells are typically
CD23 negative, CD200 negative, and FMC-7 posi-
tive and have strong surace Ig staining. Conrma-
FIGURE 3–5 A. Mantle cell lymphoma (MCL) in leukemic tion o MCL can be made by detection o the t(11;14)
phase. MCL cells (arrow) are larger than mature lymphocytes translocation or positive nuclear cyclin D1 staining
(center) with speckled chromatin; some show nuclear clet. B.
(see Fig. 3–5B).
Nuclear cyclin D1 staining in mantle cells.
A C
ChAPTER 3
B
Green: centromere 12
Red: D13S319
FIGURE 3–7 A. Highpower view o a prolymphocyte jux

taposed with a matureappearing lymphocyte. Note larger
size, less condensed chromatin, and prominent nucleolus in
prolymphocyte. B. Bone marrow smear rom a 58yearold
man with a 3year history o untreated chronic lymphocytic
leukemia (CLL). There are small lymphocytes and larger pro
lymphocytoid lymphocytes with abundant lightly basophilic
cytoplasm, ne chromatin, and variably prominent nucleoli.
C. Interphase fuorescent in situ hybridization. Almost all the
lymphocytes show deletion o one locus o D13S319 (white
arrow) (except two lymphocytes on slide 1, let low), and a
large subset o CLL cells also showed trisomy 12 (+12). Inter
estingly, +12 is almost only seen in prolymphocytoid lym
phocytes. The small lymphocytes with clumped chromatin
and scant cytoplasm usually do not show +12.
TABLE 31 Immunopenotypic Analysis in Cronic B-Cell Disorders
Disease sIg CD5 CD10 CD20 CD22 CD23 CD79B CD103 FMC7
CLL Weak ++ − + −/+ ++ −/+ − −/+
B-PLL Strong −/+ −/+ ++ + −/+ ++ − ++
HCL Strong − − ++ ++ − + + ++
SLVL Strong −/+ − ++ ++ −/+ ++ − ++
FL Strong −/+ ++ ++ ++ −/+ ++ − ++
MCL Strong ++ − ++ ++ − ++ − ++
B-PLL, prolymphocytic leukemia; CLL, chronic lymphocytic leukemia; FL, ollicular lymphoma; HCL, hairy cell leukemia; MCL, mantle cell lymphoma; sIg, surace
immunoglobulin; SLVL, splenic lymphoma with villous lymphocytes.
STAGING stages I and II as intermediate risk, and stages III and

IV as high risk. Similarly, Binet stages A, B, and C are
Staging systems or CLL include Rai and Binet stag- based on the number o lymph nodal areas involved
ing (Table 3–2).19,20 The original Rai classication and the presence or absence o cytopenia. The diag-
ChAPTER 3
dened ve stages rom 0 to IV based on the pres- nostic workup that is undertaken in patients with
ence or absence o lymphocytosis, lymphadenopathy, CLL at initial presentation at The University o Texas
organomegaly, and cytopenia; this has been modied MD Anderson Cancer Center (MDACC) is listed in
to three stages by dening Rai stage 0 as low risk, Table 3–3.
TABLE 32 Staging of Cronic Lympocytic Leukemia
Rai Stage Modied Rai Stage Description Binet Stage Description

0 Low risk Lymphocytosis only A Hemoglobin ≥10 g/dL, platelets ≥100
× 109/L, and <3 enlarged lymphoid-
bearing areas
1 Intermediate risk Lymphocytosis and B Hemoglobin ≥10 g/dL, platelets ≥100
lymphadenopathy × 109/L, and ≥3 enlarged lymphoid-
bearing areas
2 Intermediate risk Lymphocytosis and

splenomegaly and/
or hepatomegaly
with/without
lymphadenopathy
3 High risk Lymphocytosis and C Hemoglobin <10 g/dL or platelets <100
anemia (hemoglobin × 109/L (irrespective o number o
<11 g/dL) lymphoid-bearing areas)
4 High risk Lymphocytosis and
thrombocytopenia
(platelets <100 × 109/L
TABLE 33 Initial Evaluation of Patients wit Cronic Lympocytic Leukemia at MD Anderson Cancer
Center
History and physical (close attention to lymph node areas, liver and spleen size)
Constitutional symptoms (ever, chills, weight loss, night sweats)
Assessment o perormance status
CBC, electrolytes, BUN, creatinine, liver unction tests, LDH, quantitative immunoglobulins, β2-microglobulin
Examination o peripheral blood smear
Bone marrow aspiration and biopsy (in patients with cytopenias or those in need o treatment)
Immunophenotyping o peripheral blood or bone marrow lymphocytes to establish diagnosis
Prognostic marker assessment
• Interphase FISH (assessment o deletion 17p, deletion 11q, trisomy 12, deletion 13)
• IGHV mutation status
• TP53 sequencing
• Flow cytometry or CD38
• Immunostaining or ow cytometry or ZAP-70
Imaging studies (only i presenting with signifcant adenopathy or needed treatment); many clinical trials are now
incorporating CT scans as per new guidelines, but these are not standard o care outside o a clinical trial.
• CT scan or PET scan (PET scan preerred i there is a suspicion o Richter transormation)
BUN, blood urea nitrogen; CBC, complete blood count; CT, computed tomography; FISH, uorescent in situ hybridization; LDH, lactate dehydrogenase; MDACC, The
University o Texas MD Anderson Cancer Center; PET, positron emission tomography; ZAP-70, zeta-associated protein 70.
PROGNOSIS (score o 1), and high risk (score o 2 or 3). The 5-year
cumulative risks or treatment were 8.4%, 28.4%, and
In the era o CIT, several actors were associated with 61.2% among low-risk, intermediate-risk, and high-
poor prognosis. These actors included advanced Rai or risk patients, respectively.
ChAPTER 3
Binet stage, male gender, older age, lymphocyte dou-
bling time less than 12 months, presence o del(17p) or
del(11q), complex karyotype, unmutated IGHV, higher
TREATMENT
CD38 expression, higher Zap-70 expression, elevated
b2-microglobulin, elevated serum thymidine kinase,
Indications or Treatment
diuse marrow involvement, and gene mutations Unlike most leukemias, an unusual eature o CLL is
(TP53, BIRC3, NOTCH1, SF3B1).21–24 The CLL-Inter- that making the diagnosis is not necessarily an indica-
national Prognostic Index (CLL-IPI) evaluated 3472 tion to initiate treatment. Early treatment o asymptom-
patients with treatment-naïve CLL and assessed or atic CLL with chemotherapy was not shown to prolong
several demographic and CLL disease-related actors; survival. In the current era o more eective CIT regi-
ve prognostic markers or OS were identied, which mens and targeted therapies, this question is currently
included TP53 aberration, IGHV status, B2M, clinical being evaluated in clinical trials. The 2018 IWCLL crite-
stage, and age older than 65 years o age.25 Based on ria or treatment o CLL are summarized in Table 3–4.
these ve markers, our separate prognostic groups Up until recently, CIT was the standard rst-line treat-
were identied with 5-year overall survival (OS) rang- ment or patients with CLL. With the signicant advances
ing rom 93.2% to 23.3%. It is important to note that in the eld o CLL, targeted therapies have now become
the CLL-IPI was developed in patients who received standard treatment or most patients with CLL.
CIT. Given improved outcomes with targeted thera- Combination CIT such as fudarabine + cyclophos-
pies and overall decline in the use o chemotherapy or phamide + rituximab (FCR), bendamustine + rituximab
patients with CLL, the CLL-IPI will need to be reevalu- (BR), and chlorambucil + CD20 monoclonal antibody
ated with the data rom patients treated with targeted (mAB) combination were the standard rst-line treat-
therapies. More recently, an international prognos- ments or patients with CLL.1,27 In the original FCR study
tic score to predict time to rst treatment (TTFT) in conducted at MDACC, a high overall response rate
patients with CLL with early, asymptomatic disease (ORR) o 95% was noted with a complete remission (CR)
(International Prognostic Score or Early-stage CLL rate o 72%.28 In the long-term ollow-up o this trial, a
[IPS-E]) was developed.26 A total o 4933 patients were 10-year progression-ree survival (PFS) o about 55% was
analyzed. Three variables independently correlated noted in patients with mutated IGHV.11 The GCLLSG
with TTFT: unmutated IGHV, ALC greater than 15 × group conducted a phase III trial to evaluate the ecacy
109/L, and presence o palpable lymph nodes. Each o o FCR versus FC in rst-line treatment o patients with
these variables was given a risk score o 1; patients were CLL (CLL8 trial).9 A total o 817 patients were random-
categorized into low risk (score o 0), intermediate risk ized to receive six courses o either FC (409 patients) or
TABLE 34 Indications for Treatment in Cronic Lympocytic Leukemia from te International
Worksop on Cronic Lympocytic Leukemia
Active disease should be confrmed beore initiating treatment.

1. Evidence o progressive marrow ailure as maniest by the development or worsening o anemia and/or thrombocytopenia
2. Massive (ie, >6 cm below the let costal margin) or progressive or symptomatic splenomegaly
3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
4. Progressive lymphocytosis with an increase o ≥50% over a 2-month period, lymphocyte doubling time o <6 monthsa
5. Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid therapy
6. Symptomatic or unctional extranodal involvement (eg, skin, kidney, lung, spine)
7. Constitutional symptoms, defned as any one or more o the ollowing disease-related symptoms or signs:
a. Unintentional weight loss ≥10% within the previous 6 months
b. Signifcant atigue (ie, ECOG PS 2 or worse; cannot work or unable to perorm usual activities)
c. Fevers ≥100.5°F or 38.0°C or ≥2 weeks without evidence o inection
d. Night sweats or ≥1 month without evidence o inection
<TFN>aIn patients with a lymphocyte count o <30 × 109/L, lymphocyte doubling time should not be used as a single parameter to defne treatment indication. Factors
contributing to lymphocytosis or lymphadenopathy other than chronic lymphocytic leukemia (ie, inections) should be excluded.
ECOG PS, Eastern Cooperative Oncology Group perormance status.
FCR (408 patients). They reported a signicantly higher resulted in a higher ORR o 78.4% (CR 20.7% + par-
CR rate (44% vs 22%; P <.0001), ORR (90% vs 80%; P tial remission (PR) 57.7%) versus 65.1% (CR 7% +
<.0001), PFS (median PFS, 52 vs 33 months; P <.0001), PR 58.1%; P <.001). PFS was signicantly longer with
and OS (3-year OS, 87% vs 83%; P =.012) with the addi- obinutuzumab–chlorambucil compared with that seen
ChAPTER 3
tion o rituximab. This trial established the role o anti- with rituximab–chlorambucil (median PFS, 29.2 vs 15.4
CD20 mAB in the rst-line therapy o patients with CLL. months; P <.001). Both antibody-containing regimens
Bendamustine in combination with rituximab has also produced better outcomes than that seen with single-
been evaluated as rst-line treatment or patients with agent chlorambucil. This trial established the combina-
CLL. Fischer et al29 reported on the outcomes o 117 tion o chlorambucil with a CD20 mAb as a standard
patients with treatment-naïve CLL who received BR. o care or rst-line therapy in older patients with CLL
The ORR was 88% with a CR rate o 23%. The median who have comorbidities.
PFS was 34 months. Notably, one third o the patients
had a creatinine clearance o 70 mL/min or less (these
patients are typically excluded rom the FCR trials), and
B-Cell Signaling Pathway Inhibitors
these patients did equally as well as patients with a cre- CLL cells receive growth and survival signals rom
atinine clearance greater than 70 mL/min. the microenvironment o the bone marrow, lymph
The GCLLSG then conducted a randomized phase nodes, and spleen.38 Bruton tyrosine kinase (BTK) is a
III study o FCR versus BR as rst-line therapy or central molecule in signal transduction or the B-cell
patients with CLL (CLL10 trial).10,30 This trial included receptor (BCR) as well as CD19, CD38, CD40, CXCR4
patients with CLL with good physical status (Cumula- chemokine receptor, tumor necrosis actor receptors,
tive Illness Rating Scale [CIRS] score ≤6 and creatinine and Toll-like receptors (TLRs). Other important sig-
clearance ≥70 mL/min). A total o 282 patients received nal transduction molecules include phosphoinositide
FCR, and 279 patients received BR. The FCR arm had 3-kinase (PI3K) and Syk.
a signicantly higher CR/CR with incomplete count
recovery (CRi) rate (39.7 vs 30.8; P =.03) and signi-
cantly improved PFS (median PFS, 55.2 vs 41.7 months;
Bruton Tyrosine Kinase Inhibitors
P <.001). OS was not dierent between the two groups. BTK is a nonreceptor tyrosine kinase o the Tec kinase
Not unexpectedly, patients on the FCR arm experienced amily that plays a crucial role in BCR signaling. Ibru-
more grade 3 or 4 neutropenia (84.2% vs 59%; P <.001), tinib is an oral, selective, and irreversible inhibitor o
more thrombocytopenia (21.5% vs 14.4%; P =.03), and BTK. It orms a covalent bond with the cysteine-481
increased risk o grade 3 or 4 inections (39.1% vs 26.8%; o BTK. Byrd et al39 reported the outcomes o 85
P <.001). However, the treatment-related mortality rate patients with relapsed or reractory CLL who received
was similar in the two arms. This trial established FCR ibrutinib monotherapy. This was a heavily pretreated
as a standard rst-line CIT regimen or patients with population with a median o our prior therapies. The
CLL who are 65 years old or younger. Several studies median age was 66 years (range, 37–82 years). Thirty-
have been conducted with the intent o modiying the three percent o the patients had del(17p). The ORR
FCR regimen by dose-intensiying rituximab,31 adding was 90%, with 7% CR, 65% PR, and 9% PR with
mitoxantrone,32 adding alemtuzumab,33 adding granu- lymphocytosis (PR-L). The estimated PFS at 7 years
locyte-macrophage colony-stimulating actor,34 or using was 34%.40 In the treatment-naïve cohort o the same
lower doses o FCR (FCR-Lite),35 but these studies have trial, 31 patients (65 years or older) with CLL received
not shown superior results compared with those seen ibrutinib monotherapy. The estimated 7-year PFS rate
with the standard FCR regimen. was 83%. In a randomized phase III trial (RESONATE
Obinutuzumab is a humanized type II CD20 trial), patients with relapsed or reractory CLL were
mAb with a glycoengineered Fc domain that leads to randomized to ibrutinib or oatumumab.41 The ibruti-
enhanced antibody-dependent cellular cytotoxicity nib arm had a much higher ORR and superior PFS and
compared with that seen with rituximab. This type II OS compared with the oatumumab arm. In a random-
CD20 mAb is more eective at direct induction o CLL ized phase III trial (RESONATE-2), 269 older patients
cell apoptosis, which leads to more eective B-cell with previously untreated CLL were randomized to
depletion than rituximab. In the GCLLSG CLL11 trial, ibrutinib versus chlorambucil.42 The PFS was signi-
previously untreated patients with CLL with coexist- cantly longer in the ibrutinib arm (5-year PFS 70% vs
ing conditions (CIRS score >6 and/or creatinine clear- 12% or chlorambucil; P <.001).43 There was also an
ance o 30–69 mL/min) were randomly assigned to OS benet or the ibrutinib arm (5-year survival rate,
receive chlorambucil monotherapy, chlorambucil plus 83% vs 68% or chlorambucil arm; P <.001) despite
rituximab, or chlorambucil plus obinutuzumab.36,37 crossover that allowed 57% o the patients receiving
A total o 781 patients were enrolled. The median chlorambucil to receive ibrutinib at the time o disease
age was 73 years. Treatment with obinutuzumab– progression. This trial led to the approval o ibrutinib
chlorambucil, compared to rituximab–chlorambucil, or previously untreated patients with CLL. Common
adverse events with ibrutinib include diarrhea, arthral- chlorambucil + obinutuzumab. These trials (ASCEND
gia, hypertension, and atrial brillation. and ELEVATE-TN) led to the approval o acalabrutinib in
It is important to note that most patients will both relapsed or reractory and rontline CLL. There is
develop lymphocytosis upon initiating ibrutinib. This an ongoing head-to-head phase III trial o ibrutinib ver-
is expected with all BCR inhibitors, and it generally sus acalabrutinib in patients with relapsed or reractory
ChAPTER 3
resolves over the course o 6 to 9 months with contin- CLL with either a del(17p) or del(11q).
ued treatment. Development o lymphocytosis is not
detrimental to the long-term clinical outcomes The
mechanism o resistance to ibrutinib include develop-
BCL-2 Inhibitor
ment o a mutation o BTK at cysteine-481 (C481S) CLL cells express high levels o antiapoptotic proteins
and gain-o-unction mutations in PLCγ 2, a signaling o the Bcl-2 amily, rendering them long-lived and resis-
molecule downstream o BTK.44 tant to senescence and death. Navitoclax (ABT-263) is
More recently, the ECOG1912 trial evaluated the an orally administered small-molecule inhibitor o Bcl-2,
activity o ibrutinib + rituximab versus FCR. A total Bcl-w, and Bcl-xL. A phase I/II trial o orally administered
o 519 patients (age 70 years or younger) with previ- navitoclax reported antitumor activity in patients with
ously untreated CLL were randomized.45 The PFS was CLL; however, the dose-limiting toxicity was thrombo-
signicantly better with ibrutinib + rituximab than that cytopenia.49 Thrombocytopenia was secondary to the
seen with FCR (3-year PFS, 89.4% vs 72.9% P <.001). accelerated platelet senescence rom inhibition o Bcl-xL
In a subgroup analysis, the PFS benet o ibrutinib + in the platelets. Venetoclax (ABT-199) was designed as
rituximab over FCR was limited to IGHV-unmutated a molecule with greater anity or Bcl-2 and reduced
patients. The OS was also signicantly improved with anity or Bcl-xL.50 Unlike BTK inhibitors, the treatment
ibrutinib + rituximab versus FCR (3-year OS, 98.8% vs with venetoclax, especially in combination with CD20
91.5%; P <.001). As expected, there was more myelo- mABs can lead to measurable residual disease (MRD)–
suppression and inections in the FCR arm, and there negative remissions. Venetoclax was studied in a phase
were more atrial brillation and hypertension noted III study in relapsed or reractory CLL. In this study
with ibrutinib + rituximab. Like the ECOG1912 trial, (MURANO trial), 389 patients with relapsed or rerac-
the investigators or the ALLIANCE group designed a tory CLL were randomized to receive venetoclax + ritux-
rst-line treatment trial or older patients with CLL. The imab (2 years o venetoclax + 6 months o rituximab)
older patients were randomized to BR versus ibrutinib versus six cycles o BR.51 The 4-year PFS rate was higher
+ rituximab versus ibrutinib.46 The PFS was signicantly with venetoclax + rituximab versus BR (57.3% vs 4.6%
improved in the two ibrutinib-containing arms com- (P <.0001).52 Similarly, 4-year OS was in avor o vene-
pared with that seen in the BR arm (2-year PFS, 74% or toclax + rituximab arm (85.3% vs 66.8%; P <.0001). In
the BR arm vs 88% or ibrutinib + rituximab vs 87% or a landmark analysis, MRD at the end o 2 years o vene-
ibrutinib monotherapy; P <.001 or the BR vs ibrutinib toclax treatment correlated with PFS. Venetoclax was
arms). Notably, there was no dierence in the PFS or investigated in a phase III trial in rst-line CLL (CLL14
the two ibrutinib arms, indicating no additional benet trial).53 Eligible patients were aged 18 years or older with
with the addition o rituximab to ibrutinib. There was coexisting conditions (CIRS >6 or creatinine clearance o
no dierence in OS among the three treatment arms. 30–69 mL/min). Patients received venetoclax + obinu-
Acalabrutinib is a second generation BTK inhibitor tuzumab or chlorambucil + obinutuzumab. Venetoclax
currently approved or both rst-line and relapsed CLL.47 and chlorambucil were given or 1 year; obinutuzumab
In the ASCEND phase III trial, patients with relapsed or was given or 6 months in both arms. A total o 432
reractory CLL were randomized to receive acalabrutinib patients were enrolled. At a median ollow-up period o
monotherapy versus investigator choice therapy (idelal- 39·6 months, patients in the venetoclax + obinutuzumab
isib + rituximab or BR). Patients had received a median arm had a signicantly longer PFS than that seen with
o two prior therapies.48 Ater a median ollow-up period chlorambucil + obinutuzumab (P<.0001).54 The median
o 16.1 months, the median PFS was signicantly longer PFS was not reached or the venetoclax + obinutuzumab
with acalabrutinib monotherapy (PFS not reached) com- arm and was 35·6 months or the chlorambucil + obinu-
pared with investigator’s choice (16.5 months; P <.0001). tuzumab arm. The OS were similar in the two arms.
In the ELEVATE-TN phase III trial, patients with previ-
ously untreated CLL who were 65 years or older or 18
years or older with either a CIRS score greater than6 or
Phosphoinositide 3-Kinase Inhibitors
a creatinine clearance o 30 to 69 mL/min were enrolled. PI3K-δ is a critical kinase or activation, prolieration,
Patients were randomized to acalabrutinib monother- and survival o B cells and is hyperactive in many B-cell
apy versus acalabrutinib + obinutuzumab versus chlo- malignancies, including CLL. Idelalisib is a potent, selec-
rambucil + obinutuzumab. The estimated PFSs at 2 tive, reversible inhibitor o PI3K-δ. A phase I trial o ide-
years were 93% with acalabrutinib + obinutuzumab, lalisib was conducted in relapsed and reractory patients
87% with acalabrutinib monotherapy, and 47% with with CLL.55 A total o 54 patients were enrolled with a
median o ve prior therapies. The median PFS was 15.8 current CAR T-cell trials, although other targets are
months. A phase III clinical trial evaluated the activity being explored as well (Table 3–5). CAR T products
o idelalisib + rituximab versus rituximab + placebo targeting CD19 are approved by the Food and Admin-
in patients with relapsed or reractory CLL in whom istration or the treatment o patients younger than 26
ChAPTER 3
rituximab monotherapy would be considered appropri- years o age with reractory pre-B-acute lymphoblastic
ate.56,57 A total o 220 patients were enrolled. This trial leukemia (ALL) or second or greater relapse and or the
demonstrated superior ecacy or combined idelalisib treatment o diuse large B-cell lymphoma (DLBCL) in
and rituximab over that seen with rituximab and pla- patients who have received two or more prior thera-
cebo, with a hazard ratio (HR) or PFS o 0.15 (P <.001) pies. In the pivotal study o tisagenlecleucel in pre-B
and HR or OS o 0.28 (P = .02). Pneumonitis was seen in ALL, the CR rate was 83%, and the event-ree survival
4% o the patients treated on the idelalisib + rituximab (EFS) was 50% at 1 year.60 In DLBCL, the ORR with
arm. Because o immune-mediated side eects and risk axicabtagene ciloleucel was 82% (54% CR), and 42%
o inectious complications, the development o idelal- o patients remained in remission at 15.4 months.61 In
isib in rst-line CLL has been halted.58 Duvelisib is a contrast, response rates in the CLL studies have gener-
PI3K-δ and -γ inhibitor and is also approved or relapsed ally been lower (ORR, 57%–71%; CR, 21%–28%).62,63
CLL based on the results o the DUO trial.59 Nevertheless, the treatment appears to have curative
potential, as indicated by the act that two o the origi-
nal patients treated at the University o Pennsylvania62
Chimeric Antigen Receptor T-Cell Therapy remain in remission 7 years ater therapy.64
Please reer to Chapter 16 or a detailed outline o chi- The underlying reasons or poorer responses in
meric antigen receptor T-cell (CAR T) biology, general patients with CLL compared with those with ALL and
principles o use, toxicities, and their management. DLBCL are not completely clear. In particular, the inci-
Briefy, CARs are engineered immune receptors intro- dence o relapse because o loss o the CD19 target
duced ex vivo into T cells, usually autologous, that appears lower than in ALL and DLBCL.65 One study, rom
redirect these cells to react against CLL cells. The CAR the University o Pennsylvania,66 demonstrated that the
is a recombinant protein composed o an antigen- CAR T-cell phenotype in the apheresis product, beore
binding domain derived rom single-chain Ig variable inusion, was strongly associated with response. Speci-
genes and intracellular signaling domains derived rom cally, higher numbers o memory T cells and lower levels
CD3ζ and costimulatory domains derived rom CD28 o immune checkpoint molecule expression and mark-
and/or CD137. The transduced T cells are inused into ers o T-cell exhaustion were associated with a higher
the patient, where they bind to the target antigen and likelihood o CR. This suggests that a patient’s T-cell “t-
induce T-cell activation and prolieration, cytokine ness” may be important in determining the likelihood o
production, and killing o cells expressing the tar- responding to treatment with autologous CAR T cells.
get antigen. CD19 is the most common target o the Attempts are being made to use novel combination
TABLE 35 Results of Some Selected Studies of Autologous Cimeric Antigen Receptor T-Cell Terapy
Targeting CD19 in Cronic Lympocytic Leukemia
Patients (n) Co-stimulation Treatment Combination Responses

62
Porter et al (2015) 14 4-1BB None ORR, 57%
CR, 28%
MRD negative, 28%
Turtle et al63 (2017) 24 (5 Richter 4-1BB None ORR, 71%
transormation) CRR, 21%
MRD negative, 58%
Gauthier et al67 17 4-1BB Ibrutinib ORR, 88%
(2018) CRR, 83% (evaluable patients)
MRD negative, 75%
Gill et al68 (2018) 19 4-1BB Ibrutinib ORR, 71%
CRR, 43%
MRD negative, 78%
Siddiqi et al105 23 4-1BB None ORR, 82%
(2019) CR, 46%
MRD negative, 60%
CR, complete remission; MRD, Measurable residual disease; ORR, overall response rate.
strategies to enhance the response rates to CAR T-cell Research Initiative on CLL and European Society o
therapy in patients with CLL. Single-center experiences Bone Marrow Transplant released a paper outlining
rom the group at the Fred Hutchison Cancer Research a proposed risk assessment ramework or CLL that
Center and The University o Pennsylvania suggest that includes cytogenetic and molecular eatures, as well as
the combination o ibrutinib with CAR T may enhance reractoriness to CIT, targeted agents, or both.72 This
ChAPTER 3
response rates while simultaneously reducing the likeli- ramework assigns patients to high-risk I category
hood o severe cytokine release syndrome.67,68 The com- i they have ailed CIT and have a TP53 abnormality
bination o lisocabtagene maraleucel with ibrutinib is (deletion o chromosome 17p or TP53 mutation). High-
being explored in the ongoing phase 2, multicenter study risk category II comprises patients relapsed ater CIT
TRANSCEND-CLL-04 (NCT03331198). and a targeted agent, regardless o molecular eatures.
The ramework recommends consideration o cellular
immunotherapy (CAR T or allo-SCT) or patients in
Stem Cell Transplantation high risk I or high risk II categories. In general, patients
Because CLL is a disease o older adults, reduced-inten- in the high risk II category should have a lower thresh-
sity conditioning (RIC) allogeneic stem cell transplant old or proceeding to allo-SCT. However, this remains
(allo-SCT) is the most common type o transplant a complex area and numerous actors need to be care-
oered to patients with CLL. RIC allo-SCT in CLL leads ully considered when determining whether to proceed
to 5-year EFS and OS rates o 35% to 45% and 50% to with cellular immunotherapy in an individual patient.
60%, respectively.69 Khouri et al70 reviewed outcomes When assessing patients in high risk I or II categories,
o 86 patients with CLL who underwent RIC allo-SCT the physician must weigh the risk o treatment-related
at MDACC. The median age was 58 years. Eighty-three morbidity and mortality rom cellular immunotherapy
o the 86 patients experienced donor cell engratment. (particularly allo-SCT) against the risk o unsalvage-
Overall, the estimated 5-year PFS and OS rates were able CLL relapse or Richter transormation (Table 3–6).
36% and 51%, respectively. Notably, immune manipu- Complicating this decision is the lack o high-quality
lation by withdrawal o immunosuppression or donor prospective data to guide the decision.
lymphocyte inusions enhanced clinical responses,
indicating that CLL is a disease sensitive to immune
Patient Stratifcation or First-Line
manipulation. With the introduction o novel targeted
therapies, such as BTK inhibitors and venetoclax, the
Treatment
numbers o allo-SCT procedures being perormed or Based on age, comorbidities, and CLL FISH, TP53
CLL are alling dramatically.71 Nevertheless, allo-SCT mutation status, and IGHV mutation status, patients
will likely continue to remain an important strat- can be categorized into several groups:
egy or selected group o patients such as those with • Young patients (typically 65 years or younger)
high-risk CLL (del(17p) or TP53 mutation) who are without major comorbidities and IGHV-mutated,
relapsed or reractory to novel agents. The European no del(17p), and no TP53 mutation: For these
TABLE 36 Factors in Consideration for Cellular Terapy versus Targeted Terapy
Factors in Favor o Cellular Immunotherapy Factors in Favor o Continuing the Targeted Agent
Disease Features (Predictive Disease Features (Predictive
o Higher Likelihood o o Lower Likelihood o
Clinical Features (Predictive Relapse in the Absence o Clinical Features Relapse in the Absence o
o Lower TRM) Cellular Immunotherapy) (Predictive o Higher TRM) Cellular Immunotherapy)
Younger age Reractory to multiple prior Older age Received ewer lines o prior
therapies therapy
Few comorbid medical Complex karyotype Frail, many comorbid Lack o complex karyotype
conditions medical conditions
Well-matched donor (or Deep remission (eg, CR Deep remission (eg, CR with
allo-SCT) with U-MRD) U-MRD)a
Access to CAR T-cell study No well-matched donor
or access to CAR T-cell
study
Although patients who achieve deep remission with targeted therapy (eg, venetoclax + rituximab) are at lower risk o disease progression, these patients may also
a
have better post-transplant outcomes than patients with signifcant disease burden.
Allo-SCT, allogenic stem cell transplant; CAR T, chimeric antigen receptor T-cell; CR, complete remission; TRM, Transplant-related mortality; U-MRD, undetectable
measurable residual disease.
patients, treatment with FCR is appropriate given particularly rituximab, have also been used to treat
the very long-term benet seen in about hal o these patients with autoimmune complications o CLL
patients ater rst-line FCR. Additionally, in the E1912 either as monotherapy or in combination with cyclo-
trial, there was no dierence in PFS or FCR versus ibru- phosphamide and dexamethasone (RCD regimen).78
ChAPTER 3
tinib + rituximab or the IGHV-mutated group, at least Cyclosporine is another option or treatment o AIC
with the median 4 years o ollow-up. I a nonchemo- and can produce responses even in patients with ste-
therapy approach is desired, treatment with ibrutinib, roid-reractory immune cytopenias.79 The thrombo-
acalabrutinib (+/- obinutuzumab) or the combination poietin mimetic eltrombopag showed high response
o venetoclax + obinutuzumab could be considered. rates with good response durability.80,81 Splenectomy
Ibrutinib and acalabrutinib are given indenitely. Vene- is reserved or reractory cases.
toclax + obinutuzumab is a lime-limited therapy o 1 The role o novel, targeted agents in the treatment
year. o CLL-associated AIC is ill-dened, given patients
• Older adults or young patients with comorbid- with steroid-dependent or -reractory AIC were sys-
ities or young patients with IGHV-unmutated tematically excluded rom clinical trials o these
(no del(17p), no TP53-mutation): For these agents. However, a recent case series rom the Mayo
patients, a nonchemotherapy approach is preerred. Clinic demonstrated improvement in cytopenias and
Treatment with ibrutinib, acalabrutinib (+/-obinu- ability to wean or discontinue immunosuppression
tuzumab), or the combination o venetoclax + in the majority o patients with CLL who had AIC at
obinutuzumab is appropriate. the time o initiation o ibrutinib.82 An ongoing clinical
• Patients with del(17p) or TP53-mutation: trial (NCT03827603) is assessing ibrutinib plus ritux-
Treatment with a BTK inhibitor such as ibrutinib or imab treatment in the management o patients with
acalabrutinib (+/- obinutuzumab) is preerred. Che- steroid-reractory AIHA.
motherapy should not be used or these patients.
Hypogammaglobulinemia
Supportive Care Hypogammaglobulinemia is a requent complication o
Patients with CLL can have a host o complications CLL. The most common cause o morbidity in patients
ranging rom immune cytopenias to inectious issues. with CLL is inection, in part caused by hypogamma-
globulinemia. A randomized study evaluated the use
Autoimmune Complications o Chronic o IVIG versus placebo in patients with CLL showed
signicant reduction in bacterial inections but no di-
Lymphocytic Leukemia
erence in the number o lie-threatening inections or
Autoimmune hemolytic anemia (AIHA), autoim- nonbacterial inections.83 Replacement therapy with
mune thrombocytopenia (ITP), and pure red cell IVIG is indicated or patients with hypogammaglobu-
aplasia (PRCA) develop in some patients with CLL. linemia and repeated sinobronchial inections.
The incidence o AIHA is 4% to 11% and is 2% to
3% or ITP.73 PRCA and autoimmune neutropenia
(AIN) are both rare (<1%). 74 The pathogenesis is
complex. The autoantibodies in autoimmune cyto-
TRANSFORMATION
penia (AIC) associated with CLL are typically poly-
clonal and usually IgG, indicating that they are
Richter Syndrome
not produced by the leukemic clone. Patients with The term Richter syndrome (RS) reers to the devel-
unmutated IGHV and high-risk cytogenetics, as well opment o aggressive large-cell lymphoma during
as stereotyped B-cell receptor subsets 3 and 7, are the course o CLL. Rarely, disease transormation to
more likely to develop AIHA or ITP. 75,76 Therapeu- Hodgkin lymphoma is seen. RS is noted in approxi-
tic agents, particularly purine analog monotherapy, mately 5% o patients with CLL. RS is usually associ-
may trigger AIC, possibly because o an imbalance ated with worsening systemic symptoms, including
in the ratio o T-regulatory cells to T helper type B symptoms, elevated LDH, rapid tumor growth,
17 cells. 77 The risk o treatment-emergent AIC dur- or extranodal involvement. Diagnosis requires tis-
ing treatment with targeted agents appears lower. sue biopsy. Positron emission tomography scans
Prednisone is the usual treatment or patients with help identiy sites to direct tissue biopsy, and every
AIHA and ITP, with a high likelihood o response. attempt should be made to biopsy the site with the
However, the majority o patients relapse when maximum SUV. 84 In 80% o patients, the DLBCL is
treatment is stopped. Intravenous immunoglobulin clonally related to the original CLL, which is a marker
(IVIG) produces response in 40% o patients, but o poor prognosis (median survival time, ~1 year).
these responses tend to be transient. CD20 mAbs, In the other 20% o patients, the DLBCL is clonally
unrelated to the original CLL, possibly representing can be seen in the peripheral blood, but their numbers
a new neoplasm and the prognosis is similar to that vary. Most typically, cHCL presents with pancytopenia,
o de novo DLBCL (median survival time, ~5 years). monocytopenia and a paucity o circulating malignant
Risk actors associated with development o RS in cells. Patients with large numbers o circulating cells
a patient with CLL include lymph node size greater may have hairy cell leukemia variant (HCL-v) or VH4-
ChAPTER 3
than 3 cm, number o prior therapies, advanced Rai 34 molecular variant (see later). Hairy cells are twice as
stage (III or IV), del(17p), del(11q), unmutated IGHV large as normal lymphocytes, with the nuclei showing
gene, short telomere length (<5000 bp), stereotyped a loose chromatin pattern and villus-like cytoplasmic
B-cell receptors, and expression o CD38, CD49d, projections (Fig. 3–8) (best viewed under phase-contrast
or ZAP-70.85 The presence o a NOTCH1 mutation microscopy). Hairy cells typically show positive staining
is also associated with an increased risk o RS. TP53 or tartrate-resistant acid phosphatase (TRAP) (Fig. 3–9).
mutation is commonly acquired at the time o CLL Hairy cells inltrate the bone marrow in an interstitial or
transormation and is the most important negative ocal pattern, with clear zones between cells (“ried-egg”
prognostic eature, other than the clonal relation-
ship to the underlying CLL.85 Other common genetic
abnormalities seen in patients with RS include acti-
vation o C-MYC and inactivation o CDKN2A, indi-
cating possible cell cycle deregulation, and NOTCH1
mutations (commonly in conjunction with trisomy
12).86,87 The traditional treatment strategy has been
intensive CIT such as OFAR (oxaliplatin, fudarabine,
cytarabine, and rituximab), hyper-CVAD (hyperrac-
tionated cyclophosphamide, vincristine, doxorubicin,
and dexamethasone), and R-CHOP (rituximab, cyclo-
phosphamide, doxorubicin hydrochloride, = Oncovin,
and prednisone). 88 No direct comparative data exist
to guide treatment choice, and this should be indi-
vidualized according to institutional experience and
patient tness. Allo-SCT remains the only potentially
curative option or patients with RS. Two promising
approaches to improve outcomes or this group o
patients have recently been developed: the rst is the
use o programmed death 1 inhibitors, with or with-
out ibrutinib. Pembrolizumab monotherapy achieved
a 44% ORR (11% CR) among 9 patients with RS,89
and ibrutinib + nivolumab achieved an ORR o 42% FIGURE 3–8 Hairy cell in peripheral blood with cytoplasmic
(33% CR) in 24 patients.90 projections.
Prolymphocytic Transormation
The NCI-IWCLL criteria allow a diagnosis o CLL to
be made in the presence o 55% or less prolympho-
cytes. The presence o greater than 55% prolympho-
cytes indicates prolymphocytic transormation. PLL is
characterized by a high number o circulating prolym-
phocytes, splenomegaly, minimal lymphadenopathy,
and a median survival time o less than 3 years.
hAIRY CELL LEUKEMIA

Classical hairy cell leukemia (cHCL) is an uncommon
B-cell lymphoprolierative disorder aecting adults and
represents 2% o all leukemia. There is a marked male FIGURE 3–9 Hairy cell staining or tartrateresistant acid
preponderance. Most patients have cytopenias; sple- phosphatase (left). Note the absence o orangebrown stain
nomegaly is also requent at presentation. Hairy cells ing in a neutrophil.
o rituximab. Sequential therapy with 8 doses o ritux-

imab 375 mg/m2 weekly ater completion o cladribine
achieved a CR rate o 100% and increased MRD nega-
tivity rom 14% to 74% (including 76% o untreated
ChAPTER 3
patients and 64% o patients in rst relapse). Five-year

ailure-ree survival (FFS) was 95%. Longer-term ollow-
up will be required to determine whether this translates
into improved FFS or the rst-line patients.95,96 A CR
rate o 100% was reported, and ater a median ollow-
up period o 25 months, the median CR duration, PFS,
and OS had not been reached. The majority o relapsed
patients achieve second remission when retreated with
pentostatin or cladribine. The choice o agent may
FIGURE 3–10 Bone marrow involvement by hairy cell leu depend on the duration o the rst remission: i less than
kemia showing a “riedegg” appearance (hematoxylin and 3 years, use an alternate agent; i more than 5 years,
eosin stain). use the same agent. Rituximab may improve results
in relapsed cHCL and HCL-v. O note, ater a median
appearance) (Fig. 3–10). Marrow reticulin is increased, ollow-up period o 5 years, no patient has relapsed
and aspirates may result in a “dry tap.” and FFS ater second-line cladribine + rituximab was
Immunophenotypic analysis o hairy cells shows signicantly longer (P = .004) than ater initial mono-
the presence o CD19, CD20, CD22, CD25, and therapy (in which median FFS was 6 years).96 A more
CD103; in contrast to CLL, hairy cells are negative recent phase 2 randomized study has demonstrated that
or CD5 and CD23. Hairy cells also stain strongly or concurrent rather than delayed rituximab administra-
surace Ig and FMC-7. HCL-v usually lacks CD25 and tion with cladribine is associated with a higher rate o
CD123 expression. CD200 is a specic marker, being CR. Splenectomy, although perormed inrequently, can
highly expressed in cHCL but not in HCL-v or other induce hematologic remission. The use o intereron-α
morphologically similar lymphoprolierative disorders is currently limited to patients unresponsive to nucleo-
such as marginal zone lymphoma. Although CD200 side analogs. These latter two treatments are mainly
is also expressed in CLL, the immunophenotype and conned to historical interest. A percentage o patients
morphology in CLL are suciently dierent rom may relapse with cladribine-resistant disease. In addi-
cHCL that diagnostic conusion is unlikely to arise.91 tion, 10% to 20% o patients with the variant orm o
The BRAF V600E mutation is present in most patients HCL have a poor response to nucleoside analogs.
with cHCL.92 Notably, patients with HCL-v and the Classic and variant hairy cells strongly express CD22.
VH4-34 molecular variant o cHCL lack BRAF muta- Recombinant immunotoxin, BL22, has been used in the
tions, instead oten carrying MAP2K1 mutations, treatment o chemotherapy-resistant HCL. Moxetu-
which result in constitutive MEK1 phosphorylation momab pasudotox (HA22 or CAT-8015) is derived rom
and downstream ERK activation.93 This may have BL22, selected or high-anity or CD22. A second-gen-
implications or both diagnosis and treatment o HCL, eration immunotoxin was developed, known as HA22/
and vemuraenib, a BRAF inhibitor, is currently in clin- CAT-8015/moxetumomab pasudotox; this has greater
ical trials as therapy or relapsed or reractory HCL. binding anity or CD22 and was demonstrated to
Treatment decisions are usually based on the degree have greater in vitro and in vivo toxicity against lym-
o cytopenia and accompanying complications (eg, phoma cell lines and CLL/HCL cells.97 A pivotal, open-
bleeding, inections, anemia). Pentostatin and cladribine label study demonstrated impressive activity in patients
(2-CDA) are the nucleoside analogs that are the main- relapsing ater at least two lines o prior therapy.98
stay o treatment o HCL. Pentostatin is administered Among 80 patients treated, ORR was 75% and CR rate
at 4 mg/m2 every 2 weeks until maximum response and 41%; 85% o the patients in CR were MRD negative by
cladribine is given at 0.1 mg/kg/day as a continuous multiparameter fow cytometry in bone marrow. Rapid
intravenous (IV) inusion or 7 days, or the same total improvement in hematologic parameters was noted.
dose can be administered as a 2-hour inusion over 5 Median duration o CR and PFS have not been reached.
days. Because cladribine oers a more convenient sched- Treatment was generally well-tolerated, with revers-
ule (single course o therapy) and produces remission ible hemolytic uremic syndrome occurring in 7.5% o
rates comparable to those achieved with pentostatin, patients and capillary leak syndrome in 5%.
cladribine is more requently used. Estey et al94 reported The importance o constitutive BRAF-MEK-ERK
a CR rate o 78% with cladribine in patients who had signaling, induced by the BRAF V600E mutation in
newly diagnosed or previously treated HCL. One trial cHCL92 led to two separate phase II studies being con-
evaluated a strategy to improve the initial response to ducted with the BRAF inhibitor vemuraenib. This drug
nucleoside analog therapy by adding additional doses is approved or the treatment o metastatic melanoma,
which also carries the canonical BRAF V600E mutation, than 75% o patients. TCL-1 is commonly overex-
but is not currently approved or the treatment o HCL. pressed and detectable by immunohistochemistry.
The patient populations were either heavily pretreated For T-PLL, IV alemtuzumab is the treatment o choice.
or had early relapse ater pentostatin therapy. In the Ital- Dearden et al101 reported superior results in the rst-line
ian study, 6 patients had not responded to or relapsed setting with IV alemtuzumab compared with results with
ChAPTER 3
within 1 year o purine analogue (PA) therapy, and 20 subcutaneous alemtuzumab. With IV alemtuzumab, an
had either relapsed within 1 to 2 years o the rst course ORR o 91% and CR rate o 81% were reported. Allo-
or within 4 years o the second course o PA therapy. In SCT is the preerred consolidation regimen. Pentostatin
the US trial, most patients were enrolled based on hav- should be considered or patients with poor response
ing received three or more prior courses o PA therapy. to alemtuzumab or relapsed disease. Retreatment with
Patients received vemuraenib or 12 to 20 weeks in alemtuzumab is a reasonable option i the duration o
total and could be retreated at progression. ORR and the rst remission was longer than 12 months.
CRR were 96% to 100% and 35% to 42%, respectively.
In the Italian study, which had a longer ollow-up,
median relapse-ree survival was 9 months; in the US LARGE GRANULAR LYMPhOCYTIC
study, 1-year PFS was 73%. Some patients responded to LEUKEMIA
retreatment at relapse. Toxicity was generally manage-
able and was similar to that seen in studies o patients Large granular lymphocytes (LGLs) are larger than nor-
with melanoma; it included rash, photosensitivity, pal- mal lymphocytes and contain azurophilic granules in
mar or plantar brosis, warts, and arthralgias. Dose their cytoplasms (see Fig. 3–6). They normally comprise
reduction was required in 50% to 58% o patients. 10% to 15% o peripheral blood mononuclear cells.
Seven patients developed skin cancer (six nonmela- Clonal expansion o LGLs can arise rom either o the
noma, one supercial spreading melanoma).99,100 normal cellular counterparts and so may have a natural
killer (NK)- or T-cell phenotype; the T-cell phenotype
composes 80% o LGL leukemias. T-cell LGL cells have
PROLYMPhOCYTIC LEUKEMIA a CD3+/CD57+/CD56– immunophenotype, and NK-
cell LGL cells are CD3–/CD56+/CD57–.102 T-cell receptor
PLL is characterized by splenomegaly, a high number gene rearrangement studies can help establish the clon-
o circulating prolymphocytes, minimal lymphade- ality. About 40% o patients with NK- and T-cell LGL
nopathy, and a median survival o less than 3 years. leukemia were noted to have mutations in the STAT3
Prolymphocytes are larger and less homogenous gene.103 Mutations in STAT5b were noted in a smaller
than CLL cells; they have abundant clear cytoplasm, subset (2%) o patients.104 The clinical presentation o
clumped chromatin, and a prominent nucleolus (see LGL leukemia is usually indolent. Cytopenias, including
Figs. 3–7). Prolymphocytes can be o either B- or T-cell neutropenia with accompanying inections, thrombocy-
type. B-cell PLL cells usually do not express CD5 but topenia, and anemia, are common. A small percentage
stain strongly or surace Ig and FMC-7 (see Table 3–2). o patients with LGL leukemia develop a more aggres-
T-cell PLL demonstrates postthymic T-cell nature sive course; these patients tend to have an NK-cell
(TdT,– CD1a,– CD5+, CD2+, CD7+). A majority o phenotype. Several therapies, including low-dose meth-
the cases express CD4+ and are CD8.– Chromosomal otrexate, oral cyclosporine, and oral cyclophosphamide
abnormalities o chromosome 14 are present in more with or without oral prednisone, have all been eective.

J It is important to assess or TP53 aberration by per- J Approved targeted therapies in frst-line CLL
orming both FISH or del(17p) and sequencing or include ibrutinib, acalabrutinib, and the combina-
TP53 mutation. tion o venetoclax and obinutuzumab. We generally
J Repeat prognostic marker testing (CLL FISH panel, do not combine BTK inhibitors with CD20 mAB in
TP53 sequencing) at the time o disease relapse patients with CLL.
because patients may have acquired additional J Patients who have ailed targeted therapies, espe-
clonal abnormalities (clonal evolution). IGHV muta- cially those with TP53 aberrant disease, should be
tion status or an individual patient does not change reerred or cellular therapies (allo-SCT, CAR T-cell
over time, and thereore, there is no need to repeat, therapies).
i already known. J Outcomes o CIT or Richter transormation remain
J CIT is currently reserved or only young patients dismal. These patients should be reerred or clinical
with no major comorbidities with mutated IGHV trials.
and no TP53 aberration.
19. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging o

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Blood. 2017;129(26):3419-3427.
4 Chronic Myeloid Leukemia
Koji Sasaki
Elias Jabbour
Jorge Cortes
Hagop Kantarjian
KEY CONCEPTS
 The survival o patients with chronic myeloid leukemia mutation prole plays no role in selecting an initial TKI but
(CML) has improved signicantly since the advent o tyro- becomes relevant in relapse.
sine kinase inhibitor (TKI) therapy. With the availability  Most TKIs are reasonably well tolerated with close obser-
o TKI and proper management, the expected survival o vation and supportive care. However, each TKI therapy has
patients with chronic phase CML (CML-CP) is approaching a distinct toxicity prole that should be considered when
that o the general population. deciding on therapy.
 Any o the our TKIs approved or rontline therapy o  Second- and third-generation TKIs have not been compared
CML-CP may be selected. These include imatinib, dasat- head to head. Mutational analysis is required ater ailure
inib, nilotinib, and bosutinib. Second-generation TKIs o imatinib or second-generation TKIs, or ater progression
are superior to imatinib in achieving aster and deeper to accelerated phase CML (CML-AP) or blastic phase (CML-
responses compared with imatinib, but survival is simi- BP). Baseline mutational analysis are not recommended in
lar because o the availability o eective TKI salvage newly diagnosed CML-CP because it does not help predict
therapies. treatment outcome.
 Factors considered in choosing TKI therapy in the rontline  Allogeneic stem cell transplant should be considered in
setting include patient age, comorbidities, adverse events patients who progress rom CML-CP to CML-AP/CML-BP
prole, and disease risk score, as well as the TKI-associ- ater TKI therapy ailure and who ail second- or third-gen-
ated schedule o administration and cost. Kinase domain eration TKI while still in CML-CP.
Chronic myeloid leukemia (CML) is a myeloproliera- specically at inhibiting this kinase and its downstream
tive disorder o pluripotent hematopoietic stem cells. signals. Herein, we summarize the current knowledge
The Philadelphia (Ph) chromosome results rom a regarding the molecular biology o CML and the treat-
reciprocal translocation between chromosomes 9 and ment modalities, including novel BCR-ABL1 tyrosine
22 and constitutes the cytogenetic hallmark o CML. A kinase inhibitors (TKIs).
critical milestone in CML research was the demonstra-
tion that this translocation involved the ABL1 (v-abl
Abelson murine leukemia viral oncogene homolog 1) EPIDEMIOLOGY
gene on chromosome 9 and the BCR (breakpoint clus-
ter region) gene on chromosome 22 and resulted in CML has an incidence o 1 to 2 cases per 100,000 adults.
the ormation o the chimeric BCR-ABL1 usion tran- It accounts or approximately 15% o newly diagnosed
script that encodes the constitutively active BCR-ABL1 cases o leukemia in adults.9 The median age o onset
tyrosine kinase.1 This in turn is responsible or cell o CML is 60 to 65 years, and the incidence increases
growth and replication through downstream signal- with age. There are no known hereditary, geographic,
ing pathways.2–8 The discovery that BCR-ABL1 plays amilial, or ethnic associations. There are no known
a pivotal role in the pathogenesis o CML set the stage causal etiologies, although an increased risk has been
or the development o therapeutic strategies aimed noted with exposure to ionizing radiation.10
67
In 2020, it was estimated that there would be 8450 and high-sensitivity reverse transcriptase polymerase
new cases o CML in the United States, and about chain reaction (RT-PCR). Additionally, when detected
1130 people would die o this disease.11 In the TKI by conventional cytogenetics, 90% o patients have
era, the expected 5-year survival time o patients with the typical t(9;22), and 5% to 10% o the patients have
CHAPTER 4
CML chronic phase is comparable to that o the gen- variant translocations, which can be simple (involving
eral population.12 Since the introduction o imatinib in chromosome 9 and a chromosome other than chromo-
2000, the annual mortality rate in patients with CML some 22) or complex (involving one or more chromo-
has decreased rom 10% to 20% to 1% to 2%.11 Con- somes in addition to chromosomes 9 and 22). Patients
sequently, the prevalence o CML in the United States, with Ph-negative BCR-ABL1 rearranged CML, as well
estimated at about 30,000 cases in 2000, has increased as those with Ph variants have similar response rates
by approximately 7000 to 8800/year. It was previously to therapy and prognosis compared to patients with
estimated that the prevalence o CML cases would Ph-positive CML.
reach a plateau o 150,000 to 180,000 or more by the
year 2030.13 However, given the current number o
new cases o CML in the United States, the prevalence CLINICAL PRESENTATION AND
plateau is now estimated to be 400,000 to 450,000 NATURAL HISTORY
cases in the United States, which may not be reached
until 2040 to 2050. There are three separate phases o CML: chronic
phase (CP), intermediate or accelerated phase (AP),
and terminal or blastic phase (BP). Even though all
MOLECULAR BIOLOGY three represent a stepwise progression o disease
rom the typically indolent CP to the most aggres-
CML is a clonal myeloprolierative neoplasm derived sive and requently terminal BP, the natural course o
rom an abnormal pluripotent hematopoietic stem cell the disease, particularly on adequate treatment with
that has acquired the BCR-ABL1 usion gene, usually TKIs, may not include progression out o CP, nor will
through t(9;22)(q34;q11.2), also known as Ph, involv- the disease always include all three phases when
ing the long arms o chromosome 9 and 22. This is progressing. Approximately 85% to 90% o patients
translated into a constitutively active oncoprotein, present in CP. About 50% o patients diagnosed with
the BCR-ABL1 tyrosine kinase. This oncoprotein CML are asymptomatic. The diagnosis oten occurs
activates multiple downstream pathways, including during routine physical examination or blood tests.
PI3 kinase, nuclear actor-κB, JAK/STAT, RAS, RAF, When present, the symptoms mostly arise rom low
ERK, MYC, and JNK. Depending on the breakpoint counts such as anemia and thrombocytopenia caus-
on the BCR gene, three main Ph variants can occur. ing atigue and bleeding. Splenomegaly is the most
In most patients with CML and in one third o those consistent physical nding, detected in 20% to 40%
with Ph-positive acute lymphoblastic leukemia (ALL), o cases, resulting in early satiety, weight loss, and
the breakpoint maps to the major breakpoint cluster let upper quadrant pain and ullness. In rare cases,
region (M-bcr), which spans BCR exons 12 to 16 (or- patients may present with eatures o hyperviscos-
merly called b1–b5), giving rise to a usion transcript ity rom marked leukocytosis, including priapism,
with either e13a2 (b2a2) or e14a2 (b3a2) junctions that stroke, and retinal hemorrhages. Headaches, bone
translates into a 210-kDa protein (p210BCR-ABL1). In two pain, arthralgias, pain rom splenic inarction, and
thirds o patients with Ph-positive ALL and rarely in ever are more requent with CML transormation.
CML, the breakpoints within BCR localize to an area Most patients who transorm to advanced phases
o 54.4 kb between exons e2′ and e2, termed the minor evolve into AP beore BP, but 20% transition into
breakpoint cluster region (m-bcr), giving rise to a usion BP without AP warning signals. CML-AP might be
transcript e1a2, which translates to a 190-kDa protein insidious or present with worsening anemia, spleno-
(p190BCR-ABL1). A third breakpoint cluster region (μ-bcr) megaly, and organ inltration. CML-BP presents as an
has been identied giving rise to a usion transcript acute leukemia (myeloid in 60%, lymphoid in 30%,
e19a2, which translates to a 230-kDa usion protein megakaryocytic or undierentiated in 10%) with
(p230BCR-ABL1) associated with a more indolent CML worsening constitutional symptoms, bleeding, ever,
course and with a phenotype more similar to chronic and inections. Involvement o extramedullary tissues
neutrophilic leukemia. such as the lymph nodes, skin, and sot tissues is gen-
The Ph chromosome can be detected by conven- erally limited to patients with CML-BP.
tional cytogenetics in 90% to 95% o the cases. In the Various classications were used to dene the
remaining 5% to 10% o the Ph-negative cases by cyto- dierent CML phases. The European LeukemiaNet
genetics, BCR–ABL1 rearrangement can be recognized (ELN) classication denes CML-AP as the presence
with fuorescent in situ hybridization (FISH) technique o any o the ollowing eatures: 15% or more blasts
Chapter 4 Chronic Myeloid Leukemia 69
TABLE 4–1 Diagnostic Criteria of Accelerated Phase According to MD Anderson Cancer Center
MDACC, International Bone Marrow Transplant Registry IBMTR, and World Health Organization
WHO
MDACC IBMTR WHO
CHAPTER 4
Blasts (%) 15–29 10–29 10–19a
Blasts + promyelocytes (%) ≥30 ≥20 NA
b
Basophils (%) ≥20 ≥20 ≥20
9
Platelets (×10 /L) <100 Unresponsively high or persistently low <100 or >1000 unresponsive
Cytogenetics CE CE CE not at diagnosis
WBC count NA Dicult to control or doubling <5 days NA
Anemia NA Unresponsive NA
Splenomegaly NA Increasing NA
Other NA Chloromas, myelobrosis Megakaryocyte prolieration, brosis
a
In the WHO criteria, blastic phase is dened as a blast percentage o 20% or higher. In the MDACC and IBMTR, a denition o blastic phase requires the presence o at
least 30% blasts.
b
Basophils plus eosinophils.
CE, clonal evolution; NA, not applicable; WBC, white blood cell.
in the peripheral blood and/or the bone marrow, 30% rearrangement noted by FISH or by RT-PCR.16–18 A
or more blasts plus promyelocytes in the peripheral FISH analysis relies on the co-localization o large
blood and/or the bone marrow, 20% or more baso- genomic probes specic to the BCR and ABL1 genes.
phils in the peripheral blood and/or the bone marrow, Comparison o simultaneous marrow and blood sam-
platelets 100 × 109/L or less unrelated to therapy, and ples by FISH analysis shows high concordance. FISH
cytogenetic clonal evolution (Table 4–1). The average studies may have a alse-positive range o 1% to 5%
survival period o patients in CML-AP was 1 to 2 years depending on the probes used.
beore the TKI era. With TKI therapy, the estimated RT-PCR amplies the region around the splice junc-
4-year survival has increased to 60% to 70%. In con- tion between BCR and ABL1. It is highly sensitive in
trast to CML-AP ater CML-CP, de novo CML-AP has detecting and monitoring minimal residual disease.
a better prognosis with rontline TKI therapy, with an Simultaneous peripheral blood and marrow RT-PCR
estimated 8-year survival rate o more than 80%, par- studies show a high level o concordance. False-posi-
ticularly when treated with second-generation TKIs.14 tive and alse-negative results can happen with PCR.
A diagnosis o CML-BP requires the demonstration A 0.5- to 1-log dierence in some samples can occur
o at least 30% blasts (20% in the World Health Orga- depending on testing procedures, sample handling,
nization classication) in the peripheral blood and/or and laboratory experience.16–18
the bone marrow or the presence o extramedullary Although both FISH and RT-PCR can conrm the
blastic oci. The median survival o patients in CML- presence o the Ph chromosome, a bone marrow aspi-
BP beore the introduction o TKI therapy was 2 to ration should be perormed in all suspected cases o
6 months; with TKI- based therapy, it improved to a CML at diagnosis. This not only conrms the diagno-
median o 1 to 3 years, particularly when TKI is com- sis (by cytogenetics) but also helps stage the disease
bined with chemotherapy.15 (ie, percentage o blasts and o, basophils; and pres-
ence o additional chromosomal abnormalities [clonal
evolution]). The Ph chromosome is usually present in
DIAGNOSIS AND CLINICAL 100% o metaphases, oten as the sole abnormality.
WORK-UP About 10% to 15% o patients have additional chro-
mosomal changes, most requently involving trisomy
The typical presentation o CML involves leukocytosis 8, isochromosome 17, additional loss o material
with a let shit including myelocytes and metamy- rom 22q or double Ph, or abnormalities involved o
elocytes seen in the peripheral blood. Additionally, chromosome 3. Among these cytogenetic abnormali-
basophilia and in some cases eosinophilia can be ties, i(17)(q10), -7/del7q, and 3q26.2 translocations,
predominant. The diagnosis o typical CML requires are associated with a particularly poor prognosis.19
the presence o Ph abnormality, the t(9,22)(q34;q11) Clonal evolution is considered a criterion o AP,
by routine karyotype, or the presence o BCR-ABL1 particularly when it occurs during the course o the
disease. Corresponding molecular alterations that olin low-, intermediate-, and high-risk groups with
low these changes include deregulation o p53, RB1, median survival times o 105, 65, and 45 months,
C-MYC, and AML-EVI1. respectively. The EUTOS score was developed in
For correlative purpose and monitoring without the imatinib era and included spleen size and baso-
CHAPTER 4
necessarily perorming marrow evaluation studies, a phils.22 This score predicts likelihood o 18-month
complete cytogenetic response (CCyR; 0% Ph-posi- CCyR rate on imatinib therapy. Last, the ELTS was
tive metaphases by cytogenetic) is grossly equivalent developed to assess the risk o CML-related death.23
to a negative FISH test result (±2%) and BCR-ABL1 It includes the same prognostic variables as the Sokal
transcripts by International Scale (IS) less than 1%. A score. Patients are separated into three risk groups
partial cytogenetic response (Ph-positive metaphases with 8-year probabilities o dying rom CML o 2%,
1%–35%) is approximately equivalent to BCR-ABL1 6%, and 11%, respectively.
transcripts 10% or less (IS).
The RT-PCR is an important diagnostic tool in CML
and should be perormed in all suspected CML cases.
In patients with Ph-negative CML, which comprises
RESPONSE DEFINITION
5% to 10% o the cases o CML, detection o BCR-
Response to therapy is initially assessed by measure-
ABL1 rearrangement helps establish the diagnosis.
ment o hematologic response criteria. A complete
RT-PCR also helps determine the type o transcript
hematologic response (CHR) is dened as normaliza-
involved. This is helpul in monitoring disease status
tion o white blood cell (WBC) count to less than 10
and response to therapy. Ninety percent o the cases
× 109/L with a normal dierential, platelet count less
have o the classical p210 transcripts, e13a2 (b2a2),
than 450 × 109/L, and disappearance o splenomegaly
and e14a2 (b3a2). Less common types include the
and other symptoms o CML. Patients who achieve
p190 transcript, (e1a2) and the p230 transcript (e19a2).
a CHR are urther classied according to the type o
In 2% o the cases, patients may harbor other variant
cytogenetic response achieved (Table 4–2).
transcripts, such as e13a3 and e14a3. These variant
Cytogenetic responses are divided into complete,
transcripts along with the p230 transcript e19a2 are not
partial, and minor and are based on a banding karyo-
detected by the routine RT-PCR probe. Hence, i RT-
type with at least 20 metaphases counted. CCyR
PCR is not perormed at baseline, patients with these
corresponds to 0% o all metaphases remaining Ph
transcripts can be alsely considered to have undetect-
positive, partial cytogenetic response as 1% to 35% o
able transcripts because o treatment.
metaphases being Ph positive, and minor as >35% to
95% Ph-positive metaphases. Although FISH results
correlate well with the karyotypic evaluation, cyto-
PROGNOSTIC TOOLS IN CHRONIC genetic response criteria needs urther validation with
MYELOID LEUKEMIA FISH.
Molecular response is assessed by RT-PCR in the
The dierent CML phases predict or very dierent peripheral blood or bone marrow.24 A major molecu-
survival probabilities. However, the prognosis is also lar response (MMR) is considered when the BCR–
variable among patients in the same phase o the ABL1 transcript is 0.1% or less on the (IS). MR4.0
disease. Several patient and disease characteristics and MR4.5 are considered when the BCR-ABL1 tran-
have prognostic impact and were used to generate scripts are 0.01% or less and 0.0032% or less on the IS,
prognostic models. There are our dierent scoring respectively. A molecular response 5 (MR5) represents
systems: Sokal, Euro (Hasord), EUTOS (European achievement o undetectable transcripts o BCR–ABL1
Treatment and Outcome Study), and ELTS (EUTOS with at least 100,000 copies o ABL (or equivalent con-
long-term survival score). Sokal was the rst scor- trol gene).
ing system developed beore the intereron (IFN)
era. It included age, spleen size, platelet count,
and peripheral blast count. 20 It segregated patients FRONTLINE TREATMENT OPTIONS
into three risk groups with hazard ratios (HRs) o
less than 0.8, 0.8 to 1.2, and greater than 1.2, with Since 2000, the treatment o CML has changed dramati-
respective median survival times o 105, 76, and 45 cally. Conventional chemotherapeutic agents such as
months, respectively. In 1998, the EURO or Hasord hydroxycarbamide (hydroxyurea) are no longer used,
score was developed to identiy risk groups in CML except to achieve transient cytoreduction. There are cur-
patients treated with IFN.21 It included age, spleen rently our commercially available TKIs or the rontline
size, platelet count, peripheral blood blast count, treatment o CML: imatinib, dasatinib, nilotinib, and
eosinophils, and basophils. It also stratied patients bosutinib. Available guidelines support all our as viable
TABLE 4–2 Criteria for Hematologic, Cytogenetic, and Molecular Response and Relapse
Hematologic Response
Complete Normalization o peripheral blood counts; WBC count <10 × 109/L; platelets <450 × 109/L
CHAPTER 4
Absence o immature cells such as myelocytes, promyelocytes, or blasts in peripheral blood
No signs and symptoms o disease with disappearance o palpable splenomegaly
Cytogenetic Remissiona
Complete No Ph-positive metaphases
Partial 1%–35% Ph-positive metaphases
Minor >35%–95% Ph-positive metaphases
None >95% Ph-positive metaphases
Complete and partial cytogenetic responses together constitute major cytogenetic responses, ie, 0%–35% Ph-positive
metaphases
Molecular Remission (MR)b
Early MR BCR-ABL1 (IS) ≤10% at 3 and 6 months
Major BCR-ABL1 (IS) ≤0.1% or ≥3-log reduction in BCR-ABL1 mRNA rom the standardized baseline
MR4.0 BCR-ABL1 (IS) ≤0.01% or ≥ 4-log reduction in BCR-ABL1 mRNA rom the standardized baseline
MR4.5 BCR-ABL1 (IS) ≤0.0032% or ≥ 4.5-log reduction in BCR-ABL1 mRNA rom the standardized baseline
MR5 BCR-ABL1 (IS) ≤0.001% or undetectable BCR-ABL1 transcripts with ≥100,000 copies o ABL (or
equivalent control gene)
Relapse
Any sign o loss o hematologic response or cytogenetic relapse
a
Cytogenetic response is based on routine karyotype analyzing at least 20 metaphases.
b
Molecular responses is based on quantitative polymerase chain reaction (real-time polymerase chain reaction).
IS, international score; Ph, Philadelphia chromosome; WBC, white blood cell.
rontline options or the initial management o patients better than in those treated with INF-α plus cytarabine.
with CML-CP. These included the rates o CCyR rate (74% vs 9%; P
<.001) and reedom rom progression to AP or BP at 12
Imatinib Mesylate months (99% vs 93%; P <.001). With a median ollow-
up period now o 10+ years, the estimated OS rate or
Imatinib mesylate (STI-571, Gleevec) was the rst TKI patients assigned to imatinib was 83.3% with a cumu-
approved by the Food and Drug Administration (FDA) lative CCyR rate o 83% and a 10-year MMR rate o
or the treatment o patients with CML-CP. It is a 93%.28 Despite the high rate o crossover among patients
selective and potent competitive inhibitor o the ATP- assigned to receive INF-α plus cytarabine (66%) and the
binding site o the BCR-ABL1 oncoprotein, as well as short duration o therapy beore crossover (median, 0.8
c-kit, platelet-derived growth actor receptor α and β, years), the 10-year survival rates avored the imatinib
and abl-related gene (ARG).25 It is given orally with arm (83.3% vs 78.8%).28
98% bioavailability and a hal-lie o 13 to 16 hours. It Despite the impressive results with imatinib,
was rst used in patients who developed resistance or approximately hal o the patients had come o ima-
intolerance to IFN-α, and resulted in a CCyR o 60% tinib therapy at the 10-year ollow-up time. This high-
and an estimated 5-year overall survival (OS) rate o lighted the need or additional treatment options in
76%.26 CML. The development o second generation TKIs
Based on these results, the phase 3 randomized helped address this issue, especially in patients who
multinational IRIS (International Randomized study o were intolerant to imatinib therapy.
Intereron-alpha plus cytarabine versus STI571) study
compared imatinib 400 mg orally daily with IFN-α in
combination with cytarabine (the standard o care at the
Imatinib Dosage
time) in 1106 newly diagnosed patients with CML-CP.27 The phase I imatinib study in patients who had ailed
Ater a median ollow-up period o 19 months, out- prior IFN-α therapy established a clear relationship
comes or patients receiving imatinib were signicantly between dose and response.29 No signicant responses
were observed at doses below 300 mg/day. An arbi- least 12 months. In group A, the rates o early molec-
trary dosage o 400 mg/day or CP was selected in ular response (EMR, BCR-ABL1 transcript ≤10% at 3
phase II studies despite the lack o dose-limiting toxic- months), CCyR at 6 months, and MMR at 12 months
ity at doses up to 1000 mg/day (maximum tolerated (65%, 53%, and 50% respectively) were comparable to
CHAPTER 4
dose was not dened). Studies o higher dose schedules those achieved by branded imatinib. In group B, 64%
o imatinib (e.g. 400mg twice daily) were associated patients maintained their molecular response, but 15%
with more side eects and no longer term benets.30–33 had worsening o molecular response when switching
In a French Spirit study, 636 patients with newly to generic imatinib. Despite this, only 0.3% and 1.3% o
diagnosed CML-CP were randomized to receive the patients had loss o CCyR and MMR, respectively.
either imatinib 400 mg/day alone, imatinib 400 mg/ Rates o adverse events were also similar between
day with cytarabine (20 mg/m2/day on days 15–28 groups A and B and comparable to branded imatinib.
o each 28-day cycle) or pegylated (peg) IFN-α-2a Similar data were reported rom India. Among 174
(90 μg weekly), or imatinib 600 mg/day alone.34 The patients treated with imatinib generics, response and
12-month CCyR rates were similar among the our survival rates were similar to those observed among
groups, but the MMR and deeper molecular responses 1193 patients treated with the branded imatinib. Saety
rates were signicantly higher in patients receiving prole was similar as well.37
imatinib and peg IFN-α-2a compared with imatinib At MD Anderson 38 patients who switched ther-
400 mg alone arm (30% vs 14% respectively; P = .001). apy rom branded imatinib to generics were evalu-
However, this high rate o early and deep responses ated. Beore the switch, all patients were in CCyR, 36
did not translate into long-term improvement because (95%) were in MMR, and 28 (74%) in deep molecular
o the poor tolerance o peg IFN-α-2a. response (MR4.5). Patients received generic imatinib
The CML-study IV was designed to investigate i or a median o 19.4 months. Molecular responses ater
treatment with imatinib 400mg/day (n = 400) could be switching were stable in 89%, improved in 8%, and
optimized by doubling the dose (n = 420) or by add- worsened in 3% o patients. No patient lost MMR.38
ing IFN (n = 430) or cytarabine (n = 158) or by using No signicant changes in side-eects were observed
imatinib ater IFN ailure (n = 128).35 From July 2002 ater the switch to generic.
to March 2012, 1551 newly diagnosed patients with
CML-CP were randomized into a ve-arm study. The Management of Toxicity
study was powered to detect a survival dierence o
5% at 5 years. Ater a median observation time o Imatinib is overall well tolerated, although adverse
9.5 years, the 10-year OS rate was 82%, the 10-year events not requiring treatment interruptions or
progression-ree survival (PFS) rate was 80%, and the decrease in dosing may occur in 30% to 40% o
10-year relative survival rate was 92%. Despite a aster patients. A list o the most requently encountered side
response with imatinib 800 mg, the survival dierence eects and suggestions or management are included
between standard-dose and higher dose imatinib was in Table 4–3. Any grade 3 or 4 toxicities related to ima-
only 3% at 5 years (<5%). In a multivariate analysis tinib require treatment interruption and resumption
or survival, standard-dose imatinib was equivalent upon resolution o toxicity or its decrease to grade 1 or
to other treatment arms. Patients who reached the less. Subsequent doses should be reduced i recurring
6-month BCR-ABL1 transcripts (IS) less than 1% had or long-lasting side eects are encountered, keeping in
a survival advantage o 6% ater 10 years regardless mind that dosages below 300 mg/day are not recom-
o therapy. mended because o lack o adequate activity, unless the
Imatinib 400 mg/day is thereore the standard dose patient is already in deep molecular response. Only 2%
or treating patients with newly diagnosed CML-CP. to 3% o patients exhibit true intolerance to imatinib
and require permanent discontinuation. Early recogni-
tion and intervention targeting toxicities greatly reduce
Imatinib Generics
the need or unnecessary treatment interruptions and
Imatinib generics are now available. It has been ques- dose reductions.
tioned i these are comparable in saety and ecacy to Myelosuppression is common and requently seen
the branded Gleevec. In a multicenter prospective study within the rst 2 to 3 months o therapy. It is gen-
conducted by the Polish Adult Leukemia Group (PALG) erally sel-limited, and dose interruptions are not
imatinib generic registry, 726 patients with CML-CP recommended unless grade 3 neutropenia or throm-
were divided into two groups: group A (n = 99) con- bocytopenia (ie, neutrophils <1 × 109/L, platelets
sisting o patients who commenced therapy on generic <50 × 109/L) develop. Anemia alone usually does not
imatinib ater CML diagnosis, and group B (n = 627) require interruptions or dose adjustments. Treatment
consisting o patients who were switched to generic is restarted when counts recover above specied
rom branded imatinib.36 Patients were observed or at thresholds. Ater treatment interruption, the WBC
TABLE 4–3 Recommended management of the Most Common Adverse Events Associated with
Imatinib
Adverse Events Management
CHAPTER 4
Nausea or vomiting Take with ood or fuids
Antiemetics
Diarrhea Loperamide
Diphenoxylate atropine
Peripheral edema Diuretics
Periorbital edema Steroid-containing cream
Skin rash Avoid sun exposure
Topical steroids
Systemic steroids
(Early intervention is important)
Muscle cramps Tonic water or quinine
Electrolyte replacement as needed
Calcium gluconate
Arthralgia or bone pain NSAIDs
Elevated transaminases Hold therapy and monitor closely
Dose reduction on resolution
Myelosuppression
Anemia Treatment interruption or dose reduction usually not indicated
Erythropoietin or darbopoetin
Neutropenia Hold therapy i grade ≥3 (ie, ANC <1 × 109/L)
Restart at lower dose i recovery takes >2 weeks
Consider G-CSF i recurrent or persistent or sepsis
Thrombocytopenia Hold therapy i grade ≥3 (ie, platelets <50 × 109/L)
Restart at lower dose i recovery takes >2 weeks
Consider eltrombopag
ANC, absolute neutrophil count; G-CSF, granulocyte colony stimulating actor; IL-10, interleukin-10; NSAID, nonsteroidal antiinfammatory drug.
count should be monitored at least once weekly, and i imatinib, dasatinib binds to both the active and inactive
recovery occurs within 2 weeks, treatment should be conormations o BCR–ABL1 and inhibits the Src amily
resumed with the same dose at which myelosuppres- o kinases, which may be important in suppressing criti-
sion occurred. I recovery takes longer than 2 weeks, cal cell signaling pathways.44
the dose could be reduced in increments (eg, rom 400 Ater evaluation in the salvage setting post imatinib
to 300 mg). Hematopoietic growth actors may be ailure, dasatinib was assessed in the rontline setting.
benecial with recurrent or prolonged myelosuppres- The DASISION trial was a phase III, randomized study
sion (eg, erythropoietin or darbepoetin, lgrastim, and that compared imatinib 400 mg once daily to dasat-
eltrombopag).39,40 inib 100 mg once daily in 519 patients with newly
diagnosed CML-CP.45,46 The primary endpoint was
conrmed CCyR (cCCyR) at 12 months, which was
Dasatinib higher with dasatinib (77% vs 66%; P = 0.007). The
Dasatinib is a piperazinyl derivative oral second-genera- rates o molecular responses were signicantly higher
tion TKI. It has an excellent oral bioavailability and is 350 with dasatinib (MMR 76% vs 64 % P = .002; MR 4.5
times more potent in vitro than imatinib.41,42 It exhibits 42% versus 33 %, P = .025). Dasatinib induced deeper
signicant activity against most imatinib-resistant BCR– responses at early time points (3, 6, or 12 months)
ABL1 mutations, with the exception o T315I, and a compared with imatinib. At 3 months, a higher pro-
ew others, including V299L and F317L.43 In contrast to portion o patients treated with dasatinib achieved
BCR-ABL1 transcripts (IS) 10% or less (84% vs 64%; o dasatinib (100 mg vs 140 mg/day; single-dose ver-
P <.0001). Meeting this threshold in either arm pre- sus twice-daily schedule), dasatinib 100 mg single daily
dicted better PFS and OS. The rate o transormation dose was as eective as 140 mg/day with a better
to AP or BP was lower in patients treated with dasat- saety prole.51 Investigators rom the DASISION trial
CHAPTER 4
inib (4.6% and 7.3%, respectively). However, there have reported the ability to maintain the ecacy o
was no PFS and OS dierence at a minimum ollow- dasatinib among patients who had their dose reduced,
up o 5 years when the study was terminated.46 Rel- while improving its saety prole.52 Based on this ratio-
evant toxicities included a pleural eusion rate o 28% nale, we conducted a phase II study evaluating the
with dasatinib (mostly grade 1 or 2; 15 patients [6%] ecacy and saety o lower dose dasatinib 50 mg/day
discontinued dasatinib because o pleural eusion). in 81 patients with newly diagnosed CML-CP. With a
Arterio-occlusive events were higher with dasatinib minimal ollow-up o 12 months,53,54 the cumulative
(5% vs 2%). Pulmonary hypertension was reported in rates o MMR, MR4, and MR4.5 by 12 months were
14 (5%) dasatinib-treated patients, with 6 discontinu- 81%, 55%, and 49%, respectively. Twenty-one (25%)
ing the drug. patients had treatment interruptions or a median o 13
In another phase II, multicenter trial, patients with days (range, 4–64 days). Five (6%) patients developed
newly diagnosed CML-CP were randomized to either pleural eusions; our o them required a dose reduc-
dasatinib 100 mg/day or imatinib 400 mg/day.47 Simi- tion. Two (2%) patients ailed to achieve any cytoge-
lar to the DASISION study, higher rates o CCyR (84% netic or molecular response and were taken o study.
vs 69%) and 12-month MMR (59% vs 44%; P = .059) At a median ollow-up time o 24 months, none o the
were reported in patients receiving dasatinib. No di- patients had disease transormation to an AP or BP.54
erence in PFS or OS was reported. Grade 3 and 4 tox- The 2-year EFS and OS rates were 100%. Such a strat-
icities were most commonly hematologic, including egy may have a signicant impact on our uture prac-
thrombocytopenia, which was more common with tice because o equivalent ecacy, better saety, and a
dasatinib (18% vs 8%). lower cost o care.54
A third phase III randomized study, SPIRIT 2, com-
pared dasatinib 100 mg/day with imatinib 400 mg/
day.48 More than 800 patients were treated. The pri-
Nilotinib
mary endpoint was 5-year event-ree survival (EFS). Nilotinib is a structural analog o imatinib with 50
The 24-month CCyR rate was higher with dasatinib times more potent anity or the ATP binding site
compared to imatinib (43% vs 32%). The cumulative in vitro55 and more selective activity against unmu-
incidence o MMR and MR4 were also higher with tated and most mutated orms o BCR–ABL1.55,56 It is
dasatinib (MMR 83% vs 63%; MR4 78% vs 57%). approved at a dose o 400 mg twice daily or patients
More imatinib-treated patients proceeded to stem cell with CML-CP and CML-AP with resistance or intoler-
transplant (SCT). Although the 5-year ailure-ree sur- ance to imatinib. Nilotinib was also evaluated in newly
vival (FFS) rate was superior in the dasatinib arm (61% diagnosed CML-CP. The ENESTnd trial was a large
vs 53%), there was no dierence in the EFS (91% vs phase 3 international randomized study that compared
89%) or the OS (92% vs 91%) between dasatinib and two doses o nilotinib, 300 mg twice daily and 400 mg
imatinib.49 Overall, more patients came o therapy twice daily (the dose approved or CML salvage) with
because o suboptimal molecular response in the ima- imatinib 400 mg once daily as initial therapy or
tinib compared with the dasatinib arm (17% vs 2%), patients with early CML-CP.57 The primary endpoint
but more patients discontinued therapy because o was the MMR rate at 12 months, which was higher
intolerance in the dasatinib compared with the ima- with both doses o nilotinib compared to imatinib
tinib arm (30% vs 17%). (44% and 43% vs 22%; P <.001). The cumulative inci-
Dasatinib is well tolerated. Myelosuppression dence o CCyR by 24 months was 87% with nilotinib
occurs requently, with grade 3 or 4 neutropenia or 300 mg twice daily, 85% with nilotinib 400 mg twice
thrombocytopenia in 20%. The most common nonhe- daily, and 77% with imatinib 400 mg/day (P <.001).57
matologic grade 3 to 4 toxicities at the same dose were Cumulative 10-year58,59 MMR rates were 83% with
pleural eusion (9%), dyspnea (6%), bleeding (4%), nilotinib 300 mg twice daily, 80% with nilotinib 400
diarrhea (3%), and atigue (3%). mg twice daily, and 70% with imatinib.58 Cumulative
10-year MR4.5 rates were 64% with nilotinib 300 mg
twice daily, 62% with nilotinib 400 mg twice daily,
Lower Dose Dasatinib
and 45% with imatinib, respectively.58 The incidence
In early clinical trials evaluating dasatinib, the drug was o transormation to CML AP or BP was 3.9% with
noted to be active at doses lower than those initially nilotinib 300 mg twice daily, 2.5% with nilotinib 400
approved or second-line therapy, with a better saety mg twice daily, and 8.5% with imatinib. There was
prole.50 In a randomized trial o our dose schedules no signicant dierence in outcome among patients
treated with nilotinib and imatinib.58 The estimated and 27% o patients receiving imatinib discontinued
10-year EFS rates were 92.0%, 96.2%, and 90.3% treatment, most commonly or drug-related toxicity
with nilotinib 300 mg twice daily, nilotinib 400 mg (13% and 9%, respectively). Grade 3 or greater diar-
twice daily, and imatinib, respectively.58 The estimated rhea (8% vs 0.8%) and increased alanine aminotrans-
10-year survival rates were 87.6%, 90.3%, and 88.3%, erase (19% vs 1.5%) and aspartate aminotranserase
CHAPTER 4
respectively.58 Adverse events resulting in TKI discon- (10% vs 2%) levels were more common with bosuti-
tinuation were highest with nilotinib 400 mg twice nib. Cardiac and vascular toxicities were uncommon.
daily dose (35.4%) compared with nilotinib 300 mg The 2-year cumulative rates o CCyR were 76% and
twice daily and imatinib (24% and 20%, respectively). 66% among patients treated with bosutinib and ima-
Cardiovascular events were noted to be signicantly tinib (P = .0052), respectively. The 2-year cumulative
higher with nilotinib, particularly at the higher dose.58 rates o MMR, MR4, and MR4.5 were 57% and 34%
A second trial rom China used the same design and (P = .0036), 27% and 10% (P =.0249), and 15% and
enrolled 267 patients. The MMR rates at 12 months 3% (P = .0542), respectively.60 The estimated 2-year
were 52% with nilotinib and 28% with imatinib. The survival rates were similar (99% vs 97%).
rate o CCyR (84% vs 87%) and PFS (95% each) were
similar at 24 months. The rates o progression to CML The MD Anderson Cancer Center
AP or BP and o survival were similar with nilotinib
and imatinib.59
Experience
Although nilotinib is well tolerated overall, there is At MD Anderson, several rontline studies ran sequen-
a cumulative increased risk o cardiovascular events tially and in parallel and evaluated the outcomes o
on therapy. In the 10-year ollow-up o the ENESTnd patients with newly diagnosed CML treated (July
study, the cumulative cardiovascular event rates were 2000–September 2013) with imatinib 400 mg/day (n
24.8%, 33.4%, and 6.3% with nilotinib 300 mg twice = 68), imatinib 800 mg/day (n = 200), dasatinib 50 mg
daily, nilotinib 400 mg twice daily, and imatinib 400 twice daily or 100 mg/day (n = 106), and nilotinib 400
mg/day, respectively.58 Other notable side eects mg twice daily (n = 108). An analysis o the total expe-
include grade 3 or 4 myelosuppression (neutropenia rience o 482 patients is summarized in Table 4–4.55
or thrombocytopenia in 10%–20%). Nonhematologic The experience showed similar benets with high-
toxicities include headaches, skin rashes (20%–30%; dose imatinib and second-generation TKIs in relation
can be alleviated by dose reduction), elevated indirect to early surrogate endpoints o long-term outcome
bilirubin (10% to 15%), and asymptomatic elevation (CCyR, MMR, MR4.5). Patients treated with imatinib
o lipase and amylase (10% to 15%). Rare cases (<1%) 400 mg/day had a signicantly inerior 5-year EFS com-
o pancreatitis have been reported. Diabetes may also pared with those treated with high-dose imatinib and
be exacerbated with nilotinib (10% to 20%). second-generation TKIs (P = .009). However, 5-year
transormation-ree survival (TFS), FFS, and OS were
not dierent by treatment strategy (P = .353, 0.078 and
Bosutinib P = .381, respectively). As expected, among patients
Bosutinib is a potent dual SRC/ABL kinase inhibitor.60 who achieved CCyR, there was no dierence in out-
The drug was rst approved or treating adults with comes regardless o whether MMR or MR4.5 were
CML and resistance or intolerance to prior therapy. additionally achieved.61
In 2018, it was approved as rst-line treatment o The long-term results o rontline nilotinib and
patients with CML-CP.60 In the multinational phase dasatinib therapy were recently published.62,63 At a
III randomized BFORE trial, 590 patients with newly median ollow-up period o 78 months, among the
diagnosed CML-CP were randomized to bosutinib 122 patients treated with nilotinib 400 mg twice daily,
400mg/day (n = 268) or imatinib 400mg/day (n = 268). the cumulative CCyR and MMR rates were 91%. Sev-
The primary endpoint o the study was MMR at 12 enty-ve percent and 59% o patients achieved MR4.5
months. Patients treated with bosutinib had a higher and a sustained MR4.5 beyond 2 years, respectively.
rate o MMR at 12 months (47% vs 37%; P = 0.02). The estimated 5-year EFS and OS were 89% and 93%,
Similarly, the 12-month CCyR rate was signicantly respectively. The corresponding rates at 10 years were
higher with bosutinib (77% vs 66%; P = .0075). Early 85% and 88%, respectively.62 At a median ollow-
molecular responses (BCR-ABL1 transcripts ≤10% up time o 6.5 years, among the 149 patients treated
at 3 months) were associated with superior PFS and with dasatinib 100 mg/day or 50 mg twice daily, the
OS and were achieved more requently on bosutinib cumulative CCyR rate at 11 years was 92.6%. The
(75% vs 57%). At 2 years, six patients (2.2%) receiving MMR, MR4.5, and sustained MR4.5 rates were 88.2%,
bosutinib and seven patients (2.6%) receiving imatinib 79.5%, and 55%, respectively. The 10-year OS, TFS,
experienced disease progression to AP or BP. Among EFS, and FFS rates were 89%, 95%, 86%, and 65%,
treated patients, 22% o patients receiving bosutinib respectively.63
TABLE 4–4 The MD Anderson Cancer Center Experience with Frontline Tyrosine Kinase Inhibitors in
Chronic Myeloid Leukemia
Imatinib 400 mg/ Imatinib 800mg/day Dasatinib 100 mg/ Nilotinib 400 mg
CHAPTER 4
Outcome (%) day (n = 68) (n = 200) day (n = 106) BID (n = 108)

CCyR 87 90 96 93
MMR 76 86 90 91
MR4.5 57 74 73 71
5-year EFS 71 84 93 84
5-year FFS 59 70 76 70
5-year TFS 87 94 96 88
5-year OS 89 93 98 89
Discontinued 43 43 21 25
BID, twice a day; CCyR, complete cytogenetic response; EFS, event-ree survival; FFS, ailure-ree survival; MMR, major molecular response (BCR-ABL1 transcript [IS]
≤0.1%; MR4.5 BCR-ABL-1 [IS] ≤0.0032%); OS, overall survival; TFS, transormation-ree survival.
Given the equivalent ecacy and lower toxicity o baseline QT prolongation (routine monitoring o the
lower dose dasatinib in our phase II study, dasatinib 50 QT interval is essential). Potassium and magnesium
mg/day has become our standard o care or rontline should be repleted to optimal serum levels beore start-
therapy o patients with CML-CP. ing nilotinib. Nilotinib should be taken on an empty
stomach to avoid excess drug exposure. Nilotinib
has also been associated with signicantly increased
Patient Age and Comorbidities
incidence o peripheral artery occlusive disease, cere-
The patient’s age plays a signicant role in deciding brovascular accidents, and cardiovascular events.58 In
TKI therapy. Younger individuals have a longer lie the 10-year ollow-up o the ENESTnd trial,58 approxi-
expectancy. Thereore, in younger patients, the goal mately 33.4% o patients experienced vascular events.
is more requently durable deep molecular responses, Cardiovascular events are less common with bosu-
preerably undetectable BCR-ABL1 transcript levels, to tinib and with imatinib. It is thereore reasonable to
allow or consideration o treatment discontinuation. choose these or patients with cardiovascular morbidi-
This is more likely to be achieved with second-gener- ties. Nilotinib may occasionally cause pancreatitis and
ation TKIs that induce rapid and signicantly deeper should be avoided in patients with prior history or risk
molecular responses compared with imatinib. Ther- actors or pancreatic infammation.
apy discontinuation might be less relevant in older Imatinib is associated with the development o
patients in whom the goal is survival normalization peripheral edema as one o its major side eects.
with minimal adverse events, particularly serious ones Close monitoring and intermittent use o loop diuret-
(eg, arterio-occlusive events [AOEs], pleural eusions). ics might mitigate the eects o fuid retention. Other
Imatinib might be a more adequate initial therapy in common side eects associated with imatinib include
older patients. weight gain, atigue, periorbital edema, bone and
Most TKIs are reasonably well tolerated with close muscle aches, and nausea. These are mostly mild to
observation and supportive care. Each TKI therapy has moderate. A decrease in glomerular ltration rate may
a distinct toxicity prole that should be considered occur in patients treated with imatinib, but ewer than
when deciding on therapy (Table 4–5). For patients 5% to 10% experience signicant elevations in creati-
with baseline cardiopulmonary comorbidities such nine with long-term therapy.
as chronic obstructive pulmonary disease, congestive Bosutinib is associated with gastrointestinal, hepatic,
heart ailure, or uncontrolled hypertension or pulmo- and renal toxicity. Among patients with such comor-
nary arterial hypertension,64 a TKI other than dasatinib bidities, bosutinib should be avoided or used cau-
may be avored, given the risk o pleural eusions. tiously. Bosutinib should be avoided in patients with
Dasatinib also impairs platelet unction,65 and patients infammatory bowel disease and renal dysunction.67
on concomitant anticoagulants may be at increased
risk or hemorrhagic complications.66 Cost of Therapy
Nilotinib has been linked with hyperglycemia and
QT interval prolongation and should be used with The prices o TKIs are o concern, given that patients
caution in uncontrolled diabetics and in patients with can now remain on TKIs and expect to have a normal
TABLE 4–5 Selecting frontline Tyrosine Kinase Inhibitor Therapy: Comorbidities and Toxicity
Toxicity Imatinib Dasatinib Nilotinib Bosutinib

Pleural eusion - ++ - -
CHAPTER 4
Liver + + + +
Transaminases + + + ++
Bilirubin + - ++ -
Lipase - - ++ -
Glucose - - ++ -
Diarrhea + - - ++
Rash + + ++ +
Bleeding - + - -
Vascular events - - ++ -
QT interval increase - + ++ -
Muscle cramps ++ - - -
Edema or weight gain ++ - - -
liespan. The cost o cancer drugs has risen drasti- scenarios showed a good treatment value or using
cally over the past decade.68–73 Most are priced at over second-generation TKIs at the current prices in the
$120,000 to $160,000 annually.68–70 When rst approved United States or at the price o $30,000 to $40,000
in the United States, the annual price or imatinib was per year elsewhere. The Austrian groups reported
less than $30,000. Patients treated with imatinib are the rontline therapy with nilotinib yielded ICERs o
now living a “normal” lie span. 70,71 Paradoxically, with 121,400 € per QALY compared with rontline ima-
a higher number o patients and a longer duration o tinib without second-line TKI ater imatinib ailure;
therapy, the annual price o imatinib has quadrupled nilotinib ollowed by dasatinib yielded 152,400 € per
to $132,000. This price is comparable to the cost o QALY compared with imatinib ollowed by nilotinib
second-generation TKIs, all priced above $150,000 per ater imatinib ailure.72 To be cost eective, the cost
year o therapy. o second-generation TKIs should be less than $25,000
Generic ormulations o imatinib are now available per year.73–75 Under the same conditions in developing
in the United States, although at a higher initial cost nations, the annual price o second-generation TKIs
than expected. Since 2017, there are several generic should not exceed $10,000 per year o therapy.
imatinib ormulations available, and their wholesale Finally, lower dose dasatinib and generic second-
price is decreasing rapidly. The price o generic ima- generation TKIs may constitute a cost-eective
tinib is $3000 to $8000 per year in Canada and $400 strategy by allowing the achievement o an optimal
per year in India. With the availability o generic ima- response as well as TFR at a lower cost.
tinib at a relatively lower cost compared with second-
generation TKIs, one may oer generic imatinib to Disease Characteristics and Risk Score
patients in the rontline setting with low- and interme-
diate-risk disease and second-generation TKIs to those The CML risk score plays an important role in decid-
with high-risk disease.73 ing the type o TKI therapy. Patients who score low
At MD Anderson, we assessed the treatment value by the Sokal20 or Hasord21 prognostic models respond-
o second-generation TKIs compared with imatinib ing optimally to all TKIs with higher rates o deep
to achieve treatment-ree remission (TFR) in patients molecular response with second-generation TKIs. The
with CML using a decision analytical model.73 Dier- outcomes dier with intermediate- and high-risk dis-
ent modeled scenarios were considered. Incremental ease in which the use o second-generation TKIs dem-
cost-eectiveness ratios (ICERs) were calculated, and onstrate signicantly higher deep molecular response
cost eectiveness was assessed using two societal (MR4.5) and with a lower risk o transormation. In the
willingness-to-pay thresholds: $50,000 per quality- ENESTnd study, in which patients were categorized
adjusted lie-year (QALY) in all markets and $200,000 based on the Sokal scoring system, in the intermedi-
per QALY in the United States. None o the explored ate group, the rate o transormation was 10% in the
imatinib arm versus 1% to 2% in the nilotinib arm; even within the same laboratory. The trend o quan-
in the high-risk group, the rate o transormation was titative RT-PCR is more reliable to avoid the over-
14% in the imatinib arm versus 5% to 9% in the nilo- interpretation o the variability o RT-PCR results.
tinib arm.57, 58 The additional benet o the achievement o MMR
CHAPTER 4
among patients in CCyR remains unclear. Irrespec-

tive o MMR, a similar survival rate was reported in
MONITORING RESPONSE patients who received imatinib or second-generation
TKI and achieved CCyR.12,79–82
Monitoring includes routine complete blood counts The clinical impact o early molecular response has
with dierential, cytogenetics, and molecular analy- been shown in a number o studies. A BCR-ABL1 tran-
sis or BCR-ABL1 transcript levels and or BCR-ABL1 script level <10% (IS) at 3 months o TKI therapy has
kinase domain mutations (Table 4–6). The monitor- been shown to divide patients into high- and low-risk
ing o complete blood counts should be implemented categories or long-term outcomes (ie,, progression to
every 1 to 2 weeks until complete hematologic BP, death).79,83,84 The DASCERN, a randomized, open-
response and later every 3 months, more requently i label, international phase 2b trial, evaluated the impact
clinically indicated.36 Conventional cytogenetic testing o BCR-ABL1 transcripts >10% (IS) at 3 months ater ini-
should be perormed to assess the presence o addi- tial treatment with imatinib 400 mg/day in patients with
tional chromosomal abnormalities, particularly i(17) CML-CP who achieved complete hematologic response.
(q10), -7/del7q, and 3q26.2 rearrangements, associated Patients were randomized to receive dasatinib 100 mg/
with a relatively adverse prognosis.19 day or higher dose o imatinib.85 Patients who switched
At diagnosis, all patients with leukocytosis sus- to dasatinib 100 mg/day achieved a 12-month MMR
pected to be CML should undergo bone marrow aspirate o 29% compared with 13% among patients who
ration and biopsy to establish the diagnosis, assess continued imatinib (P = .005). However, the clinical out-
percentages o blasts and basophils, and evaluate the come o PFS and OS were similar between groups with
presence o clonal evolution. Currently, bone marrow the median ollow-up period o 30 months.85. A ollow-
evaluation is recommended at diagnosis, or ailure up measurement at 6 months will help dene patients
to reach suggested response milestones, and or any clearly in need o a change in therapy.87–96 Experts have
sign o loss o hematologic and cytogenetic response.76 suggested that a ollow-up measurement at 6 months
An alternative technique to determine cytogenetic will help dene patients clearly in need o a change in
response is with the use o FISH or RT-PCR (or both) therapy.93 This has been retrospectively analyzed by sev-
on peripheral blood. I a patient is responding opti- eral large groups.94–96 Two independent studies reported
mally and the FISH study result is negative at 6 or 12 similar survival in patients who did or did not achieve
months or BCR-ABL1 transcripts (IS) are less than 1%, BCR-ABL1 transcript levels >10% (IS) at 3 months.95,96
it may be reasonable to omit urther marrow exami- Patients who continued the same TKI therapy and
nation because the patient is likely to be in stable achieved BCR-ABL1 transcripts (IS) less than 10% at 6
CCyR.77,78 months o TKI therapy maintained similar long-term
For patients in durable CCyR during TKI ther- outcome compared with patients with BCR-ABL1 tran-
apy, intermittent molecular monitoring every 3 to 6 scripts (IS) <10% at 3 months o therapy. The BCR-ABL1
months using quantitative RT-PCR is acceptable and transcripts (IS) <10% at 6-month is the rst milestone
useul but may lead to erroneous changes in treatment or survival. The 4-year OS rates were 100% and 74%
because o discordant results between laboratories or in patients with the BCR-ABL1 transcripts (IS) <10% and
TABLE 4–6 Main Features of the Monitoring Techniques Available for Chronic Myeloid Leukemia
Parameter Cytogenetics FISH PCR

No cells evaluated 20 200 <10,000
Rapidity (days) 14–21 1–3 7–10
Source BM BM or PB BM or PB
Clonal evolution Yes No No
False negativity NA Yes Yes
False positivity No ≤10% NA
BM, bone marrow; FISH, fuorescent in situ hybridization; NA, not applicable; PB, peripheral blood; PCR, polymerase chain reaction.
>10% at 6-month o TKI therapy. Given the observed continuous CCyR would prompt closer monitoring and
worse survival in patients on rontline imatinib, it may a compliance assessment. Some CML experts advocate
be reasonable to switch imatinib to a second-genera- a change o therapy or a documented consistent loss
tion TKI or patients with BCR-ABL1 transcripts (IS) o MMR ater 3 to 4 years o therapy (BCR-ABL1 tran-
>10% ater 6 months o therapy. Although suboptimal scripts (IS) >0.1%), particularly i transcript levels (IS)
CHAPTER 4
response is associated with a statistically signicant are consistently above 0.3% to 0.5%.
probability o worse survival, the consideration o allo- The new ELN 2020 recommendations and the
geneic SCT should be deerred because patients with National Comprehensive Cancer Network guidelines
suboptimal response on second-generation TKI still had propose the achievement o TFR as an important goal
an estimated survival rate o 81%.46 o therapy in CML. This is discussed later.
Multiple studies consistently reported the associa-
tion o CCyR within 1 year o therapy (or later) with
WHEN TO SWITCH TYROSINE improved survival compared with lesser degrees o
KINASE INHIBITOR THERAPY response. Thus, the primary endpoint o TKI therapy
is the achievement o CCyR. MMR (BCR-ABL1 tran-
Achievement o CCyR by 12 months and mainte- scripts [IS] ≤0.1%) was not associated with improve-
nance o CCyR thereater is associated with improved ment o survival, but was associated with improved
survival, similar to that o a general population. With EFS and stable CCyR. Treatment discontinuation can
standard-dose imatinib, CCyR should be expected be considered or patients who achieved deep molecu-
by 12 months o therapy, but it may be reasonable to lar response such as CMR (nonmeasurable BCR-ABL1
expect CCyR with second-generation TKIs within 3 to transcripts). The use o allo-SCT and the switch to
6 months o treatment.98 other TKI should not be considered or patients who
Patients who do not achieve a complete hemato- achieved CCyR without MMR or CMR. The lack o
logic response by 3 months should be considered or major cytogenetic response (Ph-positive metaphases
a change in TKI treatment unless it is related to poor ≤35%; BCR-ABL1 transcripts [IS] ≤10%) by 6 months
adherence. Considering a change in treatment at 3 may justiy the TKI switch to a second-generation TKI.
or 6 months or BCR-ABL1 transcript level >10% or The achievement o CCyR within 3 to 6 months o
patients on imatinib or second-generation TKIs, very rontline second-generation TKI therapy improved
early switching has not yet been shown to infuence outcomes. Recommendations are summarized in
the long-term outcomes.99 As such, it can be advocated Table 4–7, which are mostly consistent with the 2020
that i the transcript level at 3 months is greater than ELN recommendations.93
10%, providers should perorm serial molecular mon-
itoring between 3 and 6 months or denitive treat-
ment response evaluation.93 I patients retain >10% MANAGEMENT OF TYROSINE
transcript levels (IS) at 6 months, a change in therapy KINASE INHIBITOR RESISTANCE
is indicated because the chance o CCyR would be
low. A 3-month value o 10% (IS) may not be accu- Given that the survival o patients with CML is
rate: in a report in one sample collected at 3 months approaching that o the general population with long-
and tested 96 times, the mean value was 11% (range, term TKI therapy, and given that some patients may
5%–16%), with only 31% o tests being 10% or less.100 ail on a particular TKI therapy because o intolerance
This approach also applies to patients on second-gen- or resistance, the number o patients who have a his-
eration TKIs.99 Another study randomized patients in tory o at least one TKI resistance has been increas-
CCyR on imatinib or at least 2 years to continue ima- ing. One o the mechanisms o TKI resistance is the
tinib or switch to nilotinib.101 Switching to nilotinib acquisition o point mutations in the BCR-ABL1 kinase
induced deeper molecular responses but did not trans- domain. The acquired mutation o kinase decreases
late into an improvement in PFS or in other meaningul the anity o TKI, which impairs the activity o TKIs.
outcomes. Although second-generation TKI can overcome ima-
Patients who meet all the relevant benchmarks in the tinib-resistant BCR-ABL1 kinase domain mutations,
rst 12 months are monitored periodically using molec- novel mutations resistant to second-generation TKI
ular testing with or without FISH (molecular testing emerged through clonal selection. The gatekeeper
only i BCR-ABL1 transcripts (IS) consistently <0.1%). I mutation, T315I mutation, causes resistance to cur-
there are clear signs o possible ailure, patients should rently available TKIs except ponatinib.102
undergo a bone marrow examination with cytogenetic Although suboptimal response suggests TKI resis-
analysis and molecular testing, including analysis or tance or intolerance, TKI compliance and drug–drug
mutations. Any degree o cytogenetic relapse calls or a interactions should be evaluated beore the decision to
change o therapy. Fluctuating molecular levels during switch TKI. The range o estimated rates o imatinib
TABLE 4–7 Response Denitions to Imatinib in Chronic Phase Chronic Myeloid Leukemia 2020
European LeukemiaNet Recommendations
Optimal Warning Failure

CHAPTER 4
Baseline NA High-risk ACA, high-risk ELTS score NA

3 months ≤10% >10% >10% i conrmed within 1–3 months
6 months ≤1% >1%–10% >10%
12 months ≤0.1% >0.1%–1% >1%
a
Any time ≤0.1% >0.1%–1%, loss o ≤0.1% >1%, resistance mutations, high-risk ACA
For patients aiming at treatment-ree remission (TFR), the optimal response (at any time) is BCR-ABL1 ≤ 0.01% (MR4).
A change o treatment may be considered i major molecular response (MMR) is not reached by 36–48 months.
a
Loss o MMR (BCR-ABL1 > 0.1%) indicates ailure ater TFR.
ACA, additional chromosome abnormalities in Philadelphia chromosome–positive cells; ELTS, EUTOS long-term survival score; NA not applicable.
adherence was rom 75% to 90% with worse outcome OS.106 Despite the limitations o various designs o
in patients with lower adherence.103, 104 The monitoring clinical trials, the earlier intervention beore the loss o
o adherence is encouraged in younger patients, those major cytogenetic response (or equivalent) was asso-
with chronic toxicities, and those on higher dose o TKI ciated with better outcomes.
therapy.102 Bosutinib was originally approved or the treat-
ment o patients with imatinib-resistant or -intolerant
CML.89 The bosutinib dose o 500 mg/day was chosen
SECOND- AND THIRD-GENERATION with the potential or dose escalation to 600 mg/day
TYROSINE KINASE INHIBITORs or patients with suboptimal response on the phase
2 clinical trial. Among 288 patients enrolled, more
Second-generation TKIs were originally approved as than two thirds o patients had a history o imatinib
second-line therapy or patients with CML-CP who resistance. Thirty-one percent o patients achieved
ailed rontline imatinib. Second-line TKI therapy MCyR within 6 months o bosutinib therapy (primary
with nilotinib, dasatinib, or bosutinib achieved high endpoint); 41% achieved CCyR. Although bosutinib
CCyR and MMR rates in patients who had subopti- does not have activity on T315I mutations, bosuti-
mal response or resistant to rontline imatinib ther- nib has maintained activity in most imatinib-resistant
apy ater initial optimal response. Although the dose mutations. Durable responses were observed in both
escalation o imatinib to 800 mg/day may overcome imatinib-resistant and imatinib-intolerant groups.
resistance to standard-dose imatinib, the switch to Common toxicities included gastrointestinal (GI)
second-generation TKI is a more eective strategy to symptoms (diarrhea, nausea, and vomiting) and skin
achieve response.105,106 In patients who ailed rontline rash. Eighty-our percent o patients had all grades o
imatinib therapy, second-line second-generation TKIs, diarrhea, and 9% had grade 3 diarrhea. Myelosup-
including nilotinib,107,108 dasatinib,106,108 or bosutinib,89 pression and liver unction test abnormalities were
achieved higher rates o major cytogenetic response, common. A strategy o sequential dose escalation o
CCyR, and MMR compared with high-dose imatinib bosutinib (200 mg/day or 2 weeks; 300 mg/day rom
therapy.109 The achievement o higher rates o CCyR 2 weeks to 3 months; 400 mg/day at 3 months i BCR-
and MMR translated into higher rates o PFS. These ABL1 transcript level >1% [IS] at 3 months) and oth-
consistent results o second-generation TKI studies erwise continue 300 mg/day may be considered in
ater imatinib ailure suggest that an earlier switch older patients with CML and rontline ailure to one
rom imatinib to a second-generation TKI may be prior TKI (both resistance and intolerance).111 Lower
more eective than a switch at the time o progres- BCR-ABL1 transcript levels were observed in 67%
sion or at the time o losing hematologic or cytoge- o patients. The dose-escalation strategy resulted in
netic response. Patients in suboptimal response with lower incidences o diarrhea (all grades, 16%; grade 3,
rontline standard-dose imatinib had a higher rates 8%) and liver unction test abnormalities (all grades,
o 12-month CMR when standard-dose imatinib was 22%; grade 3, 10%; and grade 4, 2%).111
switched to nilotinib compared with high-dose ima- Ponatinib is an FDA-approved third-generation
tinib.110 Earlier change rom standard-dose imatinib to TKI that exhibits activity against T315I mutation.91
dasatinib beore the loss o MCyR resulted in higher Preclinical studies showed ponatinib was 500 times
rates o responses (CCyR and MMR) and improved more active in inhibiting BCR-ABL1 than imatinib.112
clinical outcomes, including 2-year EFS, TFS, and The FDA approved ponatinib at an initial dose o
45 mg orally daily or the treatment o patients with to start ponatinib 30 mg/day (except in T315I-mutated
T315I-mutated CML and Ph-positive ALL and in CML where 45mg/D is better) and lower the dose to
patients or whom no other TKI therapy was indicated 15 mg/day when BCR-ABL1 transcript <1% (IS) are
based on the results o the phase II PACE (Ponatinib achieved.
Ph-positive acute lymphoblastic leukemia [ALL] and
CHAPTER 4
CML Evaluation) trial. The PACE trial included 449
patients with heavily pretreated all-stage CML (CP,
Novel Tyrosine Kinase Inhibitors
AP, and BP) and Ph-positive ALL. Patients who had Although currently FDA-approved TKIs have shown
a prior history o intolerance or resistance to dasat- signicant survival improvement in CML-CP, the
inib or nilotinib and who had T315I mutation were development o novel TKIs continues in order to over-
eligible.113 Patients enrolled were stratied by disease come the resistance o T315I mutation and to pur-
phase and T315I mutation status (absent or present). sue less toxic options. Asciminib is a novel allosteric
Among 267 patients with CML-CP, a 12-month MCyR BCR-ABL1 TKI that blocks BCR-ABL1 in an active
was observed in 56% and 70% o patients overall and conormation through binding a myristoyl site o the
patients with a T315I mutation, respectively. There BCR-ABL1 oncoprotein.116 The mechanism is dierent
was a trend or higher rates o response in patients rom all other TKIs and targets both the unmutated and
who received ewer prior TKI therapies. At the nal mutated BCR-ABL1, levels including T315I mutation.
5-year result o the PACE trial, 60%, 40%, and 24% o In a phase 1 trial, adults with CML-CP or CML-AP who
patients achieved MCyR, MMR, and MR4.5, respec- ailed at least two TKIs (resistance or intolerance) were
tively; 82% and 59% o patients who achieved MCyR treated with asciminib. Among 150 patients enrolled,
and MMR maintained response at 5 years.102 The 141 patients had CML-CP and 9 patients had CML-
5-year PFS and OS were 53% and 73%, respectively. AP.117 Patients received asciminib once or twice daily
AOEs, including cardiovascular, cerebrovascular, and at doses o 10 to 200 mg/day. Among 34 patients who
peripheral vascular events, were observed in 84 (31%) lost hematologic response, 32 (92%) achieved a com-
patients and severe AOEs in 69 (26%). Common treat- plete hematologic response; among 57 patients who
ment-emergent adverse events (≥40%) in patients with lost cytogenetic response, 31 (54%) achieved CCyR.
CML-CP included skin rash (47%), abdominal pain Among 91 evaluable patients, 44 (48%) achieved MMR
(46%), thrombocytopenia (46%), headache (43%), dry by 12 months, including 8 (57%) ponatinib resistant or
skin (42%), and constipation (41%).102, 113 Less com- intolerant patients. In patients with a T315I mutation
mon but notable adverse events were grade 3 or 4 skin beore asciminib, 5 (28%) patients achieved an MMR.
rashes (4%), pancreatitis (7%), atrial brillation (6%), Dose-limiting toxicities included asymptomatic eleva-
and grade 3 or 4 hypertension (14%). tions o lipase levels and clinical pancreatitis. A phase
As o June 2020, ponatinib labeling includes a warn- III randomized trial is ongoing in patients who ailed
ing or arterial thrombosis, including cardiovascular, two TKIs without T315I mutation and who are ran-
cerebrovascular, and peripheral arterial thrombosis, domized to either asciminib or bosutinib.
and hepatotoxicity.114 The PACE trial reported that Olverembatinib (HQP1315), a novel orally active
AOEs were more requent in older patients with previ- potent third-generation TKI, enrolled 101 patients,
ous history o cardiovascular events and with cardio- including 87 patients with CML-CP and 14 patients
vascular risk actors, including hypertension, diabetes, with CML-AP who were resistant or intolerant to two
or hyperlipidemia. Patients with a longer history o or more prior TKIs or with T315I mutation ater one or
CML since the diagnosis and patients taking higher more prior TKIs. Sixty-two (61%) patients had T315I
doses o ponatinib were at higher risk or AOEs.102 mutation.118 Olverembatinib was administered every
A randomized, open-label, phase 2 trial o ponatinib other day on a 28-day cycle; the dose escalation was
in patients with resistant chronic-phase CML (OPTIC) 30, 40, and 50 mg. With a median ollow-up period
evaluated the ecacy and saety o a range o pona- o 13 months, the rates o CHR, MCyR, CCyR, and
tinib doses.115 Patients were randomized to one o three MMR in patients with CML-CP were 94.5%, 69.1%,
starting doses o ponatinib at 45, 30, and 15 mg/day. 60.5%, and 37.2%, respectively. Common adverse
Doses were reduced to 15 mg/day upon achievement events included grade 3 or 4 thrombocytopenia and
o BCR-ABL1 transcript levels <1% (IS). The AOEs and grade 1 skin pigmentation and hypertriglyceridemia.
serious AOEs were 5% and 2%, 4% and 3%, and 1% Two pivotal studies in patients with CML-CP and
and 0%, respectively. The achievement o BCR-ABL1 CML-AP are ongoing.
1% or less (IS) was observed in 38.7%, 27.4%, and Vodobatinib (K0706), a novel third-generation TKI,
26.5% at the dose o 45 mg/day, 30 mg/day, and 15 was tested in a phase I trial in patients who ailed 3
mg/day, respectively; the achievement o MMR was or more TKIs or who had comorbidities that limited
observed in 14.7%, 17.8%, and 19.1%, respectively. the use o second-and third-generation TKI.119 Among
To minimize the risk o AOEs, it may be reasonable 35 patients, vodobatinib was given at dosage range o
12mg to 240mg daily. The recommended phase II dose Second- and third-generation TKIs have not been
was 174 mg/day. At 240 mg/day, two dose-limiting compared head to head. Selection o one or the other
toxicities were grade 3 dyspnea, grade 2 noncardiac is based on the side eect proles, mutation prole,
chest pain, and grade 2 shortness o breath caused by drug interactions, compliance issues, and the patient’s
CHAPTER 4
fuid retention. Among 27 patients treated 7 patients preexisting medical conditions. Mutational analysis is
achieved CCyR. A phase 2 study o vodobatinib in required ater ailure o imatinib or second-generation
patients who have received multiple prior TKIs is TKIs or ater progression to CML-AP or CML-BP.
ongoing.
PF-114 is a ourth-generation oral TKI that has
activity against wild-type and BCR-ABL1 mutations,
Allogeneic Stem Cell Transplantation
including T315I.120 A phase I trial in patients with TKI therapy has drastically changed the outcome o
CML-CP/CML-AP ailing two or more TKIs or T315I patients with CML-CP. Since 2000, the number o
mutations reported on 17 patients treated with PF-114 patients who underwent allo-SCT has decreased.
200 mg to 600 mg. The maximum tolerated dose was Although the majority o patients who achieved deep
600 mg (grade 3 psoriasis-like skin lesions). The rec- molecular remission have a stable clinical course,
ommended dose was 300 mg/day with 6 o 11 patients approximately 1% to 2% o patients develop TKI-
achieving MCyR; 4 o 11 patients achieved MMR. resistant CML every year. Given the increased prev-
alence o CML, the number o patients requiring
Selection of a Second- or Third-Line allo-SCT may start to increase. Allo-SCT is an impor-
Generation Tyrosine Kinase Inhibitor tant curative option in patients who ail at least two
TKIs or who harbor a T315I mutation i ponatinib is
Option not eective.124,125 Prior TKI exposure did not aect
Bone marrow examination should be perormed at the outcome ater allo-SCT lower burden o CML may
the time o treatment ailure to evaluate the phase o have a better outcome.125
CML and to document any evidence o clonal evolu- The nancial burden and availability o allo-SCT
tion. BCR-ABL1 kinase domain mutations should be and TKI therapy needs to be considered. The esti-
examined to guide the selection o the salvage TKI mated cost o allo-SCT, a curative one-time procedure,
option.103,104,121,122 Among second-generation TKIs, the is $500,000 in the United States but only $12,000 to
decreased sensitivity o TKI to BCR-ABL1 mutations $20,000 in developing countries.126,127 Given the low
were reported in vitro and in vivo.103,104,121,122 In the annual cost o genetic imatinib o $400 to $1000 per
presence o Y253H, E255K/V, and F359C/V, mutations year, allo-SCT should not be considered beore TKI
either dasatinib or bosutinib are avorite options. In therapy since the survival o patients with CML-CP
the presence o V299L and F317L mutations, nilotinib is approaching that o a general population12. Given
can be considered. In the absence o BCR-ABL1 muta- the estimated survival o CML-CP or 30+ years rom
tions, patient comorbidities, toxicity prole, and cost diagnosis, the total estimated cost would be $12,000
should be considered. ($400 × 30 years), which is comparable to the low-
Bosutinib has activity in most imatinib-resistant est cost o allo-SCT in developing countries. Generic
CML clones.89 Bosutinib may be a reasonable salvage imatinib therapy has also signicantly lower medical
option in patients ater rontline imatinib ailure and costs than allo-SCT. In patients with imatinib-resistant
who have comorbidities that may increase the risk o or -intolerant CML, the nancial comparison o medi-
adverse events observed with dasatinib or nilotinib cal costs with second- or third-generation TKIs versus
(eg, AOEs, pleural eusion, pulmonary hypertension). allo-SCT should be discussed.127 In nations with nan-
Common distinct adverse events include diarrhea and cial constraints, allo-SCT could be oered as a salvage
other GI complaints,123 and liver unction and renal treatment option. Recommendations or the role and
abnormalities. Patients with underlying kidney dys- timing o allo-SCT in patients with CML are outlined
unction should be monitored closely.67 in Table 4–8.128
In T315I-mutated CML, ponatinib should be con-
sidered. Ponatinib can be considered in patient with
at least one second-generation TKI resistance. Notable TREATMENT-FREE REMISSION (TFR)
toxicities include AOEs, pancreatitis, hypertension,
and severe skin rash. Although the risk o AEOs is not Multiple clinical trials o TFR evaluated the discon-
negligible, the treatment benet rom ponatinib out- tinuation o TKI therapy in patients who achieved
weighs the risks in most patients with a T315I muta- deep molecular remission to aim at a unctional cure
tion. The risks o AOEs can be minimized at reduced o CML. The Stop Imatinib (STIM) trial evaluated
doses and optimal management o cardiovascular risk treatment discontinuation in 100 patients on imatinib
actors. with undetectable transcripts or at least 2 years.129
TABLE 4–8 Recommendations Regarding the Role and Timing of Allogeneic Stem Cell Transplant
AlloSCT in Chronic Myeloid Leukemia
Status TKIs Allogeneic HSCT
CHAPTER 4
AP, BP Interim treatment to MRD I in remission
Imatinib o rst-line second-generation TKI Ponatinib I not responding well to ponatinib
treatment ailure in CP, with T315I mutation
Imatinib or rst-line second-generation TKI Long-term treatment with TKI in Third line ater second TKI treatment
treatment ailure in CP, no clonal evolution, no second-line setting ailure
mutations, good initial response to imatinib
Imatinib or rst-line second-generation TKI Interim treatment with ponatinib As soon as possible i no response to
treatment ailure in CP, with clonal evolution, eventually to MRD ponatinib
with mutations resistant to second-generation
TKIs, no CyR to imatinib
Older patients (age older than 70 years), ater Long-term treatment with TKI in Forego allo SCT or many years or
imatinib treatment ailure second-line setting or the patient lietime (maximize
quality o lie)
AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; CP, chronic phase; CyR, cytogenetic response; MRD, minimal residual disease; TKI, tyrosine kinase
inhibitor.
Molecular relapse was observed in 42 (61%) patients; discontinuation, 128 patients were treated with ront-
40 patients relapsed within 6 months o TKI discon- line imatinib (61%), rontline second-generation TKI
tinuation. At the time o molecular relapse, the reintro- (11%), and second line second-generation TKI (28%)
duction o imatinib achieved undetectable transcripts and entering rst TFR (TFR1).135 With a median ol-
in 26 (62%) patients and decreased transcript levels in low-up period o 6.5 years, 65 patients had a molecu-
16 (38%) patients. TFR was evaluated in multiple stud- lar relapse, including 9 (14%) relapses ater 2 years; 1
ies or patients with a rontline second-generation TKI patient relapsed at 6.4 years o TKI discontinuation.
with dierent criteria regarding the depth and duration Patients with late molecular relapse had a long-term
o molecular remission.130–133 period o BCR-ABL1 fuctuations between MR4 and
The European Stop Kinase Inhibitor (EURO-SKI) MMR. We have reported an anecdotal case o sudden
trial is the largest study o TKI discontinuation.133 It progression to myeloid BP under TFR.136 The incidence
included 821 patients with CML on rontline ima- o late molecular relapse and potential sudden progres-
tinib, nilotinib, or dasatinib in deep molecular remission to BP suggest the necessity o long-term ollow-up
sion, at least MR4 (BCR-ABL1 transcript [IS] <0.01%). o patients in TFR.
The molecular recurrence-ree survival, dened as the Initially, second-generation TKI therapy was
time period rom the date o TKI discontinuation to reported to have a relatively higher TFR rate compared
the date o the rst event (loss o MMR or death) or with that o rst-generation imatinib. Successul TFR
censoring was 52% at 2 years. When the same TKI without TKI therapy over years will benet younger
was resumed at the time o molecular relapse (ie,, the patients given that their expected survival is longer.137
loss o MMR) among 321 patients, 81% reachieved However, the expected percentages o TFR was low;
a molecular response (MMR or MR4). A multivariate approximately 20% to 25% and 30% to 45% with
logistic regression showed the duration o MR4 or imatinib and second-generation TKIs, respectively.
more than 3 years and the duration o TKI therapy or Multiple randomized clinical trials have consistently
more than 6 years were prognostic actors. We have reported that treatment with rontline second-gener-
reported similar ndings in our experience. With a ation TKIs achieved higher rates o deep molecular
median ollow-up period o 30 months, a longer dura- response, and more patients taking second-generation
tion o TKI therapy was associated with higher TFR TKIs will be potential candidates or TFR compared
rates. In patients who achieved a sustained MR4.5 with imatinib at the expense o nancial costs and
or more than 5 years, the TFR rate was 92%.134 This toxicities.58,73 The use o second-generation TKI will
suggests that longer duration o sustained MR4.5 may cost $917,056 additionally over 10 years to achieve
translate into improved TFR outcome. moderate improvement o QALY. The analysis o the
A long-term periodic molecular monitoring is incremental cost-eective ratio showed the use o sec-
mandatory during TFR. With a ollow-up over 15 ond-generation TKIs will cost more than $22,000,000
years o a single institution experience o treatment to achieve a gain o 1 QALY rom the replacement
o rontline generic imatinib with second-generation rontline TKI therapy than patients who progress rom
TKIs. The nancial burden o the selection o TKI CML-CP to CML-AP. The survival rate o de novo
and the decision o rontline TKI should consider the CML-AP with TKI therapy were 60%.14,149
potential cure raction careully.73–75 Allo-SCT should be considered in patients who
CHAPTER 4
Novel combinations o TKI have been under eval- progress rom CML-CP to CML-AP ater TKI therapy
uation in order to increase the raction o unctional ailure and who ail second- or third-generation TKI
cure. These combination strategies aim to target dor- in case o de novo CML-AP. The combination o TKI
mant CML stem cells in patients with deep molecular with chemotherapy is an alternative treatment option
remission over years. CML stem cells may stay in a or patients who are not optimal candidates or allo-
quiescent state, which may contribute to the relative SCT or as a bridge therapy to allo-SCT in remission.
resistance to TKI therapy.138 The strategies include TKI therapy beore allo-SCT does not increase the
the combination o TKI with pegylated IFN-α2b,139–142 risk o transplant-related mortality.152–154 When allo-
Bcl-2 inhibitors such as venetoclax,143 JAK2 inhibi- SCT is perormed in patients in CML-AP or CML-BP,
tors,144 hypomethylating agents,145 and immune-medi- posttransplant maintenance TKI therapy should be
ated treatments such as PD-1 inhibitors and dendritic considered.
cell vaccination.146
FUTURE PERSPECTIVES
ADVANCED STAGE CHRONIC
MYELOID LEUKEMIA Since the advent o TKI therapy, the survival o
patients with CML is approaching that o the gen-
Second- or third-generation TKIs should be consid- eral population. In 2021, therapeutic options have
ered as initial therapy or patients with advanced expanded, including ve commercially available TKIs
stage CML ollowed by allo-SCT.147–149 Although the (imatinib, dasatinib, nilotinib, bosutinib, and pona-
addition o TKIs to chemotherapy improves survival tinib), omacetaxine, and traditional agents, including
in patients with CML-BP, survival remains subop- hydroxyurea, IFN-α, cytarabine and hypomethylating
timal.150 Combinations o TKIs and chemotherapy agents. Optimal survival requires optimal monitoring
achieved response rates o 40% and 70% to 80% in or signs o resistance, optimal decisions regarding
nonlymphoid and lymphoid CML-BP. The median switching TKI therapy in case o resistance or intoler-
survivals are 6-12 months and 12-24 months, respec- ance, compliance and adherence to TKIs, and consid-
tively. The median survival time o 477 patients with ering allo-SCT in case o multiple TKI ailures. Once in
CML-BP treated with a TKI was 12 months.15 Stem deep molecular remission over years o TKI therapy,
cell transplant coners the best outcome or patients patients become potential candidates or TFR to aim
in remission ater the combination o TKI with inten- at unctional cure without TKI therapy. The increase
sive chemotherapy. The combination o fudarabine- in the raction o unctional cure without TKI therapy
high dose cytarabine-idarubicin with ponatinib 30 mg/ has a signicant impact on the nancial burden o
day achieved responses in 11/16 (69%) patients with patients and their amilies, as well as on the health
CML-BP.151 Five patients achieved MMR ater induc- care systems, given the prevalence o CML is expected
tion therapy; 9 patients proceeded to allo-SCT. The to increase in the United States and worldwide.
survival rate was 50% at 12 months. Thereore, it is important to continue the research
Allo-SCT remains the only curative therapy or aimed at long-term TFR in patients with CML. TKIs-
CML-AP and CML-BP (cure rates o 40% and 10% based combinations with available (Bcl-2 inhibitors,
to 20%, respectively). The presence o clonal evolu- JAK2 inhibitors, peg IFN-α2, omacetaxine, decitabine,
tion as the only AP criterion is associated with EFS immunotherapy) or other investigational therapies are
rates o 60%. In patients with CML-AP treated with in progress. These strategies may eradicate CML stem
TKI therapy, 80% achieved hematologic response; the cells and obviate the need or indenite TKI therapy
estimated 4-year survival rate was 40% to 55%. In to maintain optimal survival. Further understanding
patients with CML-BP, the response rate was 40% and o the downstream pathways o BCR-ABL1 signaling
the median survival 9 to 12 months. TKI-naïve patients may help develop new strategies to target CML stem
with de novo CML-AP have a higher survival rate with cells.

J At diagnosis, all patients with leukocytosis and sus- J To minimize the risk o arterio-occlusive AOEs, it
pected or CML should undergo bone marrow aspi- may be reasonable to start ponatinib 45mg/day in
ration and biopsy to establish the diagnosis, assess T315I-mutated CML and 30 mg/day in other resis-
CHAPTER 4
percentages o blasts and basophils, and evaluate tant CML-CP, and lower the dose to 15 mg/day when
the presence o clonal evolution. BCR-ABL1 transcripts below 1% (IS) are achieved.
J With multiple TKIs available or patients with newly J The use o allogeneic-SCT and the switch to other
diagnosed CML-CP, there are several considerations TKI should not be considered or patients who
when choosing a starting agent such as patient sta- achieve CCyR without MMR or deep molecular
tus (age and comorbidities, TKI toxicity prole), cost response.
o treatment, and disease characteristics and risk J A long-term periodic molecular monitoring is man-
score. datory during TFR. Patients with late molecular
J Given the equivalent ecacy and lower toxicity relapse had a long-term period o BCR-ABL1 tran-
o lower dose dasatinib, dasatinib 50 mg/day has scripts fuctuations between MR4 and MMR. The
become our standard o care or rontline therapy incidence o late molecular relapse suggest the
o patients with CML-CP. necessity o long-term ollow-up o patients in TFR.
19. Wang W, Cortes JE, Tang G, et al. Risk stratication o chromo-

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high-dose imatinib in early chronic phase CML patients who 125. Nicolini FE, Basak GW, Kim DW, et al. Overall survival with
have suboptimal molecular responses to standard-dose ima- ponatinib versus allogeneic stem cell transplantation in Phila-
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109. Sasaki K, Kantarjian H, Jabbour E, et al. Frontline therapy tion. Cancer. 2017;123:2875-2880.
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112. Zhou T, Commodore L, Huang WS, et al. Structural mecha- maintained complete molecular remission or at least 2 years:
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113. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial o pona- imatinib cessation or CML patients with stable undetectable
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115. Cortes JE, Lomaia E, Turkina A, et al. Interim analysis (IA) o update o the ENESTreedom study. J Cancer Res Clin Oncol.
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116. Wylie AA, Schoeper J, Jahnke W, et al. The allosteric inhibi- ular relapses ater dasatinib or nilotinib discontinuation in
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Med. 2019;381:2315-2326. SKI): a prespecied interim analysis o a prospective, multicen-
118. Jiang Q, Hunag X, Chen Z, et al. An updated saety and ecacy tre, non-randomised, trial. Lancet Oncol. 2018;19:747-757.
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BCR-ABL tyrosine kinase inhibitor (TKI), in patients with TKI inhibitor discontinuation in patients with chronic myeloid
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119. Cortes J, Kim DW, Nicolini F, et al. Phase 1 trial o K0706, 2019;12:1.
a novel oral BCR-ABL1 tyrosine kinase inhibitor (TKI): in 135. Rousselot P, Loiseau C, Delordd, et al. A report on 114 patients
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delphia positive acute lymphoblastic leukemia (Ph+ ALL) ail- tion during a 15 years period: long term ollow-up, late molecu-
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2019;134(suppl 1):4158. 136. Alayez M, Richard-Carpentier G, Jabbour E, et al. Sudden
120. Turkina AG, Vinogradova O, Lomaia E, et al. PF-114: a blastic transormation in treatment-ree remission chronic
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122. Hughes T, Saglio G, Branord S, et al. Impact o baseline lar response rates in patients with low- or intermediate-risk
BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia. Blood. 2011;118:3228-3235.
140. Hjorth-Hansen H, Stentot J, Richter J, et al. Saety and ecacy 147. Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment
o the combination o pegylated intereron-α2b and dasatinib o chronic myeloid leukemia in accelerated phase ater ima-
in newly diagnosed chronic-phase chronic myeloid leukemia tinib ailure: the START a trial. J Clin Oncol. 2009;27:3472-3479.
patients. Leukemia. 2016;30:1853-1860. 148. le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients
141. Hochhaus A, Burchert A, Saussele S, et al. Nilotinib vs nilotinib with Ph+ chronic myeloid leukemia in accelerated phase ol-
CHAPTER 4
plus pegylated intereron α (Peg-IFN) induction and nilotinib or lowing imatinib resistance or intolerance: 24-month ollow-up
Peg-IFN maintenance therapy or newly diagnosed BCR-ABL1 results. Leukemia. 2012;26:1189-1194.
positive chronic myeloid leukemia patients in chronic phase 149. Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyro-
(TIGER study): the addition o Peg-IFN is associated with sine kinase inhibitors as initial therapy or patients with
higher rates o deep molecular response. Blood. 2019;134(suppl chronic myeloid leukemia in accelerated phase. Clin Lymphoma
1):495. Myeloma Leuk. 2014;14:155-162.e1.
142. Ko TK, Chuah CT, Huang JW, et al. The BCL2 inhibi- 150. Strati P, Kantarjian H, Thomas D, et al. HCVAD plus imatinib
tor ABT-199 signicantly enhances imatinib-induced cell or dasatinib in lymphoid blastic phase chronic myeloid leuke-
death in chronic myeloid leukemia progenitors. Oncotarget. mia. Cancer. 2014;120:373-380.
2014;5:9033-9038. 151. Copeland M, Slade D, Byrne J, et al. FLAG-IDA and ponatinib
143. Carter BZ, Mak PY, Mu H, et al. Combined targeting o BCL-2 in patients with blast phase chronic myeloid leukaemia: results
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kemia stem cells. Sci Transl Med. 2016;8:355ra117. point trial. Blood. 2019;134(suppl 1):497.
144. Gallipoli P, Cook A, Rhodes S, et al. JAK2/STAT5 inhibition by 152. Jabbour E, Cortes J, Kantarjian H, et al. Novel tyrosine kinase
nilotinib with ruxolitinib contributes to the elimination o CML inhibitor therapy beore allogeneic stem cell transplantation
CD34+ cells in vitro and in vivo. Blood. 2014;124:1492-1501. in patients with chronic myeloid leukemia: no evidence or
145. Schnekenburger M, Grandjenette C, Ghel J, et al. Sustained increased transplant-related toxicity. Cancer. 2007;110:340-344.
exposure to the DNA demethylating agent, 2’-deoxy-5- 153. Oehler VG, Gooley T, Snyder DS, et al. The eects o ima-
azacytidine, leads to apoptotic cell death in chronic myeloid tinib mesylate treatment beore allogeneic transplantation or
leukemia by promoting dierentiation, senescence, and chronic myeloid leukemia. Blood. 2007;109:1782-1789.
autophagy. Biochem Pharmacol. 2011;81:364-378. 154. Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic
146. Held SA, Heine A, Mayer KT, et al. Advances in immuno- administration o imatinib ater hematopoietic cell transplanta-
therapy o chronic myeloid leukemia CML. Curr Cancer Drug tion or high-risk Philadelphia chromosome-positive leukemia.
Targets. 2013;13:768-774. Blood. 2007;109:2791-2793.
5 Myelodysplastic Syndromes:
The MD Anderson Cancer Center
Approach
Kelly Chien
Carlos Bueso-Ramos
Guillermo Garcia-Manero
KEY CONCEPTS
 The term myelodysplastic syndrome (MDS) reers to a very  For patients with lower-risk disease, treatment approaches
heterogeneous group o myeloid disorders. In a majority include growth actors, iron chelation, luspatercept,
o patients, MDS results rom deects in a primitive hema- lenalidomide (or del5q- MDS), hypomethylating agents
topoietic stem cell compartment. (HMAs; azacitidine or decitabine) or antithymocyte glob-
 Individuals with evidence o clonal hematopoiesis are at ulin–-based therapy (or patients with hypoplastic MDS).
increased risk o developing MDS. Allogeneic stem cell transplantation (allo-SCT) is reserved
or younger patients with poor risk eatures.
 Prognosis is calculated using a number o variables, includ-
ing degree o cytopenia, percentage o blasts, cytogenetic  For patients with higher risk disease, the main treatment
alterations, and more recently genomic annotation. options include the HMAs and less requently acute
myeloid leukemia–like therapy. Allo-SCT should be con-
 Using either the International Prognostic Scoring System
sidered in candidate patients early in the course o the
or the Revised International Prognostic Scoring System,
disease in responding patients. Clinical trials should be
patients are divided into those with lower and higher risk
considered or a majority o patients with MDS.
disease.
Myelodysplastic syndromes (MDSs) reer to a group we summarize our knowledge o MDS and the treat-
o hematopoietic disorders characterized by ineec- ment approach we use at MD Anderson Cancer Center
tive hematopoiesis and increased risk o transorma- (MDACC).
tion to acute myeloid leukemia (AML). The median
age o patients with MDS is 70 to 75 years. It is likely
that environmental actors play an important role in THE MD ANDERSON APPROACH TO
the pathogenesis o this disease. MDSs are classied PATIENTS WITH MyElODySPlASTIC
according to the World Health Organization (WHO) SyNDROMES
criteria, and a number o prognostic scores can be used
to calculate survival and risk o transormation. Cyto- Approximately 350 to 400 patients are reerred to
genetic, genomic, and epigenetic alterations are com- MDACC annually with a diagnosis o MDS, and
mon in MDS and help in the prediction o prognosis nearly 20% o these patients receive a dierent diag-
and potentially in the selection o therapy. Over the nosis. In most instances, the nal diagnosis is AML or
past decade, we have witnessed signicant improve- a orm o higher risk MDS. Other benign and malig-
ments in supportive care and therapeutic modalities nant conditions are also diagnosed. In a study o
or patients with MDS. These include growth actors, 915 patients reerred to MDACC between 2005 and
luspatercept, immune modulatory agents (lenalido- 2009,12% o patients were reclassied ater evaluation
mide), and hypomethylating agents (HMAs; 5-azaciti- at MDACC using very strict criteria.1 This justies our
dine and decitabine), with new oral ormulations. We practice to repeat a conrmatory bone marrow aspira-
also better understand patient subgroups, such as those tion and biopsy at the time o initial MDS evaluation
with hypomethylating ailure disease. In this chapter, at MDACC.
91
Ater the diagnosis is conrmed, the next important our group is to stratiy patients based on cytogenetics.
step is to calculate the “risk” o the patient. Many clini- Younger patients with normal karyotypes are oered
cians and investigators still use the International Prog- induction therapy with an AML-like approach ol-
nostic Scoring System (IPSS)2 score to perorm such lowed when possible by allo-SCT. In contrast, younger
CHAPTER 5
analysis, but more precise models, such as the Revised patients with abnormal karyotypes receive HMA-based
International Prognostic Scoring System (IPSS-R), have therapy ollowed by allo-SCT. It is not our routine to
been developed.3–5 Patients with low or intermediate-1 proceed with up-ront transplant in patients with excess
risk by the IPSS or those with less than 10% blasts in blasts. Older patients benet signicantly rom the use
the bone marrow are considered as having lower-risk o HMAs, and there is no upper age limit that may
disease, and those with excess blasts or intermediate-2 contraindicate their use.11 Finally, the group o patients
or high-risk disease are considered as having higher with higher risk disease and hypomethylating ailure
risk disease. When using the IPSS-R, patients with very constitute a major unmet medical need.12
low, low, and some subsets o intermediate risk are A comprehensive review o current knowledge
considered as having lower-risk disease, whereas those in MDS is provided next. Current areas o intense
with high, very high and some subsets o intermediate research are the development o newer orms o
risk are considered as having higher risk disease.6 therapy or patients with newly diagnosed disease
Patients with lower-risk disease can be candidates and strategies or patients who have relapsed or not
or a wide range o interventions, depending on their responded to HMA-based therapy.
specic characteristics and transusion needs. Patients
with minimal cytopenias, who are transusion inde-
pendent, have a low percentage o blasts in the bone EPIDEMIOlOGy AND ETIOlOGy
marrow, and have normal cytogenetics are more re-
quently observed because their 4-year survival rate is The incidence o MDS increases with age. Most patients
close to 80%.4 At the other end o the spectrum, older diagnosed with this condition are older than 60 years
patients with signicant cytopenias and transusion old; the median age at diagnosis is 75 years.13 The inci-
needs can have very poor prognoses, particularly i dence is higher in men than women, with a 2:1 ratio.13
their cytogenetics are abnormal.4 The median survival The incidence in the United States is 30 to 35 individu-
time o these patients is less than 12 months; around als per million per year with a relative yearly increase
60% to 70% o patients with MDS are in this category, in the reported incidence, probably related to increase
but there are ew interventions known to alter the nat- awareness o the disease and reporting eorts.14
ural history o these patients. Transusion and growth The risk o developing MDS is related to the indi-
actor support are usually initiated. Interventions, such vidual’s racial background. In the United States, the
as lenalidomide, have signicant activity in improving incidence is highest in the white population.13 Patients
red blood cell (RBC) counts in patients with deletion with MDS rom Asia present at a younger age.15 The
o chromosome 57 but are signicantly less active in underlying cause o this phenomenon is not known
patients without this alteration.8 The role o the HMAs but may refect genetic dierences between dierent
5-azacitidine and decitabine is less clear in this situ- racial groups. Asian patients have a similar requency
ation, although they are requently used. allo-SCT is o karyotype abnormalities as European and American
not requently used up ront in patients with lower- cohorts, although they may have less requent altera-
risk disease,9 and delaying transplantation until the tions o chromosomes 5 and 7.15–17 The combination
time o progression is associated with longer survival o younger age at diagnosis and lack o chromosome
times even i transplant outcomes are poorer when 7 alterations can explain the longer survival times
perormed at that time. A new subset o patients has observed in patients rom Asia.
emerged with lower-risk disease but also with hypo- There is no known cause o MDS, but genetic or
methylating ailure.10 The prognosis o these patients environmental risk actors may contribute. Genetic
is poor, and new investigational strategies are needed. syndromes, such as Down syndrome, Bloom syn-
Treatment decisions are relatively simpler or patients drome, and Fanconi anemia, are associated with an
with higher risk MDS. The data with HMA indicate increased risk o MDS, which oten presents earlier
that treatment with these agents improves survival sig- in lie.18,19 Genetic polymorphisms that infuence the
nicantly compared with supportive care or low-dose activity o enzymes responsible or metabolizing toxic
chemotherapy approaches. The optimal approach or chemicals or chemotherapy drugs may infuence an
patients younger than age 60 to 65 years with MDS is individual’s predisposition to MDS. Polymorphisms
unclear. These patients can be treated with HMA or an have been described in the cytochrome p450 3A,
AML-like induction therapy or can be considered or glutathione-S-transerase, and NAD(P)H quinine oxi-
up-ront allo-SCT. No study has compared these treat- doreductase enzyme systems that increase the risk o
ments in younger patients. An approach ollowed by developing myeloid malignancies.20–22
Chapter 5 Myelodysplastic Syndromes: The MD Anderson Cancer Center Approach 93
Environmental agents may contribute to the devel- and molecular studies are essential. Morphologic
opment o MDS by causing toxic damage to hema- assessment o the disease is still required or MDS.
topoietic stem cells. A causal relationship between Cytogenetic studies may conrm the presence o clonal
occupational exposures to benzene and radiation and hematopoiesis and provide additional important prog-
the development o myeloid malignancy has been nostic inormation. Analysis o specic gene mutations,
CHAPTER 5
demonstrated.23 Exposure to organic solvents and pes- such as TET2, DNMT3A, ASXL1, TP53, splicing actors,
ticides has also been implicated in the development o NRAS, FLT3, IDH1, IDH2, and JAK2, may improve our
MDS.24–26 There is no correlation between MDS and prognostic and predictive evaluation and allow or the
socioeconomic status.25 use o targeted interventions using selective inhibitors
The most signicant risk actor or the develop- (eg, FLT3, JAK2, or IDH1/2 inhibitors) or earlier consid-
ment o MDS is previous exposure to chemotherapy eration o allo-SCT. However, it should also be noted
or radiotherapy used to treat other cancers. Treatment- that these molecular abnormalities31 may be present in
related MDS (t-MDS) constitutes a minority o MDS older individuals with or without cytopenias and may
diagnoses but may be increasing in prevalence with not necessarily point to an MDS diagnosis.
improved survival rates ater successul cancer thera- Clonal hematopoiesis o indeterminate potential is
pies or tumors. Usually, t-MDS presents 5 to 6 years a phenomenon in which clonal somatic mutations are
ater initial cancer treatment and generally has a poor present in hematopoietic cells rom older individuals
prognosis.27 Patients treated or lymphoma are at risk with no evidence o a hematologic disorder.32,33 These
o this long-term complication.28 Patients who undergo patients have been ound to have an increased risk o
autologous hematopoietic stem cell transplanta- hematologic neoplasms, therapy-related myeloid neo-
tion have a higher risk, approximately 10% to 15% plasms, and cardiovascular disease.34–37 Whereas the pres-
o developing treatment-related MDS or AML, with ence o a somatic mutation in the presence o cytopenias
incidence rates in some centers o up to 10%.29 In our with no diagnostic criteria or MDS is considered clonal
experience with t-MDS at MDACC in 281 patients, cytopenia o undetermined signicance (CCUS),38,39
most o the risk was associated with complex cytoge- individuals with cytopenias but no dysplasia are con-
netics or presence and alteration o chromosome 7.30 sidered to have idiopathic cytopenia o undetermined
signicance (ICUS). The distinction between ICUS and
CCUS is important because the risk o developing MDS
ClINICAl AND lABORATORy and AML increases rom 9% to 82% at 5 years in the
FEATURES presence o highly predictive mutation patterns.39,40
Most patients with MDS are diagnosed incidentally

during routine complete blood cell count (CBC) anal- BONE MARROW FEATURES
ysis or because o nonspecic symptoms. Anemia is
the most common cytopenia in MDS and is associated Morphologic Analysis
with atigue. A lower percentage o patients presents
with bleeding or bruising secondary to thrombocyto- Table 5–1 shows the dierent subsets o MDS under
penia or with inections related to neutropenia. Physi- the 2016 WHO MDS classication.41 Morphologic
classication o MDS is based on a 500-cell dieren-
cal examination is oten normal. Hepatosplenomegaly
tial count on the bone marrow aspirate and leukocyte
may be present in patients with chronic myelomono-
cytic leukemia (CMML) or overlap myeloprolierative
neoplasms. A change in the severity o cytopenia or TABlE 51 Cassifcation o Meodspastic
rapid worsening o symptoms may indicate disease Sndromes (MDS) According to 2016 Word
transormation. Patients suspected to have MDS trans- Heath Organization Criteria
ormation require prompt investigation because 20%
to 30% o patients develop acute leukemia throughout MDS with single-lineage dysplasia (MDS-SLD)
their disease course.2 MDS with multilineage dysplasia (MDS-MLD)
Initial assessment should include a CBC, reticulo-
MDS with ring sideroblasts (MDS-RS)
cyte count, and serum chemistry, including vitamin B12
and olate, iron studies with erritin, and erythropoietin MDS-RS with single-lineage dysplasia (MDS-RS-SLD)
(EPO) level examination. Other causes o cytopenias or MDS-RS with multilineage dysplasia ()MDS-RS-MLD)
MDS-mimicking syndromes (eg, HIV [human immuno- MDS with isolated del(5q)
deciency virus], other inections, autoimmune disor- MDS with excess blasts (MDS-EB-1, -2)
ders, or copper deciency) should be ruled out through
MDS, unclassiable (MDS-U)
appropriate tests. A bone marrow aspirate and biopsy
with samples taken or an iron stain and cytogenetic Reractory cytopenia o childhood
dierential perormed on the blood smear. This analy- antituberculous therapies, vitamin B12 and olate de-
sis determines the percentage o blasts present in the ciency, HIV inection, excessive alcohol consumption,42
blood and bone marrow and provides an assessment and occasionally normal aging.44 Dysplastic eatures are
o the number o myeloid lineages involved in the dys- commonly observed ater chemotherapy or with the
CHAPTER 5
plastic process, and the iron stain determines the pres- therapeutic use o granulocyte colony-stimulating ac-
ence and number o ring sideroblasts.42 tor (G-CSF). These diagnoses should be assessed in the
As shown in Figure 5–1, blood cell abnormalities on history and may require exclusion with urther labora-
the peripheral blood smear are variable.42 RBCs may tory testing. Diagnostic diculties may occur in patients
be macrocytic and requently display anisopoikilocy- with marked hypocellularity o the bone marrow and in
tosis. Polychromasia or basophilic stippling may be patients with prominent brosis because there are oten
present. Dysplastic granulocytes may show abnor- very ew cells in the aspirate sample to allow morpho-
mal olding o the nucleus, and cytoplasmic granules logic assessment o dysplasia. For patients with promi-
are oten reduced or absent. Platelets are o variable nent hypocellularity o the marrow, it may be dicult to
size and may also be hypogranular. The presence o distinguish rom aplastic anemia, or which morphologic
circulating blast cells or an excess o monocytes is dysplasia o the erythroid lineage may also be observed.
important or the classication o high-risk MDS and In cases o marked brosis, bone marrow aspiration is
CMML, respectively. oten unsuccessul. Some patients with mild dysplastic
Denitive diagnosis requires a bone marrow aspi- changes in the bone marrow and a normal karyotype
rate and biopsy. The bone marrow is usually normo- are dicult to denitively diagnose at initial presenta-
cellular or hypercellular, refecting that hematopoiesis tion and may require a period o observation to conrm
is ineective. Abnormal maturation o hematopoietic the underlying diagnosis. These patients require review
cells results in a variable proportion o myeloblasts with repeat investigations perormed in 3 to 6 months.
that are signicantly increased in the more aggressive
MDS. Morphologic abnormalities ound in the nucleus
o erythroblasts include nuclear budding, internuclear
Cytogenetic and Molecular Analyses
bridging, karyorrhexis, multinuclearity, and megalo- A cytogenetic abnormality is ound in 40% to 50%
blastoid changes (see Fig. 5–1). Cytoplasmic eatures o patients with primary MDS and lower-risk disease;
include the presence o ring sideroblasts and abnor- it is higher in patients with more advanced MDS.
mal vacuolization. Abnormal or absent granulation Cytogenetic analysis o hematopoietic cells derived
is a common eature o dysplastic granulocyte series. rom the bone marrow aspirate provides important
Aberrant nuclear olding o the neutrophil precursor prognostic and predictive inormation and may direct
can produce a dysplastic bilobed nucleus, the pseudo– therapy (eg, lenalidomide therapy with deletion 5q or
Pelger-Huet anomaly. Megakaryocytes may have a earlier allo-SCT with complex or adverse karyotypes).
very variable morphology, and a small dysplastic orm A karyotypic abnormality provides evidence or the
called the micromegakaryocyte is a typical nding. A presence o a clonal blood disorder, which may be par-
normal megakaryocyte has a polyploid nucleus that ticularly important i the morphologic changes are not
can be altered with dysplasia to produce hypolobula- clear. Typically, cytogenetic analysis assesses 20 bone
tion or nuclei that are dispersed throughout the cell. marrow metaphases.43 Multiple dierent cytogenetic
The bone marrow biopsy provides the best assessment abnormalities have been described and are summa-
o the overall cellularity and allows examination o the rized in Table 5–2.45 No specic cytogenetic abnor-
architecture o the marrow and surrounding bone (Fig. malities characterize MDS. Unlike AML and chronic
5–2). The presence o brosis can be assessed on biopsy myeloid leukemia, genetic translocations are rare in
with specic stains or reticulin and collagen. In normal MDS, but deletions are common.
bone marrow, the immature blast cells are requently The presence or absence o a cytogenetic abnormal-
located near the endosteal surace. In MDS, these cells ity has a marked infuence on prognosis.45 The median
may be distant to this site and orm aberrant clusters survival time o patients with normal karyotypes is
reerred to as abnormal localization o immature pre- approximately 53 months compared with less than 12
cursors. Immunohistochemical staining o biopsies can months or patients with three or more cytogenetic
aid diagnosis, with CD34 staining to identiy blast and abnormalities, known as a complex karyotype. Del(5q)
progenitor cells and CD42 or CD62 or quantitation and del(20q) are associated with a avorable prognosis.
and assessment o megakaryocytes (see Fig. 5–2).43 However, when these abnormalities are present in asso-
Nonclonal diseases may cause dysplastic morpho- ciation with other cytogenetic abnormalities, especially
logic changes in blood cells. Secondary causes o dys- as a component o a complex karyotype, the prognosis is
plasia should be excluded in the initial assessment and poor. Abnormalities o chromosome 7, usually deletions,
can potentially complicate the diagnosis. Blood cell are associated with a poor prognosis regardless o the
dysplasia is seen with exposure to heavy metals or presence or absence o other abnormalities. Complex
A B
CHAPTER 5
C D
E F
FIGURE 5–1 Morphologic eatures o peripheral blood and bone marrow in the myelodysplastic syndromes. A. Peripheral
blood lm rom a patient with reractory anemia with excess blasts-1. The erythrocytes show hypochromasia, anisocytosis,
and macroovalocytes. There is also an occasional blast (center). B. Peripheral blood lm rom a patient with reractory cytope-
nia with multilineage dysplasia demonstrating pseudo–Pelger-Huet cell (center) with hypercondensed chromatin and bilobed
nuclei and hypogranular cytoplasm. C. Dysplastic small megakaryocytes, some with monolobated or with separated nuclei
and mature granular cytoplasm in the bone marrow aspirate, rom a patient with reractory anemia with excess blasts. D.
Increased blasts, dysgranulopoiesis, and dyserythropoiesis in the bone marrow aspirate rom a patient with reractory anemia
with excess blasts. E. Ring sideroblasts and Pappenheimer bodies rom a patient with reractory anemia with ring sideroblasts.
F. Hypercellular (100%) bone marrow biopsy with increased immature cells and dysplastic megakaryocytes in a 70-year-old
man with reractory anemia with excess blasts.
A
cytogenetic abnormalities are more requently observed
in patients with increased marrow blasts. Progressively
worse prognoses are observed with increasing karyo-
typic complexity. Patients with six or more abnormali-
CHAPTER 5
ties have a very poor median survival time o 5 months.45

In 2012, a comprehensive scoring cytogenetic system
was developed using data rom 2902 patients.46 This
analysis resulted in 19 new cytogenetic categories and
5 prognostic subgroups, as shown in Figure 5–3, which
serves as the basis or the IPSS-R scoring system.5
Treatment-related MDS has a particularly high inci-
dence o cytogenetic abnormalities, with karyotypic
changes observed in 70% to 90% o cases.27,30,45 A high
incidence o abnormalities is associated with an una-
vorable prognosis or this group o patients. Abnormal-
ities o chromosomes 5 and 7 are requently observed
B
ater exposure to alkylating agents.47,48 Translocations
involving 11q23 are seen ater treatment with topoi-
somerase II inhibitors.47
The high requency o chromosomal deletions has
prompted interest in the identication o epigenetic
repressive alterations, such as aberrant DNA methyla-
tion in MDS. Aberrant DNA methylation o multiple
promoter CpG islands has been associated with poor
prognosis in MDS.49 At this point, we do not have evi-
dence o specic molecular pathways that are epige-
netically inactivated in MDS.
An association between a genetic abnormality and
disease phenotype was reported in a ew specic subsets
o MDS. An example is the 5q- syndrome.50 A minority
o patients with an interstitial deletion o chromosome
C 5q display an indolent anemia with relative preservation
o the platelet count associated with hypolobated mega-
karyocytes in the bone marrow (Fig. 5–4). This array o
ndings is called the 5q- syndrome and is recognized as
a separate diagnostic entity in the current WHO classi-
cation. The genetic deect within the deleted region that
is responsible or the disease is not known. Research
has ocused on one candidate gene, SPARC, that may
potentially contribute to the malignant phenotype.51
CTNNA1 is another gene on chromosome 5q identied
to be important in MDS and AML but without specic
eatures o the 5q- syndrome.52 RPS14 was identied as
haploinsucient in 5q- MDS and is involved in ribo-
somal biogenesis; its deciency has a role in anemia in
FIGURE 5–2 Morphologic and immunohistochemical ea- this syndrome.53 It is likely that a complex network o
ture o bone marrow biopsy in the myelodysplastic syn- genes cooperate in the pathogenesis o this syndrome.
dromes. A. Trephine bone marrow biopsy with numerous Indeed, microRNA 145 and 146a have been ound to be
dysplastic monolobated megakaryocytes in a 60-year-old involved in the biology o 5q- syndrome.54
emale patient with reractory anemia with excess blasts A small number o patients have been described
type 1. B. CD61 immunohistochemical stain highlighting with a deletion o 17p associated with abnormali-
many dysplastic micromegakaryocytes. CD61 may be help- ties in the p53 gene. This specic disorder has a poor
ul in detecting dysplastic micromegakaryocytes to aid in
prognosis and may be suspected when morphologic
conrming dysmegakaropoiesis and abnormal translocation
characteristics o prominent dysgranulopoiesis, includ-
o megakaryocytes to endosteal suraces. C. CD34 immu-
nohistochemical staining highlighting the presence o an ing neutrophils exhibiting the Pelger-Huet anomaly
increased number o blasts and increased blood vessels. and abnormal vacuolization, are present.55 Acquired
TABlE 52 Frequenc o Common Karotpic Abnormaities Among 2008 Word Heath Organization
(WHO) Cassifcations and French-American-British (FAB) Subgroups
Karyotype, n (%)
CHAPTER 5
Classication Patients (n) Normal del(5q) –7/del(7q) +8 –20/del(20q) Complex
All FAB 1949 942 (48.3) 295 (15.1) 209 (10.7) 162 (8.3) 86 (4.4) 282 (14.5)
RA 573 267 (46.6) 139 (24.3) 30 (5.2) 37 (6.5) 31 (5.4) 47 (8.2)
RARS 252 147 (58.3) 23 (9.1) 24 (9.5) 14 (5.6) 9 (3.6) 20 (7.9)
RAEB 415 179 (43.1) 71 (17.1) 60 (23.8) 39 (9.4) 21 (5.1) 98 (23.6)
RAEB-t 305 132 (43.3) 38 (12.5) 50 (16.4) 30 (9.8) 16 (5.2) 68 (22.3)
CMML 272 170 (62.5) 4 (1.5) 23 (8.5) 18 (6.6) 2 (<1) 12 (4.4)
All WHO 595 285 (47.8) 110 (18.5) 53 (8.9) 40 (6.7) 22 (3.7) 71 (11.9)
5q- syndrome 61 0 (0.0) 61 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
RA 56 38 (67.9) 3 (6.5) 5 (10.9) 1 (2.2) 1 (2.2) 6 (13.0)
RARS 26 23 (88.5) 0 (0.0) 0 (0.0) 1 (3.8) 0 (0.0) 0 (0.0)
RCMD 164 88 (53.7) 11 (6.7) 20 (12.2) 12 (7.3) 8 (4.8) 18 (11.0)
RCMD-RS 77 34 (44.2) 8 (10.4) 8 (10.4) 8 (10.4) 3 (3.9) 12 (15.6)
RAEB-I 90 42 (45.7) 16 (17.8) 10 (11.1) 5 (5.6) 4 (4.4) 15 (16.7)
RAEB-II 121 60 (49.6) 11 (9.1) 8 (6.6) 13 (10.7) 5 (4.1) 19 (15.7)
RA, reractory anemia; RAEB-I, reractory anemia with excess blasts-I; RAEB-II, reractory anemia with excess blasts-II; RAEB-T, reractory anemia with excess blasts
in transormation; RARS, reractory anemia with ring sideroblasts; RCMD, reractory cytopenia with multilineage dysplasia; RCMD-RS, reractory cytopenia with
multilineage dysplasia with ring sideroblasts
hemoglobin H disease produces RBC changes on the minority o patients with MDS, and specic gene
blood smear reminiscent o a-thalassemia. This RBC deects are not identied in most patients.
phenotype is secondary to decreased expression o Several groups have used large-scale single-nucle-
a-globin within the bone marrow MDS clone and otide polymorphism (SNP) arrays in MDS.57 This
is associated with a mutation in the ATRX gene in has allowed the identication o areas o microdele-
most cases.56 These rare syndromes represent a small tions and uniparenteral disomy in MDS.58 It is likely
Very good Good Intermediate Poor Very poor

n = 80 (2.9%) n = 1844 (65.9%) n = 578 (20.7%) n = 101 (3.6%) n = 196 (7.0%)
Single: Single: Single: Single: Complex:

del(11q) Normal –7/7q– der(3)(q21)/ >3
–Y der(1;7) +8 der(3)(q26) abnormalities
del(5q) iso(17q)
del(12p) +19
Double:
del(20q) +21
Double incl.
Any other
–7/7q–
individual
Double: clones
Double incl. Complex:
del(5q) 3
Double: abnormalities
Any other
double
Median OS, Median OS, Median OS, Median OS, Median OS,
60.8 months 48.5 months 25.0 months 15.0 months 5.7 months
HR, HR, HR, HR, HR,
0.47 (0.3–0.7) 1.00 (0.8–1.3) 1.59 (1.4–1.9) 2.83 (2.2–3.7) 4.37 (3.5–5.5)
FIGURE 5–3 Cytogenetic score and corresponding prognoses. HR, hazard ratio; OS, overall survival.
B
associated with poor prognoses.31 Correlation o spe-
A
cic genomic alterations with gene expression patterns
may explain some o the phenotypic eatures o the
disease.61
CHAPTER 5
Other Bone Marrow Studies

Flow cytometry is not required or the routine diag-
nosis o MDS, but it may sometimes provide valuable
supplementary inormation. Flow cytometry can con-
rm the presence o specic myeloid lineages within
the marrow and may also identiy aberrant expres-
sion o cell surace markers indicative o a clonal cell
population. This may have diagnostic signicance in
FIGURE 5–4 A and B. Bone marrow morphology o myelo- conrming abnormal hematopoiesis, particularly in
dysplastic syndrome with deletion o chromosome 5.
the setting o inconclusive morphologic changes and
a normal karyotype. Quantitation o the number o
CD34-positive cells in the bone marrow may assist in
that these genomic regions harbor genes important in the dierentiation o hypoplastic MDS rom aplastic
MDS, such as c-CBL.59 anemia. In MDS, the number o CD34 cells is usually
Over the past several years, we have accumulated normal or increased, compared with aplastic anemia,
signicant inormation regarding genomic alterations in or which it is requently reduced.62
MDS, and the data are summarized in Figure 5–5.31,60 Fluorescent in situ hybridization techniques using
Common mutations aect genes involved in gene probes specic or specic chromosomes (ie, covering
splicing (eg, SF3B1, SRSF2, U2AF1), epigenetic regu- chromosomes 5,7, 8, and 20) have not been ully stan-
lators (eg, TET2, DNMT3A, ASXL1, and EZH2), and dardized in MDS. Their use should not be consider
DNA repair and cell cycle control genes (eg, PPM1D, standard o care in MDS and cannot yet replace con-
TP53). The presence o mutations in TP53 and EZH2 is ventional cytogenetics.
200
RA
150 RARS
Patients with mutations (n)
RARS−T
RCMD
RCMD−RS
RAEB
100
5q−
CMML
MDS−MPN
MDS−U
50 MDS−AML
0
Complex
ZRSR2
Rearr chr3
CTNNA1
del(17p)
KDM6A
SFRS2
RUNX1
STAG2
GATA2
PTPN11
CREBBP
RAD21
CDKN2A
CEBPA
SH2B3
SF3B1
del(5q)
DNMT3A
U2AF1
del(7q)
TP53
IDH2
NRAS
BCOR
del20q
CUX1
IDH1
del(12)
del(11)
NPM1
WT1
ETV6
GNAS
ASXL1
EZH2
+8
CBL
JAK2
KRAS
MLL2
IRF1
TET2
EP300
PHF6
NF1
MPL
+19
PTEN
FLT3
BRAF
ATRX
KIT
FIGURE 5–5 Molecular data in myelodysplastic syndrome.

DIAGNOSIS because o the minor impact o specic cytopenias and

classication; (2) demonstrating 1% blasts on at least
The classication systems used to group dierent MDS two separate occasions to diagnose MDS, unclassied
have evolved over time with increased understanding (MDS-U); (3) changing the denominator or calculat-
ing blast percentage to all nucleated bone marrow cells
CHAPTER 5
o the biology and genetics o the disease. The rst
widely accepted classication was that proposed by rather than “nonerythroid cells”; (4) not including +8,
the French-American-British (FAB) study group.63 The -Y, or del(20q) as MDS-dening in the absence o mor-
FAB categorized MDS primarily on the percentage o phologic eatures; and (5) excluding genomic data rom
blasts in the peripheral blood and bone marrow, with classication but including specic mutations, such as
disease entities dened by increased numbers o blasts TP53 and SF3B1, on prognosis.41
associated with a more aggressive clinical course.
Patients with a bone marrow blast percentage greater
than 30% were considered to have AML. This classi- PROGNOSIS
cation used only morphologic criteria to dene disease
groups and provided a ramework that allowed the The prognosis o patients with MDS is heterogeneous.
study o the natural history o MDS and its response The development o clinical systems that allow accu-
to therapy. rate prognostication o individual patients into low-
The WHO classication o MDS was developed and high-risk categories has proven essential to guide
with the objective o using all eatures o disease biol- rational management decisions and allow the intro-
ogy, including morphology, cytogenetics, immunophe- duction o investigational drug protocols. The IPSS,
notype, and clinical behavior.64 This classication was shown in Table 5–3, is the most widely used system
last updated in 2016 (see Table 5–1).41 In the original or assessment o prognosis and treatment planning.2
WHO classication, the importance o morphologic It provides an assessment o the prognosis o patients
assessment o blast percentage within the bone mar- with primary MDS at the time o initial diagnosis. It
row and peripheral blood was retained, although the was designed by the retrospective analysis o a large
threshold level or the diagnosis o acute leukemia was pool o 816 patients with MDS and ollowed the natu-
altered. Patients with more than 20% bone marrow ral history o the disease to determine important actors
blasts were considered to have AML. Patients with related to patient outcome. Overall survival and the
20% to 29% blasts had a similar prognosis as patients risk o transormation to acute leukemia were related
with greater than 30% blasts. Within the WHO to the number o blood cytopenias, the percentage o
MDS categories with an increased blast percentage, myeloblasts in the bone marrow, and the presence o
the magnitude o the blast elevation was quantied specic cytogenetic abnormalities. The risk associated
between MDS with excess blasts (MDS-EB) types 1 with cytogenetic abnormalities was determined to be
and 2, refecting the worse prognosis o patients with good i a normal diploid karyotype, isolated del(5q),
an elevated blast count.2,5 In patients with a normal isolated del(20q), or isolated -Y were present. Poor-risk
proportion o blast cells within the bone marrow, the abnormalities were dened as abnormalities involv-
relatively indolent MDS with ring sideroblasts (MDS- ing chromosome 7 or complex karyotypes with the
RS) introduced in the FAB system were urther delin- presence o three or more karyotypic abnormalities.
eated by assessment or the presence o multilineage All other cytogenetic abnormalities were considered
dysplasia. Patients with dysplastic maturation limited intermediate risk. The IPSS weighed these variables to
to the erythroid lineage have a more avorable progno- produce a score that straties patients into our sepa-
sis than patients with cytopenia and dysplasia present rate risk groups: low, intermediate-1, intermediate-2,
in multiple myeloid lineages. Also, the WHO intro- and high risk (see Table 5–3). Survival and risk o trans-
duced the 5q- syndrome as a separate diagnostic entity ormation to acute leukemia are then predicted rom
primarily on the basis o a genetic abnormality rather cohorts o dierent ages, as illustrated in Table 5–3B.
than morphologic eatures alone. Deletions involving Patients classied as IPSS low and intermediate-1 risks
chromosome 5q are relatively common in MDS, and are generally considered to have lower-risk MDS, and
the WHO classication tightly dened the syndrome patients classied as having IPSS intermediate-2 and
as MDS with isolated del(5q) associated with anemia, a high are grouped into those with higher-risk MDS.
preserved or increased platelet count, and hypolobated Lower-risk MDS is typically treated more conser-
megakaryocytes on the bone marrow biopsy (see Fig. vatively than higher risk MDS. Prognostication in this
5–4). The WHO classication has been validated by lower-risk group may be particularly important because
a number o independent groups.65,66 The 2016 WHO it is unclear at this time whether some lower-risk
classication included the ollowing changes: (1) patients may benet rom early therapeutic interven-
replacing the terms “reractory anemia” and “reraction. To determine which lower-risk patients should be
tory cytopenia” with “myelodysplastic syndrome” considered or treatment protocols investigating early
TABlE 53 Internationa Prognostic Scoring Sstem (IPSS)

A. IPSS Score: Sum o the Three Listed Prognostic Factors
Score 0 0.5 1 1.5 2
CHAPTER 5
BM blasts (%) <5 5–10 — 11–20 21–30

a
Karyotype Good Intermediate Poor
Cytopeniasb 0/1 2/3
B. Prognosis Determined by IPSS Score
Median Survival (years)
Risk Group IPSS Score ≤60 years >60 years ≤70 years >70 years
Low 0 11.8 4.8 9 3.9
Intermediate-1 0.5–1.0 5.2 2.7 4.4 2.4
Intermediate-2 1.5–2.0 1.8 1.1 1.3 1.2
High ≤2.5 0.3 0.5 0.4 0.4
a
Good: normal, -Y, del(5q), del(20q); poor: complex (≤3 abnormalities) or chromosome 7 anomalies; intermediate: other abnormalities.
b
Cytopenias are dened as hemoglobin concentration <10 g/dL, neutrophils <1.5 × 109/L, and platelets <100 × 109/L.
BM, bone marrow.
intervention, patients with lower-risk MDS at MDACC anemia (hemoglobin concentration <10 g/dL), older age
were analyzed to urther stratiy prognosis in low and (older than 60 years), blast count greater than 4%, and a
intermediate-1 risk IPSS groupings (Table 5–4).4 Factors karyotype that was not diploid or del(5q) (Table 5–4A).
associated with worse prognosis in this lower-risk group This model stratied lower-risk patients into three sub-
included thrombocytopenia (platelets <50 × 109/L), groups by score—0 to 2, 3 to 4, and 5 to 7—with median
TABlE 54 A lower-Risk Meodspastic Sndrome Prognostication Mode.
A
Adverse Factor Coefcient P Value Assigned Score
Unavorable cytogenetics 0.203 <.0001 1
Age 60 years or younger 0.348 <.0001 2
Hemoglobin <10 (g/dL) 0.216 <.0001 1
9
Platelets <50 × 10 /L 0.498 <.0001 2
50–200 × 109/L 0.277 .0001 1
BM blasts ≤4% 0.195 .0001 1
B
Median Survival Time
Score Patients (n) (months) 4-Year Survival (%)
0 11 NR 78
1 58 83 82
2 113 51 51
3 185 36 40
4 223 22 27
5 166 14 9
6 86 16 7
7 13 9 NA
The score is calculated in patients with myelodysplastic syndrome and an International Prognostic Scoring System score o low or intermediate-1. A. Signicant
characteristics by multivariate analysis. Each one has an assigned score. The calculated total score can then be used in B to predict the median and 4-year survival times.
BM, bone marrow.
survival periods o 80, 27, and 14 months, respectively population. This model incorporates changes in the dis-
(Table 5–4B). Increased erritin and b2-microglobulin ease risk prole over time, allowing urther renement
were also associated with worse survival, but these ac- in prediction o survival and leukemic progression as
tors were not included in the prognostic model. Because the disease progresses. A model has been developed by
patient survival was signicantly dierent between MDACC that includes CMML and accounts or both
CHAPTER 5
these lower-risk categories, investigation o early inter- de novo and secondary disease, allowing or prognos-
vention protocols in lower-risk patients with relatively tication at any time during the course o MDS.68 The
poor survival may be warranted. characteristics o this model are shown in Table 5–5.
We described the cause o death o patients with The presence o brosis on the bone marrow biopsy
lower-risk MDS.67 Approximately 80% o patients occurs in a minority o patients with MDS, but this
died rom a complication intrinsic to MDS and not pathological eature is not incorporated into routine
because o disease progression, which only occurred diagnostic classications or prognostic systems. Fibro-
in 10% to 20% o patients. The most requent cause sis is more requently observed in patients with multi-
o death was inection ollowed by bleeding. Patients lineage dysplasia or with karyotype abnormalities and,
with increased percentage o blasts and monosomy 7 when present, is associated with a more rapid progres-
had an increased risk o transormation to AML.67 sion to severe bone marrow ailure and shortened
The IPSS determines risk at the time o initial diag- survival.69 In younger patients, it may warrant early
nosis, but it does not provide inormation regarding consideration o allo-SCT.
changes in risk as patients progress through their dis- An international consortium developed a new MDS
ease course. A dynamic prognostication system has classication known as the IPSS-R.5 The basis or this
been developed to address this deciency and provides eort was to improve on known limitations o the ini-
a score that is predictive o survival and leukemic trans- tial IPSS. IPSS-R includes a rened cytogenetic anno-
ormation over time. The WHO classication-based tation and newer thresholds o cytopenias and blast
Prognostic Scoring System weighs three variables: percentages.46 Table 5–6 shows the characteristics o
WHO diagnostic classication, karyotype abnormali- this new classication. The IPSS-R divides patients
ties categorized according to the IPSS criteria, and into ve categories (very low, low, intermediate, high,
transusion requirement.3 This straties patients into and very high risk). Algorithms have been developed
ve disease groups that demonstrate dierent survival to calculate expected survival and time to progression
and risk o evolution to acute leukemia over time. Very based on age and IPSS-R score. The IPSS-R should
low-risk patients in this classication have an overall be considered the standard tool to calculate progno-
mortality rate that was not dierent rom the general sis in patients with MDS and is now incorporated
TABlE 55 MD Anderson Cancer Center Mode o Risk Stratifcation or Meodspastic Sndromes
A. Simplied Myelodysplastic Syndrome Risk Score

Prognostic Factor Coefcient Pointsa
Perormance status ≤2 0.267 2
Age (years)
60–64 0.179 1
≤65 0.336 2
Platelets (×109/L)
<30 0.418 3
30–49 0.270 2
50–199 0.184 1
Hemoglobin <12 g/dL 0.274 2
BM blasts
5–10 (%) 0.222 1
11–29 (%) 0.260 2
WBC count >20 × 109/L 0.258 2
Karyotype: chromosome 7 abnormality or complex ≤3 abnormalities 0.479 3
Prior transusion, yes 0.107 1
(Continued)
TABlE 55 MD Anderson Cancer Center Mode o Risk Stratifcation or Meodspastic Sndromes
(Cont.)
B. Estimated Overall Survival by Prognostic Score

CHAPTER 5
Survival
Score Patients, n (%) Median (Months) % At 3 Years % At 6 Years
Low
0–4 157 (16) 54 63 38
Intermediate-1
5 111 (12) 30 40 14
6 116 (12) 23 29 14
Intermediate-2
7 127 (13) 14 19 8
8 106 (11) 13 13 4
High
9 97 (10) 10 10 2
≤10 244 (25) 5 2 0
C. Estimated Overall Survival by Four Levels o Prognostic Score Points
Survival
Score Patients, n (%) Median (months) Score Patients, n (%)
0–4 157 (16) 54 63 38
5–6 227 (24) 25 34 13
7–8 233 (24) 14 16 6
≤9 341 (36) 6 4 0.4
a
Score points were obtained by dividing the coefcients by 0.15 and rounding to the nearest integer.
BM, bone marrow; WBC, white blood cell
in a majority o modern clinical trials. Furthermore, Patients with MDS are older and may have other
patients with intermediate-risk MDS by IPSS-R were comorbidities. We have calculated the impact o
urther stratied based on age (66 years or older), comorbidities using the Adult Comorbidity Evalua-
peripheral blood blast count 2% or greater, and need tion-27 (ACE-27) comorbidity score on the outcome o
or RBC transusions (Table 5–7)6; patients with scores patients with MDS.70,71 This analysis indicated syner-
o 0 or 1 were considered intermediate-avorable risk, gism between the presence o comorbidity and disease
and those with scores o 2 to 4 were considered inter- score. The same was observed when ACE-27 was cal-
mediate-adverse risk. Finally, it is likely that all these culated with IPSS-R and in conjunction with genomic
classications will be modied with the incorporation data.71,72
o molecular genomic data.
TABlE 56 Revised Internationa Prognostic Scoring Sstem (IPSS-R)
A. Prognostic Score Values

Prognostic Variable 0 0.5 1 1.5 2 3 4
Cytogenetics Very good NA Good NA Intermediate Poor Very poor
BM blast (%) ≤2 NA >2% to <5% NA 5%-10% >10% NA
Hemoglobin ≥10 NA 8 to <10 <8 NA NA NA
Platelets ≥100 50 to <100 <50 NA NA NA NA
ANC ≥0.8 <0.8 NA NA NA NA NA
(Continued)
B. Prognostic Risk Categories and Outcomes by Score (Cont.)

Risk Category Risk Score
Very low ≤1.5
CHAPTER 5
Low >1.5–3
Intermediate >3–4.5
High >4.5–6
Very high >6
Patients (n) Very Low Low Intermediate High Very High
Patients (%) 7012 19 38 20 13 10
a
Survival, all 8.8 5.3 3.0 1.6 0.8
(7.8–9.9) (5.1–5.7) (2.7–3.3) (1.5–1.7) (0.7–0.8)
Hazard ratio 0.5 1.0 2.0 3.2 8.0
(95% CI) (0.46–0.59) (0.93–1.1) (1.8–2.1) (2.9–3.5) (7.2–8.8)
Patients (%) 6,485 19 37 20 13 11
a,b
AML/25% NR 10.8 3.2 1.4 0.73
(14.5–NR) (9.2–NR) (2.8–4.4) (1.1–1.7) (0.7–0.9)
Hazard ratio 0.5 1.0 3.0 6.2 12.7
(95% CI) (0.4–0.6) (0.9–1.2) (2.7–3.5) (5.4–7.2) (10.6–15.2)
a
Median, years (95% condence interval [CI]); P <.001.
b
Median time to 25% AML evolution (95% CIs); P <.001.
AML, acute myeloid leukemia; ANC, absolute neutrophil count; NA, not applicable; NR, not reached.
TABlE 57 Prognostic Score or patients with Intermediate-Risk Meodspastic Sndromes b
IPSS-R
Adverse Factor Coefcient P Value Assigned Score

Age 66 years or older 0.87 <.0001 2
Peripheral blood blasts ≥2% 0.52 0.009 1
RBC transusion 0.51 0.003 1
RBC, red blood cell.
THERAPy o blood products, growth actor therapies (ie, EPO

with or without colony-stimulating actors), iron che-
The number o eective drug treatments available to lation, luspatercept, and non–growth actor therapies
treat MDS has expanded in recent years, providing with immune modulators (lenalidomide) and epigen-
dierent management alternatives. Some treatments etic drug treatment (azacitidine or decitabine). Higher
improve hematopoietic unction and alleviate symp- risk MDS has a poor prognosis and orms a continuum
toms related to blood cytopenias; other therapies alter with AML. Aggressive therapies may be warranted in
the natural history o the disease and improve survival. these higher risk patients to eradicate the malignant
Both approaches may be appropriate in dierent clini- clone and improve survival. Intensive therapies may
cal contexts, and many patients receive various combi- include high-dose chemotherapy and consideration
nations o treatments throughout their disease course. o allo-SCT in younger patients. Intensive treatment
The goals o therapy in MDS vary in dierent protocols are not suitable or all patients because they
patient populations. A management plan should con- expose the patient to signicant risks o treatment-
sider the patient’s age, comorbidities, and disease related morbidity and mortality. An algorithm or
risk. Patients with lower-risk MDS most commonly treatment approaches at MDACC is shown in Figure
experience problems related to chronic anemia, and 5–6, with specic therapies based on lower-risk and
the disease may remain stable or prolonged periods. higher-risk MDS shown in Figure 5–7.73
I these patients are older, they may best be managed Assessing response to treatment in MDS can be
with relatively nontoxic therapies that aim to maintain complex as treatment goals in low- and high-risk dis-
quality o lie. Treatment options include transusions ease may be dierent. Clinical response criteria in
Presumption of MDS MDS diagnosis Genetic screening
IDH1 Mutation
CHIP detected
IDH2 Mutation
CHAPTER 5
FLT-3 mutation
Refer to the
CHIP clinic NPMI mutation
TP53 mutation
Splicing mutations
Untreated
Lower-Risk MDS
HMA failure
Untreated
Higher risk MDS
HMA failure
Allo-SCT at time of best response

Close monitoring post after allo-SCT;
consideration of post-SCT therapy
FIGURE 5–6 A MD Anderson Cancer Center approach to the management o patients with myelodysplastic syndromes (MDSs).
allo-SCT, allogeneic stem cell transplant; CHIP, clonal hematopoiesis o indeterminate potential; HMA, hypomethylating agent;
SCT stem cell transplant.
MDS
Lower risk Higher risk

(IPSS low, INT-1) (IPSS INT-2, high)
(IPSS-R VL, L, INT) (IPSS-R INT, H, VH)
(BM blasts <10%) (BM blasts ≥10%)
Any age Age younger than 70–75 years Age older than 70–75 years
Iron chelation Intensive chemotherapy HMA (5-AZA/decitabine)

Growth factors HMA (5-AZA/decitabine) Clinical trial
Luspatercept Clinical trial Intensive chemotherapy
HMAs
Lenalidomide (5q-)
Immune moulation
Clinical trial Allo-SCT
FIGURE 5–7 Risk-based treatment algorithm or patients with myelodysplastic syndromes (MDs). allo-SCT, allogeneic stem
cell transplant; BM, bone marrow; 5-AZA, 5-azacitidine; HMA, hypomethylating agent; INT, intermediate; IPSS, International
Prognostic Scoring System; IPSS-R, Revised International Prognostic Scoring System; L, low; VH, very high; VL, very low; H, high
VH, very high.
lower-risk disease usually measure improvements in the International Working Group are available to assess
peripheral blood cell counts and quality-o-lie actors. response to treatment in MDS and are particularly use-
Response in higher risk disease also requires improve- ul to allow comparisons between drug trials,74 with
ment in bone marrow blasts. Standardized criteria by new hematologic response criteria recently proposed.75
Supportive Care Hematopoietic Growth Factors

Chronic blood cytopenia is a principal characteris- Hematopoietic growth actors are the primary regula-
tic o MDS. Therapies aimed at alleviating problems tors o blood progenitor cell prolieration and are used
related to anemia, neutropenia, and thrombocytopenia therapeutically to promote eective hematopoiesis. EPO
CHAPTER 5
are an essential component o management. Bacterial therapy has been explored as an alternative to RBC trans-
inections require aggressive treatment with antibiot- usion in patients with lower-risk MDS. Various orms
ics. Platelet transusions are administered or episodes o recombinant EPO (rEPO), including epoetin a, epo-
o bleeding or or prophylaxis in patients with severe etin b, and the long-acting darbepoetin, have been stud-
thrombocytopenia. Transusion thresholds at MDACC ied in dierent cohorts o patients. Overall, erythroid
include a hemoglobin level o 8 g/dL (unless the patient responses in unselected patients were modest, in the
is otherwise symptomatic) and a platelet count o less range o 10% to 20%.81 The best responses were identi-
than 10 K/UL (unless there is evidence o bleeding). ed in patients with low-risk MDS, a low serum EPO
These transusion thresholds have been challenged level (<200 IU/L), and no RBC transusion requirement.82
by the 2020 COVID-19 pandemia because o a lack In this avorable subgroup o patients with MDS, an ery-
o donors. Additional hemostatic support with the use throid response to rEPO therapy was observed in 40% to
o antibrinolytic agents may be considered or prob- 60% o patients.82 The median duration o response was
lematic mucosal bleeding or or surgical procedures. 2 years, and therapy was associated with improved qual-
The role o prophylactic antibiotics is less established ity o lie.83 Data suggest that patients who respond to
in neutropenic patients. It is our practice at MDACC growth actor therapy have better survival than historical
to use triple therapy (antibacterial with a fuoroqui- control cohorts who received supportive care alone.82
nolone, antiviral, and antiungal) in all patients with EPO in combination with G-CSF is also eec-
severe neutropenia who are receiving therapy. tive, with response rates o 40% to 50% in selected
Symptomatic anemia is oten the major clinical cohorts.61,83,84 The combination o these two hemato-
problem in patients with lower-risk MDS. In this group, poietic cytokines appears to oer a synergistic clinical
RBC transusions are eective symptomatic therapies, benet and allow improvements in hemoglobin levels
but a prolonged transusion program may cause prob- in some patients who ail to respond to EPO mono-
lems with transusion-related hemosiderosis, alloanti- therapy. The benet o this combination may be most
body ormation, and volume overload in patients with marked in reractory anemia with ring sideroblasts
impaired cardiac unction. Deposition o iron in body (RARS) and reractory cytopenia with multilineage
tissues is treated with iron chelation. The ecacy o dysplasia (RCMD), but this has not been conrmed.82
iron chelation therapy is best demonstrated in thalas- Disease transormation is a theoretical risk in patients
semia major, in which regular deeroxamine therapy receiving chronic hematopoietic growth actors, but
reduces iron deposition in organs and improves sur- long-term observations o these patients suggested that
vival.76 The parenteral administration o deeroxamine these cytokines do not promote leukemic transorma-
is inconvenient, and the development o eective oral tion.82,84 Hematopoietic growth actor therapy should
iron-chelating drugs, such as deerasirox, has allowed be considered to treat anemia in patients with lower-
iron chelation to be perormed more easily.77 In MDS, risk MDS associated with a low serum EPO level. EPO
iron chelation was hypothesized to have similar advan- can be initiated as monotherapy with the addition o
tages.78 This was conrmed in the recently published G-CSF i there is no objective response in 2 to 3 months.
randomized double-blind phase II TELESTO study,79 Thrombopoietin has been used to promote platelet
which demonstrated an increased event-ree survival production and minimize the bleeding complications
with oral deerasirox compared with placebo. Iron related to severe thrombocytopenia. Initial trials with
chelation should start with parenteral deeroxamine recombinant thrombopoietin were disappointing.
or oral deerasirox ater 20 to 40 units o RBC have New second-generation thrombomimetic agents are
been administered, particularly i there is an expecta- now being tested.85–87 Potential concerns o increased
tion o prolonged survival and continued transusion blasts and brosis, leading to an elevated risk o pro-
therapy. Serum erritin may be used as a guide to chela- gression to AML or death, led to discontinuation o the
tion therapy, with a erritin concentration greater than study drug in a phase II trial, though 5-year ollow-up
1000 μg/L typically attained ater transusion o 20 RBC data did not show a dierence.87
units.66 Iron chelation therapy should also be considered
in younger patients who may be candidates or alloge- Transforming Growth Factor β Signaling
neic transplantation. An elevated pretransplant erritin
has been associated with a lower overall survival ater
Modulators
allogeneic transplantation and an increase in the hepatic More recently, the use o luspatercept, a recombinant
transplant complication o veno-occlusive disease.80 usion protein binding transorming growth actor b
(TGF-b) ligands to decrease SMAD2- and SMAD3 sig- is myelosuppression, which may necessitate dose reduc-
naling involved in ineective erythropoiesis o MDS, tion in patients with persistent thrombocytopenia and
has been studied.88,89 A phase II study evaluating lus- neutropenia. Interestingly, the degree o myelosuppres-
patercept in patients with lower-risk MDS showed an sion has been associated with response. Thrombocyto-
CHAPTER 5
erythroid response rate o 63%, and 38% o patients penia at diagnosis (platelet count <100 × 109/L) has been
had transusion independence or 8 weeks or longer.90 associated with a worse response to lenalidomide treat-
The double-blind, randomized, placebo-controlled ment. This may refect repeated or prolonged treatment
phase III MEDALIST trial validated the previous obser- interruptions secondary to myelosuppression.
vations that luspatercept reduced anemia severity in Lenalidomide and thalidomide also demonstrated
patients with lower-risk MDS-RS who were transu- activity in low-risk MDS without the del(5q) abnor-
sion dependent and had disease that was reractory to mality. Lenalidomide has been studied in 214 patients
EPO therapy,91 leading to its Food and Drug Adminis- with low-risk MDS (IPSS low and intermediate-1) and
tration (FDA) approval in 2020. Limitations or the use predominantly a normal karyotype.8 In this cohort,
o luspatercept include the cost o therapy and no clear 26% o patients achieved transusion independence,
evidence o improved survival, and longer ollow-up and 17% developed a reduction in transusion require-
times are needed to ully understand the eects o the ment. The median duration o transusion indepen-
compound on the natural history o MDS progression. dence was 41 weeks, and cytogenetic responses were
documented in 19% o patients with karyotypic
abnormalities. These results were conrmed in a ran-
Lenalidomide domized trial.95
Lenalidomide is a chemical analogue o thalido-
mide with diverse biological actions that encom-
pass immune modulation and antiangiogenic eects.
Hypomethylating Agents
Selective activity o lenalidomide against MDS asso- 5-Azacitidine and 5-aza-2′-deoxycytidine (decitabine)
ciated with an interstitial deletion on the long arm o are chemically related drugs with a spectrum o activ-
chromosome 5 was rst suggested in a study examin- ity that includes both lower and higher risk MDS.
ing the eects o this drug on anemia in patients with The mechanism o action o these drugs is uncertain,
low-risk MDS.92 Erythroid responses were noted in although both agents reverse abnormal promoter DNA
56% o the cohort, with the most signicant response methylation that surrounds the promoter o some
ound in the subgroup with a del(5q) abnormality. tumor-suppressor genes in cancer cells. Aberrant pro-
This observation was conrmed in a larger multicenter moter methylation is associated with transcriptional
phase II study o lenalidomide. 7 This second trial repression, or silencing, and may contribute to the loss
demonstrated an overall erythroid response in 76% o tumor-suppressor gene unction in MDS. Decitabine
o patients with the del(5q) abnormality. Responses and 5-azacitidine are both cytidine analogues that incor-
were prolonged and occurred rapidly, with a median porate into DNA and orm covalent bonds with DNA
time to a hematologic response o 4 to 5 weeks. A methyltranserase enzymes. Depletion o methyltrans-
cytogenetic response was documented in 73% o erase activity within the cell then causes newly synthe-
patients, with 44% developing complete cytogenetic sized DNA to be hypomethylated compared with the
remission. Cytogenetic responses were observed in parent strand. Ater at least two cycles o cell division,
patients with the del(5q) abnormality alone and in DNA becomes globally hypomethylated with alteration
patients with the del(5q) abnormality associated with in gene expression within the leukemic cell. Both agents
additional cytogenetic deects. This clearly demon- display cytotoxicity at high doses, but hypomethylat-
strated that the activity o lenalidomide was not lim- ing activity remains prominent at lower doses. These
ited to patients with the 5q- syndrome but was also biochemical changes are an attractive target or drug
observed in patients with low-risk MDS. A random- therapy because normal tissues have little gene pro-
ized trial comparing dierent doses o lenalidomide moter methylation, so hypomethylating therapy may
versus observation urther conrmed the activity o have some degree o specicity or the malignant clone.
the drug at a dose o 10 mg/day.93 Although none o 5-Azacitidine rst demonstrated broad-spectrum
these studies were powered to document improve- activity in MDS. Comparison o azacitidine (75 mg/m2
ment in survival, a recent analysis indicated that intravenously or subcutaneously or 7 days every 28
achieving a cytogenetic response with lenalidomide days) with best supportive care in a randomized con-
was associated with prolonged survival.94 trol trial demonstrated an overall response rate o 48%
Lenalidomide therapy in MDS is usually started at 10 with azacitidine compared with 5% with supportive
mg/day. A avorable response is typically characterized by care.96,97 Azacitidine therapy was associated with a
normalization o anemia and cytogenetic response.7 The prolongation in the time to leukemic transormation
most important side eect o therapy with lenalidomide and better quality o lie. The median time to response
was three cycles, and response rates were indepen- investigating a HMA with or without a HDAC inhibi-
dent o MDS classication. Complete responses were tor showed a survival improvement.106–108
observed in relatively ew patients, approximately Guadecitabine (SGI-110) is a next-generation HMA
10%, with most patients experiencing hematologic that, unlike decitabine, is relatively resistant to deg-
improvement. A report o a multicenter phase III study radation, thus allowing or slow release o its active
CHAPTER 5
o azacitidine in patients with higher risk MDS demon- metabolite decitabine and consequently prolonged
strated an increase in overall survival o approximately exposure time and reduced maximum plasma concen-
9 months or patients receiving azacitidine compared tration.109 A phase I study identied guadecitabine 60
with other standard therapies.98 This was the rst drug mg/m2 as the biologically eective dose and 90 mg/m2
trial that demonstrated a survival advantage in MDS. A as the maximum tolerated dose,109 and a phase II study
subset analysis o the trial data suggested that azaciti- showed better-than-expected outcomes in treatment-
dine may have signicant activity in MDS associated naïve patients with MDS compared with the rst-gen-
with abnormalities in chromosome 7, a cytogenetic eration HMA decitabine and azacitidine.110
abnormality associated with a poor outcome. HMA were previously only available as IV admin-
Decitabine has similar clinical activity to azaciti- istrations, along with a subcutaneous orm o azaciti-
dine and has been studied in various intravenous (IV) dine. However, oral administration o HMA would
dose regimens in predominantly higher risk MDS and enhance patient convenience, avoid injection site reac-
AML. Comparison o decitabine (45 mg/m2 in three tions, and allow or the evaluation o alternative doses
divided doses administered or three consecutive days and schedules.111,112
every 6 weeks) with best supportive care in a ran- The oral bioavailability o decitabine was limited
domized trial demonstrated an overall response rate due to its rapid degradation by cytidine deaminase
o 17%, with complete remissions in 9% o patients (CDA) in the gut and liver, but simultaneous oral admin-
with predominantly high-risk MDS.99 Subgroup anal- istration with the CDA inhibitor cedazuridine (E7727)
ysis revealed that patients who received decitabine resulted in increased bioavailability o oral decitabine
had a longer median time to transormation to AML and similar pharmacokinetics to IV decitabine.113 A
or death i they were treatment naïve or had high-risk phase II study showed a similar saety prole and
MDS. Myelosuppression was the major drug toxicity. response rates between oral cedazuridine–decitabine
Data rom this trial may underestimate the ecacy o (ASTX727) and IV decitabine.114 Preliminary results
the drug because a signicant proportion o patients rom the phase III ASCERTAIN study comparing oral
on decitabine received a small number o treatment ASTX727 with IV decitabine in patients with higher
cycles, which may have been insucient to demon- risk MDS showed equivalent HMA exposure between
strate a response. This is supported by previous phase the two arms, saety ndings, and clinical activity,115
II trial data that suggested decitabine had an overall and this led to the FDA approval o oral decitabine and
response rate similar to azacitidine.100 Subsequent clin- cedazuridine or adult patients with MDS in July 2020.
ical trial development with decitabine has ocused on
improving response rates by lowering the daily dose
and lengthening administration schedules. One such
Cytotoxic Chemotherapy
schedule o IV administration o decitabine or 5 days The relatively poor prognosis associated with higher
every 4 weeks demonstrated a complete response rate risk MDS has initiated intensive treatment strategies
o 39% in a high-risk MDS cohort.101,102 Improvements incorporating high-dose chemotherapy in the same
in hematopoietic unction are oten delayed ater the protocols used to treat AML. In higher risk MDS, AML-
initiation o azacitidine or decitabine therapy, and type treatments produce a complete response rate o
drug treatment should continue or our to six cycles about 40% to 60%, but remissions are brie.116,117 This
beore cessation because o poor response. poor response to high-dose chemotherapy is caused,
Chemical modication o histone proteins by acety- at least in part, by the relatively greater proportion o
lation contributes to the regulation o gene expression patients diagnosed with MDS-EB having poor progno-
and probably interacts with abnormal DNA methyla- sis cytogenetics involving complex changes o chro-
tion to cause transcriptional suppression o tumor-sup- mosomes 5 and 7. Older adult patients with signicant
pressor genes. Histone deacetylase (HDAC) inhibitors, comorbidities tolerate high-dose chemotherapy poorly.
such as valproic acid and pracinostat, alter chroma- Patients with higher risk MDS have been treated
tin structure to promote gene transcription, and their with a variety o intensive chemotherapy regimens
combination with HMA demonstrates signicant in at MDACC.118,119 Studies have examined using inter-
vitro synergy.103 Initial clinical drug trials in MDS and mediate- to high-dose cytosine arabinoside (ara-C)
AML at MDACC indicated increased clinical activ- (A) in various combinations with idarubicin (I), cyclo-
ity when combining either decitabine or azacitidine phosphamide (C), fudarabine (F), and topotecan (T),
with valproic acid.104,105 None o the randomized trials as regimens: IA, FA, FAI, TA, and CAT. The overall
complete response rate or these regimens was 55% to 30% to 50%.126–130 Given the risks associated with this
58%. A short antecedent history o any hematologic procedure, patient suitability and timing o the trans-
disorder, a normal karyotype, perormance status, age, plant are important issues.
and treatment in a laminar airfow environment were Allogeneic transplantation with myeloablative con-
CHAPTER 5
all predictive o attaining a complete response. This ditioning has been examined exclusively in younger
intensive approach was benecial in some patients patients (median age in the mid-30s) in most studies.
because those who developed a complete response Patients with lower-risk disease have experienced the
within 6 weeks o chemotherapy obtained a survival best survival rate. However, this is also the subgroup
advantage. However, these regimens were toxic, with o patients predicted to experience prolonged survival
a signicant treatment-related mortality rate in the rst without aggressive therapies. This procedure is associ-
6 weeks, ranging rom 5% with TA to 21% with FAI. ated with a signicant treatment-related mortality rate
Consolidation chemotherapy was used in most cases o up to 30% to 50% in some studies.128,129 Relapse
when a remission was achieved with a regimen con- ater transplantation occurs in approximately 20%,
taining the drugs used in induction but at a reduced and the relapsed disease has a relatively poor response
intensity o 50% to 66% o the initial dose. Survival o to donor lymphocyte inusion.128,129,131 Increased risk o
patients treated with IA and TA therapies were com- allogeneic transplantation mortality in MDS is associ-
parable and superior to those patients treated with ated with older age, poor-risk cytogenetics (particu-
FA, FAI, and CAT regimens, but prognosis remained larly abnormalities o chromosome 7 or a complex
poor. Nevertheless, this approach does benet some karyotype), the presence o excess blasts in the bone
younger individuals (younger than 65 years) with a marrow, and longer duration o disease.132,133 Patients
normal karyotype, achieving an encouraging 5-year with treatment-related MDS also have a poor trans-
survival rate o 27% with intensive treatment. For plant outcome, but this is related to the requency o
older patients, the TA combination can be considered high-risk cytogenetic changes.133,134
because it has a relatively low treatment-related mor- The development o nonmyeloablative allogeneic
tality rate, and it does not contain anthracycline drugs transplantation with reduced-intensity conditioning
(relatively contraindicated in the presence o heart has allowed allogeneic transplantation to be consid-
disease). ered in older patients with MDS and in patients whose
comorbidities or organ dysunction would exclude
them rom myeloablative treatment.135 This procedure
Immunosuppressive Therapy has reduced transplant-related mortality, the major
Immune dysunction contributes to blood cytopenias in problem limiting the availability o this potentially
some patients with MDS, producing a clinical overlap curative therapy to older patients. This therapy aims
with aplastic anemia. Immunosuppressive therapy with to minimize organ toxicity related to initial chemo-
antithymocyte globulin (ATG) with or without the addi- therapy or radiation therapy and allow stable engrat-
tion o cyclosporine has been explored in small numbers ment o donor cells that provide the curative potential
o patients with MDS. Response rates o 30% to 50% associated with the grat-versus-leukemia eect.
have been observed in selected cohorts o patients with Comparison o reduced-intensity conditioning trans-
lower-risk MDS administered a course o ATG, with plantation with standard myeloablative condition-
a minority o patients experiencing prolonged remis- ing showed reduced transplant-related mortality but
sion.120–122 Features that may predict a good response increased relapse rate, resulting in comparable rates
to immunosuppressive therapy include younger age, o overall survival between the two transplantation
HLA-DR status, shorter duration o RBC transusions, strategies.132,136–138
low-risk IPSS, and bone marrow hypocellularity.122–124 Statistical modeling based on historical allogeneic
Selection o appropriate patients or immunosuppres- transplantation outcomes or matched sibling trans-
sion is important because ATG therapy is poorly toler- plantation suggested that the maximal overall survival
ated in an older population with low-risk MDS.125 is achieved by dierent transplant strategies in dier-
ent MDS risk groups.139 Patients with lower-risk disease
maximize overall survival by delaying transplantation
Hematopoietic Stem Cell Transplantation
ater diagnosis until evidence o disease progression
In MDS, allo-SCT is potentially curative, but the ther- but beore the development o overt acute leukemia.
apy carries signicant risk associated with treatment This delayed transplant approach provided the great-
toxicities, prolonged cytopenias, inections, and grat- est survival benet to younger patients (younger than
versus-host disease. In young patients with suitable 40 years).
donors, the transplant procedure oers the best chance Specic eatures o disease progression have
o cure, with a long-term disease-ree survival rate o not been dened, but evidence o new cytogenetic
abnormalities, progressive cytopenias, and increasing with antitumor activity.148,149 Azacitidine in conjunc-
blast percentage in the bone marrow are suggested tion with double immune checkpoint inhibitor block-
as potential triggers or transplantation. Patients with ade with nivolumab and ipilimumab has also shown a
higher risk disease should ideally receive the transplant tolerable saety prole and clinical activity.150 The com-
as soon as possible ater diagnosis. The presence o bination o HMA with anti–PD-L1 antibodies has also
CHAPTER 5
bone marrow brosis delays engratment in allogeneic been investigated.151,152
transplantation, and its presence is an additional risk Recently, T-cell immunoglobulin mucin-3 (TIM-3),
actor in transplant outcome in higher risk MDS. In an inhibitory immune checkpoint receptor expressed
this group, brosis considerably increases transplanta- on AML cells, is being studied as a potential thera-
tion risk. peutic target with the combination o the anti-TIM-3
Early consideration o transplantation is suggested antibody MGB453 and HMA.153,154 Furthermore,
in a younger patient with signicant MDS-associated CD47 expression on blasts rom lower-risk patients
brosis.134 The outcomes o patients older than 60 with MDS was ound to be similar to normal cells,
years o age with MDS treated with either reduced- but increased expression was observed in higher risk
intensity transplantation or HMA were studied.9 The patients with MDS,155 leading to the hypothesis that
results o this analysis indicated that transplant should increased CD47 expression could represent progres-
not be considered as rst-line therapy in lower-risk sion or transormation.156 The use o magrolimab, an
MDS. O interest, in higher risk MDS, it appears that anti-CD47 antibody, in patients with MDS is currently
there is a benet toward transplant compared with being explored; data recently presented include an
HMA-based therapy, but survival curves cross signi- overall response rate o 92% with a complete response
cantly later than ater 24 months o therapy. This indi- rate o 50%.157
cated that there is probably a specic group o patients,
not yet dened, that derives the maximal benet rom
transplantation. Venetoclax
Venetoclax is a BH3-mimetic that inhibits the antiapop-
totic Bcl-2 protein, leading to programmed cell death.158
Emerging Therapeutics Preclinical studies show synergy between venetoclax
and HMA in higher risk MDS and AML.159,160 A phase
Other Oral Hypomethylating Agents
Ib study evaluating azacitidine and venetoclax in treat-
The bioavailability and saety o oral azacitidine (CC- ment-naïve patients with higher risk MDS showed
486) was initially evaluated an open-label pharmaco- that combination therapy had a tolerable saety prole
kinetic study o patients with MDS, AML, or solid and potential ecacy.161 Multiple studies evaluating
tumors.111 In a phase I study in patients with MDS, dierent combinations o therapies with venetoclax
CMML, and AML, oral azacitidine demonstrated are underway.
biologic and clinical activity with extended dosing
schedules showing sustained epigenetic eects.112,140,141 Targeted Therapies
Its use in lower-risk MDS is being urther investi-
gated.142–144 Furthermore, ASTX030, an oral combina- With the incorporation o molecular and genomic
tion o azacitidine and cedazuridine, is currently being analysis into the diagnostic bone marrow aspiration
researched ater showing the same ecacy as paren- or biopsy, the use o therapies that target particular
teral azacitidine in mouse models.145 mutations is being studied. Many o these therapeutic
targets have been studied in AML, and clinical trials
are underway or their potential role in the treatment
Immunotherapy
o MDS. Current genomic targets under investigation
The PD-1 axis is expressed in patients with MDS, include TP53, IDH2, IDH1, and FLT3.
which may allow or the development o new orms TP53 mutations are one o the most requently
o therapy and combinations using inhibitors o this occurring mutations in myeloid malignancies and
pathway.146 Single-agent pembrolizumab (anti–PD-1 oten associated with complex karyotype and poor
antibody), nivolumab (anti–PD-1 antibody), and prognoses. 31 APR-246 covalently binds to p53 and
ipilimumab (anti–CTLA-4 antibody) did not show restores wild-type proapoptotic activity. 162 A dose
signicant responses but had acceptable toxicity pro- escalation phase 1b clinical trial showed the combi-
les.147,148 Updated results rom ongoing phase II stud- nation o azacitidine and APR-246 had manageable
ies investigating the combination o azacitidine with nausea and transient neurologic adverse events,163
pembrolizumab, nivolumab, or ipilimumab indicate and a dose expansion phase II trial showed an over-
that combination therapy is sae and well tolerated all response rate o 87% in patients with MDS and
oligoblastic AML.164 Similarly, our French colleagues Failure of Hypomethylating Agents

conducted a similar phase II trial with azacitidine
and APR-246 showing a response rate o 66%.165 A One o the major problems is the treatment o patients
randomized phase III study o rontline azacitidine who have ailed therapy with HMA. Two dier-
ent scenarios exist: primary (when the patient pro-
CHAPTER 5
with or without APR-246 in TP53-mutant MDS is

underway. gresses while on HMA therapy without experiencing
Although IDH2 and IDH1 mutations are less re- response) and secondary (when the patient has an ini-
quently observed in MDS,166,167 studies involving tar- tial response but progresses later in the course o treat-
geted inhibitors are underway. Enasidenib (AG-221) ment) HMA ailure.177 The survival o patients with
is a selective oral inhibitor o mutant IDH2 enzyme lower-risk disease and hypomethylating ailure is less
that is FDA approved in patients with relapsed or than 17 months.12 Data rom MDACC indicated that
reractory IDH2-mutated AML with response rates the prognosis is very poor or patients with higher risk
o approximately 40%.168 Preliminary results rom disease and hypomethylating ailure with a median
a phase II study o enasidenib in treatment-naïve survival o less than 5 months. Currently, no therapy
patients with higher risk IDH2-mutated MDS showed has shown signicant activity or patients with HMA
a response rate o 85%.169 Ivosidenib (AG-120) is an ailure. In general, this group o patients is reractory to
oral targeted inhibitor o mutant IDH1 enzyme. Stud- most conventional antileukemia agents available, such
ies in IDH1-mutant AML have shown transusion as cytarabine. These patients should be treated with
independence, durable remissions, and some molecu- investigational new agents, considered or allo-SCT
lar remissions.170,171 Very ew patients with MDS have as soon as possible, or both. Agents currently being
been treated with ivosidenib, but urther exploration investigated include guadecitabine, immunotherapy,
o this genomic targeted is necessary. venetoclax, targeted therapy, and rigosertib, among
FLT3 mutations are rare in patients with MDS but others.
can occur in 15% to 30% o patients who have ailed The next-generation HMA guadecitabine has been
HMA therapy.172,173 A phase 2 study showed signicant shown to have activity in patients who have ailed
activity o the addition o soraenib, a FLT3 inhibitor, decitabine and azacitidine in a phase II trial,178 lead-
to azacitidine in patients with HMA ailure.174 Several ing to an ongoing phase III ASTRAL-3 study o sin-
small studies using second- and third-generation FLT3 gle-agent guadecitabine. Its use in combination with
inhibitors in MDS are underway.73 the immune checkpoint inhibitor atezolizumab was
ound to be sae in patients with relapsed or rerac-
tory MDS,179 and a phase II study is ongoing. Although
investigative eorts into various immune checkpoint
SPECIFIC ClINICAl SITUATIONS inhibitors with and without HMA therapy have not
yielded signicant survival advantages, single-agent
Despite the clinical activity o several agents described ipilimumab had a 30% response rate in patients who
earlier, most patients with MDS will eventually suc- previously ailed HMA.148 Further studies with immu-
cumb to their disease. This emphasizes the need to notherapy in patients with relapsed or reractory MDS
develop better strategies, both up ront and in patients are warranted.
who have ailed prior therapies. Furthermore, the use o venetoclax as monotherapy
or in combination with azacitidine is undergoing inves-
tigation. A phase Ib study showed a response rate o
Patients with Lower-Risk Disease and
40% with venetoclax and azacitidine with only mod-
Poor Prognosis est clinical activity observed with single-agent vene-
It is now demonstrated that the prognosis o patients toclax,180 and multiple phase II studies are underway
with lower-risk MDS is very heterogeneous, with a to urther explore this therapeutic option. Regarding
signicant subset o patients having poor prognosis.4 targeted therapy options or IDH2- or IDH1-mutant
Because most o these patients decease as a conse- MDS that were previously discussed, multiple studies
quence o MDS, introducing therapy early in this evaluating enasidenib, ivosidenib, and ivosidenib with
selected group o patients may help. This has signi- nivolumab in the setting o relapsed or reractory MDS
cant implications not only or the role o allo-SCT are underway.169,181,182
in MDS but also or the incorporation o disease- Additional investigational agents o interest include
modiying strategies. We have studied the role o telaglenastat (a glutaminase inhibitor), H3B-8800 (a
very low-dose or oral schedules o HMA in this set- splicing modulator), and various adjunct therapies to
ting.142,143,175,176 Randomized phase III trials are being HMA. Recent studies with rigosertib have ailed to
conducted to investigate the impact o these interven- demonstrate improvement in survival in patients with
tions on survival.144 higher risk disease and primary HMA ailure.
Total Therapy Incorporating Allogeneic transplant in specic subsets o patients, such as those
Stem Cell Transplantation with TP53 mutations or complex cytogenetics.184 The
introduction o powerul new combinations including
Traditionally, therapy or MDS is viewed as a dichot- APR-247, magrolimab, and venetoclax, argues or total
omy between candidates or allo-SCT and those who therapy that results in minimal residual disease nega-
CHAPTER 5
are not candidates, and the need or bridge therapy tivity pre-allo-SCT ollowed by posttransplant mainte-
beore allo-SCT remains controversial.183 Addition- nance therapy with HMA or targeted approaches, and
ally, we also observe very high relapse rates ater urther investigation is warranted.

J Analysis o gene mutations using next-generation J Patients with mutations on IDH2 and IDH1 (~15% o
sequencing assays is important in MDS. A small rac- patients) respond to IDH inhibitors as single agents
tion o patients with MDS carry an NPM1 mutation. or in combination with HMAs.
These patients can be cured with AML-like therapy J A subset o patients with higher risk HMA ail-
ollowed by allo-SCT. ure have diploid cytogenetics. These patients can
J Low-risk patients with diploid cytogenetics without respond to combinations o lower doses o nucleo-
thrombocytopenia and anemia, as sole cytopenia, side analogues (cloarabine, cladribine) with low-
can respond to lenalidomide. dose ara-C.
J Around 20% o patients with higher risk MDS ailure J In patients with higher risk disease, we attempt to
carry a Flt-3 mutation. Usually, these patients have proceed with allo-SCT at the time o best response
leukocytosis. These patients can respond to the (morphologic, cytogenetic, molecular) in an attempt
combination o HMA and Flt-3 inhibitor. to minimize relapse posttransplantation.
18. Poppe B, Van Limbergen H, Van Roy N, et al. Chromosomal

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anemia and thrombocytopenia. BMC Hematol. 2016;16:12. azacitidine in treatment-naïve patients with higher-risk myelo-
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147. Garcia-Manero G, Tallman MS, Martinelli G, et al. Pembro- acute myeloid leukemia (AML). Blood. 2018;132(suppl 1):3091.
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148. Garcia-Manero G, Sasaki K, Montalban-Bravo G, et al. A phase acute myeloid leukemia (AML). Blood. 2019;134(suppl 1):676.
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150. Garcia-Manero G, Montalban-Bravo G, Sasaki K, et al. Dou- plastic syndromes: a Mayo Clinic study o 277 patients. Leuke-
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151. Zeidan AM, Cavenagh J, Voso MT, et al. Ecacy and saety 168. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in
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155. Pang WW, Pluvinage JV, Price EA, et al. Hematopoietic stem 174. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study o
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180. Zeidan AM, Pollyea DA, Garcia JS, et al. A phase 1b study eval- myelodysplastic syndrome ater stem-cell transplantation. N
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in combination with azacitidine or the treatment o relapsed/
6 Philadelphia
Chromosome-Negative
Myeloprolierative Neoplasms
Prithviraj Bose
Lucia Masarova
Hesham M. Amin
Srdan Verstovsek
KEY CONCEPTS
 Polycythemia vera (PV) is the most common o the Ph-  Myelobrosis can be primary (PMF) or arise as a com-
negative myeloprolierative neoplasms (MPNs). Virtually plication o PV or ET (post-PV/ET MF). Overt MF is usu-
all cases are driven by activating JAK2 mutations, and ally characterized by anemia, splenomegaly, a variety o
elevation o all three cell counts is typical. Lie expectancy symptoms, leukoerythroblastosis, and markedly reduced
is good but shorter than that o an age- and sex-matched survival compared with PV and ET. Pre-PMF is more indo-
population. Thrombosis is the major clinical concern, and lent but carries a worse prognosis than ET. The distribution
prevention o the same is the principal goal o therapy. PV o driver mutations in PMF is generally similar to that in ET,
can progress to myelobrosis (MF) or transorm to acute but mutations in “nondriver” genes are much more com-
myeloid leukemia (AML). All patients need aspirin unless mon. The risk o leukemic transormation is much higher
it is contraindicated. Low-risk patients are typically treated in MF than in ET or PV. Accurate prognosis or patients with
with phlebotomy, whereas high-risk patients need cytore- MF is critical or decisions about stem cell transplant (SCT)
ductive therapy. The target hematocrit level or all patients and depends on several clinical and genomic actors. JAK
is to be less than 45%. Leukocytosis is clearly associated inhibitors represent the cornerstone o therapy; in some
with mortality and leukemic transormation; its relation- patients, anemia-directed therapy with or without JAK
ship with thrombotic risk is less certain. Hydroxyurea (HU) inhibitors may be appropriate.
and intereron (IFN) are both reasonable rontline options  Chronic eosinophilic disorders/hypereosinophilic syn-
or cytoreductive therapy; ruxolitinib is approved or use dromes (CED/HES) are heterogeneous disorders charac-
ater ailure o HU. terized by hypereosinophilia in the blood and possible
 Essential thrombocythemia (ET) is the most indolent o eosinophilic organ inltrations. Diagnosis requires exclu-
the classic Ph-negative MPNs. Careul distinction o ET sion o secondary causes. Evaluation or end-organ dam-
rom prebrotic primary myelobrosis (pre-PMF) is neces- age is always needed. Primary CED/HES include myeloid/
sary. Lie expectancy in ET is the same as, or only slightly lymphoid neoplasms with eosinophilia and rearrange-
lower than, that o an age- and sex-matched population. ment o PDGFRa, PDGFRb, FGFR1, or with PCM1-JAK2.
Driver mutations in JAK2 underlie approximately hal the Patients might have various nonspecic symptoms or
cases, with CALR and MPL mutations accounting or most serious organ involvement (gastrointestinal system, heart,
o the remainder. ET can progress to MF and rarely trans- skin, lungs). PDGFRa/b rearrangements are sensitive to
orm to AML. Thrombosis and bleeding are the main clini- the tyrosine kinase inhibitor imatinib, and these patients
cal concerns, and the goal o therapy is to mitigate these have avorable lie expectancy. Secondary agents com-
risks. Patients are risk stratied or thrombosis by age, JAK2 monly used are steroids, IFN, HU, and, less requently, che-
mutation status, thrombosis history, and cardiovascular motherapy. Patients with FGFR1 rearrangement usually
risk actors. The platelet count does not correlate with have aggressive disease with rapid progression to acute
thrombotic risk. HU or IFN are the cytoreductive agents leukemia. Stem cell transplantation is needed or long-
o choice; anagrelide is commonly used as a second-line term survival. The novel tyrosine kinase inhibitor pemiga-
therapy. Aspirin is generally recommended, but should tinib is being evaluated in clinical trials as o this writing
be avoided in the presence o acquired von Willebrand and showing optimistic results.
disease.
119
120 Sction I Leukemia
 Chronic neutrophilic leukemia (CNL) is a very rare, KITD618V mutation occurs in more than 90% o the patients.
atypical MPN characterized by overproduction o The most important step in prognosis is evaluation or
mature neutrophils and the presence o CSF3R muta- organ damage (C ndings), which denes an aggressive
tion in nearly all patients. Patients have various, mostly subtype o SM. Clinical presentation is mostly driven by
ChapTeR 6
nonspeciic constitutional symptoms. The presence o release o vasoactive mediations rom mast cells (such
CSF3R mutation with neutrophilia is pathognomonic or as itching, ushing, diarrhea, and others). Patients with
diagnosis. CNL usually has an aggressive course, with a indolent SM have a normal lie expectancy, but those with
median survival o approximately 2 years and the ten- the aggressive orm have signicantly decreased survival
dency to progress to acute leukemia. There are no stan- rates. Higher age, advanced clinical eatures (eg, anemia,
dard therapies. Cytoreduction therapy, such as HU; IFN; thrombocytopenia, leukocytosis), and the presence o
or cladribine-based chemotherapy are used most oten. mutations in SRSF2, ASXL1, or RUNX1 predict inerior out-
The JAK inhibitor ruxolitinib is being explored in clinical come. In addition to symptom relie, the goals o therapy
trials. All patients with CNL be considered or stem cell or aggressive SM are reduction o disease burden and
transplantation. prevention o organ damage. The multikinase inhibitor,
 Systemic mastocytosis (SM) is a heterogeneous group midostaurin, represents the only approved targeted ther-
o diseases characterized by clonal expansion o malig- apy. Avapritinib is a promising agent being evaluated in
nant mast cells and their accumulation in various organs. clinical trials as o this writing.
INTRODUCTION recognized as distinct entities in the most recent 2016

revision to the World Health Organization (WHO)
The eld o myeloprolierative disorders (MPDs) has classication o myeloid neoplasms.11 Also included
evolved considerably since the sentinel observations under the broad heading o MPNs are atypical MPNs,
made by William Dameshek in 1951. He commented namely, chronic neutrophilic leukemia (CNL), chronic
in an editorial in the journal Blood: “To put together eosinophilic leukemia (CEL), and MPN-unclassiable
such apparently dissimilar diseases as chronic granulo- (MPN-U) (Table 6–1). The MPNs are, in turn, classi-
cytic leukemia, polycythemia, myeloid metaplasia and ed among the ve categories o myeloid neoplasms,
di Guglielmo’s syndrome may conceivably be with- the others being: (1) AML; (2) myelodysplastic syn-
out oundation, but or the moment at least, this may dromes (MDS); (3) MDS/MPN “overlap” syndromes,
prove useul and even productive. What more can one which include chronic myelomonocytic leuke-
ask o a theory?”1 mia (CMML), juvenile myelomonocytic leukemia
The central eature among the MPDs, now termed (JMML), atypical CML (aCML), BCR-ABL negative,
myeloprolierative neoplasms (MPNs), is eective MDS/MPN with ring sideroblasts and thrombocyto-
clonal myeloprolieration without dysplasia. Other sis (MDS/MPN-RS-T), and MDS/MPN-unclassiable
eatures shared by most MPNs include involvement (MDS/MPN-U); and (4) mastocytosis, which is no
o a multipotent hematopoietic stem/progenitor cell; longer grouped together with MPNs. There is also a
marrow hypercellularity; predisposition to throm- separate WHO category or myeloid/lymphoid neo-
bosis, hemorrhage, and marrow brosis; and pheno- plasms with eosinophilia and rearrangement o PDG-
typic “driver” mutations in tyrosine kinases (TKs), FRa, PDGFRb, or FGFR1, or with PCM1-JAK2. Major
eg, JAK2 (Janus kinase 2) 2–5 and c-KIT6; or other cel- changes to the WHO diagnostic criteria or PV were
lular proteins that aect JAK-signal transducer and introduced in the 2016 revision, and are discussed
activator o transcription (STAT) signaling (eg, the below. CML, characterized by a balanced, recipro-
thrombopoietin receptor c-MPL7,8 and the endoplas- cal translocation between chromosomes 9q34 and
mic reticulum chaperone CALR.) 9,10 When the con- 22q11, termed the “Philadelphia chromosome” (Ph),
cept o MPDs was rst proposed, it consisted o ve resulting in the BCR-ABL usion protein that drives
disorders: chronic myelogenous leukemia (CML), the disease, is discussed elsewhere. Here, we discuss
polycythemia vera (PV), essential thrombocythe- the classic, Ph-negative (Ph-) MPNs (PV, ET, and PMF),
mia (ET), chronic idiopathic myelobrosis (CIMF), as well as CEL, myeloid/lymphoid neoplasms with
and erythroleukemia. Over the years, erythroleuke- eosinophilia (MLN-Eo), CNL, and systemic mastocy-
mia was reclassied under acute myeloid leukemia tosis, in which important advances have been made
(AML), and CIMF was renamed primary myelobro- both in our understanding o its pathophysiology and
sis (PMF). Prebrotic (pre-) and overt PMF are now its clinical management.
Ctr 6 Philadelphia Chromosome-Negative Myeloprolierative Neoplasms 121
Tbl 61 2016 World hlt Orgniztion Clssifction Scm or Myloid Nolsms
1. Acute myeloid leukemia

2. Myelodysplastic syndromes (MDS)
ChapTeR 6
3. Myeloprolierative neoplasms (MPNs)
3.1 Chronic myeloid leukemia (CML), BCR-ABL1+
3.2 Polycythemia vera (PV)
3.3 Essential thrombocythemia (ET)+
32. 3.4 Primary myelobrosis (PMF)
• Prebrotic primary myelobrosis (pre-PMF)
• Overt primary myelobrosis (overt PMF)
3.5 Chronic neutrophilic leukemia (CNL)
3.6 Chronic eosinophilic leukemia, not otherwise specied (CEL)
3.7 MPNs, unclassiable
4. MDS/MPN “overlap” syndromes
4.1 Chronic myelomonocytic leukemia (CMML)
4.2 Juvenile myelomonocytic leukemia (JMML)
4.3 Atypical chronic myeloid leukemia (aCML), BCR-ABL–
4.4 MDS/MPN, unclassiable (MDS/MPN-U)
4.5 MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
5. Myeloid/lymphoid neoplasms associated with eosinophilia and abnormalities o PDGFRa, PDGFRb, FGFR1, or
with PCM1-JAK2
5.1 Myeloid neoplasms with PDGFRa rearrangement
5.2 Myeloid neoplasms with PDGFRb rearrangement
5.3 Myeloid neoplasms with FGFR1 rearrangement (8p11 syndrome)
5.4 Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2
Data rom Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the World Health Organization classication o myeloid neoplasms and acute leukemia,
Blood 2016 May 19;127(20):2391-2405.
pOLYCYTheMIa VeRa median survival is long, approximately 18.9 years

(although inerior to that o the age- and sex-matched
PV is a clonal disorder characterized by the accumula- general population), as ound in an international study
tion o phenotypically normal red cells, granulocytes, o 1545 patients that used a more contemporary (2008
and platelets. The word polycythemia is composed o WHO) denition o PV.15 However, other studies rom
the Greek words poly (“many”), cyt (“cells”), and hemia reerral centers with more complete ollow-up have
(“blood”), indicating the presence o too many blood reported the median survival o patients with PV to be
cells (red, white, and platelets). The term vera is rom shorter, around 13.5 years.16
the Latin word meaning true, making a distinction The JAK-STAT pathway has been known to play an
between PV and a host o other conditions that can important role in hematopoiesis, which is mediated in
result in an increase in the number o red blood cells part by erythropoietin (Epo) and thrombopoietin (Tpo)
(RBCs). The central eature o the disease is elevated via their cognate receptors. In 2005, our dierent
red cell mass (RCM), associated with a predisposition groups identied an activating mutation in the JAK2
to thrombosis. PV occurs mainly in older adults. The gene in as many as 97% o patients with PV.2–5 The JAK
annual incidence o PV is around 1 case per 100,000 proteins are bound to the cytoplasmic domains o type
population,12 and the US prevalence has been esti- I cytokine receptors (eg, the Epo and Tpo receptors),
mated to be 44 to 57 individuals per 100,000.13 In a and the binding o cytokines or growth actors (eg, Epo
large observational study o 1638 patients with PV, and Tpo) to their cell-surace receptors induces dimer-
the median age at diagnosis was 62.1 years, and only ization and phosphorylation o the JAKs. The activated
4% o the patients were younger than 40 years.14 The JAK then phosphorylates the cytoplasmic domains o
the cytokine receptors. STATs bind to these phosphor- a routine blood examination. The bone marrow (BM)
ylated receptor sites and in turn are phosphorylated by is typically hypercellular with panmyelosis and mega-
the JAKs. These phosphorylated and activated STAT karyocyte pleomorphism.11 Cytogenetic abnormalities
molecules regulate the transcription o the target genes are relatively inrequent but adversely aect survival.15
in the nucleus. JAK2 has two domains: JH1 (the active
ChapTeR 6
kinase domain) and JH2 (the “pseudokinase” domain

that autoinhibits the kinase domain). The most com-
Thrombosis
mon mutation in PV (and in all 3 classic, Ph- MPNs) is Thrombosis is the most serious complication o PV
a guanine-to-thymine substitution in exon 14, result- (Table 6–2) and is a presenting maniestation in 15% to
ing in a valine-to-phenylalanine substitution at posi- 20% o patients.23,24 In a study o 1213 patients with PV,
tion 617 (JAK2V617F). This gain-o-unction mutation, thrombosis (arterial and venous combined) occurred
which renders JAK2 constitutively active, results in in 41% o patients overall (64% o thrombotic events
Epo-independent prolieration o erythroid precur- occurred at presentation or beore diagnosis and 36%
sors. The pathologic nature o this mutation has been occurred during ollow-up).23 In a more recent study o
illustrated by many studies, and JAK2V617F knockin 1545 patients diagnosed using 2008 WHO diagnostic
mouse models resembling human PV have been cre- criteria, thrombosis occurred in 23.4% o patients at
ated, showing that the mutation in hematopoietic or beore diagnosis and in 21% during ollow-up.15,25
stem cells is sucient to initiate the disease.17 In con- Arterial thrombosis was more common overall than
trast to wild-type JAK2, mutated JAK2 allows or the venous thrombosis, and was predicted by prior arterial
Epo-independent growth o cell lines in culture.3–5 The events and hypertension, whereas venous thrombosis
JAK2V617F mutation is present in approximately 95% was predicted by prior venous events and age o 65
to 97% o patients with PV and is not present in sec- years or older. Ischemic stroke and transient ischemic
ondary polycythemia. Mutations in exon 12 o JAK2 attacks accounted or the majority o arterial throm-
have been identied in most o the remaining patients boses at diagnosis.23,25 The overall incidence o throm-
with PV who are negative or the JAK2V617F muta- botic events has been estimated at 2.62% to 4.4% o
tion.18 Thereore, with current sensitive testing, vir- patients per year.23,25,26 The rate o thrombotic events
tually all patients with PV should have mutations in increases with age (1.8/100 patients per year or those
either exon 14 or exon 12 o JAK2. Very recently, recur- <40 years to 5.1/100 patients per year or those >70
rent indels in exon 13 o the JAK2 gene, also aecting years).23 Older age and a history o thrombosis are the
the JH2 domain, have been described as giving rise to a two best established risk actors or thrombosis.23,25 In
novel MPN with eatures o both PV and CEL.19 Loss- the Polycythemia Vera Study Group studies, one third
o-unction mutations in LNK, a physiologic-negative o the individuals who survived the initial thrombotic
regulator o JAK2, have been implicated in some cases event had recurrent thrombosis.27 Budd-Chiari syn-
o JAK2–wild type erythropoiesis.20 drome (BCS) can be a presenting maniestation o PV.
PV is the underlying cause in 50% o patients with
BCS,28 and the JAK2 mutation has been ound in 40%
Clinical Features to 58% o patients with BCS.29 Leukocytosis (white
Presenting symptoms include vasomotor maniesta- blood cells [WBCs] >11 × 109/L or >15 × 109/L)30,31 has
tions such as headache, dizziness, trouble concentrat- been ound to be a risk actor or thrombosis in some,
ing, blurry vision, tinnitus, erythromelalgia, and acral but not all, studies.32,33
paresthesias, as well as constitutional symptoms such
as atigue, pruritus (especially ater a hot shower or
Disease Evolution, Causes o Death, and
bath), bone and muscle aches, ever, weight loss, and
drenching night sweats.21 In an internet-based survey
Prognostic Models
o 405 patients with PV, the most requently reported Progression to myelobrosis (MF; termed post-PV MF)
constitutional symptoms were atigue (85%), itching and transormation to AML are the two major late
(65%), night sweats (49%), and bone pain (43%).22 complications o PV. Post-PV MF develops in 4.9% to
Thrombosis and hemorrhage are the most common 6% o patients with PV at 10 years and 6% to 14%
serious complications. Palpable splenomegaly is ound at 15 years,34 and is characterized by clinical eatures
in about 40% o patients and may cause abdominal similar to PMF (anemia, serum lactate dehydrogenase
discomort and/or early satiety.21 The peripheral blood elevation, leukoerythroblastosis, and progressive sple-
picture is typically one o “pancytosis.” Thrombocyto- nomegaly). Major diagnostic criteria include a history
sis can be associated with ocular migraine and erythro- o PV and grade 2 or higher brosis in the BM.35 Pas-
melalgia (burning pain in the eet or hands associated samonti et al developed the Myelobrosis Secondary
with warmth and erythema). Some patients are asymp- to PV or ET Prognostic Model (MYSEC-PM) or predic-
tomatic and are diagnosed ater abnormal ndings on tion o overall survival (OS) and leukemia-ree survival
Tbl 62 Trombosis nd Blding in polycytmi Vr (t Dignosis nd t Follow-U)
At Diagnosis At Follow-Up
Major Major Deaths
Ctr 6 Philadelphia Chromosome-Negative Myeloprolierative Neoplasms

Thrombosis Thrombosis Major Deaths From From
No. o (%) (Arterial %, Bleeding (%) (Arterial %, Bleeding Thrombosis Thrombosis Bleeding
Study Patients Asymptomatic Venous %) (%) Venous %) (%) Rate (%) (%)
PVSG01 431 NR 13.9 (61, 39) 14.9 27.6 (NR, NR) 2.7 31 5
Groupo Italiano 1,213 NR 34 (67, 33) NR 19 (63, 37) NR 3.4%/y 29.7 2.6
Studio
Policitemia
(GISP)
ECLAP 1,638 NR 36 (75, 25) 8.1 10.3 (70, 30) 7.1 4.4%/y 26 3.7
Passamonti 163 37 34 (64, 36) 3 18 (80, 20) NR 19 6
(2000a)
CYTO-PV 365 NR 25 (60, 40) 4.9 7.4 (56, 44) 1.9 2.7%/y 44 NR
IWG-MRT 1,545 NR 23 (68, 32) 4.2 21 (57, 43) 4.2 2.6%/y 21 1.4
a
Data rom Passamonti F, Brusamolino E, Lazzarino M, et al. Ecacy o pipobroman in the treatment o polycythemia vera: long-term results in 163 patients, Haematologica 2000 Oct;85(10):1011-1018.
123
ChapTeR 6
(LFS) based on a cohort o 685 molecularly annotated thrombosis as independent predictors o worse sur-
patients with post-PV or post-ET MF.36 In this cohort, vival. Independent risk actors or shorter LFS included
the median OS or patients with post-PV MF was 8.1 older age, abnormal karyotype, and leukocyte count
years. PV transorms to blast phase (leukemic transor- ≥15 × 109/L. This study conrmed the associations
mation) in 2.3% to 14.4% o patients at 10 years and o chlorambucil, pipobroman and 32P, but not HU or
ChapTeR 6
5.5% to 18.7% o patients at 15 years.34 In the European busulan, with leukemic transormation. A nested case
Collaboration on Low-Dose Aspirin in Polycythemia control study rom Sweden also ound high exposures
Vera (ECLAP) study, AML/MDS developed rom the to 32P and alkylating agents, but not HU, to be associ-
diagnosis o PV in 22 o the 1638 patients (1.3%) ater ated with signicantly higher risks o transormation to
a median o 8.4 years. Older age and exposure to che- AML/MDS.38 More recently, targeted deep sequencing
motherapy (32P, busulan, and pipobroman; P = .002), eorts have identied mutations in ASXL1, SRSF2, and
but not hydroxyurea (HU) alone, were associated with IDH2 as prognostically adverse in PV.39 The mutation-
an increased risk o AML.14 Very-long-term ollow- enhanced International Prognostic Scoring System or
up (median, 16.3 years) o the French Polycythemia PV integrates clinical and molecular inormation into a
Study Group study comparing HU with pipobroman three-tiered (low, intermediate, and high risk) system
in 285 patients also ound a much higher cumulative to predict OS in PV built on hazard ratio–based points
incidence o AML/MDS in the pipobroman group.37 allocation to age more than 67 years, SRSF2 mutation,
In a prospective study o 338 PV patients, post-PV MF leukocyte count ≥15 × 109/L, and thrombosis history.40
developed in 8 patients and AML developed in 10 ater
a median o 3.2 years. JAK2V617F allele burden was
signicantly related to the risk o development o MF
Diagnosis
but not AML.32 Very recently, a retrospective study o The 2016 revision to the WHO classication o
520 PV patients seen at 10 US centers ound that per- myeloid neoplasms and acute leukemia11 saw major
sistent leukocytosis was signicantly associated with changes to the diagnostic criteria or PV (Table 6–3).
disease evolution to MF, MDS, or AML.33 These include lowering o the hemoglobin (Hgb) and
The most common causes o death in PV are throm- hematocrit (Hct) cutos or diagnosis, largely based
botic complications and leukemic transormation. In a on the recognition that individuals with so-called
study o 1213 patients, the most requent atal com- “masked” PV (mPV) have worse outcomes,41,42 at least
plications were thrombosis (30%) and cancer (15% in part because o less recognition and treatment,43 and
acute leukemia, 15% other cancers).23 In the ECLAP elevation o BM biopsy changes characteristic o PV to
study (N = 1638), the most common causes o death a major criterion, although BM biopsy is not required
were cardiovascular complications, leukemic transor- or diagnosis in cases that ulll the 2008 WHO criteria
mation, and solid tumors in 45%, 13%, and 19.5%, or Hgb (>18.5 g/dL in men and >16.5 g/dL women) or
respectively.26 In the International Working Group or Hct (>55.5% in men and >49.5% in women), are JAK2-
Myelobrosis Research and Treatment (IWG-MRT) mutated, and have a low serum Epo level. Compared
study (N = 1545), the most common causes o death with the Polycythemia Vera Study Group criteria, or
were cancer (36% acute leukemia, 36% other cancers) which RCM measurement was mandatory, the WHO
and thrombotic complications (32%).15 A prognostic criteria have placed less reliance on direct RCM mea-
model developed rom this study included age (57–66 surement and established Hgb and Hct cutos (Hgb
or ≥67 years), leukocytosis (≥15 × 109/L), and venous >16.5 g/dL in men and >16 g/dL in women; Hct >49%
Tbl 63 2016 World hlt Orgniztion Dignostic Critri or polycytmi Vr
Major criteria
• Hgb >16.5 g/dL in men and Hgb >16 g/dL in women or Hct >49% in men and Hct >48% in women, or other evidence o
increased red cell mass
• Bone marrow biopsy showing hypercellularity or age with trilineage growth (panmyelosis) including prominent erythroid,
granulocytic, and megakaryocytic prolieration with pleiomorphic, mature megakaryocytes (diferences in size)
• Presence o JAK2V617F or JAK2 exon 12 mutation
Minor criterion
• Subnormal serum erythropoietin level
Diagnosis: All 3 major criteria, or the rst 2 major criteria and the minor criterion
Reproduced with permission rom Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the World Health Organization classication o myeloid neoplasms and
Hgb, hemoglobin; Hct, hematocrit.
ChapTeR 6
FIGURe 6–1 Bone marrow biopsy rom a patient with PV FIGURe 6–2 Extensive bone remodeling and osteoscle-
shows remarkable hypercellularity because o myeloid hyper- rosis are occasional eatures encountered in bone marrow
plasia and markedly increased megakaryocytes. Although biopsies during the postpolycythemic myelobrosis phase
some o the megakaryocytes morphologically demonstrate o PV (×40).
slight size variations, most o the megakaryocytes are unre-
markable (×200).
in men and >48% in women in the 2016 criteria) or

diagnostic purposes. These cutos were ound to dis-
criminate best between mPV and JAK2-mutated ET.44
This view is not universally held, however, and some
experts still advocate use o direct RCM measurement
or PV diagnosis45; however, RCM measurement is not
available virtually anywhere in the United States, out-
side o a select ew centers where this is still routinely
perormed. For patients suspected to have PV (based on
elevated Hgb/Hct, presence o symptoms, or throm-
botic/hemorrhagic complications), initial evaluation in
most cases should include a BM biopsy with testing
or the JAK2 mutation (on either peripheral blood or
BM)46 and measurement o serum Epo. Because red cell
prolieration is autonomous in PV, serum Epo is gener-
ally low but can be within the normal range. Classical
FIGURe 6–3 In contrast to the relatively normal
morphologic eatures seen in BM biopsies in PV and
megakaryocytes seen during the early stages o PV,
post-PV MF are shown in Figs. 6–1 to 6–3.
megakaryocytes become markedly atypical during the post-
polycythemic myelobrosis phase. The atypical morpho-
Treatment logic eatures include pronounced size variations, usually
because o the presence o numerous small orms. Classi-
The main goal o therapy in PV is to prevent throm- cally, megakaryocyte nuclei become hyperchromatic during
botic events.47 In general, this is achieved with the this advanced stage o PV (×200).
use o phlebotomy and low-dose aspirin in low-risk
patients, and with cytoreductive therapy and low-dose
aspirin in high-risk patients. The target Hct is <45%, the impact o therapeutic lowering o elevated WBC
established by the seminal Cytoreductive Therapy counts in PV is unclear, most clinicians try to control
in Polycythemia Vera (CYTO-PV) study, discussed leukocytosis, given its known associations with ine-
below.48 Regular phlebotomy induces iron deciency, rior survival and risk o leukemic transormation, and
which has not been shown to be detrimental in the possibly with thrombotic events.15,30,31,33,40 Guidelines
absence o anemia. Patients with PV who become rom the US National Comprehensive Cancer Network
iron decient as a result o phlebotomy use should (NCCN) recognize the need or cytoreductive therapy
not routinely receive iron supplementation. Although in low-risk patients under certain circumstances—eg,
new thrombosis or disease-related major bleeding, patients and during pregnancy, but discontinuation
requent and/or persistent need or phlebotomy but rates are high (range, 20%–25%) because o side
with poor tolerance o phlebotomy, splenomegaly, eects such as depression and fulike symptoms.57 A
symptomatic thrombocytosis, progressive leukocyto- newer, longer-acting orm o monopegylated IFN-α
sis, and troublesome disease-related symptoms such as (PEG-proline-IFN-α-2b, also called ropegintereron-
ChapTeR 6
pruritus, night sweats, and atigue.49 Hepcidin mimet- α-2b), which allows or subcutaneous dosing every
ics (NCT04057040) represent a novel class o agents two weeks, has recently been approved in Europe or
that may have the potential to reduce the need or patients with PV without symptomatic splenomegaly.
phlebotomy.50 In the pivotal PROUD/CONTINUATION-PV phase 3
Platelets rom patients with PV have been shown RCTs,58 ropegintereron-α-2b was compared 1:1 with
to prooundly overproduce thromboxanes, and this HU in 257 patients with PV who had never received
can eectively be suppressed by low-dose aspirin.51 In cytoreductive therapy or had received HU or less
the ECLAP study, Landol et al randomized 518 PV than 3 years without achievement o CR or develop-
patients o any age without a clear indication or, or ment o resistance/intolerance to HU (Table 6–4).59
contraindication to aspirin, to low-dose aspirin (100 mg The primary end point o PROUD-PV, a noninerior-
daily) or placebo.52 All patients continued to be treated ity study—complete hematologic response (CHR)
with phlebotomy, cytoreductive therapy, and stan- with normal spleen size at 12 months—was met (21%
dard cardiovascular drugs; the median Hct was 46%. or ropegintereron-α-2b and 28% or HU). One hun-
The use o aspirin resulted in a 60% reduction in the dred seventy-one patients were rolled over into the
risk o nonatal myocardial inarction, nonatal stroke, CONTINUATION-PV trial. Fity-three percent o the
pulmonary embolism, major venous thrombosis, and patients in the ropegintereron-α-2b group versus 38%
death rom cardiovascular causes (P = .03). The inci- in the HU/standard therapy group (P = .044) met the
dence o major bleeding episodes was not signicantly coprimary end point o CHR with improved disease
increased in the low-dose aspirin group; virtually all burden at 36 months. Tolerability o ropegintereron-
excess bleeding in the aspirin group was caused by an α-2b was good, and both hematologic and molecular
83% increase in the rate o minor bleeding episodes. responses to it improved over time, showing superior-
Largely based on this trial, all patients with PV should ity over HU ater two and three years o treatment.
receive low-dose aspirin unless contraindicated. The histone deacetylase inhibitor givinostat is also in
The CYTO-PV randomized controlled trial (RCT) clinical development or PV.60
evaluated the benet o maintaining stringent control The oral JAK1/2 inhibitor ruxolitinib was approved
o Hct (target <45%) versus less intense treatment (tar- by the FDA or HU-resistant/intolerant PV in Decem-
get 45%–50%) in 365 adults with JAK2-mutated PV ber 2014, based on the results o a randomized phase
treated with phlebotomy or HU or both.48 Patients 3 clinical trial, RESPONSE, in which 222 patients
with tight control o Hct (<45%) had a signicantly were randomized 1:1 to receive ruxolitinib (start-
lower rate o major thrombosis and death rom cardio- ing dose 10 mg twice daily) or standard therapy.61
vascular causes (2.7% vs 9.8% ater a median ollow- Twenty-one percent o the patients in the ruxolitinib
up o 31 months). arm achieved the primary end point (Hct control
Although not based on prospective RCT data, HU without phlebotomy through week 32 and a ≥35%
is the most preerred rst-line cytoreductive therapy spleen volume reduction [SVR] rom baseline at week
or patients with PV; however, weekly subcutane- 32) versus 1% in the standard therapy arm (P < .001).
ously administered pegylated IFN-α-2a, which has Sixty percent versus 20% o the patients achieved Hct
been associated with high rates o both hematologic control, 38% versus 1% saw ≥35% SVR, 24% versus
and molecular responses in single-arm, noncompara- 9% achieved CHR and 49% versus 5% o patients
tive phase 2 trials.53,54 is also a reasonable option. in the standard therapy arm had a ≥50% improve-
The Myeloprolierative Disorders Research Consor- ment in the MPN-Symptom Assessment Form total
tium (MPD-RC) conducted a global phase 3 RCT, the symptom score (TSS), a validated measure o MPN
MPD-RC 112 study, comparing HU with pegylated patient-reported symptoms.62 Herpes zoster reactiva-
IFN-α-2a in 168 patients with high-risk PV or ET.55 tion was more common in the ruxolitinib arm. Cross-
No meaningul dierences were apparent between over was permitted ater week 32, and all standard
the two treatment arms at 1 or 2 years o ollow-up, therapy patients had crossed over to receiving ruxoli-
with respect to rates o complete response (CR) by tinib by week 80. A similarly designed phase 3 trial,
IWG-MRT/European LeukemiaNet (ELN) criteria56 or RESPONSE-2, conducted in HU-resistant/intolerant
BM histopathologic or molecular responses. However, patients without splenomegaly, produced very simi-
the rate o grade 3/4 toxicity was higher in the IFN lar results.63 The benets o ruxolitinib were sustained
group. Intereron’s lack o leukemogenicity and tera- ater 5 years o ollow-up, and no new saety concerns
togenicity makes it attractive or treatment o young emerged.64 Thromboembolic events were numerically
Tbl 64 euron Lukmi Nt (eLN) Dfnition o hydroxyur Rsistnc/Intolrnc in pV
1. Need or phlebotomy to keep hematocrit <45% ater 3 months o at least 2 g/day o hydroxyurea, OR
2. Uncontrolled myeloprolieration, ie, platelet count >400 × 109/L AND white blood cell count >10 × 109/L ater 3 months o at
least 2 g/day o hydroxyurea, OR
ChapTeR 6
3. Failure to reduce massivea splenomegaly by >50% as measured by palpation, OR ailure to completely relieve symptoms
related to splenomegaly, ater 3 months o at least 2 g/day o hydroxyurea, OR
4. Absolute neutrophil count <1.0 × 109/L OR platelet count <100 × 109/L or hemoglobin <10 g/dL at the lowest dose o
hydroxyurea required to achieve a complete or partial clinicohematologic responseb, OR
5. Presence o leg ulcers or other unacceptable hydroxyurea- related nonhematologic toxicities, such as mucocutaneous
maniestations, gastrointestinal symptoms, pneumonitis, or ever at any dose o hydroxyurea
a
Organ extending by more than 10 cm rom the costal margin.
b
Complete response was dened as: hematocrit <45% without phlebotomy, platelet count ≤400 × 109/L, white blood cell count ≤10 × 109/L, and no disease-related
symptoms. Partial response was dened as: hematocrit <45% without phlebotomy, or response in three or more o the other criteria.
Reproduced with permission rom Barosi G, Birgegard G, Finazzi G, et al: A unied denition o clinical resistance and intolerance to hydroxycarbamide in polycythaemia
vera and primary myelobrosis: results o a European LeukemiaNet (ELN) consensus process, Br J Haematol 2010 Mar;148(6):961-963.
lower in the ruxolitinib group than in the standard at opposite conclusions on whether persistent need or
therapy group. A recent meta-analysis also ound a phlebotomies while receiving HU is associated with
numerically, but not statistically signicant (P = .098), adverse outcomes.71,72 Although HU is widely used as
lower incidence o thrombotic events with ruxolitinib rst-line cytoreductive therapy, data support the use
in patients with PV.65 o pegylated IFN-α-2a/ropegintereron-α-2b up ront
Pegylated IFN-α-2a is also a therapeutic option as well. Both ruxolitinib and pegylated IFN-α-2a are
ater ailure o HU in PV. In the single-arm, phase 2 reasonable options in the setting o HU resistance/
MPD-RC 111 trial, the overall response rate (ORR) intolerance.
to pegylated IFN-α-2a at 12 months in 50 HU-resis-
tant/intolerant patients with PV was 60% (22% CR
+ 38% partial response [PR]). 66 Retrospective studies eSSeNTIaL ThROMBOCYTheMIa
have demonstrated that resistance/intolerance to HU
(Table 6–4) has prognostic implications. In a Span- Essential thrombocythemia (ET) is characterized by
ish registry study, resistance and intolerance to HU persistent thrombocytosis with a predisposition to
were ound in 11% and 13% o patients with PV, and thrombosis and bleeding. ET is not a cytogenetically or
resistance to HU was associated with a higher risk a morphologically dened disease entity and remains a
o death and leukemic transormation. 67 In another diagnosis o exclusion, although the discovery o driver
such study, development o cytopenias at the low- mutations in exon 9 o CALR, detected in the vast major-
est dose o HU needed to achieve CR or PR was an ity o JAK2/MPL-wild-type cases,9,10 has substantially
independent risk actor or transormation to acute simplied the diagnosis. Generally, it is a disease o older
leukemia, whereas the risk o progression to MF adults; the median age at diagnosis is 55 to 60 years. ET
was higher in patients in whom cytopenia or mas- is more common in women than in men. Survival in
sive splenomegaly developed.68 Based on induction ET has been reported to be no dierent rom to slightly
o murine double minute 2 (MDM2) by JAK2V617F,69 worse (median, 19.8 years) than that o the age- and sex-
MDM2 inhibition has been pursued as a therapeu- matched general population in dierent studies.16,73 The
tic strategy or HU-resistant/intolerant PV. However, annual incidence o ET has been reported to be 0.21 to
although clearly active,70 the toxicity o these agents 2.27 per 100,000 population.12 The US prevalence o ET
(eg, idasanutlin) has thwarted their clinical develop- has been estimated to be in the range o 38 to 57 indi-
ment or PV. viduals per 100,000.13
Reactive causes o thrombocytosis should be
excluded. Most oten, the underlying cause is appar-
Treatment Conclusions ent (postsplenectomy, acute inection, blood loss, iron
All patients with PV should receive low-dose aspirin deciency). Other MPNs, such as PV or CML, can also
unless contraindicated. Patients who are at high risk present with thrombocytosis, as can MDS with iso-
or thrombosis (age >60 years or a history o thrombo- lated deletion 5q and the overlap syndrome, MDS/
sis) should receive cytoreductive therapy. The targeted MPN-RS-T, and should be ruled out. The magnitude o
Hct is <45% in all patients. We believe that when elevation in the platelet count does not help distinguish
cytoreductive therapy is used, the goal should be to between reactive and clonal causes o thrombocytosis.
eliminate phlebotomy, although studies have arrived Reactive thrombocytosis, irrespective o the degree o
elevation o platelet counts, does not increase the risk needs to physically bind to the extracellular domain
o thromboembolic or bleeding complications. Such o MPL to exert its oncogenic eects.80–85 Another
complications, i seen, are the consequences o under- unction o mutant CALR shown to be essential or
lying disease conditions (malignancy, iron deciency oncogenic transormation, termed its rogue chaperone
rom gastrointestinal bleeding) rather than o elevated activity, is its ability to stabilize and transport MPL
ChapTeR 6
platelets. and mutants thereo to the cell surace in states that

would not normally pass quality control.86 Types 1 and
2 CALR mutations occur at approximately equal re-
Pathophysiology quencies in ET and do not appear to impact progno-
Approximately 50% o patients with ET harbor the sis,87 although one study has shown that type 1 CALR
JAK2V617F mutation, and 3% to 5% have a muta- mutations may coner a higher risk o progression to
tion in the thrombopoietin receptor (MPL) (W515L/K; post-ET MF.88 MPL mutations have been associated
tryptophan to leucine or lysine substitution at residue with shorter myelobrosis-ree survival in ET.87 Male
515),74 both o which lead to dysregulated JAK-STAT sex may be associated exclusively with type 1 CALR
signaling. Most patients with ET are heterozygous or mutations, and younger age with type 2; this study
JAK2V617F, with allele burdens less than 50%, sug- also ound platelet counts to be signicantly higher in
gesting that lower JAK2V617F gene dosage may lead type 2 than in type 1 CALR-mutated patients.89
to the development o ET versus PV, in which the
allele burden is generally higher.75 The order o muta-
tion acquisition has also been shown to infuence dis-
Clinical Features
ease phenotype, with JAK2-rst mutation acquisition With the increasing use o automated blood counters
more likely to lead to a PV phenotype with a greater and routine blood count screenings, more patients
predisposition to thrombosis, as opposed to TET2-rst with ET are being diagnosed while they are asymp-
mutation acquisition, which is associated with an ET tomatic. In an international, internet-based survey o
phenotype.76 304 patients with ET, 72% reported atigue, and about
Recently, mutations in the gene encoding the 40% o ET patients reported itching, night sweats,
endoplasmic reticulum chaperone protein calreticulin and bone pain.22 Vasomotor maniestations such as
(CALR) have been ound in nearly 70% o patients dizziness, lightheadedness, acral paresthesia, livedo
with ET negative or JAK2 or MPL mutations (20%– reticularis, and erythromelalgia were noted in 34% o
30% o all patients with ET).9,10 The CALR mutation patients in one study o 147 patients with ET.90 Mild
may dene a distinct subset o ET. In a series o 717 splenomegaly (<5 cm) was noted in up to 40% o
patients with ET, those with CALR mutations were patients, leukocytosis in 30% to 40%, and mild ane-
younger and predominantly male and had a lower mia in 10% to 20%. Thromboembolic and bleeding
incidence o thrombosis, lower hemoglobin levels, complications are the major cause o morbidity and
lower leukocyte counts, and higher platelet counts mortality in ET. A series o 322 patients with ET rom
than those with the JAK2V617F mutation.77 Other one institution reported a 26% incidence o major
studies have conrmed these observations and also thrombosis and 11% incidence o major bleeding at
noted that “triple-negative” ET patients (ie, those diagnosis.91 Hemorrhagic complications increase with
without detectable JAK2, CALR, or MPL mutations, extreme thrombocytosis (platelet count >1.5 million/
~10%–15%) share some o the same characteristics mL) and with the use o antiplatelet therapy such as
(ie, younger age, lower Hgb levels, lower leukocyte aspirin.
counts, and lower risk o thrombosis than JAK2- The most serious late complications o ET include
mutated patients).78 Survival has been reported to be transormation to AML and progression to post-ET
the longest or these “triple-negative” patients, and MF. In a single-institution study o 605 patients with
shortest or MPL-mutated patients.78 There are data ET who were ollowed or a median o 7 years, the
suggesting that the avorable impact o CALR muta- incidence o AML transormation was 3.3%.92 Risk
tions on thrombosis risk in ET might be conned to actors or transormation included anemia and plate-
younger patients.79 let count >1000 × 109/L. In a more contemporary large
There are two major types o CALR mutations: series rom seven centers in Europe, the diagnosis o ET
type 1 (52 base-pair deletions) and type 2 (5 base-pair (per 2008 WHO criteria) was conrmed in 891 patients
insertions). Both result in an altered C-terminal o and revised to early/prebrotic MF in 180 patients.93
the mutant protein with loss o negative charge that Among the patients with ET, the 10- and 15-year
impairs calcium binding, and in loss o the endoplas- cumulative incidences o transormation to AML and
mic reticulum retention moti, culminating in JAK- progression to post-ET MF were 0.7% and 2.1%, and
STAT pathway activation. Several studies have shown 0.8% and 9.3%, respectively. In another study o 292
that mutant CALR requires its altered C-terminal and patients with ET with a median ollow-up o 17.3
Tbl 65 2016 WhO Critri or Dignosis o essntil Trombocytmi
Major Criteria
1. Platelet count ≥450 × 109/L
ChapTeR 6
2. Bone marrow biopsy specimen showing prolieration mainly o the megakaryocytic lineage with increased numbers
o enlarged, mature megakaryocytes with hyperlobulated nuclei; no signicant increase or let shit in neutrophil
granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin bers
3. Not meeting WHO criteria or PV, PMF, BCR-ABL1+ CML, MDS, or other myeloid neoplasm
4. Presence o JAK2, CALR, or MPL mutation
Minor Criterion
Presence o a clonal marker or absence o evidence or reactive thrombocytosis
Diagnosis o ET requires meeting all our major criteria or the frst 3 major criteria and the minor criterion.
years, the cumulative incidence o AML was 3.8% and

o progression to MF was 10.3%.16 Overall, the risk o
progression to post-ET MF has been reported in the
literature to be 0.8% to 4.9% at 10 years and 4% to
11% at 15 years; the corresponding rates or post-ET
AML are 0.7% to 3% at 10 years and 2.1% to 5.3% at
15 years.34
Diagnosis
The diagnostic criteria or ET did not change appre-
ciably rom the 2008 to the 2016 WHO classica-
tion, other than the addition o CALR mutations to
the list o known driver mutations (Table 6–5).11 An
important change in the 2008 WHO classication was
lowering the platelet count threshold or ET diagno- FIGURe 6–4 Essential thrombocythemia is characterized by
sis rom >600 × 109/L to >450 × 109/L.94 BM biopsy increased bone marrow cellularity, myeloid hyperplasia, and
is mandatory or diagnosis to rule out “masked” PV, notably increased megakaryocytes (×200). The megakaryo-
PMF (especially pre-PMF), and MDS/MPN. A BM cytes in ET tend to display larger than normal size, and they
biopsy typically shows large but mature-appearing also contain large hyperlobulated nuclei (inset, ×400).
megakaryocytes with deeply lobulated or hyperlob-
ulated nuclei (Fig. 6–4). The peripheral blood smear
shows markedly increased platelets (Fig. 6–5). Reticu-
lin staining should be done to rule out any underly-
ing brosis; very rarely, a grade 1 increase in reticulin
bers is encountered.11 The presence o megakaryo-
cytic atypia in the BM biopsy suggests “prebrotic”
MF, which implies a higher risk o progression to overt
MF and transormation to AML, and poorer OS. 93
Also, pre-PMF oten exhibits decreased erythropoi-
esis and granulocytic prolieration, and some reticulin
brosis (but not >grade 1). 11 CML should be ruled out
by testing or the BCR-ABL1 usion gene. Beyond test-
ing or JAK2, MPL, and CALR mutations, a myeloid
mutation (targeted next generation sequencing) panel
is recommended to establish the clonal nature o the
disease, ruling out reactive thrombocytosis in “triple- FIGURe 6–5 Peripheral blood smear rom a patient with
negative” cases. ET shows markedly increased platelets with scattered large
orms (×400).
Thrombotic Risk Stratifcation and patients.77,78 Platelet count does not correlate with risk
Survival Prediction in ET o thrombosis in ET (Table 6–6). Some studies have
ound an inverse relationship between the platelet
As in PV, thrombosis and hemorrhage are the main count and the thrombotic risk. This is thought to be
complications o ET. Older age and a history o prior the result o acquired von Willebrand disease (AVWD)
ChapTeR 6
thrombosis have been shown to predict or uture with elevated platelet counts (eg, >1.5 million/mL),
thrombotic events in most studies, whereas cardiovas- predisposing the patient to more bleeding and relative
cular risk actors have been predictive in only some. protection rom thrombosis.
As discussed previously, CALR-mutated and triple- A study rom the IWG-MRT on a cohort o 891
negative patients with ET appear to be at lower risk patients rom seven centers in Europe diagnosed with
o thrombosis compared with JAK2/MPL-mutated WHO 2008–dened ET reported a 6% cumulative
Tbl 66 Risk Fctors or Trombosis in ptints wit eT
Risk Factors Studied

Risk Factors or
Age >60 Cardiovascular
Years, Odds Events
Ratio/ (Smoking,
Hazard Ratio/ Diabetes,
No. o Signicance History o Hypertension, Platelet Count JAK-2
Study Patients Level Thrombosis Hyperlipidemia) >1000 × 109/L Leukocytosis Status
Colombi 103 NS P < .001 — NS — —
(1991a)
Cortelazzo 100 10.3 13 NS NS — —
(1990b)
Besses 148 3.3 3.0 4.7 NS — —
(1999c)
Bazzan 187 NS — NS NS — —
(1999d)
Jantunen 132 NS — P = .01 NS — —
(2001e)
Chim (2005) 231 P = .01 NS — NS — —
Wolanskyj91 322 1.51 2.3 (arterial NS – 1.74 (WBC > NS
only) 15,000)
Carobbio 439 2.3 (age and 2.3 — NS 2.3 (WBC NS
(2007)98 previous >8700)
thrombosis
evaluated
together)
Alvarez- 126 NA NS Smoking NS — NS
Larrán (<40
(2007g) y)
Radaelli 306 NS 7.6 P < .05 NS — —
(2007h)
Teferi (2007i) 605 NS P < .001 NS — WBC NS
(≥15,000)
P < .01 or
thrombosis
at baseline
(NS or
thrombosis
on
ollow-up)
(Continued)
Tbl 66 Risk Fctors or Trombosis in ptints wit eT (Cont.)
Risk Factors Studied

Risk Factors or
ChapTeR 6
Age >60 Cardiovascular
Years, Odds Events
Ratio/ (Smoking,
Hazard Ratio/ Diabetes,
No. o Signicance History o Hypertension, Platelet Count JAK-2
Study Patients Level Thrombosis Hyperlipidemia) >1000 × 109/L Leukocytosis Status
Passamonti 605 P < .001 P = .03 NS NS NS —
(2008j)
Carobbio97 1063 1.7 (age and 1.7 — Patients with
previous WBC <11,000
thrombosis and platelet
evaluated <1000: most
together) likely to
have JAK-2
mutation and
highest risk o
thrombosis
Carobbio 891 1.5 1.93 1.56 0.50 1.14 2.04

(re. 94)
a
Colombi M, et al. Cancer. 1991;67(11):2926-2930.
b
Cortelazzo S, et al. J Clin Oncol. 1990;8(3):556-562.
c
Besses C, et al. Leukemia. 1999;13(2):150-154.
d
Bazzan M, et al. Ann Hematol. 1999;78(12):539-543.
e
Jantunen R, et al. Ann Hematol. 2001;80(2):74-78.

Chim CS, et al. Arch Intern Med. 2005;165(22):2651-2658.
g
Alvarez-Larrán A, et al. Leukemia. 2007;21(6):1218-1223.
h
Radaelli F, et al. Hematol Oncol. 2007;25(3):115-120.
i
Teferi A, et al. Blood. 2007;109(9):4105.
j
Passamonti F, et al. Haematologica. 2008;93(11):1645-1651.
NS, nonsignicant; —, not studied.
incidence o major bleeding at a rate o 0.79 patients/ thrombosis, consistent with previous reports show-
year.95 The cumulative incidence o thrombosis (atal ing an inverse relationship between platelet count and
and nonatal events) was 25% at a rate o 1.9% o thrombotic risk.97 The link between leukocytosis, both
patients/year.93,96 The rate o nonatal arterial events at diagnosis and during ollow-up, and thrombosis in
(1.2% o patients/year) was higher than that o venous ET has been conrmed in other studies.98,99
events (0.6% patient/year).96 Factors independently Using these risk actors, a prognostic model was
associated with bleeding included previous hemor- proposed to predict risk o thrombosis in patients with
rhage and aspirin therapy.95 Factors independently ET (International Prognostic Score or Thrombosis in
associated with major thrombosis included age older Essential Thrombocythemia [IPSET-thrombosis]).100
than 60 years, cardiovascular risk actors (diabetes, The model assigned relative weights to the our risk
hypertension, or smoking), previous thrombosis, and actors, and the patients could be stratied into three
presence o the JAK2V617F mutation.96 Leukocytosis risk categories, with an annual risk o thrombosis rang-
(>11 × 109/L) was an additional independent risk actor ing rom 1.03% o patients/year or the low-risk group
or arterial thrombosis (though not when the analy- to 3.56% o patients/year or the high-risk group
sis was restricted to JAK2-mutated cases), whereas (Table 6–7). CALR mutational status has been shown
male gender increased the risk o venous thrombosis. not to modiy the IPSET-thrombosis score.101
Extreme thrombocytosis (platelet count >1000 × 109/L) In a more recent “practice-relevant” revision o the
was independently associated with a reduced risk o IPSET-thrombosis model, patients with ET were sub-
arterial thrombosis.96 This is thought to be caused divided into our groups—very low, low, intermedi-
by AVWD with elevated platelet counts, predispos- ate, and high—based on thrombotic risk, using age,
ing to more bleeding and relative protection rom thrombosis history, and JAK2 mutation status as the
Tbl 67 Intrntionl prognostic Scor or essntil Trombocytmi (IpSeT) nd
IpSeT-Trombosis100,103
Risk Factor IPSET IPSET-Thrombosis (IPSET-t)

ChapTeR 6
a
Age >60 years 2 1
Previous thrombosis 1 2
WBC count ≥11 × 109/L† 1
Cardiovascular risk actors 1
JAK2V617F positive 2
Prognostic Score (Median Survival or Rate o Thrombosis)
Low 0 points (not reached) <2 points (1.03% patients/y)
Intermediate 1–2 points (24.5 y) 2 points (2.35% patients/y)
High 3–4 points (13.8 y) >2 points (3.56% patients/y)
a
≥60 years or IPSET, >60 years or IPSET-t.
†
≥11 × 109/L or IPSET, >11 × 109/L or IPSET-t.
Tbl 68 T rvisd IpSeT-t nd Trtmnt Rcommndtions or essntil Trombocytmi102
Risk Category Description Recommended Intervention

Very low Age ≤60 years, JAK2 WT, no h/o thrombosis Observation, low dose aspirina i CV risk actors
Low Age ≤60 years, JAK2 V617F+, no h/o Low-dose aspirina; consider twice daily i CV risk actors
thrombosis
Intermediate Age >60 years, JAK2 WT, no h/o thrombosis Cytoreductive therapy and low dose aspirina, possibly twice
daily aspirina without cytoreductive therapy
High Age >60 years AND JAK2 V617F+, or h/o Cytoreductive therapy and low-dose aspirina
thrombosis
a
Use aspirin with caution in patients with extreme thrombocytosis; always rule out acquired von Willebrand disease rst. WT, wild type; CV, cardiovascular.
variables (Table 6–8).102 Consensus guidelines rom sequencing has identied some adverse mutations/
the NCCN recommend the use o this model to risk sequence variants, viz. SH2B3, SF3B1, U2AF1, TP53,
stratiy patients with ET or disease management IDH2, and EZH2.39 The recently published MIPSS-ET
decisions.49 model integrates clinical and molecular inormation
Data rom the same cohort o patients were used to into a three-tiered (low, intermediate, and high) prog-
develop a prognostic score to predict OS o ET at diagnostic model or ET that allocates points, based on haz-
nosis (IPSET).103 The nal prognostic score included age ard ratios, to age older than 60 years, male sex, SF3B1/
60 years or older (2 points), leukocyte count 11 × 109/L SRSF2 mutations, and leukocytosis >11 × 109/L.40
or greater (1 point), and prior thrombosis (1 point) as
independent risk actors or survival (see Table 6–7).
The model stratied patients into three risk categories,
Treatment
with median survival not reached in the low-risk group The goal o therapy in ET is to prevent the major cause
to 24.5 years in the intermediate-risk group to 13.8 o morbidity and mortality: thromboembolic events.
years or the high-risk group. Although the JAK2 V617F Because the majority o patients have a normal lie
mutation was associated with increased thrombosis expectancy, aggressive treatments that could cause
risk,93 it was not predictive o survival, which was con- potentially dangerous side eects should be avoided.
sistent with ndings rom other studies.16 In another Cardiovascular risk actors should be aggressively
study, JAK2 V617F was identied as an independent managed in all patients. Smoking was an important
predictor o pregnancy complications104; however, sub- risk actor or thrombosis in many studies; all patients
sequent studies ailed to conrm this observation.105,106 should be counseled regarding smoking cessation. The
Although cytogenetic abnormalities are uncommon in two major classes o therapies used or the treatment
ET (<10% at diagnosis) and have not been correlated o ET are antiplatelet drugs and cytoreductive drugs
with survival or transormation risk,107 targeted deep (Table 6–8).
Antiplatelet Therapy (P = .004) and serious hemorrhage (P = .008), but a

lower rate o venous thromboembolism (P = .006)
Antiplatelet therapy with aspirin is useul in treating
compared with the HU arm. Serious hemorrhage with
the microvascular symptoms o ET, such as erythro-
anagrelide was likely the result o a synergistic anti-
melalgia. The role o antiplatelet therapy in reducing
platelet eect o aspirin. The risk o developing post-
ChapTeR 6
thrombotic episodes in ET is less clear because no pla-
ET MF was signicantly higher in the anagrelide arm
cebo-controlled, randomized trial is available. In a ret-
(5-year risk, 7% vs 2% in the HU arm, P = .01), and
rospective study, Van Genderen et al showed decreased
signicantly more patients in the anagrelide arm with-
thrombosis risk and improvements in microvascular
drew rom the study because o side eects (22% vs
symptoms with aspirin monotherapy.108 Extrapolat-
11%, P < .001). The risk o developing MDS/AML was
ing rom the ECLAP study results in PV,52 the general
similar in the two arms. Largely based on this trial, HU
consensus is to use low-dose aspirin (75–100 mg daily)
has been widely adopted as the rst-line treatment o
in patients with ET unless contraindicated by bleeding
choice in high-risk ET. However, the more recently
history. Caution should be exercised in using aspirin
reported ANAHYDRET study showed nonineriority
in patients with a very high platelet count (>1500 ×
o a controlled release preparation o anagrelide to HU
109/L) because o the increased risk o bleeding rom
in 259 patients with WHO-dened ET; aspirin was not
AVWD.109 In the UK Medical Research Council Primary
allowed in either arm o this trial.117 The utility o add-
Thrombocythemia 1 (MRC PT-1) trial comparing HU
ing HU to aspirin in young patients (age 40–59 years)
and anagrelide in ET, all patients received antiplatelet
with ET without high-risk eatures (thrombosis, embo-
therapy unless it was contraindicated.110 An increased
lism, hemorrhage, hypertension, or diabetes requiring
risk o bleeding was noted in the anagrelide arm com-
therapy) or extreme thrombocytosis (platelet count
pared with the HU arm, possibly because o the syn-
≥1500 × 109/L) was assessed in a randomized trial (N =
ergistic antiplatelet eect o aspirin with anagrelide. It
382).118 Ater a median ollow-up o 73 months, there
has been suggested that low-dose aspirin given twice a
was no signicant dierence between the arms in the
day may be eective in patients whose symptoms are
likelihood o patients reaching the primary end point
not controlled with once-daily dosing.111 Several stud-
(arterial or venous thrombosis, serious hemorrhage,
ies have shown that once-daily aspirin incompletely
or death rom vascular causes, P = 1.0). There were
suppresses platelet thromboxane biosynthesis, pos-
also no dierences in OS, the composite end point o
sibly a result o accelerated renewal o platelet cyclo-
disease evolution to MF, AML, or MDS; adverse event
oxygenase in ET,112 and that twice-daily dosing more
(AE) prole; or patient-reported quality o lie (QOL).
eectively inhibits platelet aggregation.113–115 A recent pooled analysis o 1500 cases o MPN-asso-
ciated thrombosis showed that although HU reduced
the rate o recurrent arterial thrombotic events, this
Cytoreductive Therapy
could not be conclusively shown with respect to recur-
Hydroxyurea, anagrelide, and IFNs are the main cyto- rent venous thrombotic events, in particular, recurrent
reductive agents currently used in patients with ET. splanchnic vein thrombosis.119
Hydroxyurea is a nonspecic, cytotoxic, and myelo- The experience with IFN in ET generally mirrors that
suppressive drug that works through inhibition o in PV. Response rates, both hematologic and molecular,
ribonucleotide reductase. Anagrelide has a selective are high,54 but patients with nondriver mutations out-
eect on the megakaryocyte lineage. Two random- side the JAK-STAT pathway have a lower likelihood
ized studies in ET have established HU as the rontline o achieving complete molecular response.120 Although
cytoreductive therapy o choice. In an Italian study by pegylated IFN-α-2a is better tolerated and allows or
Cortelazzo et al, 114 patients with high-risk ET (age weekly dosing, discontinuation rates because o AEs
>60 years, history o thrombosis, or both) were ran- remain substantial.57 As discussed in the section on PV,
domized to receive either placebo or HU, with a goal the MPD-RC 112 trial showed no meaningul dier-
platelet count o <600 × 109/L.116 Ater a median ollow- ences between HU and pegylated IFN-α-2a ater one
up o 27 months, 3.6% o patients in the HU group had or two years o treatment in patients with previously
thrombotic episodes compared with 24% in the pla- untreated high-risk PV or ET.55 Intereron’s lack o leu-
cebo group (P = .003). This study established the anti- kemogenicity and teratogenicity make it attractive or
thrombotic eect o HU in ET. Harrison et al reported use in very young patients with ET in need o cyto-
the results o the UK MRC PT-1 study o 809 high- reductive therapy,47,49 and it is the cytoreductive drug
risk patients with ET who were randomly grouped to o choice in pregnant patients.121 Ropegintereron-
receive HU plus aspirin or anagrelide plus aspirin.110 α-2b will be compared with anagrelide in patients
The goal platelet count was <400 × 109/L. Ater a with ET who are resistant to or intolerant o HU
median ollow-up o 39 months, anagrelide therapy (NCT04285086). Pegylated IFN-α-2a has been stud-
was associated with higher rates o arterial thrombosis ied in this setting and led to a 69.2% ORR (43.1% CR
Tbl 69 Consnsus Critri or hydroxyur Rsistnc or Intolrnc in essntil

Trombocytmi
Platelet count >600,000/μL ater 3 months o at least 2 g/day o HU (2.5 g/day in patients with a body weight >80 kg)
ChapTeR 6
Platelet count >400,000/µL and WBC <2500/µL at any dose o HU

Platelet count >400,000/µL and Hgb <10 g/dL at any dose o HU
Presence o leg ulcers or other unacceptable mucocutaneous maniestations at any dose o HU
HU-related ever
Reproduced with permission rom Barosi G, Besses C, Birgegard G, et al: A unied denition o clinical resistance/intolerance to hydroxyurea in essential thrombocythemia:
results o a consensus process by an international working group, Leukemia 2007 Feb;21(2):277-280.
+ 26.2% PR) in 65 patients with ET; CR rates were that o maternal complications was 9%; there were
higher in patients with CALR mutations.66 no maternal deaths or thrombotic events. Eighty-ve
Ruxolitinib was compared with best available ther- percent delivered at term. There were no neonatal
apy (BAT) in 110 patients with HU-resistant/intoler- deaths; 22% o neonates were below the 10th decile
ant ET in the MAJIC-ET trial.122 At one year, there was or growth. Pregnant women with MPNs should
no signicant dierence in CR rates, and at two years, be cared or in a multidisciplinary setting by both
rates o thrombosis, bleeding, and disease evolution to an obstetrician experienced in managing high-risk
MF or AML were not signicantly dierent; however, pregnancies and a hematologist.121 In general, low-
some disease-related symptoms were signicantly dose aspirin is recommended throughout pregnancy
improved in the ruxolitinib arm. Other studies have unless contraindicated (eg, by AVWD). Whether low-
suggested ecacy o ruxolitinib in providing sustained molecular-weight-heparin provides additional benet
count control and symptom benets in patients with is controversial,126 but some experts recommend it
HU-resistant/intolerant ET123. Table 6–9 lists consen- or women with prior thrombosis or poor pregnancy
sus criteria or HU resistance/intolerance in ET.124 The outcome, and those with at least one other risk actor
RUXO-BEAT study compares ruxolitinib with BAT or thrombosis (besides pregnancy), with appropriate
in high-risk PV or ET (NCT02577926). Bomedemstat, interruption around delivery.121 When cytoreductive
an oral inhibitor o lysine demethylase-1, will also be therapy is indicated, eg, by prior thrombosis or hem-
studied in patients with ET in whom at least standard orrhage, or platelets >1500 × 109/L, IFN-α is preerred.
therapy has ailed (NCT04254978). Low-molecular-weight heparin should generally be
oered postpartum or six weeks.
Special Issues
pRIMaRY MYeLOFIBROSIS
Management o Extreme Thrombocytosis
(Platelet Count >1.5 Million/mL) Primary myelobrosis is a clonal disorder o a multipo-
Aspirin should be avoided because o the risk o bleed- tent hematopoietic stem/progenitor cell o unknown
ing secondary to AVWD. The use o cytoreductive etiology; it is characterized by myeloid cell proliera-
agents is suggested, especially when bleeding is pres- tion, megakaryocytic atypia, BM brosis, a leukoeryth-
ent, to lower platelet counts and decrease the risk o roblastic peripheral blood picture, anemia, occasional
bleeding. Many experts regard extreme thrombocyto- extramedullary hematopoiesis (EMH), splenomegaly,
sis as a high-risk category and treat all such patients and poor survival.127 Primary myelobrosis was pre-
with cytoreductive therapy; others reserve it or viously known as CIMF, myelobrosis with myeloid
patients with bleeding complications or symptoms.111 metaplasia, or agnogenic myeloid metaplasia. Myelo-
brosis can occur either de novo (PMF) or as a late com-
plication o PV or ET (post-PV/ET MF). In either case,
Management o Essential Thrombocythemia in
it maniests as a stem/progenitor cell–derived clonal
Pregnancy myeloprolieration accompanied by intense marrow
Essential thrombocythemia is the most common o stromal reaction, including collagen brosis, osteoscle-
the Ph- MPNs encountered in pregnancy. In a prospec- rosis, and angiogenesis. The US prevalence o MF has
tive study rom the UK, pregnancies in 58 women been estimated to be 4 to 6 individuals per 100,000
with underlying MPN, 47 (81%) with ET, were iden- population.13 The annual incidence o MF ranges rom
tied.125 The incidence o miscarriage was 1.7% and 0.1 to 1 per 100,000.12,128
Pathophysiology weight loss, pruritus, low-grade ever, night sweats)

are a prominent eature o PMF and can be debilitating.
Fibrogenesis and angiogenesis have long been thought In an internet-based survey o 456 patients with MF,
to develop consequent to the release o growth-promot- 84% reported atigue, 50% itching, 56% night sweats,
ing actors (such as vascular endothelial growth actor, and 47% bone pain.22 Myeloprolieration is one o the
ChapTeR 6
platelet-derived growth actor [PDGF], basic broblast major eatures o the disease and can lead to sequestra-
growth actor, and transorming growth actor b) rom tion o immature cells and production o blood cells
prolierating atypical megakaryocytes in the BM.129 in sites other than the BM, a phenomenon known as
More recently, however, brocytes, the brosis-driving extramedullary hematopoiesis (EMH). This commonly
cells in the BM o persons with PMF, have been shown maniests as marked hepatosplenomegaly, with asso-
to be clonal (neoplastic) and derived rom blood mono- ciated pain, early satiety, portal hypertension, anemia,
cytes.130,131 The JAK2 V617F mutation is ound in 50% and thrombocytopenia. Splenomegaly is present in
to 60% o patients with PMF. Persistent JAK-STAT sig- 80% o the patients and may extend into the pelvis.
naling, resulting in the overproduction o proinfamma- Hepatomegaly is seen in 40% to 70% o patients. EMH
tory cytokines, has been observed in all patients with might cause symptoms in various other organs, lead-
PMF, regardless o driver mutation status.132,133 Proin- ing to respiratory distress, pulmonary hypertension,
fammatory cytokines have been associated with many ascites, pericardial tamponade, cord compression, and
o the symptoms o MF, as well as splenomegaly, trans- paralysis. Teardrop red cells and a leukoerythroblastic
usion dependence, thrombocytopenia, and shortened picture (presence o immature myeloid cells includ-
survival.134 Mutations in the thrombopoietin receptor ing blasts in the peripheral blood) are characteristic o
(MPL) are ound in 5% to 10% o patients, and CALR MF. Anemia is present in about one third o patients at
mutations are ound in an additional 25%.9,10 Approxi- diagnosis and eventually develops in all patients, many
mately 10% o patients are “triple negative” (discussed o whom require transusion.138 Some patients may
previously in this chapter). Rare inactivating mutations present with leukocytosis and thrombocytosis; how-
in negative regulators o JAK-STAT signaling (eg, LNK, ever, leukopenia and thrombocytopenia develops in
SOCS, and CBL) also contribute to the dysregulated later stages o the disease in most patients. Among the
JAK-STAT signaling in PMF.135 most eared complications o PMF is transormation
As in ET, disease phenotype appears to dier by to AML, with an actuarial probability o 20.6% in the
driver mutation. In a study o 617 patients with PMF, rst 100 months rom diagnosis in one study.139 The
those with CALR mutations had a lower risk o devel- outcome ater transormation is poor, with a median
oping anemia, thrombocytopenia, and leukocytosis.136 survival o 6 to 8 months, even with modern, targeted
In another series o 428 patients with PMF, CALR muta- approaches.140,141 Transormation to AML is the most
tions were associated with younger age, lower leuko- common cause o death in MF, ollowed by MF pro-
cyte count, and higher platelet count, whereas MPL gression without acute transormation, thrombosis,
W515K/L mutations were associated with younger age and cardiovascular complications, inection, bleeding,
and lower leukocyte count when compared with JAK2 and portal hypertension.
V617F mutations.16 A number o other mutations have As discussed previously, prebrotic PMF is now
also been ound in PMF, albeit at much lower requen- a separate entity rom overt PMF in the 2016 WHO
cies than JAK2 and CALR mutations (eg, mutations in classication.11 The vast majority o patients now con-
ASXL1, EZH2, SRSF2, CBL, IDH1/IDH2, TP53, TET2, sidered to have pre-PMF would previously have been
and DNMT3A).135 These “nondriver” mutations can be categorized as having ET. Compared with ET, pre-
extremely helpul in establishing the clonal nature o PMF is characterized by signicantly worse survival
the disease in triple-negative cases. and higher rates o progression to overt MF (12.3% at
10 years and 16.9% at 15 years) and transormation
Clinical Features
to AML (5.8% at 10 years and 11.7% at 15 years).93
PMF is a heterogeneous disorder with variable age o Thrombotic risk is similar, and the IPSET-thrombosis
onset, presenting eatures, phenotypic maniestations, model or ET has been ound to accurately risk stratiy
and prognosis. The incidence o PMF increases with patients with pre-PMF.142 Bleeding risk is higher in pre-
age. In a series o 1054 patients, the median age at diag- PMF than in ET. Compared with patients with overt
nosis was 64 years; 17% o patients were younger than PMF, patients with pre-PMF have lower rates o cyto-
50 years and 5% were younger than 40 years.137 Clini- penias, lower blast counts, ewer symptoms, and are
cal presentation can range rom no or minimal symp- less likely to exhibit large splenomegaly or unavorable
toms, where disease is discovered during a workup or karyotypes.143 The distribution o driver mutations is
leukocytosis or splenomegaly, to severe symptoms and similar, but patients with overt PMF are enriched or
poor QOL. Severe atigue is the most common pre- “high molecular risk (HMR)” nondriver mutations
senting symptom. Constitutional symptoms (atigue, (discussed below) and are more likely to be in higher
Tbl 610 2016 WhO Critri or Dignosis o prfbrotic nd Ovrt primry Mylofbrosis (pMF)
Major Criteria
1. Megakaryocyte prolieration and atypia:
ChapTeR 6
a. without reticulin brosis >grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic prolieration, and
oten decreased erythropoiesis (pre-PMF);
b. accompanied by either reticulin and/or collagen brosis grades 2 or 3 (overt PMF)
2. Not meeting WHO criteria or PV, ET, BCR-ABL1+ CML, MDS, or other myeloid neoplasms
3. Presence o JAK2, CALR, or MPL mutation or in the absence o these mutations, presence o another clonal markera, or
absence o (minor, in the case o pre-PMF) reactive bone marrow reticulin brosisb
Minor Criteria: Presence o At Least One o the Following, Conrmed on Two Consecutive Determinations
1. Leukocytosis ≥11 × 109/L
2. Serum lactate dehydrogenase level above upper limit o normal
3. Anemia not attributed to a comorbid condition
4. Palpable splenomegaly
5. Leukoerythroblastosis (this criterion is only applicable to overt PMF and is absent rom the minor criteria or pre-PMF)
Diagnosis o PMF, whether overt or prefbrotic, requires meeting all three major criteria and at least one minor
criterion.
a
In the absence o any o the 3 major clonal mutations, the search or the most requent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/2, SRSF2, SF3B1) are o
help in determining the clonal nature o the disease.
b
BM brosis secondary to inection, autoimmune disorder, or other chronic inammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic
malignancy, or toxic (chronic) myelopathies.
International Prognostic Scoring System (IPSS) risk cat- o 368 patients diagnosed in our European countries
egories. Median survival was 7.2 years or overt PMF between 1996 and 2007.144 Median OS was 5.9 years
and 17.6 years or pre-PMF in one large study.143 in another cohort o 267 patients with PMF seen at
the Mayo Clinic.16 Over the years, many studies have
Diagnosis
The 2016 WHO criteria or diagnosis o both overt
and prebrotic PMF are listed in Table 6–10. Marrow
brosis by itsel is not specic or a diagnosis o PMF.
Various degrees o brosis are observed in other MPNs,
and MDS with brosis must be excluded. Morphologic
eatures o the BM during the prebrotic (cellular) phase
o PMF are shown in Fig. 6–6, and those during the
brotic phase are depicted in Figs. 6–7 to 6–9. Classical
morphologic eatures consistent with PMF and seen in
the peripheral blood smear are displayed in Fig. 6–10.
BM histology, especially megakaryocyte morphology,
is a critical diagnostic criterion or PMF. All patients
suspected o having PMF should undergo BM biopsy
with reticulin and collagen staining and molecular test-
ing, rst or JAK2 V617F and then or CALR and MPL
FIGURe 6–6 It is dicult to distinguish the prebrotic
mutations. Myeloid mutation panels can support the
phase o PMF rom other types o chronic myeloprolierative
diagnosis by uncovering mutations in nondriver genes
neoplasms based on morphologic criteria alone. However,
in triple-negative cases. Diagnostic criteria or post-PV careul microscopic examination o the bone marrow biopsy
and post-ET MF appear in Table 6–11. usually reveals scattered atypical megakaryocytes with
morphologic criteria classical or PMF in the brotic phase.
Prognosis As shown, some o the megakaryocytes in this bone mar-
row biopsy are remarkably variable in size and shape and
Survival in PMF is much shorter than in ET or PV; characteristically contain markedly hyperchromatic nuclei
median OS was reported to be 6.5 years in a cohort (×200).
ChapTeR 6
FIGURe 6–7 During the brotic phase o PMF, bone mar-
row hematopoietic cellular elements tend to decrease in
number with interstitial inltration o the bone marrow by
broblasts, which leads to a streaming efect. Characteristi-
cally, the megakaryocytes demonstrate variability in size and
shape, and megakaryocytes containing hyperchromatic and
hyperlobulated nuclei are requently encountered during
the brotic phase o PMF (×200).
FIGURe 6–9 During the brotic phase o PMF, the bone mar-
row is characterized by increased interstitial reticulin bro-
sis (upper panel, ×100), which might be associated with the
abnormal presence o collagen bers that are detected by
trichrome staining (lower panel, ×200).
(DIPSS), published in 2010, rened the IPSS by assign-

ing two points, rather than one, to anemia (Hgb <10 g/
dL), based on a higher hazard ratio or death, and was
FIGURe 6–8 During the brotic phase, another common ound to prognosticate patients accurately at any point
eature o the bone marrow is marked expansion o bone in their disease course, not just at diagnosis.146 The
marrow sinusoids, which are usually rudimentary under nor- DIPSS was also shown to predict leukemic transorma-
mal conditions (×100). Hematopoietic cellular elements can tion.147 Cytogenetic abnormalities associated with an
be detected within the bone marrow sinuses; a megakaryo- unavorable prognosis in PMF include complex karyo-
cyte is shown, comprising what is known as intrasinusoidal type, and a single or two o the ollowing abnormali-
hematopoiesis (inset, ×400).
ties: +8, i(17q), -7/7q-, -5/5q-, 12p-, inv(3), and 11q23
rearrangement.148 A “very-high-risk” karyotype (single/
identied a number o clinical variables as adversely multiple abnormalities o -7, i(17q), inv(3)/3q21,12p-
aecting survival.145 These eorts culminated in the /12p11.2,11q-/11q23, or other autosomal trisomies not
development o the IPSS in 2009, which uses ve including +8/+9 [eg, +21, +19]) has also been recently
readily available pieces o inormation at the time o recognized.149 The DIPSS-plus model adds a point
diagnosis—age, Hgb, WBC count, circulating blasts, each or thrombocytopenia (platelets <100,000/µL),
and constitutional symptoms—to separate patients RBC transusion need, and unavorable karyotype to
into our prognostic categories: low, intermediate-1, the DIPSS score and can also be used at any time point
intermediate-2, and high risk.137 The Dynamic IPSS in the patient’s disease course.150 These models are
summarized in Table 6–12. O note, all these models

were developed or overt PMF, although the IPSS has
been shown to eectively risk stratiy patients with
pre-PMF.143 Growing recognition that these models do
not work well or patients with post-PV/ET MF151–153
ChapTeR 6
led to the development o the MYSEC-PM, discussed

urther below.
Recent studies have explored the prognostic rel-
evance o various mutations. In a study o 617 patients
with PMF, CALR mutations were associated with lon-
ger survival (median, 17.7 years).136 Patients with triple-
negative PMF had a higher incidence o transormation
to AML and a shorter survival (median, 3.2 years).
Another study o 253 patients with PMF reported simi-
lar ndings.154 Patients with CALR mutations had the
longest survival (median, 8.2 years), whereas patients
without any o these mutations (triple negative)
had the shortest survival (median, 2.5 years). Triple-
negative patients also displayed inerior LFS. How-
ever, unlike in ET, the avorable prognostic impact
o CALR mutations in PMF appears to be restricted
to the much more common type 1/type 1–like muta-
tions.155–157 In 2013, in a seminal paper, Vannucchi and
colleagues identied several nondriver mutations as
being associated with worse OS and LFS in a cohort
o 879 patients with PMF—these were termed HMR
(high molecular risk) mutations and included ASXL1,
SRSF2, IDH1, IDH2, and EZH2, although only ASXL1
mutation status provided additional prognostic inor-
mation beyond the IPSS or DIPSS-plus.135 This group
went on to show that the presence o two or more
FIGURe 6–10 Careul examination o peripheral blood
smears rom patients with PMF usually reveals teardrop red HMR mutations urther reduced survival (median OS,
blood cells (arrows, upper panel; ×400). In addition, nucle- 2.6 years or ≥2 mutations, 7 years or one, and 12.3
ated red blood cells (upper panel) and let-shited granu- years or none).158 Much more recently, the U2AF1
lopoiesis (lower panel; ×400) are seen, two morphologic Q157 mutation has been added to the list o prognosti-
criteria collectively described as leukoerythroblastosis. cally unavorable mutations in PMF.159 This wealth o
Tbl 611 Dignostic Critri or post-polycytmi Vr/essntil Trombocytmi

Mylofbrosis102
Required Criteria
1. Documentation o a previous diagnosis o PV or ET as dened by the WHO criteria
2. Bone marrow brosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale)
Additional Criteria (2 Required)
1. A leucoerythroblastic blood picture
2. Increasing splenomegaly dened as either an increase in palpable splenomegaly o ≥5 cm (distance o the tip o the spleen
rom the let costal margin) or the appearance o a newly palpable splenomegaly
3. Development o ≥1 o 3 constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained ever (>37.5 °C)
4. Anemia or sustained loss o requirement o either phlebotomy (in the absence o cytoreductive therapy) or cytoreductive
treatment or erythrocytosis (or post-PV MF);
Anemia and a ≥2 g/dL decrease rom baseline Hgb level (or post-ET MF)
5. Increased serum LDH (or post-ET MF only)
Tbl 612 T IpSS, DIpSS, nd DIpSS-lus prognostic Modls or primry Mylofbrosis137,146,150
Factors IPSS DIPSS DIPSS-plus

Age >65 years 1 1 Calculate DIPSS rsta
ChapTeR 6
Constitutional symptoms 1 1 Calculate DIPSS rsta
Hemoglobin <10 g/dL 1 2 Calculate DIPSS rsta
Leukocytes >25 × 109/L 1 1 Calculate DIPSS rsta
Circulating blasts ≥1% 1 1 Calculate DIPSS rsta
Platelet count <100 × 109/L 1
RBC transusion need 1
Unavorable karyotype 1
Risk stratifcation (Median Survival)
Low 0 points (11.25 y) 0 points (not reached) 0 points (15.4 y)
Intermediate-1 1 point (7.9 y) 1–2 points (14.2 y) 1 point (6.5 y)
Intermediate-2 2 points (4 y) 3–4 points (4 y) 2–3 points (2.9 y)
High 3–5 points (2.25 y) 5–6 points (1.5 y) 4–6 points (1.3 y)
a
To arrive at the DIPSS-plus score, calculate the DIPSS score rst. Assign 0 points or DIPSS low risk, 1 point or DIPSS intermediate-1 risk, 2 points or DIPSS
intermediate-2 risk, and 3 points or DIPSS high risk. Then add 1 point each or RBC transusion need, platelets <100,000/µL, and unavorable karyotype.
RBC, red blood cell.
genetic inormation that has become available in the The model, which places a heavy emphasis on patient
last ew years has since been integrated into a number age, also allocates points or anemia (Hgb <11 g/dL),
o newer prognostic models or patients with PMF.160 thrombocytopenia (platelets <150 × 109/L), circulating
These include the mutation-enhanced IPSS and muta- blasts (≥3%), driver mutation status (CALR wild type),
tion-enhanced IPSS-plus or transplantation-age (≤70 and constitutional symptoms to assign patients to one
years) patients with PMF (MIPSS70/MIPSS70-plus).161 o our prognostic categories: low, intermediate-1,
Compared with the MIPSS70, the MIPSS70-plus adds intermediate-2, and high. The score can be calculated
karyotypic inormation (unavorable vs avorable), but at www.mysec-pm.eu. The superiority o the MYSEC-
omits BM brosis grade, leukocytosis and thrombocy- PM over the IPSS or prognostication in patients with
topenia as prognostic variables, and classies patients post-PV/ET MF has been independently validated.164
into our prognostic categories (the MIPSS70 model Among patients with post-ET MF, the MYSEC study
has 3 prognostic categories: low, intermediate, and documented superior survival or CALR-mutated
high). There is also a version 2.0 o the MIPSS70-plus, patients compared with JAK2-mutated patients, with
which incorporates U2AF1 Q157 status, very-high- no dierences observed between type 1/-like and type
risk karyotype, and sex- and severity-adjusted Hgb 2/-like CALR mutations in terms o clinical presenta-
thresholds into the MIPSS70-plus to urther enhance tion or outcome (in contrast to PMF); thrombosis inci-
its power to discriminate between prognostic catego- dence did not dier by driver mutation status, unlike
ries, o which there are ve in this model.162 Both the in ET.165
MIPSS70 and the MIPSS70-plus version 2.0 scores can
readily be calculated in the clinic at http://mipss70s-
core.it. Finally, the genetically inspired prognostic scor-
Treatment
ing system, distinguished by its reliance on genomic Beore the approval by the FDA o the JAK1/2 inhibi-
inormation alone or prognostication, is not widely tor ruxolitinib in 2011, treatment o MF was largely
used.163 unsatisactory. Cytoreductive drugs such as HU or
Although managed similarly and characterized by cladribine were used to control hyperprolieration,
the same general clinical eatures and complications, although their eects are transient and rarely result
the underlying biology o post-PV and post-ET MF di- in complete spleen regression. Oral alkylating agents
ers undamentally rom that o PMF. Passamonti and have also been used, but oten induce severe myelo-
colleagues studied 685 molecularly annotated patients suppression and are associated with an increased risk
with post-PV/ET MF to develop a prognostic model, o transormation to AML. Corticosteroids, erythroid-
the MYSEC-PM, specically or this population.36 stimulating agents (ESAs), immunomodulatory drugs
Median OS or the entire cohort was 9.3 years (8.1 (IMiDs), and androgens have proven helpul in the
years or post-PV MF and 14.5 years or post-ET MF). treatment o anemia. Patients with low endogenous
serum Epo (<125 U/L) can benet rom ESAs; response rates improved over time, although the median dura-
rates range rom 23% to 60% and median duration tion o spleen response was about 3 years. No new
o response is about one year.166 Oral danazol (200 toxicity concerns emerged. Importantly, ruxolitinib
mg 2 or 3 times daily) can be useul or both anemia improved survival, reducing the risk o death by 30%
(30% ORR) and thrombocytopenia.167 Prostate cancer in a pooled analysis o 5-year data rom both COM-
ChapTeR 6
should be ruled out beore starting danazol, and liver FORT trials (median OS, 5.3 vs 3.8 years).181 Spleen
enzymes should be monitored in patients taking it. responses to ruxolitinib are dose-dependent and corre-
IMiDs (low-dose thalidomide and lenalidomide) have late with survival.182,183 Furthermore, anemia caused by
anticytokine and antiangiogenic eects and have been ruxolitinib does not carry the adverse prognosis o dis-
shown to reduce splenomegaly and improve anemia ease-associated anemia, and ruxolitinib overcomes the
(in 20%–30% o patients).166 They are usually used negative prognostic impact o the latter.184,185 For these
with tapering doses o prednisone or three months. reasons, we attempt to optimize ruxolitinib dosing
Pomalidomide showed signicant promise in a phase whenever possible and manage the anemia with trans-
2 study,168 but ailed to improve rates o transusion usions, ESAs, danazol, IMiDs, etc. However, although
independence in a phase 3 study.169 Low-dose tha- the ruxolitinib prescribing inormation suggests initial
lidomide (50 mg/d) may be particularly useul to treat dosing based on the platelet count, an alternative dos-
thrombocytopenia.170–172 Intereron-α has been used ing strategy o 10 mg twice daily or the rst 12 weeks
with some success, but signicant toxicity prevents its beore escalating in anemic patients is also reason-
use in many patients. It may slow disease progression able.186,187 Although the recommended starting dose
in patients with early MF, as well as reverse BM brosis or patients with 50–99 × 109/L platelets is 5 mg twice
in some patients.173 I used, IFN-α should be prescribed daily, studies support using the more eective 10 mg
early in the disease because patients with HMR muta- twice daily dose in this population.188,189 Patients tak-
tions tend not to respond well.174 Splenectomy is used ing ruxolitinib should be vaccinated against shingles
only rarely in the JAK inhibitor era. When perormed, and be monitored regularly or weight gain and hyper-
it should be perormed in careully selected patients, lipidemia. Although the US approval o ruxolitinib is
because perioperative morbidity and mortality can be restricted to patients with intermediate- and high-risk
substantial.175 Splenic irradiation is eective or palliat- disease, NCCN guidelines support its use in symptom-
ing splenomegaly, but its benets are transient and it atic low-risk patients when required.190 There is no
can result in prolonged and proound cytopenias and guidance or or published experience with the use o
make subsequent splenectomy more dicult.176 ruxolitinib in patients with platelets <50 × 109/L.
The JAK2 inhibitor edratinib was approved by the
FDA or patients with intermediate-2/high-risk MF in
JAK Inhibitors August 2019. In the placebo-controlled JAKARTA trial,
Two pivotal phase 3 randomized trials provided evi- edratinib produced rates o 35% or greater SVR and
dence or the regulatory approval o the oral JAK1/2 50% or higher TSS improvement at week 24, which
inhibitor ruxolitinib. The COMFORT-I trial randomly were signicantly superior to those observed with
assigned patients to receive ruxolitinib (n = 155) or placebo and similar to those seen with ruxolitinib
placebo (n = 154),177 whereas the COMFORT-II trial in the COMFORT trials.191 Apart rom anemia and
compared ruxolitinib (n = 146) with BAT (n = 73).178 thrombocytopenia (expected rom inhibition o JAK2),
Patients in both trials had to have baseline platelets edratinib was also associated with a relatively high
≥100 × 109/L and IPSS intermediate-2/high-risk dis- incidence o gastrointestinal side eects, likely because
ease. Signicantly more patients in the ruxolitinib arms o its inhibition o ms-like tyrosine kinase 3 (FLT3).
had 35% or higher SVR (roughly approximating ≥50% JAKARTA enrolled patients with baseline platelets ≥50
reduction in spleen size by palpation) rom baseline at × 109/L, and while the numbers were small, there were
week 24 (COMFORT-I) or week 48 (COMFORT-II). no signicant dierences in response rates between
Both studies showed signicant improvements in MF- the ≥50–99 × 109/L and ≥100 × 109/L platelet groups.192
related symptoms and QOL in patients treated with Fedratinib dosing is not based on platelet count. Devel-
ruxolitinib. Thrombocytopenia and anemia were the opment o edratinib had been halted owing to con-
most common toxicities associated with ruxolitinib cerns over Wernicke encephalopathy but was recently
therapy. These were most pronounced in the rst resumed given that this complication is very rare
3 to 6 months o treatment and were managed with and o uncertain relationship to edratinib193; how-
dose reductions or transusions. Headaches, dizziness, ever, thiamine levels must be checked beore edra-
and bruising are the most common nonhematologic tinib initiation, repleted i low, and monitored during
adverse eects o ruxolitinib. therapy. In the setting o ruxolitinib ailure, edratinib
Long-term ollow-up analyses have demonstrated yielded a 35% or higher SVR rate o 30% and a 50%
that the eects o ruxolitinib are durable.179,180 Response or higher TSS reduction rate o 27% at 24 weeks in a
relatively small trial (JAKARTA-2),194 and is being stud- some laboratory-based synergistic combinations, eg,
ied urther in the FREEDOM trials (NCT03755518, those with the BH3-mimetic navitoclax206 and the bro-
NCT03952039). modomain inhibitor CPI-0610207; these combinations
are moving into phase 3 trials in the JAK inhibitor–
naïve setting.
ChapTeR 6
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplant (alloSCT) is potentially
curative in MF; however, ew patients undergo alloSCT Treatment Conclusions
because o older age or severe comorbidities. Reduced- Patients with MF should rst be assigned to a risk cat-
intensity conditioning regimens are an option in older egory using one o the standard prognostic models.
patients and those with comorbidities.195 In general, For patients with low-risk disease, a watch-and-wait
patients in a risk category with a predicted median approach is acceptable, although ruxolitinib may be
OS o ewer than 5 years should be considered or needed or symptom control. Patients in the interme-
alloSCT.47 Indeed, the primary goal o prognostication diate- and high-risk groups should be treated based
in MF is to inorm selection o patients or alloSCT. on their clinical needs, eg, anemia, splenomegaly,
This typically includes patients younger than 70 years symptoms, EMH, and increased blasts. For younger
with intermediate-2 or high-risk disease by the IPSS, patients in the intermediate-2 and high-risk categories
DIPSS, or DIPSS-plus.196 AlloSCT should also be con- and select intermediate-1 risk patients, alloSCT should
sidered in patients younger than 65 years who have be oered. Patients who are not eligible or alloSCT
intermediate-1–risk disease but have reractory, trans- and are intolerant o, have a suboptimal response, or
usion-dependent anemia, more than 2% circulating lose their response to JAK inhibitors should be oered
blasts, adverse cytogenetics (as dened in the DIPSS- enrollment in clinical trials. Ruxolitinib and edra-
plus model), are triple negative or driver mutations, tinib have been eective in reducing splenomegaly,
or have ASXL1 mutations. Our practice is to transplant in improving symptoms and QOL, and, in the case
patients at best response to ruxolitinib. Consensus rec- o ruxolitinib, prolonging survival in patients with
ommendations are to initiate ruxolitinib at least two MF. JAK inhibitors have not been shown to eradicate
months beore transplant and optimize the dose or the mutant clone, and patients lose their response to
best spleen response.196 Ruxolitinib should then be therapy over time. Results rom ongoing trials o new
tapered over 5 to 7 days to avoid a “fare” and stopped targeted agents and rational combinations are eagerly
the day beore conditioning. The recently published awaited.
myelobrosis transplant scoring system incorporates a
number o clinical and genomic pretransplant variables
(age, perormance status, platelet count, leukocyte
count, donor type, driver mutation, and ASXL1 status)
ChRONIC eOSINOphILIC
to predict outcomes ater alloSCT.197 DISORDeRS: hYpeReOSINOphILIC
SYNDROMe/ChRONIC
Combination and Novel Therapies
eOSINOphILIC LeUKeMIa
Momelotinib, a JAK1/2 inhibitor that can improve Chronic eosinophilic disorders (urther reerred to as
anemia, and pacritinib, a JAK2/FLT3 inhibitor that hypereosinophilic syndromes/chronic eosinophilic
is relatively nonmyelosuppressive, are active agents leukemia [HES/CEL]) are a heterogeneous group o
that are reentering phase 3 pivotal studies with new rare disorders characterized by chronic eosinophil
end points and eligibility criteria (NCT04173494, overproduction (an absolute eosinophil count [AEC]
NCT03165734) ater previous phase 3 trials showed in peripheral blood >1.5 × 109/L) and eosinophilic
mixed results.198–201 Regulatory approval o these tissue inltration with possible end-organ damage.
agents would ulll important unmet needs in the JAK Although the largest portion o these disorders rep-
inhibitor space. The activin receptor ligand trap luspa- resent primary BM diseases classied as myeloid/
tercept has shown promise or the treatment o ane- lymphoid neoplasms with eosinophilia (MLN-Eo),
mia, both as a single agent and in combination with clinical presentation is mostly driven by the presence
ruxolitinib.202 Imetelstat, a telomerase inhibitor, has o eosinophils irrespective o the underlying cause.
demonstrated an intriguing apparent OS benet in the HES/CEL can be clinically subdivided into six variants:
“ruxolitinib ailure” setting.203 A phase 3 trial o this 1. myeloprolierative, 2. lymphoprolierative, 3. over-
agent and one o the antibrotic drug PRM-151204 are lap, 4. associated, 5. amilial, and 6. Idiopathic.208 The
planned. Many other novel agents are being studied in rst 2 categories represent primary MLN-Eo diagno-
the ruxolitinib ailure and/or suboptimal response set- ses. The classication, as revised by the 2016 WHO
tings.205 Encouraging results have been reported with criteria, is shown in Table 6–1. Hypereosinophilia >1.5
× 109/L or more than 6 months, absence o obvious expansion o cytokine-producing, immunophenotypi-
reactive and clonal causes, and evidence o end-organ cally aberrant T cells, leading to clonal as well as reac-
damage dene HES. Idiopathic hypereosinophilia tive hypereosinophilia (abnormal overstimulation o
is the preerred diagnosis when end-organ damage eosinophilopoietic growth actors), and might be clas-
is absent. Patients ound to have clonal disease (ie, sied as a lymphoprolierative variant.
ChapTeR 6
a cytogenetic or molecular abnormality proving the HES/CEL are more common in men than women,
existence o a malignant clone), or peripheral blood and patients are usually younger (20–50 years old).
blasts 2% or higher, or BM blasts 5% or higher (but The clinical presentation varies; patients might have
both <20%) have chronic eosinophilic leukemia, not minimal nonspecic symptoms (such as atigue, myal-
otherwise specied (CEL, NOS).11 Per WHO 2016, the gias, low-grade ever), “allergic” symptoms (urticaria,
major category o MLN-Eo represents myeloid/lym- pruritus, angioedema, erythematous papules, cough
phoid neoplasm with eosinophilia and rearrangement with pulmonary inltrates), or serious organ involve-
o PDGFRa, PDGFRb, FGFR1, and provisional entity ment (acute heart ailure, mural thrombi, cardiomyop-
o PCM1-JAK2 (Table 6–1 and Tables 6–13 to 6–18). athy, polyneuropathies, optic neuritis).213 Despite the
The identication o the clonal marker, used FIP1L1 act that the skin, lungs, and gastrointestinal tract are
gene to the PDGFRa gene located on 4q12 chromo- the most commonly aected organs, congestive heart
some in 2003 by Cools et al,209 led to recognition o ailure represents a prototypical illustration o eosino-
other causes o primary eosinophilic disorders driven phil-mediated tissue injury.214
by constitutively active TKs: genes encoding PDG-
FRb (chromosome 5q31–q33; >30 gene usion partners
[Table 6–14]),210,211 broblast growth actor receptor
Diagnosis
1 (FGFR1, chromosome 8p11; ~15 gene usion part- The initial step in diagnosis o HES/CEL is to rule out
ners212 (Table 6–16); and recently, provisionally added secondary, or reactive, causes o eosinophilia such as
Janus kinase 2 gene, JAK2 (chromosome 9p24; mostly inections (especially parasitic), atopy, drug reactions,
PCM1-JAK2 usion).11 Some patients, including those connective tissue disorders, or vasculitis. Assessment
with the above classied HES/CEL, may exhibit o organ involvement should always be perormed as
Tbl 613 Dignostic Critri or Cronic eosinoilic Lukmi, NOS
• Eosinophilia (eosinophil count ≥1.5 × 109/L)

• WHO criteria or BCR-ABL1–positive chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary
myelobrosis, chromic neutrophilic leukemia, chronic myelomonocytic leukemia, and BCR-ABL1–negative atypical chronic
myeloid leukemia are not met
• No rearrangement o PDGFRa, PDGFRb, or FGFR1, and no PCM1-JAK2, ETV6-JAK2, or BCR-JAK2 usion
• Blast cells constitute <20% o the cells in the peripheral blood and bone marrow, and inv(16)(p13.1q22), t(16;16)(p13.1;q22),
t(8;21)(q22;q22.1), and other diagnostic eatures o acute myeloid leukemia are absent
• There is a clonal cytogenetic or molecular genetic abnormality or blast cells account or ≥2% o cells in the peripheral blood
or ≥5% in the bone marrow
Tbl 614 Dignostic Critri or Myloid/Lymoid Nolsms wit eosinoili associtd wit
FIP1L1-PDGFRa or  Vrint Fusion Gn
A myeloid or lymphoid neoplasm, usually with prominent eosinophilia AND

The presence o FIP1L1-PDGFRα usion gene or a variant usion gene with rearrangement o PDGFRα or an activating mutation
o PDGFRα
Tbl 615 Dignostic Critri or Myloid/Lymoid Nolsms associtd wit ETV6-PDGFRb or
Otr Rrrngmnt o PDGFRb
A myeloid or lymphoid neoplasm, oten with prominent eosinophilia and sometimes with neutrophilia or monocytosis AND
The presence o t(5;12)(q32;p13.2) or a variant translocation or demonstration o ETV6-PDGFRb usion gene or other
rearrangement o PDGFRb
Tbl 616 Vrint Trnsloction-associtd Myloid/Lymoid Nolsms wit PDGFRb

Rrrngmnt
Translocation Fusion Gene Hematologic Diagnosis
ChapTeR 6
t(1;3;5)(p36;p22.2;q32) WDR48-PDGFRb CEL
der(1)t(1;5)(p34;q32), CEL
der(1)t(1;5)(p34;q15), CAPRIN1-PDGFRb
der(11)ins(11;5)(p13;q15q32)
t(1;5)(q21.3;q32) TPM3-PDGFRb
t(1;5)(q21.2;q32) PDE4DIP-PDGFRb MDS/MPN with eosinophilia
t(2;5)(p16.2;q32) SPTBN1-PDGFRb
t(4;5;5)(q21.2;q31;q32) PRKG2-PDGFRb Chronic basophilic leukemia
t(3;5)(p22.2;q32) GOLGA4-PDGFRb CEL or aCML with eosinophilia
Cryptic interstitial deletion o 5q TNIP1-PDGFRb CEL with thrombocytosis
t(5;7)(q32;q11.2) HIP1-PDGFRb CMML with eosinophilia
t(5;7)(q32;p14.1) HECW1-PDGFRb JMML
t(5;9)(q32;p24.3) KANK1-PDGFRb Essential thrombocythemia without eosinophilia
t(5;10)(q32;q21.2) CCDC6-PDGFRb aCML with eosinophilia or MPN with eosinophilia
Uninormative SART3-PDGFRb MPN with eosinophilia and myelobrosis
t(5;12)(q32;q24.1) GIT2-PDGFRb CEL
t(5;12)(q32;p13.3) ERC1-PDGFRb AML without eosinophilia
t(5;12)(q32;q13.1) BIN2-PDGFRb aCML with eosinophilia
t(5;14)(q32;q22.1) NIN-PDGFRb Ph-negative CML (13% eosinophils)
t(5;14)(q32;q32.1) CCDC88C-PDGFRb CMML with eosinophilia
t(5;15)(q32;q15.3) TP53BP1-PDGFRb Ph-negative CML with prominent eosinophilia
t(5;16)(q32;p13.1) NDE1-PDGFRb CMML
t(5;17)(q32;p13.2) RABEP1-PDGFRb CMML
t(5;17)(q32;p11.2) SPECC1-PDGFRb JMML
t(5;17)(q32;q11.2) MYO18A-PDGFRb MPN with eosinophilia
t(5;17)(q32;q21.3) COL1A1-PDGFRb MDS or MPN with eosinophilia
t(5;20)(q32;p11.2) DTD1-PDGFRb CEL
Tbl 617 Dignostic Critri or Myloid/Lymoid Nolsms wit FGFR1 Rrrngmnt
A myeloprolierative or myelodysplastic/myeloprolierative neoplasm with prominent eosinophilia and sometimes with

neutrophilia or monocytosis OR
Acute myeloid leukemia, T- or B-lymphoblastic leukemia/lymphoma or mixed-phenotype acute leukemia (usually associated
with peripheral blood or bone marrow eosinophilia) AND
The presence o t(8;13)(p11.2;q12) or a variant translocation leading to FGFR1 rearrangement, demonstrated in myeloid cells,
lymphoblasts, or both
guided by clinical presentation, and should include evaluation o primary marrow disorders, including
various laboratory and imaging tests such as chest examination o peripheral blood smear, BM, cytoge-
radiograph, pulmonary unction tests, electrocardio- netic and molecular analysis or FIP1L1-PDGFRa (by
gram, echocardiogram, computed tomography o the using polymerase chain reaction or fuorescence in situ
chest/abdomen/pelvis, and measurement o serum hybridization analysis aimed at detecting a deletion/
troponin levels, vitamin B12, or tryptase. When sec- excision o the CHIC2 locus at chromosome 4q12),
ondary causes are excluded, patients must undergo because treatment modalities or patients with this
Tbl 618 Cytogntics (Cromosoml Rrrngmnts) nd Molculr Gntics (Fusion Gns)
Rortd in Myloid/Lymoid Nolsms wit FGFR1 Rrrngmnt
Cytogenetics Molecular Genetics

ChapTeR 6
t(8;13)(p11.2;q12.1) ZMYM2-FDFR1
t(8;9)(p11.2;q33.2) CNTRL-FGFR1
t(6;8)(q27;p11.2) FDFR1OP-FGFR1
t(8;22)(p11.2;q11.2) BCR-FGFR1
t(7;8)(q33;p11.2) TRIM24-FGFR1
t(8;17)(p11.2;q11.2) MYO18A-FGFR1
t(8;19)(p11.2;q13.3) HERV-FGFR1
ins(12;8)(p11.2;p11.2;p22) FGFR1OP2-FGFR1
t(1;8)(q31.1;p11.2) TPR-FGFR1
t(2;8)(q13;p11.2) RANBP2-FGFR1
t(2;8)(q37.3;p11.22) LRRFIP1-FGFR1
t(7;8)(q22.1;p11.2) CUX-FGFR1
t(8;12)(p11.2;q15) CPSF6-FGFR1
mutation are dierent. Figures 6–11 and 6–12 illustrate clonal–not otherwise classied abnormalities, urther
the morphologic ndings in HES/CEL. The requency deciphering HES/CEL diagnoses.
o the FIP1L1-PDGFRa rearrangement in patients with A diagnostic and therapeutic algorithm o a patient
hypereosinophilia has been reported between 3% and with suspected primary eosinophilia is summarized in
88%,209,215 with the largest series (741 and 376 patients, Fig. 6–13.
respectively) showing more realistic percentages o
3%216 and 11%.216 Absence o FIP1L1-PDGFRa usion
should prompt evaluation or other clonal disorders,
Treatment
including rearrangements o PDGFRb (5q31–q33), Clinical presentation and its acuity direct initial treat-
FGFR1 (8p11), and usion o PMC1-JAK2. Additional ment in patients with HES/CEL. For asymptomatic
workup with genetic molecular sequencing, cyto- patients with no organ damage and normal troponin
genetic analysis, T-cell immunophenotyping, and levels, no active therapy is recommended, and these
T-cell receptor gene rearrangement might reveal other patients should be ollowed closely. There is no ocial
FIGURe 6–11 In CEL/HES, the bone marrow typically shows FIGURe 6–12 Markedly increased, morphologically unre-
increased cellularity with striking interstitial inltration by markable eosinophils are typically detected in the bone mar-
eosinophils (×400). row aspirate smears rom patients with CEL/HES (×400).
transl. 5q33-31 ~ transl. 9p24 ~

Myeloid/Lymphoid transl. 8p11-12 ~
Myeloid/Lymphoid Myeloid/Lymphoid
Peripheral (+) Neoplasms with Myeloid/Lymphoid
Neoplasms with Neoplasms with
blood & bone Eosinophilia and or or Neoplasms with or
Eosinophilia and Eosinophilia and
marrow FIP1L1-PDGFRaα Eosinophilia and
PDGFRβ PCM1-JAK2
workup: rearrangement FGFR1 rearrangement
rearrangement rearrangement
FGFR1-inh. JAK2-inh.
ChapTeR 6
*vitamin B12 Imatinib/steroids Imatinib/steroids
(pemigatinib), trial, SCT (ruxolitinib), trial, SCT
*Tryptase
*T-cell receptor Clonal abnormality Other WHO-defined

Chronic Eosinophilic HU, interferon, APPROACH
gene and/or 5-19% Myeloid Neoplasms
Leukemia, NOS imatinib, trial, SCT as indicated
Eosinophils > rearrangement marrow blasts (MDs, AML)
(-)/(+)
1.5 x 109 / L
*Karyotype
Abnormal T cell IHC Steroids, IL-5/
*FISH, RT-PCR for Lymphoid
and clonal TCR - IL-5R Ab / trial, HU,
FIP1L1-PDGFRA variant
gene rearrangement interferon, SCT
*Molecular gene
panel
Idiopathic Steroids, IL-5/IL-5R
Hypereosinophilic Ab / trial, HU,
*Marrow (+) syndrome interferon, imatinib, SCT
morphology,
dysplasia, (-)
blasts % End organ damage?
(-) Always assess for end organ damage

Idiopathic Monitor, • Cardiac enzymes, echo, ekg
Rule out Hypereosinophilia steroids if needed • Bronchoscopy, pulmonary function test
secondary • Nerve conduction studies
causes • Radiologic imaging
• Biopsy
FIGURe 6–13 Diagnostic and treatment algorithm o eosinophilic disorders based on the 2016 WHO classication. Ab, anti-
body; FGFR1, broblasts–growth actor receptor 1; HU, hydroxyurea; IL, interleukin; inh, inhibitor; PDGFRa, platelet-derived
growth actor receptor alpha; PDGFRb, platelet-derived growth actor beta; SCT, stem cell transplant; transl, translocation.
consensus to recommend therapy solely based on receive imatinib mesylate as a rst therapy at a starting
the degree o hypereosinophilia, but AEC 1.5–2 × dose o 100 mg daily with the possibility to increase
109/L is generally accepted as a treatment threshold. to 400 mg daily. Imatinib is also approved as therapy
The exceptions are patients with imatinib-sensitive or patients with HES/CEL, whose FIP1L1-PDGFRα
PDFGRA/B rearrangement, who should be treated status is negative or unknown, at a recommended
even in the absence o organ dysunction to decrease dose o 400 mg daily. The response to imatinib in
the risk o end-organ damage. For the remaining FIP1L1-PDGFRa–negative patients is limited, and it
patients with symptomatic disease or evidence o end- might represent a second-line treatment or reractory
organ damage, therapy or HES generally entails the patients, unless they have typical clinical presenta-
use o corticosteroids, IFN-α, or cytoreductive agents tion (male gender, splenomegaly, elevated tryptase,
such as HU, vincristine, or cyclosporine. Glucocor- and typical marrow eatures) where rontline imatinib
ticosteroids (usually prednisone at starting dose o 1 shall be considered. Imatinib mesylate, a highly potent
mg/kg/day) are the rst line or the treatment o most tyrosine kinase inhibitor against ABL, PDGFR, and
orms o HES/CEL, and also remain the initial therapy KIT protein kinases, could induce complete hemato-
o choice or patients who show lie-threatening mani- logic and complete molecular remission in as much as
estations. ORR to rst-line prednisone is about 70% 99% and 95% o patients with FIP1L1-PDGFRa and
to 80%,214 but relapses oten occur with cessation o HES, respectively.211,223,224 Long-term ollow-up stud-
therapy. In patients with possible exposure to Stron- ies (median duration o imatinib therapy o 6.6 years)
gyloides stercoralis, empiric ivermectin therapy (200 µg/ showed that these responses are durable in the majority
kg orally × 2 days) should be given concomitantly with o patients,225–227 but maintenance therapy is required;
steroids to prevent potentially atal steroid-induced otherwise, relapses occur. O note, in patients with
hyperinection syndrome and disseminated disease.217 eosinophil-mediated heart damage or even elevated
Second-line options ater steroids include IFN-α, HU, troponin, it is recommended to co-initiate glucocorti-
cyclosporin, or low-dose methotrexate. Other agents, coids or the rst 10 days o imatinib therapy to avoid
such as vincristine, cyclophosphamide, cladribine, sudden heart deterioration.
or cytarabine, are mostly useul or acute reductions Patients with FGFR1 rearrangement usually have
when the total eosinophil count is very high (≥50 × a very aggressive disease course with progression
109/L).214,218–222 to acute leukemia within one to two years.228 Until
Patients with known imatinib-sensitive mutations, recently, high-dose chemotherapy ollowed by alloSCT
including FIP1L1-PDGFRa and PDGFRb involvement represented the only therapeutic option, and SCT still
(chromosomal translocations o 5q31–q33), should represents the only curative tool. As o this writing,
the oral, small-molecule inhibitor o FGFR1-3, pemi- compassionate use o mepolizumab at multiple cen-
gatinib (INCB054828), showed excellent ecacy in ters, CR was 43% versus 83% in steroid-reractory
patients with FGFR1-rearranged myeloid/lymphoid versus -sensitive disease.234 Mepolizumab is currently
neoplasms in interim analysis o the currently ongoing available on a compassionate-use basis or patients
phase 2 FIGHT-203 study (NCT03011372). Among 10 with lie-threatening HES/CEL in whom other thera-
ChapTeR 6
evaluable patients with FGFR1-rearranged myeloid/ pies ailed.

lymphoid neoplasms in whom at least one previous Monoclonal antibody against interleukin-5 recep-
therapy ailed, 8 (80%) achieved a major cytogenetic tor, benralizumab, which is currently approved or
response (including 6 patients with complete cytoge- adults with severe eosinophilic asthma, has been eval-
netic response) ater therapy with pemigatinib or a uated in a double-blind, placebo-controlled, random-
median o 6.9 cycles.229,230 ized phase 2 study in 20 patients with PDFRA-negative
For patients with HES/CEL reractory to conven- HES.235 The primary end point was a reduction o 50%
tional therapies, the use o monoclonal antibody or higher AEC by week 12, and it was met in 9 o 10
therapy should be considered. So ar, antibodies that patients who received benralizumab vs 3 o 10 patients
have been explored include those against interleukin-5 receiving placebo (P = .02). Clinical and hematologic
and its receptors, mepolizumab and benralizumab; responses with benralizumab were sustained or 48
and the antibody targeting CD52 antigen expressed weeks in 14 o 19 patients (74%) during the open-label
by eosinophils, alemtuzumab. Initial saety and e- phase, with a median duration o 84 weeks. Adverse
cacy o mepolizumab, a humanized antibody against events, mostly headache and elevated lactate dehydro-
interleukin-5, were shown in a randomized, double- genase, did not limit therapy. Patients with lymphoid
blind, placebo-controlled phase 2 trial in 85 PDGFRa- variant HES and those with JAK2 mutation lacked any
negative patients with HES without lie-threatening response to benralizumab.
complications.231 The primary end point (reduction o Alemtuzumab is another monoclonal antibody that
the prednisone dose to ≤10 mg/day or ≥8 consecutive is used o label in patients with HES/CEL. Among
weeks) was achieved in 84% o the patients receiv- 11 patients with HES/CEL (9 previously treated) pre-
ing mepolizumab (750 mg monthly intravenously) scribed alemtuzumab,236 10 achieved CHR (reduc-
compared with 43% o the patients in the placebo tion o the AEC and the percentage o eosinophils in
group (P < .001). Long-term saety and ecacy o peripheral blood to normal values) and 9 had com-
mepolizumab were conrmed in a long-term exten- plete symptoms resolution ater a median o two
sion study in which 78 patients received mepolizumab weeks. The median duration o CHR was short-lived
or a median o 251 weeks (range, 4–302): 69% were (3 months), and 7 o the 10 patients with CHR expe-
still receiving mepolizumab at the end o the study, rienced relapse. In a long-term ollow-up study o 12
and 62% o the patients were prednisone-ree with- patients (9 rom original report),237 10 achieved CHR
out other HES treatments or 12 weeks or more.232 and elimination o disease symptoms ater a median
A registrational, placebo controlled, phase 3 study o one week; this was sustained or a median dura-
o mepolizumab (300 mg subcutaneously monthly) tion o 66 weeks. Five patients with CHR receiving
to prevent fares o HES (NCT02836496) has been maintenance alemtuzumab or a median duration o
recently published.233 Eligible patients with uncon- 20 weeks (range, 1–266) had a signicantly longer time
trolled HES (2 or more fares o symptoms or increased to disease progression than those who were not given
eosinophils in the previous 12 months) were random- maintenance therapy (P = .01). Eleven patients eventu-
ized 1:1 to mepolizumab (n = 54) vs placebo (n = 54) ally experienced relapse (only one was on maintenance
or 32 weeks. The primary outcome, reduction o HES therapy). Five o six patients achieved a second CHR
fares, was signicantly lower with mepolizumab: the or a median duration o 123 weeks ater re-challenge
proportion o patients experiencing 1 or more fares with alemtuzumab. Alemtuzumab side eects, mostly
was 28% with mepolizumab vs 56% with placebo, prolonged myelosuppression and the necessity or
P = 0.002). Rate o adverse events was comparable in maintenance therapy, limit its use in clinical practice.
both arms (89% vs 87% with mepolizumab vs pla- Another agent explored in patients with PDGFRa-
cebo, respectively), with the most common adverse negative HES (n = 10) was a small-molecule, orally
events on mepolizumab being upper respiratory track bioavailable aminobenzothiazole, dexpramipexole
inections and extremities pain.233 Based on these nd- (150 mg orally twice daily), as a glucocorticoid-sparing
ings, FDA has approved mepolizumab or the therapy agent.238 The two primary end points were: the propor-
o primary HES in patients older than 12 years who tion o 50 or more patients with a decrease in the mini-
had HES or 6 months or older in September 2020. It is mum eective glucocorticoid dose (MED) to maintain
possible that ecacy o mepolizumab in patients with AEC lower than 1000/µL and control symptoms, and
steroid-reractory HES/CEL will be lower than when it the MED ater 12 weeks o treatment as a percentage
is used as a steroid-sparing agent. In a trial evaluating o the MED at the start o therapy. O 10 patients, our
Tbl 619 Dignostic Critri or Cronic Nutroilic Lukmi
1. Peripheral blood white blood cell count ≥25 × 109/L

– Segmented neutrophils plus banded neutrophils constitute ≥80% o the white blood cells
– Neutrophil precursors (promyelocytes, myelocytes, metamyelocytes) constitute <10% o the white blood cells
ChapTeR 6
– Myeloblasts rarely observed
– Monocyte count <1 × 109/L
– No dysgranulopoiesis
2. Hypercellular bone marrow
– Neutrophil granulocytes increased in percentage and number
– Neutrophil maturation appears normal
– Myeloblasts constitute <5% o the nucleated cells
3. Not meeting WHO criteria or BCR-ABL1–positive chronic myeloid leukemia, polycythemia vera, essential thrombocythemia,
or primary myelobrosis
4. No rearrangement o PDGFRα, PDGFRb , or FGFR1, and no PCM1-JAK2 usion
5. CSF3RT618I or another activating CSF3R mutation OR
Persistent neutrophilia (≥3 months), splenomegaly, and no identiable cause o reactive neutrophilia including absence o a
plasma cell neoplasm or, i a plasma cell neoplasm is present, demonstration o clonality o myeloid cells by cytogenetic or
molecular studies
achieved 50% or higher reduction in MED, and the mutational variants were identied: most were point
median ratio o MEDs at 12 versus 0 weeks was 66% mutations on the membrane proximal region (T618I
(signicantly reduced, P = .03). All adverse events were or T615A); others were nonsense mutations leading
sel-limited and did not lead to therapy discontinua- to a premature truncation o the cytoplasmic tail o
tion. In responders, BM biopsy samples showed selec- CSF3R. The proportion o patients with CNL/aCML
tive absence o mature eosinophils. Dexpramipexole harboring only membrane proximal region mutation
appears to be a promising steroid-sparing agent in versus compounding mutations o both was 75% and
patients with HES, and evaluation o its ecacy in a 25%, respectively. Under normal conditions, CSF3R,
phase 3 clinical trial is planned. which is activated by binding its ligand granulocyte
colony-stimulating actor, promotes the dierentiation
o granulocyte progenitor cells into neutrophils. Muta-
ChRONIC NeUTROphILIC tions in the membrane proximal region lead to consti-
LeUKeMIa tutive activation o the JAK-STAT pathway, whereas
truncation mutations result in ligand hypersensitivity
Chronic neutrophilic leukemia (CNL) is an extremely and activation o the downstream SRC kinase path-
rare neoplasm and was rst included as a distinct entity way. Other pathways involved in neutrophilic dieren-
in the 2001 WHO classication system. Diagnostic cri- tiation, prolieration, and survival include nonreceptor
teria in 2016 refected recent changes in the genomic tyrosine kinase SYK, Ras/Ra/MAP kinases, and PI3K/
landscape o CNL, endorsing strong association o the Akt.240 This study revealed two major dysregulated
colony-stimulating actor 3 receptor (CSF3R) mutation signaling pathways in CNL and represents a proo o
with CNL (Table 6–19). The presence o activating concept or the use o targeted therapies: JAK inhibitor
CSF3R mutation (most requently T618I) now com- ruxolitinib or membrane proximal region mutations
prises one o the ve diagnostic criteria o CNL. The (via JAK-STAT pathway), and tyrosine kinase inhibitor
disease is characterized by the chronic overproduction dasatinib or truncating mutations (via SRC pathway).
o mature neutrophils (>80% segmented neutrophils Studies in mice support the leukemogenic role
and bands out o WBCs ≥25 × 109/L) and an increased o CSF3R mutations in CNL; deletion o CSFR3 in
number o granulocytes in the BM. mice leads to neutropenia, and mice transplanted
In 2013, the discovery o disease-dening onco- with CSF3RT618I-positive hematopoietic cells develop
genic mutations in the CSF3R revolutionized our a CNL-like phenotype, with mature granulocytosis,
understanding o the pathogenesis o CNL and pro- marrow hypercellularity, and inltration o the spleen
vided a biomarker or diagnosis as well as a poten- and liver with mature granulocytes.241
tial therapeutic target.239 Deep sequencing o coding In another study, the coding region o CSF3R was
regions o 1862 genes in patients with CNL (n = 9) and sequenced in patients with clinically suspected CNL (n
atypical CML (aCML) (n = 20) identied mutations = 35) or aCML (n = 19), as well as 170 cases o CMML
in the CSF3R gene in 8 o 9 patients with CNL. Two and PMF.242 The diagnoses were reevaluated using
WHO criteria. Twelve cases o CNL were conrmed, 75% o the patients, with a median duration o about
5 were associated with a monoclonal gammopathy- 12 months. 243 Second-line agents evaluated in these
associated CNL, and 9 were conrmed as aCML. O patients include IFN-α, cladribine, or thalidomide,
the 13 patients ound to have the CSF3R mutation, with limited success in decreasing leukocytosis, but
12 had WHO-dened CNL, and one had unconrmed they do not possess any ability to modiy the natural
ChapTeR 6
CNL. All mutations were ound in the membrane disease course.243 Splenic radiation and splenectomy
proximal region, with T618I being the most common have been used, but splenectomy has been associated
(10 patients). None o the cases o monoclonal gam- with urther increases in neutrophil counts.243 Induc-
mopathy–associated CNL had CSF3R mutations, sug- tion chemotherapy ollowed by SCT has been used to
gesting that patients with evidence o a plasma cell treat patients in the blast phase, oering possible long-
dyscrasia should not be classied as having CNL. term remission in selected cases.243,245 Ater CSF3R-
mutated cells were shown to be sensitive to the JAK1/2
inhibitor ruxolitinib, this agent was evaluated in a
Clinical Features ew patients with CNL and some were encouraging,
The median age at diagnosis is around 66 years. The although transient responses, including hematologic,
clinical presentation o CNL is heterogeneous, but the symptomatic, and molecular were observed.246–248 The
majority o patients are asymptomatic at diagnosis, role o ruxolitinib in patients with CNL is currently
or have nonspecic constitutional symptoms, such as under evaluation in a phase 2 study (NCT02092324).
atigue, palpable splenomegaly, weight loss, easy bruis- Preliminary results in 21 patients with CNL reported
ing, bone pain, and night sweats. The median survival clinical response (dened as at least 50% improve-
in CNL is about 24 months.242,243 Intracranial hemor- ment in counts and spleen size) in 65% o patients.
rhage is the most common cause o death, ollowed Median time on study was 15.3 months with 86% o
by leukemic transormation,243 eventually occurring in patients receiving > 6 cycles.249
a substantial proportion o the patients. There are no
prognostic scores to predict survival o patients with
CNL, but presence o ASXL1 or SETBP1 mutations
as well as thrombocytopenia may be associated with MaST CeLL DISeaSe/SYSTeMIC
shorter survival or blast phase.242,244 MaSTOCYTOSIS
Mast cell disease is a heterogeneous group o disor-
Diagnosis ders characterized by clonal expansion o mast cells
Most patients are asymptomatic at presentation and are (MCs) and their excessive accumulation in various
diagnosed ater nding leukocytosis on routine blood organs such as the skin, BM, gastrointestinal tract,
testing. Most patients have mild anemia, and platelet lymph nodes, liver, and spleen. Its clinical course can
counts are usually normal or slightly low. Diagnosis vary rom minimal symptoms to diuse systemic
requires exclusion o a number o potential causes o involvement. In the revised 2016 WHO classica-
neutrophilia, such as inections and occult malignancy, tion, mastocytosis was removed as one o the sub-
as well as other myeloid neoplasms (Table 6–19). Until types o MPN and listed as a separate major disease
the discovery o CSF3R mutation, the absence o BCR- entity,11 urther divided into: cutaneous mastocyto-
ABL1 and rearrangement o PDGFRa, PDGFRb, and sis, systemic mastocytosis (SM) with subvariants o
FGFR1 were key diagnostic criteria. The presence o indolent SM (ISM), smoldering SM (SSM), aggressive
mostly mature neutrophils, and the notable absence o SM (ASM), SM with an associated hematologic neo-
circulating blasts, monocytes, basophilia, and eosino- plasm (SM-AHN), and MC leukemia (MCL) (Table
philia are important eatures o CNL that distinguish 6–20 through Table 6–22). SM requires the presence
it rom other myeloprolierative disorders (especially o one major (multiocal, dense inltrates o ≥15 MC)
rom CML). BM is hypercellular (>90% cellularity) as and one minor or at least three minor (presence o
a result o granulocytic hyperplasia, with no dysplastic atypical MCs/presence o KIT D618V mutation/aberrant
eatures. Unlike other MPNs, megakaryocytic hyper- expression o CD25 with or without CD2 on MC or
plasia or clusters o large atypical megakaryocytes are persistently elevated tryptase >20 µg/mL) diagnostic
not seen. Most patients have normal cytogenetics. criteria (Table 6–22). The presence or absence o B
and C ndings denes SM subtype: (1) indolent SM
with no B/C ndings, (2) smoldering SM with B nd-
Treatment ings (higher disease burden but no organ damage),
There is no standard treatment or CNL. HU has his- and (3) aggressive SM with C ndings (organ dam-
torically been the most requently used agent and age by MC inltration) as shown in Table 6–23. MCL
could control leukocytosis and splenomegaly in about is dened by the presence o ≥20% neoplastic MC
Tbl 620 Clssifction o Mstocytosis Vrints
The complete diagnosis o these variants requires inormation regarding B (burden o disease) and C (cyto-reduction-requiring)
(Table 6–21), all o which may not be available at the time o initial tissue diagnosis.
Cutaneous Mastocytosis
ChapTeR 6
Urticaria pigmentosa/maculopapular cutaneous mastocytosis
Difuse cutaneous mastocytosis
Mastocytoma o skin
Systemic Mastocytosis
Indolent systemic mastocytosisa (including the bone marrow mastocytosis subtype)
Smoldering systemic mastocytosisa
Systemic mastocytosis with an associated hematologic neoplasma
Aggressive systemic mastocytosisa
Mast cell leukemia
Mast Cell Sarcoma
a
This variant is equivalent to the previously described entity “systemic mastocytosis with an associated clonal hematologic non–mast cell lineage disease,” and the terms
can be used synonymously.
Tbl 621 Dignostic Critri or Cutnous nd Systmic Mstocytosis
Cutaneous Mastocytosis
Skin lesions, demonstrating the typical ndings o urticaria pigmentosa/maculopapular cutaneous mastocytosis, difuse
cutaneous mastocytosis, or solitary mastocytoma, and typical histologic inltrates o mast cells in a multiocal or difuse
pattern in an adequate skin biopsya
In addition, eatures/criteria sucient to establish the diagnosis o systemic mastocytosis must be absent. There are three
variants o cutaneous mastocytosis (see Table 6–20).
Systemic Mastocytosis
The diagnosis o systemic mastocytosis can be made when the major criterion and at least 1 minor criterion are present, or
when ≥3 minor criteria are present.
Major Criterion
Multiocal dense inltrates o mast cells (≥ 15 mast cells in aggregates) detected in sections o bone marrow and/or other
extracutaneous organ(s).
Minor Criteria
In biopsy sections o bone marrow or other extracutaneous organs:
• >25% o the mast cells in the inltrate are spindle shaped or have atypical morphology OR
• >25% o all mast cells in bone marrow aspirate smears are immature or atypical
• Detection o an activating point mutation at codon 816 o KIT in the bone marrow, blood, or another extracutaneous
organ
• Mast cells in bone marrow, blood, or another extracutaneous organ express CD25, with or without CD2, in addition to
normal mast cell markersb
• Serum total tryptase is persistently >20 ng/mL, unless there is an associated myeloid neoplasm, in which case this
parameter is not valid
a
This criterion applies to both the dense ocal and the difuse mast cell inltrates in the biopsy.
b
CD25 is the more sensitive marker, by both ow cytometry and immunohistochemistry.
in the BM, and mostly presents as an acute leuke- Clinical Features

mia with C ndings/organ damage. Interestingly, the
aleukemic variant with ewer than 10% circulating Symptoms o mastocytosis refect MC mediators
MCs is more common. Advanced SM (AdvSM) is a release or MC organ inltration. Vasoactive mediators
combined term or ASM, SM-AHN, and MCL and (histamine, leukotrienes, prostaglandins) released rom
indicates subtypes with requent organ damage and MCs can lead to itching, fushing, lightheadedness,
reduced OS. syncope, palpitations, diarrhea, heartburn, atigue,
and headache and can be exacerbated by inections,
Tbl 622 Dignostic Critri or t Vrints o Systmic Mstocytosis
Indolent Systemic Mastocytosis

Meets the general criteria or systemic mastocytosis
ChapTeR 6
No C ndingsa
No evidence o an associated hematologic neoplasm
Low mast cell burden
Skin lesions are almost invariably present
Bone Marrow Mastocytosis
As above (indolent systemic mastocytosis), but with bone marrow involvement and no skin lesions
Smoldering Systemic Mastocytosis
≥2 B ndings; no C ndingsa
No evidence o an associated hematologic neoplasm
High mast cell burden
Does not meet the criteria or mast cell leukemia
Systemic Mastocytosis With an Associated Hematologic Neoplasm
Meets the criteria or an associated hematologic neoplasm (ie, a myelodysplastic syndrome, myeloprolierative neoplasm,
acute myeloid leukemia, lymphoma, or another hematologic neoplasm classied as a distinct entity in the WHO
classication)
Aggressive Systemic Mastocytosis
≥1 C ndinga
Does not meet the criteria or mast cell leukemia
Skin lesions are usually absent
Mast Cell Leukemia
Bone marrow biopsy shows difuse inltration (usually dense) by atypical, immature mast cells
Bone marrow aspirate smears show ≥20% mast cells
In classic cases, mast cells account or ≥10% o the peripheral blood white blood cells, but the aleukemic variant (in which mast
cells account or <10%) is more common
Skin lesions are usually absent
a
B and C ndings indicate organ involvement without and with organ dysunction, respectively; these ndings are listed in Table 6–23.
Tbl 623 B (Burdn o Diss) nd C (Cytorduction-Rquiring) Findings in Symmtric

Mstocytosis, Wic Indict Orgn Involvmnt Witout nd Wit Orgn Dysunction, Rsctivly
B ndings
• High mast cell burden (shown on bone marrow biopsy): >30% inltration o cellularity by mast cells (ocal, dense,
aggregates) and serum total tryptase >200 ng/mL
• Signs o dysplasia or myeloprolieration in non–mast cell lineage(s), but criteria are not met or denitive diagnosis o an
associated hematologic neoplasm, with normal or only slightly abnormal blood counts
• Hepatomegaly without impairment o liver unction, palpable splenomegaly without hypersplenism, and/or
lymphadenopathy or palpation or imaging
C ndings
• Bone marrow dysunction caused by neoplastic mast cell inltration, maniested by cytopenia: absolute neutrophil count
<1.0 × 109/L, hemoglobin level <10 g/dL, and/or platelet count <100 × 109/L
• Palpable hepatomegaly with impairment o liver unction, ascites, and/or portal hypertension
• Skeletal involvement, with large osteolytic lesions with or without pathologic ractures (pathologic ractures caused by
osteoporosis do not qualiy as a C nding)
• Palpable splenomegaly with hypersplenism
• Malabsorption with weight loss caused by gastrointestinal mast cell inltrates
alcohol, exercise, and medications. Common sites o

organ inltration include the skin and gastrointestinal
tract. Urticaria pigmentosa is the most common skin
maniestation, characterized by reddish-brown mac-
ules and papules. Scratching o aected skin character-
ChapTeR 6
istically leads to development o urticaria and erythema
(Darier sign). Gastrointestinal involvement can present
as chronic diarrhea, steatorrhea, malabsorption, nau-
sea, vomiting, and ascites. Cardiovascular symptoms
include dizziness, palpitations, and anaphylaxis with
hypotension and syncopal events. Anemia is the most
common hematologic abnormality caused by BM inl-
tration, and peripheral eosinophilia is seen in around
20% o the patients. Bone and muscle pain and bone
ractures can also occur.
FIGURe 6–15 In SM, in the bone marrow biopsy, mast cells
Diagnosis tend to have abundant, colorless cytoplasm and contain
elongated-to-oval nuclei (×400). In the bone marrow aspirate
Diagnosis relies primarily on the identication o neo- smear, the mast cells increase in number and size and attain a
plastic MCs in various organs (see Table 6–11). Bone spindle shape (inset; original magnication ×400).
marrow examination is imperative or diagnosis o
SM, because most patients would have underlying BM
involvement. Figures 6–14 and 6–15 illustrate a case
o SM detected in the BM. Neoplastic MCs are char- aspartate at codon 816 (D816V) in the TK domain o
acteristically spindle shaped and present in multiocal the KIT receptor (KITD816V mutation), is noted in more
aggregates (≥15 MCs in aggregates) and, unlike nor- than 90% o patients with SM.250 KIT is a TK recep-
mal MCs, neoplastic MCs express the surace marker tor encoded by the c-KIT gene located on chromosome
CD25, with or without CD2. Serum tryptase and uri- 4q12 in humans, and KITD816V is located in exon 17.
nary histamine are generally increased. One o the Binding o stem cell actor to KIT leads to receptor
most reliable indicators o progressive SM is a steadily dimerization and phosphorylation o the downstream
increasing serum level o tryptase. Using a sensi- signaling molecules,251 playing an important role in
tive polymerase chain reaction–based assay, a point normal hematopoiesis. Furitsu et al rst showed that
mutation, resulting in the substitution o valine or KIT was constitutively activated and expressed in the
absence o stem cell actor in a MC cell line derived
rom a patient with MC leukemia.252
Molecular analysis not only led to the discovery o
KITD816V as a major oncogenic driver o MC dierentia-
tion, prolieration, and survival, but also enhanced our
prognostic abilities or this disease. A ew prognostic
scores were developed and identied the negative
prognostic impact o increased age (>60 years), mark-
ers o advanced disease (eg, anemia, thrombocytope-
nia, leukocytosis, high tryptase levels, splenomegaly,
BM blasts >5%), poor risk karyotype (eg, monosomy
7 or complex), and additional molecular mutations,
especially the presence and number o non-KIT muta-
tions: SRSF2/ASXL1/RUNX1 (S/A/R), or EZH2, CBL,
DNMT3A.253–261 The mutation-adjusted risk score or
AdvSM (MARS) (N = 383) identied three risk groups
with distinct OS (not reached, median 3.9, and 1.9
years, respectively) based on the presence o age older
than 60 years, hemoglobin lower than 10 g/dL, plate-
FIGURe 6–14 Bone marrow biopsy rom a patient with SM
demonstrates total ocal replacement o the normal cellular lets <100 × 109/L, and one or two S/A/R mutations.254
elements by mast cells (×100). Immunohistochemical stain- The International Prognostic Scoring System or Mas-
ing perormed on this specimen demonstrated that the neo- tocytosis (IPSM) (N = 1639) stratied patients with
plastic mast cells aberrantly expressed CD2 and CD25. AdvSM as well as ISM into subgroups with dierent
outcomes based on the ollowing risk actors: (1) ISM: Cytoreductive therapies (IFN-α and cladribine) are
age 60 years or older, alkaline phosphatase 100 U/L or used or severe disease symptoms and in the case o
more; and (2) AdvSM: age 60 years or older, tryptase organ damage. IFN-α plays an especially important
level 125 ng/mL or higher, leukocyte count ≥16 × 109/L, role in pregnant patients or in patients with slowly
hemoglobin 11 g/dL or lower, platelets ≤100 × 109/L, progressive disease. In a multicenter trial in 20 patients
ChapTeR 6
and absence o skin involvement.253 with SM, IFN-α-2b led to a partial or minor response
Although ISM has no impact on lie expectancy, in 13 patients.268 The combination o IFN-α-2b with
patients with AdvSM have signicantly shortened prednisone has also been studied. Cladribine was the
OS, estimated at about 4 years or ASM, 2 years or most requently evaluated chemotherapeutic agent in
SM-AHD, and less than 6 months or patients with AdvSM, especially in patients requiring rapid debulk-
MCL.262,263 ing o disease, and can induce overall RR in as much as
Excellent guidance or diagnosis, symptom man- 72% o patients.269,270 Stem cell transplantation should
agement, prognostic evaluation, and therapy o SM is be considered in patients with AdvSM and acute MCL
provided in the recent NCCN guidelines or systemic at remission.271
mastocytosis.264 Mutation in KITD816V is an attractive target because
o its high requency in patients with SM. It con-
ers primary resistance against the tyrosine kinase
Treatment
inhibitor imatinib, which is approved by the FDA or
Treatment o the most common orm o noncuta- patients with AdvSM without the KITD816V mutation
neous SM, ISM, is ocused exclusively on symptom or unknown KIT mutation status (at 400 mg daily) and
relie, whereas reduction o MC burden and preven- or AdvSM associated with eosinophilia (starting dose
tion o organ damage are the goals in treating AdvSM. 100 mg daily with dose escalation to 400 mg daily as
All patients should avoid actors that can trigger MC needed). An important subgroup o patients with SM
degranulation, such as emotional stress, cold expo- and imatinib responsiveness is the subset with the
sure, alcohol use, strenuous exercise, and the use o FIP1L1-PDGFRa mutation. In a study by Pardanani
nonsteroidal antiinfammatory drugs. Symptomatic et al, 56% o the patients with SM and eosinophilia
treatments include the use o oral antihistamines had the FIP1L1-PDGFRa usion oncogene,272 and all
and MC stabilizers. Both sedating and nonsedating responded to imatinib (100 mg daily).
H1 antihistamines can be used to alleviate pruritus Midostaurin, an oral multikinase inhibitor includ-
and itching. Cetirizine has been shown to be equiva- ing KIT,D816V was approved by the FDA in April 2017
lent to hydroxyzine in relieving pruritus in patients or patients with AdvSM irrespective o KIT muta-
with chronic urticaria, with the advantage that it tional status. In an open-label study o 116 patients
does not cause sedation and thus is usually initi- with AdvSM (≥1 measurable C nding), 100 mg o
ated rst.265 Higher doses o sedating antihistamines midostaurin orally twice daily resulted in an overall
could be used or patients with severe symptoms. RR o 60% (45% with a major response, eg, complete
Because both H1 and H2 receptors are present in the resolution o ≥1 C nding). 273 Responses were simi-
skin (85% cutaneous histamine receptors are H1 and lar across all subtypes (75% or ASM, 58% SM-AHD,
15% are H2), the addition o an H2 blocker should 50% or MCL), regardless o KIT mutation or number
be considered or patients who do not respond to H1 o previous therapies. Symptoms and QOL were sig-
antihistamines alone. 265 Cromolyn sodium is bene- nicantly improved with midostaurin. The median OS
cial in patients with gastrointestinal symptoms (eg, and PFS were the longest in patients with ASM (not
diarrhea, vomiting, abdominal pain).266 Short courses reached and 29 months, respectively) than in patients
o prednisone can be considered or patients with with SM-AHN (21 and 11 months, respectively) and
severe symptoms, especially malabsorption and asci- MCL (9 and 11 months, respectively). Additionally,
tes. Aspirin can cause MC degranulation but may 40% (8/20) and 100% (4/4) patients achieved RBCs
help with fushing. Thereore, patients should be and platelets transusion independence. Therapy with
given H1 and H2 antihistamine therapy beore start- midostaurin was associated with a high incidence
ing aspirin therapy.266 Patients with a history o ana- o adverse events. The most common AEs included
phylaxis or cardiovascular collapse should carry an nausea (79% all grades), vomiting (66%), and diar-
epinephrine pen. Omalizumab (a humanized murine rhea (54%); grade ≥3 AEs occurred in ewer than
monoclonal antibody that inhibits immunoglobulin E 10% o patients, but prophylactic antiemetics were
binding to MCs and basophils) is eective in patients recommended beore each dose. Grade ≥3 anemia,
with SM and syncopal episodes and skin maniesta- thrombocytopenia, and neutropenia (new or wors-
tions.267 Patients with osteoporosis might be treated ening) occurred in 41%, 29%, and 24% o patients,
with bisphosphonates or the anti-RANKL monoclo- respectively, and were more common in patients with
nal antibody, denosumab. preexisting cytopenias. Long-term ollow-up (median
duration o 10 years) conrmed a similar spectrum o responses deepened over time. Median OS was not
side eects without a new unexpected toxicity, and reached or any subtype o AdvSM. Nonhematologic
durable activity with the ORR o 69% (50% major AEs were observed at similar rates over a long time,
response), 50% or higher reduction in MC burden with grade ≥3 anemia and thrombocytopenia at 29%
and serum tryptase in 68% and 46% o the patients, and 26%, respectively. Importantly, these responses
ChapTeR 6
respectively. OS or ASM, SM-SHN, and MCL patients were noticed in patients regardless o previous expo-
was not reached, 40 months, and 18.5 months, respec- sure to midostaurin (ORR o 60% and 85% with and
tively.274 The negative impact o ASXL1/SRSF2/ without previous midostaurin, respectively). 278 Phase
RUNX1 mutations and the lack o 25% or more reduc- 2 study PATHFINDER enrolled 62 patients with
tion in the KITD816V allele burden during therapy with advSM at the 200 mg daily dose. 81% o patients
midostaurin was shown on ORR, treatment duration, had SM-AHN, 13% had MCL and 6% had ASM.
and OS.275 Interim results in 32 evaluable patients showed over-
Another eective agent in SM is the highly selec- all response o 75% with a median time to response
tive TKI inhibitor, avapritinib (BLU-285), with an o 2 months. Median OS was not reached at the time
approximately tenold higher potency or KITD816V o the analysis. The most common adverse events
inhibition than midostaurin, which has just received included peripheral (50%) and periorbital (35%)
FDA approval in June 2021 or aggressive SM with edema and thrombocytopenia (32%). Treatment dis-
platelets > 50×10e9/L at a dose o 200 mg daily. continuation due to treatment related AE was in 5%
The approval was based on results rom phase 1 o patients.
(EXPLORER, NCT02561988) and phase 2 (PATH- Avapritinib is also being evaluated in symptom-
FINDER, NCT03580655) trails showing an objective atic patients with ISM and SSM in a randomized,
response rate o 57% in all 53 evaluable patients in placebo-controlled registration trial, PIONEER, and
both trials with a median duration o response o part 1, the dose-nding phase (25 mg, 50 mg, and 100
38.3 months (95% CI, 19-NE).276,278 A phase 1 clini- mg daily), has already completed enrollment. Prelimi-
cal trial o avapritinib in AdvSM with at least 1 C nary data were reported on 39 patients (10 patients
nding (EXPLORER trial) began in 2016. Preliminary in each avapritinib dose cohort and 9 patients in the
data were reported on 52 patients treated in the ini- placebo cohort). Across all avapritinib dose cohorts,
tial escalation phase (32 patients), exploring 7 doses mean percent reductions in serum tryptase occurred
ranging rom 30 mg to 400 mg once daily, and in the rapidly during cycle 1, with 48%, 67%, and 62%
expansion phase (20 patients) on 300 mg daily. Six reduction on 25 mg, 50 mg, and 100 mg o avapritinib
patients (12%) did not carry KIT mutation. Overall per day at 12 weeks. The placebo cohort showed no
RR was noticed in 83% o patients, including 50% change in serum tryptase at 12 weeks (0.39%). All
or higher BM MC reduction in 33% (undetectable tested dose levels o avapritinib were well tolerated,
BM MCs in 58%), reduction o serum tryptase to less with 5 patients (16.7%) having grade 3 AEs (including
than 20 µg/L in 66%, and complete resolution o sple- one cognitive eect on 100 mg). The recommended
nomegaly in 47% o the patients. Decrease in 50% phase 2 dose or the next phase was 25 mg daily.279
or more o BM KITD861V allele burden was noticed in Updated data showed a statistically signicant mean
88% o the patients. Treatment-related grade 3 or decline in symptoms (30% vs 3%), improved QOL,
4 AEs were noticed in 28 (54%) patients. The most and reduction o MC burden, serum tryptase level,
common AEs, most o which were mild, were perior- and KIT D816V allele burden at 16 weeks in patients
bital edema (62%), atigue (31%), and nausea (33%). treated with avapritinib versus those who received
Concerning AEs included ascites (10%), pleural eu- placebo. 280
sion (10%), and cognitive impairment, eg, conusion Masitinib, an inhibitor o pathways involved in MC
and short-term memory eects (19%). Grade ≥3 ane- pathogenesis (eg, KIT, FLN, and LYN), was evaluated in
mia and thrombocytopenia occurred in 15% and 17% patients with indolent or smoldering SM in a phase 3
o the patients, respectively.277 Updated results on 80 randomized, placebo-controlled trial (N = 135, 1:1 ran-
patients (48 evaluable or response) showed 77% domization). The response rate measured by improve-
overall RR; with 50% or higher BM MC reduction, ment o symptoms (pruritus, fushes, depression,
50% or higher reduction o serum tryptase, and 35% asthenia) was 18.7% taking masitinib versus 7.4%
or higher reduction in spleen size by imaging were taking placebo. Most AEs were mild and included diar-
seen in 93%, 99%, and 80% o patients, respectively. rhea, rash, or asthenia.281 Masitinib has not yet been
Median time to initial response was two cycles, and tested clinically in patients with AdvSM.

J Polycythemia Vera: Risk stratiy patients by age evaluate or organ damage. Pay particular attention
and thrombosis history. The goal is to keep the to possible heart involvement and use steroids up
ChapTeR 6
hematocrit (Hct) under 45% at all times. Monitor to 1 mg/kg with any lie-threatening maniestation.
leukocyte counts and symptoms and watch or Consider using empiric therapy or Strongyloides,
signs o resistance to or intolerance o hydroxyurea especially when using steroids. Evaluate or clonal-
(HU). Aspirin is generally recommended. Intererons ity and identiy PDGRA/B rearrangements because
(IFNs) are a reasonable alternative to HU or rst-line these are sensitive to imatinib. Responses are high,
therapy, particularly in very young patients. Ruxoli- but lielong maintenance may be necessary. For all
tinib is the cytoreductive drug o choice ater ailure other patients, use steroids as rst-line treatment
o HU. but try to nd a steroid-sparing agent or a long-
J Essential Thrombocythemia: Risk stratiy patients term benet. Consider clinical trials with novel
by the revised IPSET model and consider obser- agents or patients with FGFR1 rearrangement and
vation or “very-low-risk” patients. Low-, inter- utilize stem cell transplantation.
mediate-, and high-risk patients should receive J Chronic Neutrophilic Leukemia: Rule out second-
aspirin unless it is contraindicated by acquired ary causes and conrm the presence o CSF3R muta-
von Willebrand disease or extreme thrombocyto- tion. There are no prognostic models or survival,
sis (>1.5 million platelets/μL). Some patients may but patients with advanced clinical eatures and
benet rom twice-daily administration o aspi- multiple molecular abnormalities have inerior out-
rin. Hydroxyurea is generally the drug o choice comes. Disease oten progresses to acute leukemia.
when cytoreductive therapy is indicated; IFNs are Use cytoreduction to control counts, such as HU or
acceptable as well and may be preerred in very IFN. Consider clinical trials (ruxolitinib) when pos-
young patients. sible. Chemotherapy and stem cell transplantation
J Myelofbrosis: Pre-PMF is managed similarly to is reserved or aggressive course and blast phase.
ET but carries an inerior prognosis. A number o J Systemic Mastocytosis: It is important to dis-
models exist or risk stratication o overt PMF; one tinguish between cutaneous mastocytosis and
that incorporates both clinical and genomic risk systemic mastocytosis (SM) by perorming a BM
actors, eg, MIPSS70/MIPSS70 plus v2.0 is recom- evaluation. Test or KITD816V mutation and measure
mended or use in transplantation-age patients. tryptase. Once SM is conrmed, patients need to
Use the MYSEC-PM or patients with post-V/ET MF. be evaluated or the presence o B and C ndings,
In general, consider allogeneic stem cell transplan- indicating indolent versus aggressive SM. Treat
tation in patients whose predicted lie expectancy symptoms and advise patients to avoid triggers.
is less than 5 years. Ruxolitinib is the mainstay o Aggressive SM has limited lie expectancy, and
therapy and coners a survival benet in patients patients experience various organ involvements.
with intermediate-2/high-risk disease. Fedratinib Monitor or the presence o advanced eatures/
is a reasonable choice ater ailure o ruxolitinib. molecular mutations that suggest inerior outcome.
Patients with anemia as their main or only dis- Use o kinase inhibitors, midostaurin, or avapritinib
ease maniestation may not need JAK inhibition in clinical trials, is recommended. Chemotherapy,
and could be better served by anemia-directed such as a cladribine-based regimen, has a role in
therapies. aggressive mast cell leukemia and reractory dis-
J Chronic Eosinophilic Disorders/Hypereosino- ease. Stem cell transplantation shall be considered
philic Syndromes: Rule out secondary causes and in all patients with aggressive disease.
aCKNOWLeDGeMeNT
The authors thank Helen Chiotides, PhD, or excel-
lent scientic editing o the chapter.
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2013;13(3):287-291. 257. Jawhar M, Schwaab J, Hausmann D, et al. Splenomegaly,
238. Panch SR, Bozik ME, Brown T, et al. Dexpramipexole as an oral elevated alkaline phosphatase and mutations in the SRSF2/
steroid-sparing agent in hypereosinophilic syndromes. Blood. ASXL1/RUNX1 gene panel are strong adverse prognostic
2018;132(5):501-509. markers in patients with systemic mastocytosis. Leukemia.
239. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R muta- 2016;30(12):2342-2350.
tions in chronic neutrophilic leukemia and atypical CML. N 258. Schwaab J, Schnittger S, Sotlar K, et al. Comprehensive muta-
Engl J Med. 2013;368(19):1781-1790. tional proling in advanced systemic mastocytosis. Blood.
240. Corey SJ, Burkhardt AL, Bolen JB, et al. Granulocyte colony- 2013;122(14):2460-2466.
stimulating actor receptor signaling involves the ormation o 259. Jawhar M, Schwaab J, Schnittger S, et al. Additional mutations
a three-component complex with Lyn and Syk protein-tyrosine in SRSF2, ASXL1 and/or RUNX1 identiy a high-risk group o
kinases. Proc Natl Acad Sci U S A. 1994;91(11):4683-4687. patients with KIT D816V(+) advanced systemic mastocytosis.
241. Fleischman AG, Maxson JE, Luty SB, et al. The CSF3R Leukemia. 2016;30(1):136-143.
T618I mutation causes a lethal neutrophilic neoplasia in 260. Pardanani A, Lasho T, Elala Y, et al. Next-generation sequenc-
mice that is responsive to therapeutic JAK inhibition. Blood. ing in systemic mastocytosis: derivation o a mutation-aug-
2013;122(22):3628-3631. mented clinical prognostic model or survival. Am J Hematol.
242. Pardanani A, Lasho TL, Laborde RR, et al. CSF3R T618I is a 2016;91(9):888-893.
highly prevalent and specic mutation in chronic neutrophilic 261. Naumann N, Jawhar M, Schwaab J, et al. Incidence and
leukemia. Leukemia. 2013;27(9):1870-1873. prognostic impact o cytogenetic aberrations in patients
243. Elliott MA, Hanson CA, Dewald GW, Smoley SA, Lasho TL, with systemic mastocytosis. Genes Chromosomes Cancer.
Teeri A. WHO-dened chronic neutrophilic leukemia: a 2018;57(5):252-259.
262. Lim KH, Teeri A, Lasho TL, et al. Systemic mastocytosis in 274. DeAngelo DJ, George TI, Linder A, et al. Ecacy and saety
342 consecutive adults: survival studies and prognostic actors. o midostaurin in patients with advanced systemic mastocy-
Blood. 2009;113(23):5727-5736. tosis: 10-year median ollow-up o a phase II trial. Leukemia.
263. Georgin-Lavialle S, Lhermitte L, Dubreuil P, et al. Mast cell leu- 2018;32(2):470-478.
kemia. Blood. 2013;121(8):1285-1295. 275. Jawhar M, Schwaab J, Naumann N, et al. Response and
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264. National Comprehensive Cancer Network. Systemic Mastocy- progression on midostaurin in advanced systemic masto-
tosis (Version 1.2020). Accessed May 31, 2020. http://www. cytosis: KIT D816V and other molecular markers. Blood.
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265. Kaplan AP. Clinical practice. Chronic urticaria and angioedema. 276. DeAngelo DJ, Reiter A, Radia D, et al. CT023 – PATHFINDER:
N Engl J Med. 2002;346(3):175-179. Interim analysis o avapritinib (ava) in patients (pts) with
266. Worobec AS. Treatment o systemic mast cell disorders. Hema- advanced systemic mastocytosis (AdvSM). Abstract #CT023;
tol/Oncol Clin North Am. 2000;14(3):659-687. American Association or Cancer Research Annual Meeting,
267. Carter MC, Robyn JA, Bressler PB, et al. Omalizumab or the April, 2021.
treatment o unprovoked anaphylaxis in patients with systemic 277. DeAngelo DJ, Quiery A, Radia D, et al. Clinical activity in a
mastocytosis. J Allergy Clin Immunol. 2007;119(6):1550-1551. phase 1 study o Blu-285, a potent, highly-selective inhibitor
268. Casassus P, Caillat-Vigneron N, Martin A, et al. Treatment o KIT D816V in advanced systemic mastocytosis (AdvSM).
o adult systemic mastocytosis with intereron-alpha: results Blood. 2017;130(suppl 1): abstract 2.
o a multicentre phase II trial on 20 patients. Br J Haematol. 278. Gotlib J RD, George T, Robinson W, et al. Avapritinib induces
2002;119(4):1090-1097. responses in patients with advanced systemic mastocytosis
269. Lortholary O VJ, Feger F, et al. Ecacy and saety o cladribine (AdvSM), regardles o prior midostuaurin therapy. Presented
in adult systemic 64 mastocytosis: a French multicenter study at: 25th Congress o the European Hematology Association
o 33 patients. Blood. 2004;104(11):661. (EHA25), June 12, 2020; virtual only. Abstract EP1079.
270. Barete S, Lortholary O, Damaj G, et al. Long-term ecacy and 279. Akin C EH, Gotlib J, Sabato V, et al. Results rom PIONEER: A
saety o cladribine (2-CdA) in adult patients with mastocyto- randomized, double-blind, placebo-controlled, phase 2 study
sis. Blood. 2015;126(8):1009-1016; quiz 1050. o Avapritinib in patients with Indolent Systemic Mastocytosis
271. Ustun C, Gotlib J, Popat U, et al. Consensus opinion on (ISM). 25th Congress o the European Hematology Association
allogeneic hematopoietic cell transplantation in advanced (EHA25), 12 June 2020; abstract EP1082.
systemic mastocytosis. Biol Blood Marrow Transplant. 280. Hartmann K, Siebenhaar F, Oude Elberink H, et al. Avapri-
2016;22(8):1348-1356. tinib reduced cutaneous symptoms and mast cell burden in
272. Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDG- patients with indilent systemic mastocytosis in the PIONEER
FRA usion: prevalence and clinicopathologic correlates in 89 study. European Academy o Allergy and Clinical Immunology
consecutive patients with moderate to severe eosinophilia. (EAACI) Digital Congress, 12 June 2020; Abstract 1832.
Blood. 2004;104(10):3038-3045. 281. Lortholary O, Chandesris MO, Bulai Livideanu C, et al. Masi-
273. Gotlib J, Kluin-Nelemans HC, George TI, et al. Ecacy and tinib or treatment o severely symptomatic indolent systemic
saety o midostaurin in advanced systemic mastocytosis. N mastocytosis: A randomised, placebo-controlled, phase 3
Engl J Med. 2016;374(26):2530-2541. study. Lancet. 2017;389(10069):612-620.
Section II Lymphoma and
Myeloma
Section Editor: Nathan H. Fowler
7 Follicular Lymphoma
8 Marginal Zone and Other Small Cell Lymphomas
9 Aggressive B-Cell Lymphomas
10 Mantle Cell Lymphoma
11 Nodal Peripheral T-Cell Lymphoma
12 Cutaneous Lymphomas
13 Hodgkin Lymphoma
14 Systemic Immunoglobulin Light Chain Amyloidosis
15 Waldenström Macroglobulinemia
16 Multiple Myeloma
17 Cellular Therapy for Lymphoma

7 Follicular Lymphoma
Paolo Strati
Jillian R Gunther
L. Jefrey Medeiros
Loretta J. Nastoupil
KEY CONCEPTS
 Patients with early-stage ollicular lymphoma (FL) can  Both chemoimmunotherapy and immunotherapy (with
experience prolonged remissions with radiation therapy, lenalidomide) are potential treatment options or patients
particularly in the presence o stage I disease and lesions with advanced-stage, high tumor burden FL; pretreatment
smaller than 3 cm; as such, surveillance should be reserved positron emission tomography–computed tomography
only to patients who are not candidates or radiation. (PET-CT) scan may identiy patients who would benet
 High tumor burden in patients with FL is dened by the rom an anthracycline-based regimen.
presence o one or more Groupe d’Etude des Lymphomes  PET-CT scan perormed at the end o chemoimmuno-
Folliculaires (GELF) criteria; these include: signicant therapy is considered prognostic. Response to rontline
lymphadenopathies (one >7 cm or three each >3 cm), therapy may inorm pursuit o maintenance therapy given
splenomegaly, impending organ compromise, pleural retrospective data suggesting the largest impact o main-
efusion, elevated circulating lymphoma cells, and cyto- tenance rituximab observed among those achieving a
penia. Among patients with advanced-stage FL, those partial response to rontline chemoimmunotherapy.
with high tumor burden should be considered or active  Patients with FL who progress within 24 months rom the
treatment; in the presence o low tumor burden, observa- initiation o rontline chemoimmunotherapy may have a
tion or single-agent rituximab are potential management shorter overall survival; these patients should be evalu-
strategies. ated or clinical trials with novel agents or cellular therapy
INTRODUCTION EPIDEMIOLOGY
Follicular lymphoma (FL) is a neoplasm composed o FL, the second most commonly occurring lymphoma
centrocytes and centroblasts that are derived rom the in the United States, represents 22% o all B-cell
germinal center o lymphoid ollicles.1 Most cases o FL non-Hodgkin lymphomas (NHLs)2 and 80% o all
have a diuse pattern but these neoplasms rarely have indolent B-cell lymphomas. FL occurs almost exclu-
an entirely diuse pattern. Being derived rom germi- sively in adults, with an equal requency in men and
nal center B cells, these neoplasms commonly express women. The incidence rates are highest among Cau-
CD10, Bcl-6, HGAL, and LMO2 and carry t14;18(q32;q21). casians, and median age at diagnosis is approximately
Importantly, knowledge o FL has increasing led to 63 years.3 In the United States, rom 2012-2016, the
the recognition o variants o FL (e.g. in situ ollicu- number o new cases o FL was 2.7 per 100,000 men
lar neoplasia) as well as distinct types o FL, the latter and women per year ater age-adjustment. The num-
including primary cutaneous ollicle center cell lym- ber o deaths was 0.5 per 100,000 men and women
phoma, pediatric-type ollicular lymphoma, and ol- per year.4 Risk o FL increased in persons who have
licular lymphoma with IRF4 rearrangement. a rst-degree relative with NHL or who worked as
In this chapter we ocus on the common orm o FL a spray painter and among women with Sjögren
that represents about 80-85% o all cases o FL. syndrome.3 About 2% to 3% o patients with FL
165
166 Sction II Lymphoma and Myeloma
per year undergo transormation to aggressive B-cell composed o centrocytes (small-cleaved cells) and
lymphoma, usually diuse large B-cell lymphoma centroblasts (large-noncleaved cells). The method cur-
(DLBCL), with a lie-time risk o 11%. However not rently recommended in the World Health Organization
all cases are typically biopsy-proven, diagnosis o (WHO) classication or grading FL is based on counting
transormation being sometimes based on clinical, centroblasts.6,10 In grade 1 FL, centroblasts are rare, less
laboratory and radiological eatures, and this number than 5 per ×400 microscopic eld. Grade 2 FL contains
may need minor adjustment.5 Survival or patients 5 or more but less than 15 centroblasts per ×400 micro-
with FL is improving, with a median survival o 8 scopic eld. Grade 3 FL Has more than 15 centroblasts
to 10 years in the pre-rituximab era6-8; while in the per ×400 microscopic eld are present. Importantly, this
more modern era, the median survival o FL patients system was proposed initially when most microscopes
has been reported to be greater than 18 years, with a had a smaller eld o view. With newer microscopes
5-year overall survival (OS) o 88.4% in the United that have a larger led o view these counts need to be
States between 2009 and 2015.4,9 adjusted. The WHO classication states that there is no
prognostic benet derived rom distinguishing grade 1
rom grade 2 cases and designates these tumors as FL
CLINICAL FEATURES grade 1-2. In contrast, grade 3 cases o FL are subdivided
into A and B categories. In grade 3A FL, more than 15
Patients with FL most oten present with asymptomatic centroblasts per ×400 microscopic eld are present. In
lymphadenopathy. Constitutional symptoms such as grade 3B cases, sheets o centroblasts are present with
ChapTeR 7
ever, drenching night sweats, and signicant weight loss rare or absent centrocytes.6 Recent data suggest that FL
occur in approximately 15% o patients. Patients may grade 3B has many eatures in common with DLBCL,
have symptoms related to lymph node enlargement, although some eatures o indolent FL are also present.11
especially when there are bulky masses. Other symp- Histologic concordance is not uncommon in patients
toms can include atigue and, occasionally, end-organ with FL. In the 1970s when staging laparotomy was per-
consequences, such as obstructive uropathy or bone mar- ormed or FL patients, discordance o grade between
row compromise. Central nervous system (CNS) disease anatomic sites was observed in 20-30% o patients.12
is rare. Urgent situations, such as superior vena cava syn- Currently, histologic discordance between the bone
drome or spinal cord compression, are rare, in part related marrow and lymph node may be observed most oten.
to the usual slow pace o growth o lymphadenopathy Typically the bone marrow shows low-grade FL and
in FL. Spontaneous regression o lymphadenopathy can the lymph node may show grade 3 FL or even DLBCL.13
occur in FL patients. Such regressions, however, are usu- Follicular lymphoma is a neoplasm o mature B-cell
ally partial and are typically short-lived. The potential o lineage. Most grade 1 and 2 tumors express surace
FL to wax and wane provides one o several clues that immunoglobulin (Ig), but a subset o FLs, mostly grade
suggest that host immune surveillance can play an impor- 3, may be Ig negative. All FLs express pan B-cell mark-
tant role in the disease course. Consequently, FL has been ers and typically express Ig and B-cell antigens at high
a prime ocus or immunotherapy approaches. density (“bright” immunofuorescence by fow cytom-
Approximately 80% to 90% o patients with FL etry). These neoplasms also express the germinal cen-
present with advanced-stage disease (stage III or IV) ter-associated markers CD10, Bcl-6, HGAL, and LMO2
with generalized lymphadenopathy. The bone mar- and are negative or T-cell antigens. Bcl-2 is expressed
row is involved in approximately 50% o patients. in 80% to 90% o FLs but can be negative, most oten
Clinical eatures suspicious or transormation to in grade 3 neoplasms.6 Because Bcl-2 is negative in
DLBCL include rapidly progressive lymphadenopa- reactive germinal centers, this marker is helpul in
thy, systemic (B) symptoms, localized pain, and a rise making a dierential diagnosis (Fig. 7–1).
in serum lactate dehydrogenase (LDH) level. While With conventional cytogenetic analysis, approxi-
elevated β2-microglobulin may be secondary to renal mately 75% o FL cases grow in culture and can be
insuciency and does not typically raise concern or successully karyotyped. The cytogenetic hallmark o
transormation, in the rituximab era it has shown to FL is t14;18(q32;q21), which is identied in 80% to 90%
play a prognostic role, and has been incorporated in o cases. A small subset o FLs lack the t,14;18 suggesting
novel prognostic models (see below). that a minor pathway o ollicular lymphomagenesis
may exist that is independent o t14;18. This appears to
apply particularly to grade 3B nodal FL, FLs arising in
HISTOLOGIC, IMMUNOPHENOTYPIC, extranodal sites (such as skin), and rare FLs that occur
AND MOLECULAR FEATURES in children, which commonly lack the t14;18.
As a result o the t14;18, BCL2 on chromosome 18q21
In lymph nodes, the normal architecture is partially is translocated adjacent to the joining region o (IGH)
or completely replaced by FL, which typically orms on chromosome 14q32. BCL2 is dysregulated by being
ollicles, but rarely can have a diuse pattern. FL is placed under the infuence o IGH regulatory elements
Ctr 7 Follicular Lymphoma 167
A
normal individuals without clinical evidence o lym-
phoma.20 In this regard, recent data show that alterna-
tive antiapoptotic proteins, such as Bcl-w (encoded by
BCL2L2), may also play a crucial role in the pathogen-
esis o FL.21
Other cytogenetic abnormalities have been reported
in FL. O these, trisomy 7 and 18, abnormalities o
3q27-28 and 6q23-26, and 17p deletions are most re-
quent. Abnormalities o 3q27-28 involve BCL6 and
most oten occur in the orm o translocations. Second-
ary cytogenetic and molecular genetic abnormalities
also have been extensively studied, including in the
context o transormation o FL to DLBCL.22–24
The second most common genomic aberration
B observed in FL is represented by inactivating muta-
tions o KMT2D (MLL2), ound in about 80% o FL
cases. These mutations interere with the ability o
KMT2D/MLL2 to activate gene transcription through
H3K4 methylation. Although less requent, mutations
ChapTeR 7
o other histone modiers are also observed, includ-
ing CREBBP, EZH2, MEF2B, and EP300, suggest-
ing that overall epigenetic dysregulation combined
with dysregulated apoptosis may be responsible or
the transormation o germinal center B cells into FL
cells.25–28
In addition, disruption o the epigenome can also
alter the tumor immune microenvironment: mutations
FIGURe 7–1 Follicular lymphoma, grade 1. A. In this needle in CREBBP, or example, are associated with a signa-
biopsy specimen, neoplastic ollicles partially replace archi- ture o decreased antigen presentation characterized
tecture. B. The neoplastic cells are Bcl-2 positive, supporting by reduced transcript and protein abundance o MHC
lymphoma (A, hematoxylin-eosin, ×100; B, Bcl-2 immunos- class II on tumor B cells, because o its role in promot-
tain ×100). ing class II transactivator–dependent transcriptional
activation o these genes.29
The importance o the immunologic microenviron-
(enhancer region). Insights about the role o the BCL2 ment in the clinical behavior o FL has been an area
in FL were a gateway to the identication o a large o intensive study; reduced intratumoral inltration by
amily o proapoptotic and antiapoptotic genes, which host immune cells is associated with a more aggressive
play a role in a wide variety o hematopoietic and solid clinical course.30 Gene expression proling methods
neoplasms.14–16 have shown molecular signatures attributable to sub-
The breakpoints on chromosome 18 are primarily sets o T cells and macrophages in FLs, the ormer asso-
clustered at two sites: the major and minor breakpoint ciated with a milder and the latter with more aggressive
cluster regions, involved in 50% to 60% and 10% to clinical eatures.31–34 In light o these ndings, multiple
20% o cases, respectively.17 Other breakpoint clusters attempts are ongoing, aimed at characterizing the phe-
also are described; or example, the intermediate clus- notype o tumor-associated macrophages with a more
ter region (ICR). The ICR is involved in approximately pronounced protumoral unction, using markers such
5% o cases; there may be geographic variations in the as CD163 and CD172 (or SIRPα).35–38
requencies o t14;18 breakpoints.18
The Bcl-2 protein is a 25-kDa molecule that is over-
expressed in FL and protects cells rom programmed IN SITU FOLLICULAR NEOPLASIA
cell death (apoptosis).14,15,19 Inhibition o apoptosis
prolongs cell lie, resulting in an expanded compart- This lesion, previously known as “ollicular lymphoma
ment o B cells, thereby providing more opportunity in situ,” is thought to be a preneoplastic stage o FL.39
or additional molecular deects, which presumably Most oten, in situ ollicular neoplasia (ISFN) is an
are involved in histologic transormation. The pres- incidental nding that occurs in lymph nodes excised
ence o the t14;18 alone appears to be insucient or or a variety o reasons (eg, axillary lymph nodes in a
neoplastic transormation. The t14;18 has been iden- patient with breast carcinoma). The overall requency
tied in rare cells in the tonsils and lymph nodes o o ISFN is low, approximately 2%.
Morphologically, ISFN is dicult to recognize in o all accessible lymph node sites, including epitroch-
routine tissue sections stained with hematoxylin- lear and occipital lymph nodes, and assessment o the
eosin. The lymph node architecture is normal, with abdomen or splenomegaly or hepatomegaly.
widely scattered ollicles that are o normal size and The diagnosis is best established by an excisional
inconspicuous. The germinal centers have a sharp lymph node biopsy to provide adequate tissue or
peripheral margin and are monotonous, composed assessment o lymph node architecture. The most
almost exclusively o centrocytes, a morphologic clue easily accessible lymph node may not be the most
to the diagnosis o ISFN.40 Immunohistochemical inormative or representative one. For example, i a
analysis is essential or the recognition o ISFN. The small peripheral lymph node shows grade 1 FL but
germinal center cells are strongly positive or Bcl-2 the patient has a large abdominal mass, a high serum
and CD10.40,41 Typically, Bcl-2 expression by the ISFN lactate dehydrogenase (LDH) level, elevated standard-
cells is brighter than the expression level by mantle ized uptake value (SUV) on PET scan, and other ea-
zone cells surrounding the germinal center. The cells tures suggestive o transormation, then an additional
o ISFN also express pan B-cell antigens and other biopsy to exclude higher-grade disease should be con-
germinal center B-cell markers, such as BCL6, HGAL, sidered, because this would infuence the selection o
and LMO2. appropriate therapy. Core needle biopsies guided by
Cytogenetic and molecular studies have shown that radiographic or imaging techniques may be perormed
the cells o ISFN carry t14;18(q32;q21) and monoclonal on masses that are not easily accessible. Fine-needle
IGH and Ig light chain gene rearrangements. Array aspiration can be misleading or initial diagnosis; com-
ChapTeR 7
comparative genomic hybridization and other meth- plete classication may not be possible because the
ods perormed on ISFN lesions have shown that the limited tissue sample prevents the assessment o archi-
cells o ISFN carry t14;18 but have relatively ew sec- tecture, and there is the possibility o sampling error.
ondary genetic abnormalities, in contrast with ully In the initial staging evaluation, ne-needle aspiration
developed FL.42 EZH2 mutations have been detected may play a role in documenting and dening sites o
in ISFN, suggesting this is another early lesion in FL involvement.
pathogenesis. Once the diagnosis o FL is established, patients
Evidence o overt lymphoma at another anatomic should undergo testing to determine stage, assess
site also is present in a small subset o patients with prognostic risk actors, and evaluate their general
ISFN.40 In addition, some patients with ISFN subse- health. A complete blood cell count may show ane-
quently have development o a histologically discor- mia or thrombocytopenia, which can result rom bone
dant type o lymphoma. These cases suggest that ISFN marrow involvement or occasionally rom hypersplen-
could be a marker o genetic instability or a marker ism or autoimmune problems. Leukemic involve-
o genetic predisposition to lymphoma. Lymphomas ment can occur in 10% o patients. Serum LDH and
most oten reported in association with ISFN include β2-microglobulin (B2M) levels may be elevated and
classical Hodgkin lymphoma, splenic marginal zone are o prognostic signicance. Bilateral bone marrow
lymphoma, and small lymphocytic lymphoma/chronic biopsies with unilateral aspiration are recommended
lymphocytic lymphoma.41 or the staging workup because o the patchy nature
In aggregate, the data suggest that ISFN is a neoplas- o involvement. In FL, the bone marrow characteris-
tic process representing an early step in FL pathogen- tically shows a paratrabecular pattern o involvement
esis that is unlikely to aect patient survival i it is an (Fig. 7–2). Because the lymphoma cells are associated
isolated nding. However, because a subset o some with stroma and are not easily aspirated, bone marrow
patients with ISFN also have or may develop overt aspirate smears assessed by routine light microscopy
lymphoma at other anatomic sites, staging studies are may not be inormative. Flow cytometry and molecu-
indicated. I ISFN is the only disease discovered, over- lar assessment (eg, polymerase chain reaction [PCR])
treatment is to be avoided. o aspirate material can increase the sensitivity o bone
marrow assessment, but in the absence o morpho-
logic abnormalities, positive PCR or fow ndings are
DIAGNOSTIC WORKUP AND traditionally not taken as evidence to warrant assign-
STAGING ment o stage IV.43 For example, it is well established
that patients at Ann Arbor stage I or II can have cells
Clinical evaluation requires a comprehensive history, with the t14;18 detected in the peripheral blood or bone
including age; sex; presence o B symptoms (evers, marrow by PCR.
chills, drenching night sweats, unexplained weight Imaging studies should include neck and chest CT
loss o >10% o body mass over 6 months, pruritus); or delineation o lymphadenopathy. Abdominal and
atigue; and a history o malignancy. Physical exami- pelvic CT scans are essential or assessing lymph-
nation should include identication and measurement adenopathy as well as organomegaly. PET using
Recent consensus guidelines recommend the use o

A
PET-CT or staging in clinical practice, and clinical tri-
als or patients with FL, and may be used to select the
best site to perorm biopsy.
pROGNOSTIC FaCTORS
The prognostic importance o distinguishing grade 1
or 2 FL rom the more aggressive grade 3 FL is well
accepted. However, most investigators have not ound
a clear dierence in long-term survival between patients
with grades 1 and 2 FL, although older literature sug-
gested that FL grade 2 (nodular mixed-cell lymphoma,
B in older nomenclature) was more prone to early pro-
gression than grade 1 i therapy was deerred.52 Higher
degrees o nodularity have been associated in some
reports with improved outcome. An increased pro-
lieration rate is associated with a poorer prognosis,
ChapTeR 7
although Ki-67 is not yet acknowledged as an indepen-
dent prognostic or predictive actor.53,54
Variables shown to correlate with survival in
patients with FL include tumor burden, host actors,
and response to therapy. Tumor burden is estimated
according to GELF criteria, by assessing presence o B
symptoms, number and size o nodal disease, spleno-
megaly, compression syndrome, presence o pleural or
peritoneal eusions, leukocytosis, and cytopenias.
FIGURe 7–2 Follicular lymphoma involving bone marrow.
The International Prognostic Index (IPI) was devised
A. The neoplasm is infltrating the bone marrow with a para-
trabecular pattern. B. Neoplastic small-cleaved cells adjacent or aggressive lymphomas and consists o ve vari-
to bone are seen in this feld (A, B, hematoxylin-eosin; A, ables, increased risk being associated with: (1) age
×100; B, ×400). older than 60 years, (2) Eastern Cooperative Oncology
Group perormance status 3–4, (3) Ann Arbor stage
III–IV, (4) more than one extranodal involvement, and
fuorine-18 fuorodeoxyglucose (FDG) combined (5) elevated serum LDH level.55 The IPI is also a use-
with CT scan (PET-CT) is a useul tool or assessing ul predictor o survival in patients with indolent B-cell
patients with FDG-avid lymphomas. Compared with lymphomas. One important limitation o this system
CT scans, PET-CT can improve the accuracy o staging is that only about 10% o the patients all into the
or nodal and extranodal sites and leads to a change in high-risk group, and most o these patients have poor
stage in 10% to 30% o patients, more oten upstaging perormance status and would be poor candidates or
these patients.44 In addition, PET-CT can help identiy aggressive therapy.
areas at risk or transormation, as each unit increase Partly or that reason, a Follicular Lymphoma Interna-
in SUV is associated with a 1.25-times increased risk tional Prognostic Index (FLIPI) was developed. Initially,
o transormation.45,46 Recent data show that, even an eight-parameter model was proposed, including age
in absence o histologic evidence o transormation, 60 years o age or older, male gender, Ann Arbor stages
baseline elevated SUV and total metabolic tumor vol- III and IV, at least 5 nodal sites, bone marrow involve-
ume may be a surrogate marker or more aggressive ment, serum LDH level greater than normal, hemo-
biologic eatures and may help guide treatment selec- globin level lower than 12 g/dL, and lymphocytes at
tion.47–50 Improving staging accuracy is important to least 1000/mL. However, a simplied version o this
ensuring patients are appropriately treated. Although model was ound to be comparably predictive, using
most lymphomas are FDG avid, there is great variabil- the ve parameters o age, Ann Arbor stage, serum
ity in FDG uptake.46,50,51 Imaging by PET can be less LDH, hemoglobin level, and number o nodal sites.56
reliable in indolent lymphomas. Thereore, adoption This prognostic model separates patients into three
o PET scanning or staging patients with indolent prognostic groups: good risk, with 0 to 1 actors; inter-
lymphoma has not been embraced to the same extent mediate risk, with 2 actors; and poor risk, with 3 or
that it has been or DLBCL and Hodgkin lymphoma. more actors. The overall ve-year survival rate was
90% or the good-risk group, 78% or the intermedi- durable remission o more than 24 months ater ini-
ate-risk group, and 53% or the poor-risk group.56 The tial therapy, and being less than 60 years o age. Pro-
validity o the FLIPI model has been demonstrated in gression o disease within 24 months rom the type
rituximab-treated patients.57 A FLIPI-2 model was o chemoimmunotherapy used as rontline treatment
developed through the prospective collection o prog- (POD24), in particular, has been shown to be the
nostic data, producing a ve-actor model that incor- strongest predictor o long-term outcome in these
porates age (>60 years adverse), hemoglobin level (<12 patients.60,61
g/dL adverse), serum B2M level (adverse i above nor-
mal range), bone marrow (adverse i involved), and
size o lymphadenopathy (>6 cm adverse), which has pOSTTReaTMeNT MONITORING
not been validated.58
There are more similarities than dierences in these An international working group has recommended
models. For instance, the importance o serum B2M end-o-treatment assessment and dened response
was shown in the univariate analyses o both the IPI criteria or NHL. These criteria have been updated
and FLIPI datasets, but the B2M data were collected recently, with important modications, including
prospectively only in the FLIPI-2 report. The impor- incorporation o PET-CT.44 In FDG-avid FL, PET-CT
tance o sampling the bone marrow, as shown in the should be used or response assessment, using the ve-
FLIPI-2 report, deserves particular emphasis, because point scale (1, no uptake above background; 2, uptake
practice patterns indicate that the important data ≤mediastinum; 3, uptake >mediastinum but ≤liver; 4,
ChapTeR 7
oered are oten not collected. Easily applied models uptake moderately >liver; 5, uptake markedly higher
such as the IPI, FLIPI, or FLIPI-2 can provide a rame- than liver and/or new lesions). The criteria based on
work or selecting the timing or intensity o therapy, PET-CT eliminate the complete response uncon-
and can acilitate the interpretation o clinical trials, rmed criteria and improve the prognostic value o a
by providing a tool to assess or disparities in patient partial response (PR). A complete metabolic response
selection when results o various trials are compared using PET-CT (5-point scale scores o 1–3), even with
(Table 7–1). a persistent mass, is considered a complete remission
Recently, a model combining the mutational status (CR). With CT-based assessment, a complete radio-
o seven genes relevant both to FL and the microen- logic response is determined by nodal masses regress-
vironment (EZH2, ARID1A, MEF2B, EP300, FOX01, ing to 1.5 cm or less in the longest diameter and no
CREBBP, and CARD11) with the FLIPI has been pro- extralymphatic sites o disease. In FL, multiple stud-
duced, and termed m7-FLIPI. Although not extensively ies have shown the association between posttreat-
used, it has been shown to be superior to the FLIPI ment response assessment by PET-CT scan and risk o
score to identiy very high-risk patients.59 relapse, justiying its use in this setting.62–65
At the time o relapse, avorable predictors or sur- Bone marrow reevaluation is perormed to conrm
vival in patients with FL include having achieved a clinical remission i the bone marrow involvement was
complete response with initial therapy, having had a initially positive.
Although the monitoring o patients with molecular
studies is not currently considered standard practice,
Tbl 71 prognostic Modls for Lymom detection o the t14;18/IGH-BCL2 by PCR techniques,
used to measure circulating tumor cells, has been use-
Model ul in the monitoring o subclinical disease. “Molecu-
Prognostic Factor IPI FLIPI FLIPI-2 lar remission,” the disappearance o cells with t14;18
Age detected by PCR, used to be considered a rarity in
ü ü ü
patients with FL treated with standard therapy. Grib-
PS ü ben et al reported that only 1 o 212 (0.5%) patients
Stage ü ü achieved molecular remission ater conventional che-
No. o E sites ü motherapy.66 With high-dose therapy and stem cell
transplantation (SCT), however, molecular remissions
Bone marrow ü
could be attained, and patients with molecular remis-
No. o nodal sites ü sion experienced more durable remissions. Improve-
Size o nodes ü ments in therapy have changed this. Even beore the
LDH ü ü advent o anti-CD20 monoclonal antibody (MAb)
therapy, more potent chemotherapy regimens were
Hgb ü ü
capable o inducing molecular remission in more than
B2M ü hal o patients. With the availability o rituximab and
B2M, serum β-2-microglobulin; Hgb, hemoglobin; PS, perormance status. obinutuzumab, which can largely eradicate B cells
rom the blood and bone marrow, it is now com- TReaTMeNT OF eaRLY-STaGe
mon to see molecular remission. Some recent studies FOLLICULaR LYMphOMaS
also showed that molecular remission correlates with
more durable clinical remission,67–69 but other studies At diagnosis, approximately 15% to 20% o patients
did not.70 Finally, novel techniques to assess minimal with FL have early-stage disease (stages I and II).
residual disease in FL are now available or clinical Retrospective studies have shown that observation
research, measuring circulating ree DNA, including is an option or these patients, with disease in 50%
droplet digital PCR and targeted capture ultradeep o patients not progressing and remaining untreated
next-generation sequencing (The Cancer Personal- when actively ollowed.75,76 However, this approach
ized Proling by Deep Sequencing or CAPP-seq).71 is usually reserved or elderly or comorbid patients
It is important to note, however, that although their unable to tolerate treatment, in light o the limited
application is quickly progressing in the eld o aggres- toxicity o available treatment options. Several series
sive lymphoma, their use in FL is limited, particularly have reported long-term disease-ree survival rates o
in patients with low tumor burden disease, because approximately 35% to 50% or stage I to II patients
o requently low quantity o measurable circulating treated with involved-eld radiotherapy (RT), so it
DNA. appears that many o these patients are cured, partic-
ularly patients with stage I disease and small disease
SURVeILLaNCe IMaGING size (<3 cm).76–82 Studies with extended-eld or total
lymphoid RT, in an attempt to increase cure rates,
ChapTeR 7
There are limited data supporting patient benet have not shown convincing additional benet. It is
rom surveillance imaging or patients with FL. As important to note that recent studies have shown that
a consequence, there is considerable variation in outcomes ater RT in PET-CT–staged patients could
practice. Zinzani et al perormed one o the only be better than reported in earlier series, particularly in
prospective studies o surveillance imaging, which stage I disease (where cure rate can be as high as 74%),
included 78 patients with FL in rst CR ater induc- and although longer ollow-up is needed, the curative
tion therapy. 72 Patients received PET-CT scans every potential o RT or truly localized FL may have been
6 months or two years, with annual scans therea- underestimated.83
ter. The relapse rate was 8% to 10%, as shown by The integration o chemotherapy with involved-
scans perormed until 36 months, and decreased ater eld RT has shown promising results in some trials.
that time. Because the purpose o the study was to Investigators at MDACC prospectively treated 85
describe specicity o scans, the impact on manage- patients with stage I or II FL with 10 cycles o COP-
ment and subsequent outcome was not reported. Bleo (cyclophosphamide, vincristine, prednisone,
Gerlinger et al perormed surveillance with annual and bleomycin) or CHOP-Bleo (COP-Bleo plus doxo-
CT scans and bone marrow evaluation in 71 patients rubicin) and involved-eld RT “sandwiched” ater
with FL in second or subsequent remission ater the third cycle. The disease-ree survival at 5 and 10
SCT. 73 Although approximately hal o relapses were years was 80% and 72%, respectively—an apparent
detected on CT scan, ew patients required immedi- improvement over results with RT alone.84 Analysis
ate treatment; there was no dierence in OS between o the National LymphoCare Study also demonstrated
patients in whom disease relapse was detected by improvement in progression-ree survival (PFS) in
imaging compared with clinical presentation. They patients who received systemic therapy in combina-
concluded that surveillance imaging was utile in tion with RT.85 In addition, a recently published ran-
this setting. Surveillance CT scans result in radiation domized trial showed that systemic therapy with
exposure, patient anxiety, and signicant healthcare R-CVP ater RT reduced relapse outside radiation
costs, and these issues need to be careully weighed elds and signicantly improved PFS in early-stage
against any potential benet. The National Compre- FL.86 Given the eects o RT on the tumor microenvi-
hensive Cancer Network guidelines suggest “surveil- ronment—and in particular macrophages,87 crucial or
lance CT scans up to every 6 months or the rst 2 antibody-dependent cellular cytotoxicity—the combi-
years ollowing completion o therapy, and not more nation o RT with rituximab is currently being inves-
than annually thereater.” In contrast, the European tigated in clinical trials, particularly in patients with
Society or Medical Oncology guidelines are more residual disease ater RT.
conservative, suggesting minimal adequate radiologic In summary, early-stage FL appears to be poten-
or ultrasound investigations every 6 months or two tially curable. The role o RT in these patients is well
years and annually thereater. Regular CT scans are established, and involved-site RT remains the standard
not mandatory outside clinical trials, and PET-CT treatment (see Table 7–1). Larger extended-eld or
should not be used or surveillance.74 involved-eld RT techniques targeting nodal regions
are no longer recommended; smaller techniques target- noncytotoxic therapeutic strategies are being incorpo-
ing involved nodal disease, termed involved-site radiation rated into rontline clinical trials. The range o thera-
therapy, should be used.81 However, when patients are peutic options or patients with advanced-stage FL
treated with RT alone (without systemic therapy), the remains broad (see Table 7–2). The therapeutic goals
target volumes should be slightly more generous to continue to ocus on minimizing toxicity, providing
also include nearby lymph nodes that might contain palliation, and attaining durable CR. Consideration o
microscopic disease. These smaller elds have been a clinical trial when available is advisable.
validated in patients with FL treated with denitive
RT, with no signicant increase in regional relapses.25,88
Despite the established role o RT and its endorsement
Frontline Treatment of Low Tumor
by experts, RT appears to be underutilized in standard Burden FL
clinical practice.85,89 Total lymphoid RT and combined- For patients with asymptomatic FL with a low tumor
modality therapy approaches remain controversial and burden, deerment o therapy until development o
are seldom used. symptoms or tumor burden becomes high has been
accepted based on three randomized trials demon-
strating survival rates equivalent to those o patients
MaNaGeMeNT OF aDVaNCeD- treated with immediate therapy in the prerituximab
STaGe FOLLICULaR LYMphOMaS era.90–92 With the long-term saety and ecacy o ritux-
imab established, observation has been challenged
ChapTeR 7
For decades, the treatment o patients with advanced- in the modern era with rituximab monotherapy in
stage FL has been built on two pillars that lean in patients with low tumor burden. The goal is to delay
opposite directions. First, there are numerous eec- the rst cytotoxic chemotherapy and to have an impact
tive therapeutic options that can induce remission on health-related quality o lie.
(Table 7–2); second, relapse appears to be inevitable. The ndings o a randomized trial o rituximab
I and when therapeutic advances lead to more com- versus a watch-and-wait approach in asymptomatic,
prehensive control o FL, then there may be a consen- patients with nonbulky FL suggested that patients
sus about early intervention, because a smaller tumor who received rituximab monotherapy had a delay
burden would presumably be more easily treatable, in progression compared with those with an initial
analogous to the stage I or II situation. Until then, it watch-and-wait approach.93 Those who received
is still the case that deerral o therapy is a common rituximab maintenance ater rituximab induction also
consideration or many asymptomatic patients with reported improved quality o lie, mainly because o
low tumor burden. a decrease in anxiety. No signicant dierence in OS
When treatment is appropriate, there are a number was reported.
o considerations in choosing an initial management The Rituximab Extended Schedule or Retreat-
strategy. With advances in supportive care, we have ment Trial was a randomized cooperative group
seen improvement in the tolerability o chemotherapy study evaluating two dosing strategies o rituximab
and SCT. With a better understanding o B-cell lym- monotherapy in patients with untreated grade I or II
phomagenesis and the role o the microenvironment, FL and low tumor burden.94 There were 289 patients
randomly assigned to receive either rituximab main-
tenance or retreatment ater responding to rituximab
Tbl 72 Stndrd Frontlin Strtgis for induction (4 weekly doses). The median time to treat-
Folliculr Lymom ment ailure was similar (3.9 vs 4.3 years), quality o
lie was similar, and signicant toxicity was inrequent
Stages I-II Deerral o therapy (or older and/
among both strategies. For patients with FL with a low
or inrm patients)
Radiation therapy tumor burden, rituximab monotherapy ollowed by
a retreatment strategy was associated with less ritux-
Stage III-IV Deerral o therapy (i no
imab use while providing comparable disease control
Low tumor burden threatening disease)
Rituximab to that achieved with a maintenance strategy.
For patients with untreated FL o low tumor bur-
Stages III-IV Rituximab-CHOP
den not eligible or a clinical trial or or more intensive
High tumor burden Obinutuzumab-CHOP
Rituximab-bendamustine
therapy, an initial management strategy o rituximab
Obinutuzumab-bendamustine monotherapy was associated with a delay in the need
Rituximab-lenalidomide or cytotoxic therapy, was well tolerated, and was
Obinutuzumab-lenalidomide perceived by some to enhance their health-related
well-being. Hence, the decision between observation
CHOP, cyclophosphamide, adriamycin, vincristine, and prednisone.
and rituximab monotherapy should be made ater a
detailed discussion with the patient about the goals monoclonal antibodies in combination with chemo-
o treatment. Because clinical studies have shown that therapy have been investigated in patients with high
low levels o vitamin D are associated with worse out- tumor burden FL. In a randomized phase III trial, named
comes in patients with B-cell NHL, and in light o its the GALLIUM study, obinutuzumab was compared
pleotropic antitumoral eect, the combination o vita- with rituximab in combination with chemotherapy in
min D with rituximab is currently being investigated patients with previously untreated FL; obinutuzumab
in a multicenter phase 3 randomized trial in patients was associated with a signicantly longer PFS, despite
with low tumor burden FL.95 a higher incidence o late myelosuppression, particu-
larly when combined with bendamustine.103
Although the most common initial management
Frontline Treatment of High Tumor strategy in the United States currently is chemoimmu-
Burden FL notherapy, the paradigm is changing.89 A phase II study
Several trials have convincingly shown that the addi- conducted at MDACC reported the ecacy and saety
tion o rituximab to chemotherapy leads to improved o a novel, nongenotoxic strategy o rituximab and
outcomes in FL (Table 7–3). Incorporation o rituximab lenalidomide in untreated FL with high response rates
has become standard. Suitable partners or rituximab (overall response rate [ORR] 98%, CR 87%) and man-
in induction regimens include cyclophosphamide, vin- ageable toxicity.104 This study provided the rationale or
cristine, and prednisone (CVP); cyclophosphamide, conducting a large, global phase III, randomized study
doxorubicin, vincristine, and prednisone (CHOP); and investigating rituximab chemotherapy (R-CVP, R-CHOP,
ChapTeR 7
bendamustine (B). Few randomized studies have been or BR) versus rituximab-lenalidomide in patients with
conducted to inorm selection o rontline chemoim- untreated FL, named the Rituximab Lenalidomide ver-
munotherapy. Bendamustine-rituximab (BR) has been sus Any Chemotherapy (RELEVANCE) study. The pri-
compared with R-CHOP in two randomized trials: the mary end points were complete response (conrmed or
Study group indolent Lymphomas study in Europe and unconrmed) at 120 weeks and PFS, though only the
the BRIGHT study in the United States. In both stud- ormer was mature enough and published. Among 1030
ies, and with extended ollow-up, BR was better toler- randomized patients, rituximab and lenalidomide were
ated and modestly more eective than R-CHOP.100,101 not superior to rituximab and chemotherapy, with a CR
Retrospective studies conducted at MDACC, however, rate at 120 weeks o 48% and 53%, and a 3-year PFS
show that R-CHOP may be a better rontline option o 77% versus 78%, respectively.105 Although the e-
than BR or patients with elevated SUVmax, also in cacy results were similar, the saety prole diered, with
absence o histologic evidence o transormation.47,48 less requent grade 3 or 4 neutropenia and ebrile neu-
A randomized study comparing R-CVP versus tropenia, but high rates o grade 3 or 4 cutaneous reac-
R-CHOP versus R-FM (fudarabine and mitoxantrone) tions in the rituximab and lenalidomide arm. Attempts
reported R-CHOP and R-FM were superior to R-CVP to improve on this regimen by adding ibrutinib, an oral
in regard to time to treatment ailure and PFS; how- Bruton tyrosine kinase (BTK) inhibitor, to lenalidomide
ever, both, particularly R-FM, were associated with a and rituximab have been limited by toxicity, particu-
higher rate o adverse events.102 Thereore, the latter is larly skin rash.106,107 Recent data rom a phase II study
not currently used in standard practice. To improve the conducted at MDACC show that obinutuzumab in
ecacy o chemoimmunotherapy, novel anti-CD20 combination with lenalidomide was associated with
Tbl 73 Frontlin RituximbplusCmotry Trils in Indolnt Lymom
Regimen Trial Design % CR % PR % FFS (Time) % Survival (Time)

a a a
R-CVP Phase III 41 40 52 (3 y) 89 (30 mo)
R-CHOPa Phase III 20 77 75 (3 y)a 96 (2 y)
a a a
R-MCP Phase III 50 42 71 (4 y) 87 (4 y)a
a,b a a
R-Bendamustine Phase III 40 53 58 (4 y) —
c
R-FND Phase III 88 12 76 (3 y) 96 (3 y)
R-FCM Phase II 83 11 58 (5 y) 89 (5 y)
O-chemotherapyd Phase III 86 20 85 (3 y) 98 (3 y)
a
Signicantly better than comparator arm. For R-CVP, survival benet noted in 2008 update.
b
Comparator arm R-CHOP.
c
Comparator arm FND, ollowed by rituximab (maintenance).
d
Comparator R-chemo.
avorable outcomes, with an impressive 2-year PFS o benet reported or patients who had not achieved CR
more than 90%, although a direct comparison with the at the end o chemoimmunotherapy.109 Factors infu-
combination o lenalidomide and rituximab is currently encing the decision to pursue a maintenance strategy
missing.108 In the next ew years, chemotherapy-ree should include consideration o the patient’s risk o
approaches could potentially become the standard ront- early relapse, the response to induction therapy, and
line treatment or patients with high tumor burden FL. the nancial burden o extended dosing.
A large multicenter, randomized trial o radioimmu-
notherapy (RIT) consolidation therapy has shown a sig-
MaINTeNaNCe aND nicant ailure-ree survival benet when used ater a
CONSOLIDaTION TheRapY variety o induction therapy regimens.110 Notably, the
induction therapy included rituximab in only a minority
Rituximab maintenance (Table 7–4) has been widely o the patients. Still, the easibility and impact o such
used ater rontline chemoimmunotherapy, with the a strategy is noteworthy. Prolongation o disease con-
goal o extending the disease-ree interval ater induc- trol was signicant in subset analyses o both complete
tion. A randomized study investigated the ecacy and partial responders to the induction therapy. Patients
o two years o rituximab maintenance ater ritux- who attained only partial remission ater chemotherapy
imab plus chemotherapy in patients with previously commonly attained CR ater RIT (77%) (Table 7–5).
untreated FL, named the (Primary RItuximab and Other trials have also studied RIT consolidation. A
Maintenance) PRIMA study.62 Rituximab maintenance SWOG trial compared CHOP ollowed by RIT versus
ChapTeR 7
ater chemoimmunotherapy with R-CHOP/R-CVP R-CHOP in patients with advanced-stage FL.111 With a
signicantly improved PFS (HR [hazard ratio], 0.55; ollow-up o 4.9 years, there was no signicant dier-
95% CI, 0.44–0.68) and was generally well tolerated ence in the two-year PFS (80% vs 76%) or OS (93%
but had no impact on OS. Retrospective data have vs 97%) rates. With the benets and saety prole o
recently shown similar ndings or patients receiving rituximab as part o induction or as maintenance estab-
maintenance rituximab ater rontline BR, the greatest lished, the role o RIT in the modern era is unclear.
Tbl 74 Mintnnc Rituximb
Induction Response ↑ FFS With

Induction % CR % PR Maintenancea
A. Frontline trials Rituximab 9 58 Yes
CVP 13 60 Yes
Various +R — — Yes
B. Frontline retrospective studies BR 41 18 Yes (or CR patients)
C. Salvage trials Rituximab 0 28 Yesb
R-CHOP 30 55 Yes
R-FCM 41 54 Yes
a
Maintenance schedules and duration variable (see text).
b
Benet o maintenance was matched by retreatment at time o progression.
Tbl 75 Consolidtion Try arocs
% CR Ater % CR Ater
Induction Consolidation Induction Consolidation % CR + PR % FFS (Time)
a a
CHOP Rituximab 57 94 44 (3 y)
FN Rituximaba 68 a
96 63 (3 y)
CHOP Tositumomab 39 69 98 67 (5 y)
Various Ibritumomab/Y-90 51b 87b 100b 53 (3 ya)
R-FND Ibritumomab/Y-90 69 89 89 73 (3 y)
Fludarabine Tositumomab/I131 9 86 100 60 (5 y)
a
In these trials, rituximab crossover only or subset who did not attain molecular response: conversion to molecular remission occurred in 74% and 61% in the two trials.
b
Trial design accepted only CR and PR patients or RIT. FFS measured rom study entry, beore RIT but ater induction chemotherapy.
Tbl 76 Stndrd Slvg Strtgis for construct; MAbs with enhanced capacity or media-
Folliculr Lymom tion o complement-dependent cytotoxicity; MAbs
with enhanced mediation o antibody-dependent
Chemoimmunotherapy Rituximab-CHOP cellular cytotoxicity; and other modications. In this
Obinutuzumab-CHOP regard, in a phase III randomized study comparing
Rituximab-bendamustine obinutuzumab (combined with bendamustine) ol-
Obinutuzumab- lowed by single-agent obinutuzumab maintenance to
bendamustine single-agent bendamustine, a signicantly longer PFS
Monoclonal antibodies Rituximab was observed (29 vs 14 months) with the addition o
Obinutuzumab obinutuzumab; these results led to its FDA approval
Targeted therapy Idelalisib (third line) or patients with rituximab-reractory relapsed FL.112
Duvelisib (third line) Monoclonal antibodies that target antigens other
Copanlisib (third line) than CD20 have been developed, including those used
Immunotherapy Rituximab-lenalidomide alone and as immunotoxins, the latter link a toxin to
Obinutuzumab Lenalidomide an antibody that delivers the toxin to the lymphoma
Cellular therapies Autologous SCT cells, analogous to the delivery o isotopes with RIT.
Allogeneic SCT These agents include polatuzumab vedotin (targeting
SCT, stem cell transplant. CD79b) and taasitamab (monoclonal antibody tar-
geting CD19). Polatuzumab has been investigated in
ChapTeR 7
combination with rituximab in a randomized phase II
study (termed ROMULUS) and in combination with
SaLVaGe TheRapY obinutuzumab and lenalidomide in a phase I/II study.
Taasitamab has been studied as a single agent in a
There are many eective therapeutic options or
phase II study; all studies showed a promising saety
patients with relapsed disease, including chemoimmu-
and ecacy signal.113–115
notherapy, anti-CD20 monoclonal antibodies, targeted
agents, immunomodulatory agents, and cellular thera-
pies (Table 7–6). Targeted Agents
Many therapeutic options under study in the past
Chemoimmunotherapy decade have been developed against specic cell
Numerous non–cross-resistant chemotherapeu- growth regulatory pathways. These agents include
tic agents can be eective in patients with indolent those targeting the B-cell receptor pathway, such as
lymphomas. Typically, those agents not chosen or BTK inhibitors (eg, ibrutinib) and phosphatidylino-
a patient’s rontline treatment are candidates or sal- sitol-3-kinase (PI3K) inhibitors (eg, idelalisib); agents
vage use. It is notable that retreatment o previously targeting apoptosis, such as BCL2 inhibitors (eg, vene-
responsive patients with the same agents is a legiti- toclax); and agents targeting epigenetic regulators,
mate option. Long-term ollow-up studies have shown such as EZH2 inhibitors (eg, tazemetostat).
that second and later responses can be attained, even Single-agent ibrutinib has been investigated as a
with the same agents, but the ensuing clinical remis- treatment or patients with relapsed FL in one phase
sions become progressively more brie. Some physi- I and in two phase II studies; although it was shown
cians advocate the avoidance o the toxicities o certain to be sae and well tolerated, the ORR was only 21%
agents (eg, doxorubicin or the nucleoside analogs) in to 37.5% and the CR rate was only 11% to 12.5%,
the rontline setting; their role in the salvage setting is thus ibrutinib is not currently approved or this indi-
an important consideration. cation.116–118 Acalabrutinib, a more potent and specic
oral BTK inhibitor than ibrutinib, is being currently
investigated as a single agent and in combination with
Monoclonal Antibodies
rituximab in patients with relapsed FL. Although it has
The ecacy o single-agent rituximab has been dem- been shown to be sae, only more mature ollow-up
onstrated reproducibly, although most responses to will shed light on its activity in this setting.119
salvage rituximab show PR rather than CR. Attempts The ecacy o the oral PI3Kδ inhibitor idelalisib has
at improving the rate o CRs and enhancing the dura- been investigated or the treatment o patients with
tion o response are evolving. relapsed FL (previously exposed to both rituximab and
Newer anti-CD20 MAbs are being investigated, an alkylating agent) in a phase II study, showing an
with modications that theoretically represent ORR o 56%, a CR rate o 6%, and a median PFS o
enhancements over rituximab, such as ully human- 11 months.120 Similar results have been observed or
ized MAbs as opposed to a chimeric mouse–human the oral PI3Kαγ inhibitor duvelisib and the intravenous
PI3Kαγ inhibitor copanlisib.121,122 Based on the ecacy be achieved through enhancement o the macrophage
o these agents, and in light o dis-immune toxicity, component o the tumor microenvironment. This
more pronounced in less heavily treated patients, all aim has been achieved through inhibition o CD47, a
three agents are currently approved or third-line treat- “do not eat me” signal that FL cells provide to macro-
ment o patients with relapsed FL. In addition, eorts phages. In a phase I/II study employing the combina-
are ongoing to identiy potentially saer PI3K inhibition o 5F9, an intravenous anti-CD47 antibody, and
tors, such as umbralisib.123,124 rituximab in patients with relapsed FL, there was an
Despite BCL2 translocation and overexpression ORR o 71% and a CR rate o 43%, supporting the
being the hallmark o FL, its inhibition with the oral development o novel ongoing experimental combina-
BCL2 inhibitor venetoclax has not been successul, tions or these patients.132
with an ORR o 38% and a CR rate o 15% in the
relapsed setting.125 Multiple attempts are now ongoing Cellular Therapy
to identiy alternative antiapoptotic proteins as targets
or uture trials.21 Stem cell transplantation approaches can be ardu-
Finally, given the requency o mutations in genes ous but deserve strong consideration in patients with
involved in epigenetic regulation in FL, targeted inhibi- recurrent high-risk FL. Autologous SCT strategies
tors o this pathway have been investigated. Tazemeto- result in substantially more durable remissions than
stat is a rst-in-class, selective, oral EZH2 inhibitor conventional-dose salvage therapy, particularly or
that has demonstrated antitumor activity in patients patients with POD24.133,134 Allogeneic SCT is a strat-
ChapTeR 7
with relapsed FL, independently rom the presence o egy that is contingent on availability o a donor, and is
an EZH2 mutation. In a multicenter, open-label phase a complex undertaking that includes substantial risks
I/II study including 90 patients with relapsed FL, 45 o treatment-related mortality. Nonetheless, allogeneic
with mutated EZH2 and 45 with WT EZH2, ORR SCT not only can result in long-term remission but
was 98% and 71%, respectively, with a median PFS can potentially lead to cure, presumably through its
o 14 months and 11 months, respectively.126,127 Based grat-versus-lymphoma eect. Data suggest that non-
on these data, a new drug application or accelerated myeloablative allogeneic SCT is associated with less
approval has been recently submitted to the FDA. toxicity than conventional myeloablative allogeneic
SCT, and augmentation o the conditioning regimen,
including incorporation o bendamustine, has resulted
Immunomodulatory Agents
in reduced myelosuppression and grat-versus-host
As previously discussed, immune modulation is an disease.135 With improved tolerance o SCT and the
attractive approach or patients with indolent lym- potential or cure, this remains a management strategy
phoma. The activity o lenalidomide in combination or eligible patients, and can be preerred to autolo-
with rituximab has been investigated as treatment or gous SCT, particularly in patients with bone marrow
patients with relapsed FL in a key phase II study, yield- involvement. It is important, however, to remember
ing an ORR o 76% and a CR rate o 35%.128 These that nonrelapse mortality is signicantly higher or
results were ollowed by a randomized phase III study, allogeneic compared with autologous SCT, and or
termed the AUGMENT study, in which the combina- matched unrelated donors compared with matched-
tion o lenalidomide and rituximab was compared sibling donors.136 Chimeric antigen receptor (CAR)
with single-agent rituximab. The results showed a T-cell therapy may represent a more eective and saer
signicantly prolonged duration o response (39 vs 14 alternative to SCT: two phase II studies investigating
months), leading to its FDA approval or this patient its use or patients with relapsed FL have completed
population.129 Obinutuzumab instead o rituximab accrual, and results are eagerly awaited. Early promis-
has been recently investigated in combination with ing results have been reported or the bispecic anti-
lenalidomide in patients with relapsed FL in two phase body mosunetuzumab, bringing together CD3+ T cells
II studies, showing an ORR as high as 98%, and a CR to CD20+ FL cells, and triggering antitumoral activity
rate as high as 72%, representing a viable therapeutic similar to what is observed with the use o chimeric
option in clinical practice or these patients.130 antigen receptor T-cell therapy.137
Enhancement o the endogenous antitumor response
by targeting the microenvironment may be achieved
Palliative Treatment
with immune checkpoint inhibitors, such as anti-PD1
MAbs. The activity o pidilizumab with rituximab has Palliative treatment or patients with FL can include
been investigated in 32 patients with relapsed FL and involved-site RT to sites o problematic or painul
reported an ORR o 66% and CR rate o 52% with no disease (eg, or obstructive uropathy). In this set-
autoimmune or treatment-related grade 3 or 4 adverse ting, it is important to consider the use o lower RT
events.131 An alternative, antitumoral activity can also doses (eg, 4 Gy), because prior studies have conrmed
high response rates even with low-dose RT.138 This approaches to therapy continue to be explored,
approach also minimizes treatment-related toxicity. including next-generation MAbs, pathway inhibi-
Among chemotherapy options, one historically mild tors, and immune modulators. These approaches to
option is chlorambucil. Observation without therapy therapy and novel combinations will likely play an
is also an option, even at the time o initial diagnosis, increasingly important role in the management o
in patients with active but no threatening or symp- patients with indolent FL. Allogeneic transplantation
tomatic disease. The approach o deerral o therapy in indolent FL continues to be an area o heightened
is common, but it should be done thoughtully and interest, especially with the development o more
with monitoring. Older patients are oten selected or eective and better tolerated cellular therapies. As
a “watch-and-wait” strategy, but this option should be emerging therapies become integrated with the best
weighed against the observation that older patients o conventional therapies, it is optimistic that a cura-
with FL have a tenold increased risk o dying within tive approach or more patients with indolent FL is
one year compared with age-matched controls.58 achievable. Equally promising is widespread use o
Finally, consideration o a clinical trial in the setting o well-tolerated therapy that is associated with dura-
relapsed or reractory FL is strongly recommended given ble disease control, resulting in chronic management.
the vast trial options available and evolving manage- Also worthwhile o clinical exploration is identiy-
ment strategies, particularly or patients with POD24. ing the most eective sequencing o therapy over
an individual’s disease course. With so many unan-
swered questions and emerging novel strategies,
ChapTeR 7
CONCLUSIONS consideration o clinical trials or FL is strongly rec-
ommended to acilitate the translation o important
To date, most advanced-stage indolent B-cell lym- scientic breakthroughs.
phomas, including FL, remain incurable. Novel

J Although the Follicular Lymphoma International (chemotherapy vs immunotherapy; 6 months vs 18
Prognostic Index (FLIPI) score has prognostic value months o treatment; insurance coverage).
and can help guide requency o surveillance and J In young patients without signicant comorbid
stratication strategies or clinical trials, it has no health conditions, obinutuzumab should be consid-
predictive value and should not be used to deter- ered over rituximab in combination with rontline
mine initiation o treatment or treatment selection. chemoimmunotherapy, given improved survival in
J There is currently no universal agreement about the the GALLIUM study.
optimal treatment o patients with FL grade 3A; an J Elevated SUV on PET-CT scan may identiy patients
elevated Ki-67 (>40%) may help identiy those in with FL who would benet rom an anthracycline-
need o anthracycline-based approaches. based regimen.
J The selection o bendamustine and rituximab com- J Outcomes among patients with FL experiencing
pared with lenalidomide and rituximab as rontline disease progression within 24 months o rontline
treatment or patients with advanced-stage FL and chemoimmunotherapy remain suboptimal, and
high tumor burden should be driven by patient experimental approaches are preerred in these
comorbid health conditions and preerences patients.
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ChapTeR 7
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Engl J Med. 2018;379(10):934-947. lent lymphoma. J Clin Oncol. 2017;35(35):3898-3905.
106. Ujjani CS, Jung SH, Pitcher B, et al. Phase 1 trial o rituximab, 122. Flinn IW, Miller CB, Ardeshna KM, et al. DYNAMO: a phase II
lenalidomide, and ibrutinib in previously untreated ollicular study o duvelisib (IPI-145) in patients with reractory indolent
lymphoma: Alliance A051103. Blood. 2016;128(21):2510-2516. non-Hodgkin lymphoma. J Clin Oncol. 2019;37(11):912-922.
107. Nastoupil LJ, Lee HJ, Hagemeister FB, et al. Saety and ecacy 123. Lunning M, Vose J, Nastoupil L, et al. Ublituximab and
o ibrutinib in combination with rituximab and lenalidomide in umbralisib in relapsed/reractory B-cell non-Hodgkin
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remission in advanced ollicular lymphoma. J Clin Oncol. 127. Morschhauser F, Tilly H, Chaidos A, et al. Phase 2 multi-
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ChapTeR 7
8 Marginal Zone and Other Small
Cell Lymphomas
Melody Becnel
Felipe Samaniego
KEY CONCEPTS
 Marginal zone lymphoma (MZL) is an indolent B-cell recurrent chromosomal abnormalities are noted in nodal
non-Hodgkin lymphoma composed o three subtypes: MZL. MYD88 L265P mutations (as seen in Waldenström
extranodal (mucosal-associated lymphoid tissue [MALT] macroglobulinemia) have been identifed in 10% to 20%
lymphoma), splenic, and nodal. o cases o splenic MZL.
 MALT lymphoma, the most common subtype, is com-  WHO classifcation restricts small lymphocytic lymphoma
posed o gastric and nongastric MALT and is oten associ- (SLL) to tumors involving lymph nodes with the same B-cell
ated with inectious organisms such as Helicobacter pylori. immunophenotype as CLL without leukemic involvement
 Nongastric MALT is oten associated with inammatory and considers SLL to be the nodal or tissue counterpart o
conditions such as Sjögren syndrome and Hashimoto chronic lymphocytic leukemia (CLL).
thyroiditis.  Abnormalities o the p53 or MYC genes correlate with
 Translocations well characterized in MALT lymphomas increased risk o histologic transormation (Richter syn-
include t(11;18), t(14;18), t(1;14), and t(3;14). No unique drome) and poorer prognosis in CLL/SLL.
MARGINAL ZONE LYMPHOMA Extranodal Marginal Zone B-Cell

Lymphoma
Marginal zone lymphoma (MZL) is the second most
common B-cell–indolent non-Hodgkin Lymphoma
Clinical Features
(NHL; <10% o NHL cases in adults). MZL generally Patients with MALT lymphoma present with extra-
presents at a median age o 60 years old, and women nodal disease that is oten localized (stage I-E or II-E).
have a slightly increased propensity toward MZL devel- There may be a history o inection or autoimmune
oping compared with men.1,2 There are three subtypes disease, which are conditions that lead to chronic
o MZL: extranodal MZL o mucosa-associated lym- B-cell receptor activation.5 Peripheral lymph node
phoid tissue (MALT lymphoma), which represents 7% involvement is uncommon in patients with MALT
to 8% o all NHLs; nodal marginal zone lymphoma, lymphoma. The most common site o involvement is
which represents approximately 2% o all NHLs; and the stomach, but numerous other extranodal locations
splenic B-cell marginal zone lymphoma (SMZL), rep- can be involved, including lung, skin, orbit, salivary
resenting less than 1% o all NHLs.3,4 Splenic MZL glands, other parts o the gastrointestinal tract, thyroid
can be associated with circulating lymphocytes with gland, and other rare sites.2 Dissemination occurs in up
villous cytoplasmic projections. The entity previously to 30% o cases, most oten in patients with nongastric
described as splenic lymphoma with villous lympho- MALT lymphoma, and dissemination generally occurs
cytes is, in most cases, SMZL. to other extranodal sites. In patients with nongastric
183
184 Secion II Lymphoma and Myeloma
MALT lymphomas, subclinical gastric involvement is resembling mature plasma cells (see Fig. 8–3). In some
not uncommon. The bone marrow is involved in only cases, the cells have markedly irregular nuclear con-
10% to 20% o patients. tours and resemble small cleaved cells. All o these cell
The stomach is the best-studied site o involve- types may have abundant pale cytoplasm, imparting a
ment. Patients oten present with signs and symptoms
suggestive o peptic ulcer disease, such as epigastric
A
pain and dyspepsia. Anemia, weight loss, and gastro-
intestinal bleeding can be seen in patients with more
advanced disease. Helicobacter pylori is present in the
gastric mucosa o many patients with MALT lym-
phoma. Antibiotic elimination o H pylori has resulted
in regression o MALT lymphoma in more than hal o
treated patients.6,7 Thus, H pylori is thought to be essen-
tial to lymphomagenesis in gastric MALT lymphoma.
In nongastric MALT lymphomas, symptoms are
related to the anatomic site involved. Disseminated
disease is generally more common in these patients
than in patients with gastric MALT lymphoma.
Despite the higher requency o stage IV disease, the
CHAPtER 8
ve-year survival rate is 90% when treated with a vari- B

ety o therapies.2,5
Histologic Features
Four ndings are present in most MALT lymphomas:
a population o neoplastic small lymphoid (centrocyte-
like) cells that may have monocytoid eatures, occasional
large lymphoid cells (blasts), lymphoepithelial lesions,
and reactive lymphoid ollicles (Figs. 8–1 through 8–3).4
The neoplastic small lymphoid cells exhibit a range
o cytologic appearances. In some cases, the cells
resemble small lymphocytes with or without plasma-
cytoid dierentiation. In other cases, the neoplasm
FIGURE 8–2 A MALT lymphoma o a salivary gland. A. The
appears biphasic: one component is a population o
neoplastic cells have a pale (monocytoid) low-power appear-
small lymphoid cells, and the other is a population ance and surround ducts. B. Lymphoepithelial lesions are
o cells with extensive plasmacytoid dierentiation, prominent in this case (A, B, hematoxylin and eosin; A, ×20;
B, ×400).
FIGURE 8–1 Extranodal marginal zone B-cell lymphoma o

MALT (MALT lymphoma) involving the stomach. The neo- FIGURE 8–3 A MALT lymphoma o the conjunctiva. In this
plasm partially replaces gastric mucosa and inltrates epi- eld, the neoplasm has a biphasic pattern, with the subepi-
thelium. A reactive ollicle is present at the bottom let o the thelial portion exhibiting extensive plasmacytoid diferentia-
eld. tion (periodic acid–Schif, ×400).
Chaper 8 Marginal Zone and Other Small Cell Lymphomas 185
table 81 translocaions and Gene Abnormaliies in MALt
Translocation Tissues Involved Genes Involved

t(11;18) 15%–40% o MALT, most commonly BIRC3, MALT1 to orm a usion gene
present in lung and stomach MALT
t(14;18) In 15%–20% o MALT; seen in Juxtaposes IGH and MALT1, causing
nongastrointestinal MALT lymphoma overexpression o MALT1
t(1;14) In 1%–2% o MALT; seen in lung and Juxtaposes BCL10 and IGH, truncating BCL10 and
stomach causing loss o proapoptotic unction
t(3;14) Most commonly present in MALT o skin, Juxtaposes FOXP1 and IGH, causing
thyroid, and ocular adnexal site overexpression o FOXP1
monocytoid appearance. In most MALT lymphomas, CD10, CD21, CD23, Bcl-6, cyclin D1, or T-cell anti-
occasional large lymphoid cells (blasts) are also pres- gens, including CD5. Four chromosomal transloca-
ent. However, when large cells are numerous and orm tions are well characterized in MALT lymphomas:
confuent sheets, the neoplasm has evolved to diuse t(11;18), t(14;18), t(1;14), and t(3;14). The requency
large B-cell lymphoma.4 o these translocations varies by anatomic site o the
CHAPtER 8
The small neoplastic cells have a marked tendency lymphoma, and each translocation results in dysregu-
to inltrate epithelium, orming so-called lymphoepi- lation o specic genes (see Table 8–1).8,10 Vinatzer et
thelial lesions (see Fig. 8–2). In well-ormed lesions, al identied additional chromosomal translocations or
aggregates o neoplastic cells are ound within the partner genes in MALT lymphomas, including t(1;14)/
epithelium. Reactive lymphoid ollicles are also IGH-CNN3, t(5;14)/IGH-ODZ2, t(3;14)/IGH-BCL6,
usually present in MALT lymphomas, generally sur- t(9;14)/IGH-JMJD2C, and t(6;7)(q25;q11).8 The trans-
rounded by neoplastic small lymphoid cells. Neoplas- locations alter signaling associated with prolieration
tic cells can also accumulate in these ollicles (termed or inhibit apoptosis. Activation o NF-κB may be a
colonization), imparting a vaguely nodular appearance nal common pathway in MALT lymphomas. API2-
at low-power magnication.4 MALT1 is known to activate NF-κB. Similarly, over-
Anatomic site–specic histologic ndings are also expression o MALT1 or BCL10, by binding with each
observed in MALT lymphomas, involving chronic anti- other, can orm a complex in the cell and act to activate
genic stimulation caused by the presence o either an NF-κB.11
inectious organism or autoimmune disease. For exam-
ple, normal lymphoid tissue is not usually present in Workup and Management
the stomach. However, some orms o MALT are
acquired in response to H pylori inection. Chlamydia The diagnosis o gastric MALT lymphoma and pres-
psittaci, Borrelia burgdorferi, and Campylobacter jejuni are ence o H pylori is established by endoscopy, with
other inectious agents that have been associated with multiple biopsies obtained rom abnormal and nor-
orbital, skin, and small intestinal MALT lymphomas, mal mucosa.6 Endoscopic ultrasound and computed
respectively, although the data linking B burgdorferi to tomography scans may also be helpul in determining
skin lymphomas do not appear to be strong. Like the the depth o the lesion and or staging. Early-stage dis-
stomach, normal lymphoid tissue is also poorly devel- ease can be successully treated initially with antibiotic
oped in the lung. However, two infammatory diseases therapy, with complete regression in 35% to 100% o
are requently associated with lung MALT lymphoma: patients with a low rate o recurrence.6,11 Thereore,
Sjögren syndrome and lymphoid interstitial pneumo- the recommended therapy or stage I or II disease is
nia. Similarly, MALT lymphomas o the salivary gland a standard regimen o antibiotic therapy or H pylori
are usually associated with Sjögren syndrome, and with ollow-up endoscopy two to three months later
Hashimoto thyroiditis usually precedes MALT lym- to document H pylori eradication. I patients remain
phoma o the thyroid gland.8,9 H pylori–positive, a second-line anti-Helicobacter regi-
men is administered until the patient tests negative
or H pylori. The time between H pylori eradication
Immunophenotypic, Cytogenetic, and Molecular
and complete remission o gastric MALT lymphoma
Features varies and can take longer than one year. More exten-
The MALT lymphomas express monotypic immu- sive disease, as documented by endoscopic ultrasound
noglobulin (Ig) light chain, pan–B-cell antigens, and demonstrating lymphoma involvement beyond the
Bcl-2. These tumors typically do not express IgD, mucosa and in regional nodes, is less likely to respond
to antibiotic therapy.6,12 Lack o response has been cor-

related with the presence o the t(11;18) translocation.9
Surgery, radiotherapy (RT), chemotherapy, and
anti-CD20 monoclonal antibody therapy have been
used or both gastric and nongastric types o MALT
lymphomas and other MZLs. The treatment o choice
is dependent on the site and stage o disease and the
patient’s clinical presentation. Surgery and RT are
prime therapeutic approaches or localized MALT
lymphoma, including gastric MALT lymphoma that
does not respond adequately to antibiotic therapy and
H pylori–negative disease.12 Chemotherapy and mono-
clonal antibody therapy are also options or advanced-
stage MZL. Conconi et al studied rituximab in patients
with MALT lymphoma and ound signicant clinical
activity in both untreated and relapsed patients.13 By
extrapolation rom small lymphocytic lymphoma/ FIGURE 8–4 Nodal marginal zone lymphoma. In this eld,
the neoplastic cells have abundant pale cytoplasm and sur-
chronic lymphocytic leukemia (SLL/CLL) data, combi-
round a reactive germinal center composed o large cells
nations that include nucleoside analogues have been
CHAPtER 8
(center o eld) (hematoxylin and eosin, ×400).

explored.14 In recent years, nonchemotherapy treat-
ment approaches have been explored, such as the
use o the ibrutinib, a Bruton tyrosine kinase inhibi- cytologic eatures o nodal MZL are the most distinc-
tor that was FDA approved in 2017 or the treatment tive aspect o this neoplasm. The tumor cell cytoplasm
o MZL, and the immunomodulatory agent lenalido- is relatively abundant and pale, with well-delineated
mide in combination with rituximab, which was cell borders (Fig. 8–4). The tumor cell nuclei are small,
FDA approved in 2019.15–17 In addition, other targeted chromatin is relatively clumped, and mitotic gures
agents such as PI3 kinase inhibitors such as umbralisib are inrequent. Rare large cells are also present.5
(FDA granted breakthrough therapy designation.) and Nodal MZLs are mature B-cell neoplasms that
copanlisib have been explored.18 The best systemic express monotypic Ig, pan–B-cell antigens, and Bcl-
treatment option is not clear, but therapy or relapsed 2. These tumors do not express CD10, CD21, CD23,
or extensive disease should be approached in the BCL6, cyclin D1, or T-cell antigens, including CD5.
same manner as relapsed ollicular lymphoma (reer to Conventional cytogenetics and fuorescence in situ
Chapter 7, Indolent Follicular Lymphomas).9,12 hybridization (FISH) studies have identied a variety
o abnormalities, most oten trisomy.3 However, there
are no unique recurrent chromosomal abnormalities in
Nodal Marginal Zone Lymphoma nodal MZL. The t(11;18), t(14;18), and t(1;14) have not
Clinical Features and Management been identied in nodal MZL5.
Patients with nodal MZL typically present with periph-
eral or para-aortic lymphadenopathy and bone mar- Splenic Marginal Zone Lymphoma
row involvement. The ve-year overall and ailure-ree
Clinical Features and Management
survival rates are lower or patients with nodal MZL
compared with patients with MALT lymphoma (56% Patients with SMZL usually present with spleno-
vs 81% and 28% vs 65%, respectively). The major- megaly, cytopenias, and circulating malignant lym-
ity o eective treatment regimens and outcomes o phocytes. They commonly have modest abdominal
patients with nodal MZL are similar to that o patients lymphadenopathy and bone marrow involvement.
with advanced ollicular lymphoma (FL). Monoclonal gammopathy, usually o IgM type, can
be observed in 10% to 20% o patients. Peripheral
lymphadenopathy and B-type symptoms are uncom-
Histologic, Immunophenotypic, and Molecular
mon. The clinical course is indolent, with the ve-year
Features
overall survival rate ranging rom 65% to 78%.19
Nodal MZLs have a propensity to involve the mar- Approximately one third o patients with SMZL
ginal zones o a lymph node. In most cases, how- will never require therapy. Splenectomy is indicated
ever, the neoplasm also expands into the periollicular in patients with symptomatic splenomegaly or cyto-
compartments with sparing o germinal centers, or it penias secondary to hypersplenism. I splenectomy
may completely replace lymph node architecture. The is contraindicated, low-dose splenic irradiation may
A B
FIGURE 8–5 Splenic marginal zone lymphoma. A. At low power, the white pulp o the spleen is markedly expanded by
lymphoma, which has a biphasic pattern. B. One white pulp nodule at higher magnication (A, B, hematoxylin and eosin; A,
×20; B, ×200).
CHAPtER 8
be an alternative. Alkylating agents have been used, involving the protection o telomere 1 (POT1) genes in
but responses are usually partial and not durable. SMZL.20 MYD88 L265P mutations have been identi-
Patients treated with fudarabine demonstrate a higher ed in 10% to 20% o cases o SMZL and correlate
response rate and longer lasting remission than those with IgM gammopathy.21
treated with alkylating agents. Rituximab has signi-
cant activity in SMZL. In addition, in SMZL associated
with hepatitis C, treatment o the underlying inec- SMALL LYMPHOCYtIC LYMPHOMA/
tion may be sucient treatment or the lymphoma as CHRONIC LYMPHOCYtIC LEUKEMIA
well.19
Small lymphocytic lymphoma represents approxi-
Histologic, Immunophenotypic, and Molecular mately 7% o all NHLs.3,4 The WHO classication
restricts SLL to tumors involving lymph nodes with
Features
the same B-cell immunophenotype as CLL without
In SMZL, the white pulp is expanded by a neoplasm leukemic involvement and considers SLL to be the
that initially replaces the marginal and mantle zones nodal or tissue counterpart o CLL.4 Cases o SLL and
and then eventually replaces the white pulp (Fig. 8–5). CLL combined represent about 12% o all B-cell NHLs.
Lesser red pulp involvement is also usually present.
At high-power magnication, the neoplastic cells are
small lymphocytes with abundant pale (monocytoid)
Clinical Features and Management
cytoplasm. The neoplastic cells may exhibit plasma- Patients with SLL oten present with asymptomatic
cytoid dierentiation. Occasional large lymphoid cells lymphadenopathy. B symptoms are uncommon and
are present. In a peripheral blood smear, the neoplastic are observed in less than 10% o patients. Spleno-
cells can have villous cytoplasmic projections.19 megaly is common. Bone marrow is oten involved,
Splenic MZL is a mature B-cell neoplasm that aecting approximately 70% o patients.3,4 Although
expresses monotypic immunoglobulin, pan–B-cell the traditional staging systems or SLL and CLL dier,
antigens, and Bcl-2. A subset o cases is positive or these systems share common eatures, and the prog-
IgD or CD5 (dim intensity detected by fow cytom- nosis o patients with SLL is similar to that o patients
etry). These neoplasms are negative or CD10, Bcl6, with CLL.
cyclin D1, and T-cell antigens (other than CD5). Management strategies or patients with FL and
Conventional cytogenetics and FISH analysis have CLL are oten applicable to patients with SLL, but
identied a variety o abnormalities, most oten tri- there are some caveats (reer to Chapter 3, Chronic
somy o chromosomes 3 and 7. Deletion o 7q is pres- Lymphocytic Leukemia and Associated Disorders,
ent in approximately 50% o cases. A recent study and Chapter 7, Indolent Follicular Lymphomas). For
using array-based comparative genomic hybridization instance, because CD20 is usually expressed at low
has demonstrated the presence o del(7q36.2) involv- levels in SLL/CLL, anti-CD20 antibody therapy or SLL
ing the sonic hedgehog (SHH) gene and del(7q31.32) may be better modeled on the results o studies in CLL
rather than the results o studies in patients with FL. are not expressed4. CD38 and ZAP70 are expressed
Nonchemotherapy drug therapy consisting o veneto- in a subset o cases, and expression correlates with
clax and obinutuzumab is FDA approved or SLL, with unmutated Ig genes and poorer prognosis.22 The neo-
an overall response rate o 85%. plastic cells are negative or CD10 and Bcl-64.
Conventional cytogenetic analysis has shown chro-
mosomal abnormalities in 50% to 60% o SLL/CLL
Histologic, Immunophenotypic, and cases. This low requency is partly attributable to
Molecular Features poor cell growth in culture. Translocations involving
The lymph node architecture is diuse and usually the Ig genes are rare in SLL/CLL. The t(14;19)(q32;q13)
totally eaced by SLL/CLL4. The neoplastic cells are translocation involving the BCL3 gene at 19q13 is most
predominantly small, round lymphocytes. Vague pale common but is present in less than 5% o SLL/CLL
areas composed o lymphocytes, prolymphocytes, and cases. The t(14;19) translocation is associated with
paraimmunoblasts, known as prolieration centers (or atypical morphologic or immunophenotypic eatures
pseudoollicles), are usually present and are diagnos- and a poorer prognosis.23
tic o this neoplasm. In 5% to 10% o SLL/CLL cases, FISH analysis has shown a higher requency o
residual reactive lymphoid ollicles are present, sur- abnormalities in SLL/CLL because this technique can
rounded by neoplasm; this represents the so-called assess interphase as well as metaphase nuclei and
interollicular pattern o SLL/CLL. In this morphologic does not require cell growth in culture. At our center,
variant, prolieration centers can surround benign ol- SLL/CLL cases are routinely assessed by FISH with a
CHAPtER 8
licles, mimicking nodal MZL. panel o probes, including those specic or 6q, 11q
The SLL/CLL cells express monotypic immuno- (ATM), trisomy 12, 13q14, and 17p (p53). Deletion
globulin light chain, IgM, usually IgD, pan–B-cell o the 13q14 locus is the most common abnormality
antigens, and Bcl-2. CD23 is usually positive in 90% in SLL/CLL. Trisomy 12 is detected in approximately
to 95% o cases, and CD22, CD79B, and FMC7 are 15% to 20% o cases and appears to be a secondary
negative in most cases. The density o Ig and CD20 event, because it is usually ound in only a subset o
antigen expression on the surace o SLL/CLL cells is the neoplastic cells.24 Both del (11q) has been corre-
characteristically low (“dim” immunofuorescence by lated with poorer prognosis. Abnormalities o the p53
fow cytometry). These neoplasms almost invariably or MYC genes correlate with increased risk o histo-
express the CD5 antigen, a pan–T-cell antigen that is logic transormation (Richter syndrome) and poorer
not expressed on normal B cells. Other T-cell antigens prognosis.

J Many patients with MZL and SLL present asymp- disease and patients with translocation t(11;18)
tomatically. There are currently no data to sug- may not respond to antibiotics alone and may need
gest that the early initiation o treatment leads to systemic treatment extrapolated rom studies o FL.
improved overall survival; thereore, a close obser- J Nodal MZL should be treated in the same manner
vation approach is indicated in many patients as is as FL.
the case with other low-grade lymphomas.
J Splenic MZL that is associated with hepatitis C
J Patients with gastric MALT oten present with should be frst managed by treating the hepati-
symptoms o gastroesophageal reux disease and tis C. Rituximab is the treatment o choice in most
abdominal pain. In addition to endoscopic evalu- cases o splenic MZL; splenectomy can be consid-
ation, H pylori testing and advanced imaging is ered in specifc circumstances such as symptomatic
important to determine the extent o disease. splenomegaly and reractory cytopenias cause by
J Localized H pylori–positive gastric MALT is treated splenic sequestration.
with triple or quadruple antibiotics targeting J In SLL, abnormalities o the p53 or MYC genes corre-
H pylori. Treatment should be continued until the late with increased risk o histologic transormation
patient is negative or H pylori. More extensive (Richter syndrome) and poorer prognosis.
13. Conconi A, Martinelli G, Thiéblemont C, et al. Clinical activity

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9 Aggressive B-Cell Lymphomas
Raphael Steiner
Jason R. Westin
Sergej N. Konoplev
Luis E. Fayad
L. Jerey Medeiros
KEY CONCEPTS
 Evaluation o pretreatment prognostic actors o diuse Cooperative Oncology Group [ECOG] Perormance Status
large B-cell lymphoma (DLBCL) includes scores such as the ≥2, extranodal disease >1 site, stage III/IV, elevated lac-
International Prognostic Index (IPI); cell-o-origin (germi- tate dehydrogenase, kidney/adrenal involvement); extra-
nal center B-cell subtype [GCB] and activated B-cell [ABC] nodal disease with testicular, uterine, breast, epidural,
subtype); genetic proling (such as uorescence in situ skin involvement); aggressive B-cell lymphoma subtypes
hybridization studies [FISH] or MYC rearrangement, i MYC (Burkitt lymphoma, double/triple-hit lymphoma/high-
rearrangement is detected, additional FISH studies or grade B-cell lymphoma, double-expressor lymphomas,
BCL2 and BCL6 rearrangements should be perormed); and HIV-associated lymphoma, DLBCL with ABC subtype,
immunophenotypic studies (such as MYC, BCL2, and BCL6 intravascular DLBCL, CD5+ DLBCL, IgM-secreting DLBCL).
expression).  The baseline workup o a suspected primary CNS lym-
 The baseline workup o aggressive B-cell lymphoma phoma should include magnetic resonance imaging (MRI)
should not omit testing or hepatitis B and HIV, echo- o the brain and biopsy o the lesion, search or addi-
cardiogram, or multigated acquisition scan (i planned tional disease sites, such as testicular ultrasound or men
therapy with anthracycline), and ertility counseling or >60 years old, ull ophthalmologic examination including
eligible patients. slit-lamp eye examination, spine MRI, positron emission
 Besides a clinical trial, the standard-o-care rontline ther- tomography/computed tomography (PET/CT) scan, and
apy o DLBCL not otherwise specied is still rituximab bone marrow biopsy.
cyclophosphamide, doxorubicin, vincristine, and pred-  The optimal rontline therapy o Burkitt lymphoma has
nisone (R-CHOP). However, many studies are ongoing to yet to be dened in a prospective randomized trial, but
outperorm this combination. R-CHOP is not an adequate therapy. I a patient cannot
 The treatment plan o aggressive B-cell lymphoma should be enrolled in a clinical trial, aggressive combination
evaluate the potential need or central nervous system chemotherapy such as R-Hyper-CVAD/MA, R-CODOX-M/
(CNS) prophylaxis or patients presenting with the ollow- IVAC, or DA-EPOCH-R with adequate CNS prophylaxis is
ing risk actors: elevated CNS-IPI (age >60 years, Eastern recommended.
It is clinically useul to divide B-cell non-Hodgkin lym- the clinical characteristics, pathology, and treatment o
phomas (NHLs) into indolent and aggressive groups aggressive B-cell NHLs.
based on their clinical behavior.1 Patients with indolent
NHLs typically have a survival o many years, even
i the NHL is untreated, but paradoxically, the NHLs EPIDEMIOLOGY
are usually incurable. Patients with aggressive NHL
have a survival time measured in weeks to months Globally, lymphoma incidence rates have declined
i untreated yet the NHLs are usually chemosensitive slightly (0.3% per year) since 2001 in emales and since
and requently curable. In this chapter, we ocus on 2004 in males in the US. Earlier, lymphoma incidence
191
192 Section II Lymphoma and Myeloma
rates increased steadily during the 1970s and 1980s, common variable immune defciency, and ataxia-tel-
leveled o in the 1990s, and began a slight decline by angiectasia.8 These diseases and other inherited dis-
the end o that decade. This drop, independent o HIV orders are associated with an increased lietime risk
inection may in part reect International Classifcation o developing NHL, with aggressive B-cell NHL being
o Diseases coding changes in 2001, when the World most common.
Health Organization (WHO) classifcation system was Patients who are immunosuppressed or thera-
frst published.2 peutic reasons—or example, ater organ transplanta-
Among mature lymphoid neoplasms, the astest tion—are also at increased risk o NHL, especially i
increase over the 12-year period rom 2001 through the disease is treated with cyclosporine, azathioprine,
2012 was or plasma cell neoplasms. The trend in prednisone, or monoclonal antibodies or the removal
increasing body size may partly explain this increase, o T cells.9 A loose association can be drawn between
because obesity was steadily increasing over this time the level o immune suppression and lymphoma risk.
period and is a risk actor or plasma cell neoplasms.2 Transplant patients treated with the highest doses
In 2020, the American Cancer Society estimated that o immunosuppressive agents, such as heart trans-
77,240 individuals would be diagnosed with NHL in plant recipients, are at greater risk o lymphomas
the United States during the year, and 19,940 patients developing. These lesions are also more likely to be
would succumb to disease. aggressive and are oten extranodal orms. Individu-
Diuse large B-cell lymphoma (DLBCL), the most als treated with pharmacologic immune suppression
common NHL subtype, has an aggressive behavior and or autoimmune disorders—such as systemic lupus
CHAPTER 9
is more common in Whites than Arican Americans in erythematosus, Sjögren syndrome, or rheumatoid
the United States; however, 5-year survival outcomes arthritis—are also at increased risk or NHL, includ-
are worse in Arican Americans.3,4 ing the tumor necrosis actor antagonists. 10 A subset
o these NHLs is histologically aggressive and associ-
ated with Epstein-Barr virus (EBV) inections. These
ETIOLOGY
Most cases o aggressive B-cell NHL do not have a
well-defned etiology. Recent work has shown that the Table 9–1 Risk Factors Associated With
lietime risk or many cancers correlates with the total Aggressive NonHodgkin Lymphomas
number o divisions o normal sel-renewing cells.5 The
implications o these fndings suggest that many can- Inherited and acquired immune deciency
cers may not be caused by hereditable genetic aberran- – Wiskott-Aldrich syndrome
– Ataxia-telangiectasia
cies, environmental exposures, inectious etiologies,
– Chédiak-Higashi syndrome
or other known causes, but instead are attributable – X-linked immunoprolierative disorder
to a combination o actors that may include chance. – Severe combined immunodeciency
For the NHLs that appear to have currently identif- – Common variable immune deciency
able drivers, there are fve groups o drivers: immune – Iatrogenic immune suppression
suppression (both acquired and primary), inectious – Solid organ or bone marrow transplant
agents, toxic exposure, liestyle, and amilial actors Toxic exposures
(Table 9–1). Moreover, risk actors may be dierent or – Prior chemotherapy
children and adults.2 – Phenoxyherbicides
Most cases o DLBCL not otherwise specifed arise – Dioxin
de novo (reerred as primary) but can also represent – Radiation or radiation therapy
a transormation o an indolent/less aggressive lym- Inectious exposures
phoma, such as chronic lymphocytic leukemia/small – Epstein-Barr virus
lymphocytic lymphoma, ollicular lymphoma, mar- – Hepatitis C virus
ginal zone lymphoma or nodular lymphocyte-predom- – Human T-cell leukemia/lymphoma virus
inant Hodgkin lymphoma.6 – Human herpesvirus type 8 (HHV-8)
– HIV
Liestyle
Immunosuppression – Higher young-adult body mass index
The strongest association with aggressive B-cell NHLs Autoimmune disorders
is immune suppression, both primary and acquired.7 – Sjögren syndrome
Examples o primary immunodefciency include – Celiac sprue
inherited immune disorders, such as Wiskott-Aldrich – Systemic lupus erythematosus
– Rheumatoid arthritis
syndrome, severe combined immune defciency,
Chapter 9 Aggressive B-Cell Lymphomas 193
lesions may regress ater withdrawal o the immuno- maintenance, woodworking, and dry cleaning. One o
suppressive agent, speaking to a complex interaction the common exposures in these industries is the use o
between the immune system and an immune clonal organic solvents.21
population.11
Inectious Exposure Liestyle and Family History

Higher body mass index in young adults has been
Inectious agents associated with development o
described as a risk actor or DLBCL.19 Family history
aggressive B-cell NHLs include HIV, EBV, human her-
o NHL is also a potential risk actor or some types o
pesvirus type 8, and human T-cell lymphotropic virus
NHL. Individuals who have relatives with NHL may
type 1.12 The greatest actor involved in the worldwide
be at a slightly higher risk o acquiring NHL, but data
increase in NHLs, although lessened with the advent
are inconclusive and mechanisms are unclear.22
o highly active antiretroviral therapy, is HIV inec-
tion. The risk o NHL is increased by up to 300% in
untreated HIV-inected patients, rising in proportion to
the duration o the HIV inection. Although the risk o CLINICAL PRESENTATION
NHL in HIV-inected patients appears to be decreased
by highly active antiretroviral therapy, the relative The clinical presentation o patients with aggressive
risk o NHL in these patients remains much higher B-cell NHL varies substantially based on histologic
CHAPTER 9
than that or those not inected with HIV. Aggressive type and anatomic site o disease. The likelihood o
B-cell NHLs can occur in HIV-inected patients at any B symptoms, including ever greater than 38 °C, night
stage o inection, but the risk increases as CD4 counts sweats, or weight loss more than 10% o body weight
drop to <100 × 103/μL. In addition, Burkitt lymphoma in the preceding 6 months, increases with NHL aggres-
(BL), DLBCL arising in the CNS, and DLBCL–immu- siveness.23 Approximately 13% to 53% o patients
noblastic variant are considered as AIDS-defning ill- present with these B symptoms, oten with atigue,
nesses.13–15 Further inormation can be ound in the malaise, and pruritus, although these are less common
Chapter 52 on acquired immunodefciency syndrome– initially.24
related cancers. Most patients present with painless lymphadenopa-
EBV also plays a role in lymphomagenesis, in part thy, which is oten frst treated with antibiotics or pre-
because o chronic antigenic stimulation.16 EBV is vir- sumed inection and then eventually lymph nodes are
tually always associated with certain types o NHL, biopsied when lymphadenopathy ails to regress. The
such as endemic BL and extranodal T-cell/natural most common scenario involves a diagnosis based on
killer (NK)-cell lymphoma o nasal type, with many examination o peripheral lymph nodes, which may
other NHL types occasionally positive or EBV. Many be detectable beore internal lymph nodes become
patients with HIV-related lymphomas are coinected enlarged and cause symptoms. Peripheral lymph
by EBV, including HIV-associated primary CNS nodes are not usually painul, unless they enlarge
lymphoma, which is inected in essentially 100% o rapidly or are massive. Symptoms vary with the ana-
cases.17 tomic site o internal lymphadenopathy. Patients with
Hepatitis C virus has been associated with dierent mediastinal lymphadenopathy requently experience
types o B-cell NHL, notably marginal zone lympho- cough, chest pain, and, less commonly, superior vena
mas, lymphoplasmacytic lymphoma, and DLBCL.18,19 cava syndrome. Patients with large nodal masses in
Human herpesvirus type 8 (HHV8) is associated the abdomen or retroperitoneum requently experi-
with primary eusion lymphoma (PEL), which tends ence pain, abdominal ullness, or early satiety. Retro-
to occur in HIV-inected patients, but also occurs less peritoneal lymphadenopathy can cause back pain and
oten in endemic geographic regions (eg, sub-Saharan discomort.
Arica). Human T-cell lymphotropic virus type 1 is Extranodal disease is common in patients with
integrated into the genome o the neoplastic cells o aggressive NHL. The most common extranodal sites
adult T-cell lymphoma/leukemia. are the gastrointestinal (GI) tract, tonsils, and skin,
although the requency o involvement o these sites
varies across reports. Disease in the GI tract can
Toxic Exposure maniest as nonspecifc symptoms, including gastric
Environmental and occupational exposures to toxins obstruction, blood loss with subsequent anemia, or
are associated with an increased risk o NHL. Her- diarrhea. Other extranodal sites include liver, lungs,
bicides have been implicated.20 Occupations held by testes, breasts, ovaries, bones, CNS, and spleen; how-
individuals reported to be at increased risk or NHL ever, aggressive extranodal NHL may involve nearly
include arming, metalworking, orestry, aircrat any organ system.23
CLINICOPATHOLOGIC not otherwise specifed (NOS). However, about 20%

CHARACTERISTICS o cases, are designated as specifc variants o DLBCL.
These variants, are specifed on the basis o distinc-
The current WHO classifcation o lymphoid neo- tive morphologic or immunophenotypic fndings or
plasms has refned the diagnostic criteria or some distinctive biological or clinical issues associated with
entities, detailed the expanding genetic/molecular their diagnoses.26
landscape o numerous lymphoid neoplasms and their
clinical correlates, and reers to investigations leading Diuse Large B-Cell Lymphoma, Not
to more targeted therapeutic strategies. This new clas- Otherwise Specifed
sifcation o large B-cell lymphomas is illustrated in
Table 9–2.1,25 Most cases o DLBCL are designated as Epidemiology
Table 9–2 2016 WHO Classication o Large DLBCL–NOS is the most common type o lymphoma
BCell Lymphoma and accounts or approximately 25% o all NHLs in
the developed world.2
DLBCL, NOS DLBCL–NOS occurs mainly in adults, with a
Morphological variants median age in the sixth decade o lie. Men are aected
Centroblastic slightly more oten than women.2
Immunoblastic
CHAPTER 9
Clinical Presentation
Anaplastic
Other rare variants B-type symptoms or bulky disease occurs in one-third
Molecular subtypes o patients. Nodal presentation is most common, but
extranodal sites are involved in approximately 40% o
Germinal center B-cell subtype
patients (Figs. 9–1 and 9–2), and more than one-third
Activated B-cell subtype o patients have more than one extranodal site o dis-
Other lymphomas o large B-cells ease.27 Slightly more than hal o patients have stage
T-cell/histiocyte-rich large B-cell lymphoma III or IV disease. Bone marrow involvement occurs
Primary diuse large B-cell lymphoma o the central in approximately 10% to 20% o patients.27 DLBCL
nervous system uncommonly involves privileged sites, such as the
Primary cutaneous DLBCL, leg type testes and CNS, o which the latter portends a poorer
prognosis.
EBV-positive DLBCL, NOS
DLBCL associated with chronic inammation
EBV-positive mucocutaneous ulcer
Lymphomatoid granulomatosis
Large B-cell lymphoma with IRF4 rearrangement
Primary mediastinal (thymic) B-cell lymphoma
Intravascular large B-cell lymphomas
ALK-positive large B-cell lymphoma
Plasmablastic lymphoma
HHV8-positive diuse large B-cell lymphoma
Primary eusion lymphoma
High-grade B-cell lymphoma
High-grade B-cell lymphoma, with MYC and BCL2
and/or BCL6 rearrangements
High-grade B-cell lymphoma, NOS
B-cell lymphoma, unclassifable
B-cell lymphoma, unclassiable, with eatures
intermediate between DLBCL and
Classic Hodgkin lymphoma
DLBCL, diuse large B-cell lymphoma; EBV, Epstein-Barr virus; HHV, human
herpesvirus; NOS, not otherwise specied. FIGURE 9–1 Computed tomography scan showing diuse
Reproduced with permission rom rom Swerdlow SH, Campo E, Harris NL, et al: large B-cell lymphoma with extensive lymph node involve-
WHO Classifcation o Tumors o Haematopoietic and Lymphoid Tissues, 4th ed.
IARC, Lyon; 2017.
ment in the neck.
CHAPTER 9
FIGURE 9–2 Computed tomography scan showing diuse
large B-cell lymphoma as a periorbital mass.
Interestingly, patients with limited-stage DLBCL

tend to present a pattern o continuing relapse ater
completion o therapy, likely a result o biological
dierences between limited- and advanced-stage
lymphoma.28
FIGURE 9–3 Diuse large B-cell lymphoma. A. The neoplas-
Microscopic Morphology tic cells are large with vesicular chromatin and are arranged
in a diuse pattern. B. The neoplastic cells are positive or
DLBCL is defned as a neoplasm with a diuse growth CD20. (A, hematoxylin-eosin, ×1000; B, immunohistochem-
pattern composed o medium-size or large B cells istry, ×400.)
whose nuclei are the same size as, or larger than, the
nuclei o normal macrophages, or more than twice the
size o normal lymphocytes.25
Morphologic, biologic, and clinical studies have
subclassifed DLBCLs into subtypes and distinct enti-
ties, as illustrated in Table 9–2. However, there remain
many cases that may be biologically heterogeneous,
or which there are no universally accepted criteria or
subdivisions. These cases are classifed as DLBCL–NOS
(Figs. 9–3 and 9–4).25
The most common morphologic variant is the cen-
troblastic variant. Centroblasts are medium to large
lymphoid cells with oval to round, vesicular nuclei
containing fne chromatin and two to our membrane-
bound nucleoli.
The immunoblastic variant (Fig. 9–5) represents
about 10% o all cases o DLBCL–NOS and is com-
posed o more than 90% immunoblasts, defned as a
large cell with a central round nucleus and a prominent FIGURE 9–4 Diuse large B-cell lymphoma. Fine-needle
single, centrally located nucleolus. One study demon- aspiration o cervical lymph node. The neoplastic cells are
strated that DLBCL with immunoblastic variant more large (compared with neutrophils in eld) with abundant
oten demonstrated MYC rearrangement (13 o 39 basophilic cytoplasm (Wright-Giemsa, ×1000).
MYC, BCL2, and Double-Expressor Lymphoma

Immunohistochemistry is also commonly used to
detect MYC expression in DLBCL cases. MYC is
detected in 30% to 50% o cases o DLBCL using a
40% cuto (which is most commonly used in the lit-
erature). MYC expression correlates loosely with the
presence o MYC rearrangement. Concomitant expres-
sion o BCL2 (50% cuto) and MYC occurs in 20% to
35% o cases o DLBCL, and this is known as a dou-
ble-expressor phenotype or “double-expressor lym-
phoma.” The incidence o double protein expression is
estimated to be 19% to 34%.30 Most o these tumors
do not carry MYC/BCL2 chromosomal alterations. In
most studies, the double-expressor lymphomas are
FIGURE 9–5 Diuse large B-cell lymphoma, immunoblastic
more requently o the ABC subtype and have a worse
variant. The neoplastic cells are large with prominent central outcome than other DLBCL–NOS, but they oer
nucleoli imparting a “target-like” appearance (hematoxylin- a better outcome than aggressive B-cell lymphoma
eosin, ×1000). with rearrangements o MYC and BCL2 and/or BCL6.
CHAPTER 9
Overall, double expression o MYC and BCL2 proteins

without gene aberrations is be considered a prognos-
immunoblastic DLBCLs including 10 with MYC rear- tic indicator in DLBCL–NOS, but is not considered a
rangement as a single hit compared with 5 o 68 non- separate category.1,31–34
immunoblastic DLBCLs).29 Some studies have ound
an adverse impact o immunoblastic morphology.
The anaplastic variant represents 2% to 3% o all Genetic Prole
cases o DLBCL and is characterized by large to very
large cells with bizarre pleomorphic nuclei, which may Common somatic mutations in DLBCL are inactivat-
resemble partially Hodgkin/Reed-Sternberg cells or ing mutations o TP53 and genes involved in immu-
the neoplastic cells o anaplastic large cell lymphoma. nosurveillance (B2M, CD58), alterations in epigenetic
CD30 is oten expressed by the neoplastic cells o the regulators (CREBBP/EP300, KMT2D/C [MLL2/3], MEF
anaplastic variant.25 2B), and oncogenic activation o BCL6.1
There are also rare morphologic variants including DLBCLs are heterogeneous at the molecular level.
cases with myxoid stroma, fbrillary matrix, signet ring A subset o cases carries the t(14;18)(q32;q21) involv-
morphology, spindle-cell morphology, and microvil- ing BCL2, as shown by conventional cytogenetic or
lous morphology (by electron microscopy). Because o molecular studies.35,36 Another subset o DLBCLs has
the rarity o those variants, their clinical signifcance translocations or other abnormalities involving BCL6
is unclear, but occasionally these unusual morphologic at chromosome 3q27. BCL6 is rearranged in approxi-
eatures might create diagnostic challenges. mately 20% to 40% o DLBCLs, more oten in tumors
arising at extranodal sites.37 MYC translocation occurs
in 10% to 15% o DLBCL cases.
Immunophenotype
Immunophenotypic studies have shown that DLB-
Cell o Origin
CLs are o mature B-cell lineage. Approximately two-
thirds o cases express monotypic immunoglobulin The WHO classifcation recommends determining
(Ig). These tumors express pan–B-cell markers such the COO in all cases o DLBCL. The best approach
as CD19, CD20, CD22, CD79a, and PAX5, although is to use gene expression profling (GEP) methods,
occasionally the neoplasm might demonstrate an aber- which requires resh tissue to extract RNA. A number
rant loss o one o the pan–B-cell markers. About 60% o studies using this approach was published about
to 70% o DLBCL–NOS cases express BCL2, and a 20 years ago, but the most popular system classifed
40% to 60% subset is positive or CD10 and BCL6. cases into germinal center B-cell (GCB), activated
The Ki-67 prolieration index is high, usually more B-cell (ABC), and an unclassifed group, the latter rep-
than 40% and may be even as high as more than 90% resenting about 15% o all cases. This COO classifca-
in some cases. p53 is expressed in more than 50% o tion not only defned subgroups with distinct biology
cells in 20% to 60% o cases.25 Immunohistochemistry and pathogenesis, but in many studies (but not all)
also can be used to determine cell o origin (COO; see identifed groups o patients with dierent outcomes
below). ater therapy. 38
Although the COO classifcation was an important

A
frst step, more recent studies have shown the limita-
tions o this system, which is not sufciently precise.
Studies by Schmitz and colleagues and Chapuy et al.
showed our and fve groups, respectively and a recent
study by Conley et al showed six groups, with one
divided into two subgroups: MCD, N1, A53, BN2,
EZB MYC+, and EZB MYC–. Analysis o genetic path-
ways suggested that MCD and BN2 DLBCLs rely on
“chronic active” B-cell receptor signaling that will be
amenable to therapeutic targeted inhibition.39,40 Out-
side a clinical trial, these genetic groups do not have
currently therapeutic consequences.
Nevertheless, in our opinion, this system will likely
be refned and applied to cases o DLBCL in routine
practice, although this approach may take some time B
to institute. Recent technologies such as Nanostring
assays (Nanostring) will likely acilitate this progress.41
Because gene expression profling is not available
CHAPTER 9
in many laboratories, immunohistochemistry surro-
gates are considered acceptable using markers such as
CD10, MUM-1, BCL6, GCET1, and FOXP1. The most
popular system is the one proposed by Hans and col-
leagues, which used CD10, MUM-1, and BCL6, and
subclassifes DLBCL groups into germinal center B-cell
subtype (GCB) and non-GCB, with relatively good
concordance with GEP.42,43
Other Lymphomas o Large B Cells FIGURE 9–6 T-cell/histiocyte-rich large B-cell lymphoma. A.
T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Scattered large neoplastic lymphoid cells in a background o
numerous small lymphocytes. B. The large neoplastic cells
T-cell/histiocyte-rich large B-cell lymphoma are positive or CD20, and the small lymphocytes are T cells
(THRLBCL) accounts or less than 5% o DLBCL and is (immunostain not shown). (A, hematoxylin-eosin, ×630]; B,
a diuse neoplasm in which most o the cells are reac- immunohistochemistry, ×200.)
tive T cells and histiocytes. The large, neoplastic B cells
represent less than 10% o all cells in the infltrate (Fig.
9–6). THRLBCL requently harbors genetic mutations DLBCL develop contralateral tumors and parenchymal
in JUNB, DUSP2, SGK1, SOC1,or CREBBP.26 Patients brain lesions. Interestingly, dissemination to extraneu-
with THRLBCL commonly have a history o nodular ral sites is rare.25
lymphocyte-predominant Hodgkin lymphoma, and Patients present ocal neurologic defcits in 56% to
THRLBCL may represent a transormation event in 70% o cases and other signs and symptoms include
some patients.25,44 mental and behavioral alteration, intracranial pressure
symptoms, and seizures.26
Although these lymphomas are remarkable or their
Primary Diuse Large B-Cell Lymphoma o the
unique clinical presentation, histologically and at the
Central Nervous System
immunophenotypic level, these neoplasms closely
This entity includes DLBCL arising within the brain, resemble other cases o systemic DLBCL. The neo-
spinal cord, leptomeninges, or eye. It notably excludes plasm demonstrates pan–B-cell markers such as CD19,
lymphomas o the dura, intravascular large B-cell lym- CD20, CD22, CD79a, and PAX5. Most cases are posi-
phoma, and lymphomas with evidence o systemic tive or BCL6 and IRF4/MUM1, whereas only a small
disease. Primary DLBCL o the central nervous sys- proportion (<10%) o neoplasms is positive or CD10.
tem (PCNSL) accounts or less than 1% o all NHL and The Ki-67 prolieration rate is usually high (>70%), and
2.4% to 3% o all brain malignancies. Approximately BCL2 and MYC expression is common (>80%). EBV
20% o patients present with or develop intraocular inection is consistently absent. Central nervous sys-
lesions and 80% to 90% o patients with intraocular tem (CNS) DLBCLs show a high prevalence o MYD88
mutations and CDKN2A biallelic loss and alteration which contains mostly large cells.1,25 Geographical
o the B-cell receptor/toll-like receptor/NF-κB path- necrosis is common, and the neoplastic cells usually
ways.45 PCNSL may be considered a post–germinal have a non–GCB immunophenotype. The lymphoma
center disease associated with the ABC-DLBCL type cells express B-cell markers such as CD19, CD20,
in origin.46 Approximately one-third o the cases dem- CD22, and CD79. CD30 is expressed in about 40%
onstrate translocations involving BCL6. o cases.52
In HIV-positive patients, DLBCL arising in the brain The prognosis o EBV-positive DLBCL tends to
is an AIDS-defning malignancy. These neoplasms di- be signifcantly worse in older adult patients than in
er rom cases o PCNSL in which a history o immu- young-adult patients.53
nodefciency is not accepted. In HIV-associated DLBCL
o the brain, CD4 counts in aected patients are com- Diuse Large B-Cell Lymphoma Associated With
monly less than 50 cells/μL. The neoplastic cells oten Chronic Infammation
have immunoblastic cytologic eatures and are posi-
tive or EBV.47 However, the incidence o DLBCL in The prototype DLBCL associated with chronic inam-
patients living with HIV has declined with widespread mation (DLBCL-CI) is known as pyothorax-associated
adoption o antiretroviral therapy.48 lymphoma. These neoplasms typically develop in
patients with a longstanding (oten >10 years) history
Primary Cutaneous Diuse Large B-Cell o therapeutically-induced pyothorax as part o treat-
ment or pulmonary tuberculosis. These neoplasms
Lymphoma, Leg Type
CHAPTER 9
are oten large with a poor prognosis. This type o

Primary cutaneous diuse large B-cell lymphoma, leg lymphoma occurs worldwide but appears to be more
type (PCLBCL-LT), as the name suggests, presents as common in Japan and China.25
cutaneous lesions without extracutaneous disease. A second group o cases included in the DLBCL-CI
PCLBCL-LT, originally described in the lower extremi- are very dierent. These neoplasms are small, oten
ties, presents in legs in 85% to 90% o patients. microscopic in size, and arise at sites o chronic inam-
However, all skin sites may be aected. PCLBCL-LT mation, such as chronic osteomyelitis, metallic implant
accounts or 4% o all primary cutaneous B-cell lym- insertion, surgical mesh implantation, and chronic skin
phomas.25,49 Lesions are oten red or blue-red and venous ulcer.54 Another name proposed or these neo-
eventually become diuse and ulcerated. Histologic plasms is fbrin-associated lymphoma.
sections show diuse sheets o monotonous neoplastic DLBCL-CI (both groups) is composed o large cells
cells, oten with immunoblastic morphology with re- with centroblastic, immunoblastic, or, less commonly,
quent mitotic fgures.50 The neoplastic cells are positive anaplastic eatures.26 Most cases express CD20 and
or CD20, CD79a, BCL2, IRF4/MUM1, FOXP1, and CD79a; some cases show CD30 expression. Many
monotypic Ig. Up to 80% o cases are MYC positive cases show plasmacytic dierentiation; in some cases
and about two-thirds o cases have a double-expressor the plasmacytic dierentiation becomes so prominent
immunophenotype. Fluorescence in situ hybridization that the neoplasm shows loss o CD20 and/or CD79a
(FISH) studies can show rearrangements o MYC in up and acquires IRF/MUM1 and CD138. DLBCL-CI are
to one-third o cases.26,51 uniormly EBV-positive and are believed to arise rom
post–germinal center B cells in a hypoxic and perhaps
immune protected environment.
Epstein-Barr Virus–Positive Diuse Large B-Cell
Lymphoma, Not Otherwise Specied
Epstein-Barr Virus–Positive Mucocutaneous
This nomenclature replaces EBV-positive DLBCL
Ulcer
o the elderly because this neoplasm may occur in
younger patients. However, this lymphoma occurs EBV-positive mucocutaneous ulcer (EMCU) pres-
usually in individuals older than 50 years, with a peak ents with isolated circumscribed ulcerative lesions,
in the eighth decade o lie. This neoplasm accounts typically in patients with age-related or iatrogenic
or 10% to 15% o DLBCLs among Asian and Latin immunosuppression. EMCU is associated with deec-
American patients and less than 5% o Western tive host immunosurveillance o EBV inection. The
patients. The increased incidence o this lymphoma lesions are most common in the oral mucosa but may
in the elderly is believed to be related to physiologic also occur in the skin or in the GI tract. The lesions
immunosenescence. Histologically, these neoplasms contain a polymorphous inammatory infltrate mixed
have a diuse pattern and show a spectrum o ea- with scattered EBV-inected B cells, which requently
tures, and two morphologic variants are recognized: include cells resembling Hodgkin/Reed-Sternberg cells
polymorphous, with a broad range o B-cell matura- morphologically and immunophenotypically (CD30+,
tion in the reactive background, and monomorphous, CD15+/–).25,55,56
Lymphomatoid Granulomatosis approximately 80% o cases but is usually weak and

heterogeneous. PD-L1/PD-L2 is positive in approxi-
Lymphomatoid granulomatosis (LYG) is an angiocen-
mately 50% to 75%. CD10 positivity is less com-
tric and angiodestructive lymphoprolierative disease,
mon (∼25%).
composed o EBV-positive CD20+ B cells and reactive
Major pathways involved in the pathogenesis o
T cells. This entity is EBV-driven and can present in
PMBL include the NF-κB, cell cycle dysregulation, apop-
a subset o patients with underlying immunodef-
tosis, JAK-STAT, and immune evasion pathways. Major
ciency, such as in Wiskott-Aldrich syndrome, X-linked
genetic alterations involving the NF-κB pathway include
lymphoprolierative syndrome, and other conditions
amplifcation o REL (∼75%) and BCL11A (∼50%).
linked to immunodefciency.
Gains/amplifcation o chromosome 9p24.1, the site o
Patients with LYG typically present with extrano-
JAK2 as well as PD-L1 and PD-L2, are also common
dal disease, almost always in the lungs, ollowed by
(∼70%).25,26 Decreased expression o HLA molecules,
the CNS, skin, liver, mediastinum, adrenal glands,
CD58, and other immune recognition molecules on
kidneys, and breasts. Bone marrow and lymph node
the surace o the lymphoma cells as a result o molec-
involvement are rare.57
ular alterations (eg, mutations, translocations o CIITA)
Histologically, LYG is characterized by atypical large
are also common.
B cells in a pleomorphic background o lymphocytes,
plasma cells, and histiocytes. Angiocentricity and
necrosis are common. Histologic grading o LYG ranges Intravascular Large B-Cell Lymphoma
rom I to III and is based on the number and density o
CHAPTER 9
Intravascular large B-cell lymphoma (IVLBCL) is a rare
EBV-positive atypical B cells and degree o coagulative
neoplasm that is mostly confned within the lumina
necrosis.58 The clinical behavior ranges rom indolent
o small- to medium-sized blood vessels, particularly
process to aggressive large B-cell lymphoma.1,59
capillaries (Fig. 9–7). In general, larger blood arteries
and veins are not involved. There are three clinical
Large B-Cell Lymphoma with IRF4 variants o IVLBCL: classic, hemophagocytic syn-
Rearrangement drome–associated, and cutaneous. Patients with the
This neoplasm is characterized by strong expression classic orm (mostly present in Western countries)
o MUM1/IRF4 and is associated with chromosome present nonspecifcally with B symptoms and organ-
6p25/IRF4 rearrangement. The histologic pattern can related maniestations, particularly involving the CNS
be ollicular, ollicular and diuse, or entirely di- and the skin. The hemophagocytic syndrome–associ-
use. These neoplasms represent 0.05% o all cases o ated orm is characterized by pancytopenia, hepato-
DLBCL, and aected patients are usually children and splenomegaly, multiorgan ailure, and bone marrow
younger adults with a median age o 12 years (range, involvement. An isolated cutaneous variant, identi-
4–79). fed invariably in Western emales, is characterized by
Patients generally present with localized disease restriction o the tumor to the skin and is associated
involving head and neck lymph nodes or components with a better prognosis. The lymphoma cells express
o Waldeyer ring. These neoplasms are composed o pan–B-cell markers and most cases have a complex
medium or large cells that can exhibit blastoid ea- karyotype, with chromosome 1 commonly involved
tures, usually without starry-sky pattern. BCL-6 and in 72% o cases.25,26
CD10 are usually positive, supporting a germinal cen-
ter B-cell immunophenotype.25,26 ALK-Positive Large B-Cell Lymphoma
ALK-positive large B-cell lymphoma (ALK+ LBCL)
Primary Mediastinal (Thymic) B-Cell Lymphoma
accounts or less than 1% o all cases o DLBCL.
Primary mediastinal (thymic) B-cell lymphoma These neoplasms are more common in young men
(PMBL) accounts or 2% to 3% o all NHLs and 6% (median age, 43 years) and present with nodal and/
to 10% o all DLBCL. The median age o diagnosis or extranodal disease. Approximately 60% o patients
is 35 to 37 years, and women are aected more than present with stage III/IV disease. By defnition, the
men. 60 Patients present with an oten-bulky medias- neoplastic cells express ALK and have a plasmablastic
tinal mass, potentially leading to compressive symp- phenotype, positive or plasma cell–associated mark-
toms, including superior vena cava syndrome. The ers that are usually positive, including CD138, VS38,
lymphoma cells have round or pleomorphic nuclei IMUM-1/IRF-4, XBP-1, and BLIMP-1. Other pan–B-
and Reed-Sternberg–like cells may be observed cell markers (CD20, CD79a, and PAX5) are usually
occasionally. The lymphoma cells are positive or negative or show only ocal and weak expression.
pan–B-cell antigens, BCL-6 (∼95%), MUM-1/IRF-4 IPI score and Ann Arbor stage are signifcant risk
(∼95%), and MYC (∼65%); CD30 is positive in actors. 61,62
CD45 (LCA) and most pan–B-cell markers. Many cases

A
show expression o CD30 and Epithelial Membrane
Antigen (EMA). CD79a is positive in 40% to 50% o
cases. The Ki-67 prolieration rate is usually over 90%.
In situ hybridization or EBV-encoded RNA (EBER) is
positive in about 70% o cases.25,26
HHV8-Positive Diuse Large B-Cell Lymphoma,

Not Otherwise Specied
HHV8+ DLBCL–NOS is an extremely aggressive and
rare disease. Approximately 50% o patients are HIV+.
Notably, patients with HIV+ HHV8+ multicentric
Castleman disease are at 15 times higher risk o devel-
oping HHV8+ DLBCL. However, most oten, HHV8+
B DLBCL–NOS arises in association with HHV8+
multicentric Castleman disease, but very rarely neo-
plasms present de novo without known Castleman
disease. Lymphadenopathy occurs in about 80% o
CHAPTER 9
patients and disseminated disease, hepatomegaly, and

splenomegaly may occur. Moreover, coexistent Kaposi
sarcoma may occur. Patients have an aggressive clini-
cal course and oten a poor prognosis. HHV8+ DLBCL
is composed o sheets o plasmablasts that disrupt
normal architecture, sometimes with a background o
multicentric Castleman disease. In addition to HHV8,
the lymphoma cells are positive or cytoplasmic IgM
and lambda. HHV8 virus induces B-cell receptor revi-
sion to lambda, with CD20, CD38, CD45, or CD79a
positive in subsets o cases. Unlike PEL, HHV8+
FIGURE 9–7 Intravascular large B-cell lymphoma involv-
DLBCL–NOS are EBV-negative.25,26
ing bone marrow. A. Large neoplastic cells are present with
a small blood vessel. B. The anti-CD20 antibody highlights
numerous large neoplastic cells within many blood vessels. Primary Eusion Lymphoma
(A, hematoxylin-eosin, ×1000; B, immunohistochemistry,
×400.) PEL is a human herpesvirus 8 (HHV8)-driven malig-
nancy that involves the pleural, pericardial, or peritoneal
cavities without usually orming a mass. Extracavitary
PEL reers to a solid neoplasm that has characteristics
similar to conventional PEL.
In the United States, most PEL patients are HIV-pos-
Plasmablastic Lymphoma
itive adult men; ew are HIV-negative patients, notably
Plasmablastic lymphoma (PBL) represents less than in the posttransplant or physiologic immunosenes-
1% o all cases o DLBCL and occurs commonly in cence setting. Patients with conventional PEL present
the setting o immunodefciency. PBL commonly pres- with symptoms associated with an eusion. The GI
ents in patients with HIV inection and represents tract and lymph nodes are most requently involved by
approximately 3% o HIV-related lymphomas. PBL extracavitary PEL.
can also occur in patients ater allogeneic transplant PEL cells are pleomorphic, resembling immuno-
and in patients with other orms o immunodefciency, blasts, plasmablasts, or anaplastic cells with Hodgkin/
including physiologic immunosenescence. The most Reed-Sternberg–like eatures. Moreover, PEL cells usu-
requent sites o involvement include the oral/nasal ally lack pan–B-cell markers such as CD19, CD20, and
cavity and the GI tract. CD79a, but are positive or HHV8, MUM-1/IRF-4 (up
PBL is composed o immunoblast- or plasmablast- to 100%), CD38 (up to 100%), CD45 (>80%), CD138
like cells with variable degrees o plasmacytic di- (35%–75%), and CD30 (>50%). These neoplasms
erentiation. The neoplastic cells are usually positive have an ABC/non-GCB immunophenotype. Interest-
or plasma cell markers such as CD38, CD138, IRF/ ingly, extracavitary PEL more oten expresses CD20 or
MUM1, BLIMP1, and cytoplasmic Ig, and negative or CD79a.25,26
Table 9–3 Diagnostic Table or the Diferential Diagnosis o HighGrade BCell Lymphomas
B-Lymphoblastic HGBL
Leukemia/Lymphoma HGBL, NOS DLBCL DHL/THL BL
Blastoid Yes Yes Yes
DLBCL Yes Yes
DLBCL/BL Yes Yes Yes
Morphology BL Yes
TdT Positive Negative
CD10 Positive Positive
BCL6 Negative Positive
CCND1 Negative Negative
BCL2 Negative
IHC Ki-67 ~100%
No DH Yes Yes
SH MYC-IG Yes
FISH DH/TH Yes Yes
CHAPTER 9
BL, Burkitt lymphoma; CCND1, c-terminal Cyclin D1; DH(L), double-hit (lymphoma); DLBCL, diuse large B-cell lymphoma; IHC, immunohistochemistry; FISH,
uorescence in situ hybridization; HGBL, NOS, high-grade B-cell lymphoma, not otherwise specied; SH MYC-IG, single-hit with IG/MYC usion but no translocation
involving BCL2, BCL6, or CCND1; TdT, Terminal deoxynucleotidyl transerase; TH(L), triple-hit (lymphoma).
Data rom Swerdlow SH, Campo E, Harris NL, et al: WHO Classifcation o Tumors o Haematopoietic and Lymphoid Tissues, 4th ed. IARC, Lyon; 2017 and Swerdlow SH,
Campo E, Pileri SA, et al: The 2016 revision o the World Health Organization classication o lymphoid neoplasms, Blood 2016 May 19;127(20):2375-2390.
High-Grade B-Cell Lymphoma cytomorphology. Unlike B-cell lymphoblastic leuke-

mia/lymphoma, staining or terminal deoxynucleo-
High-grade B-cell lymphoma (HGBL) is a subset o very tidyl transerase is negative and, unlike the blastoid
aggressive tumors with eatures intermediate between variant o mantle cell lymphoma, cyclin D1 is nega-
DLBCL and BL, or with a blastoid appearance, as illus- tive (Table 9–3, Fig. 9–8).
trated in Table 9–3. These lymphomas are o mature B-cell lineage
with expression o CD19, CD20, CD79a, and PAX5.
High-Grade B-Cell Lymphoma, With MYC and
Rearrangements, usually as a result o translocations,
BCL2 and/or BCL6 Rearrangements occur in MYC (chromosome 8q24), BCL2 (chromo-
HGBL with MYC and BCL2 and/or BCL6 rearrange- some 18q21), and/or BCL6 (chromosome 3q27).
ments, also called “double-hit lymphoma” and “tri- These lymphomas are predominantly observed in the
ple-hit lymphoma” (DHL and THL), are aggressive GCB subset o DLBCL. Lymphoma with both MYC
lymphomas that account or around 7% to 10% o and BCL6 translocations (MYC/BCL6) is likely a di-
DLBCL. erent disease biologically compared with DHL with
Similar to DLBCL, these lymphomas present mostly MYC/BCL2 translocations. Indeed, MYC/BCL6 lym-
in the sixth to seventh decade o lie. More than hal phoma is much less common and more likely to be o
o patients present with Ann Arbor stage IV and more ABC/non-GCB type. Interestingly, MYC/BCL2 DHL
than one extranodal site o disease, notably with CNS requently exhibits TP53 mutations, whereas MYC/
involvement in up to 45% o cases. BCL6-rearranged lymphomas do not. THL has a prog-
At least hal o DHL and THL have the morphol- nosis comparable with DHL.30 Most double-hit lym-
ogy o DLBCL–NOS, and starry-sky macrophages phomas have a double-expressor phenotype, but the
may be present. The number o mitotic fgures and reverse is not true.25
apoptotic fgures are highly variable, occasionally At MDACC, we routinely perorm FISH studies
with a somewhat low (50%–70%) Ki-67 proliera- or MYC rearrangement on all new cases o DLBCL,
tion index. Another subset o DHL and THL shows irrespective o Ki-67 index. I MYC rearrangement is
a morphology with eatures intermediate between detected, additional FISH studies or BCL2 and BCL6
DLBCL and BL. For these cases, starry-sky macro- rearrangements are perormed. I a lymphoma does
phages are generally present, with many mitotic fg- not demonstrate MYC rearrangement, no additional
ures. Other cases o DHL and THL can have a blastoid studies are required.
A B C
FIGURE 9–8 High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements. Similar to Burkitt lymphoma, the
neoplastic cells are intermediate-sized and demonstrate brisk mitotic activity, but unlike Burkitt lymphoma, cells have promi-
nent single nucleoli (A). Although the prolierative rate is similar to Burkitt lymphoma (B), the neoplastic cells strongly express
BCL2 (C). In this case, fuorescence in situ hybridization detected both translocations t(8;14) and t(14;18), so-called double-hit
lymphoma (lymph node; A, hematoxylin-eosin, ×1000; B, Ki-67 (Mib-1), ×400; C, BCL2, ×400).
High-Grade B-Cell Lymphoma, Not Otherwise Immunophenotype does not appear to dier based on
Specied presentation with MGZL versus NMGZL disease.63
CHAPTER 9
GZL is a highly heterogeneous disease harboring

HGBL–NOS is a rare and heterogeneous category with somatic driver events shared with PMBL and cHL.
cases that appear with blastoid cells and cases that Chromosomal aberrations in GZLs show gains includ-
appear intermediate between DLBCL and BL. About ing amplifcations in 2p16.1 (REL/BCL11A locus) in
20% to 35% o cases have a MYC rearrangement, but 33% o all cases, alterations o the JAK2/PDL2 locus
by defnition lack BCL2 and/or BCL6 rearrangement in 9p24.1 in 55%, rearrangement o the CIITA locus at
(Table 9–3). Some cases show increased copy num- 16p13.13 in 27%, and gains o 8q24 (MYC) in 27%.64,65
bers o BCL2 or, rarely, amplifcation o 18q21 involv- These lymphomas are oten aggressive and resistant
ing BCL2. In addition, some cases demonstrate BCL2 to chemotherapy, and patients have worse outcomes
rearrangement and increased copy numbers o MYC than patients with either cHL or PMBL.64,66
gene.1,25
Burkitt Lymphoma
B-Cell Lymphoma, Unclassifable, With
There are three variants o BL: endemic (Arican),
Features Intermediate Between DLBCL
sporadic (nonendemic), and immunodefciency-asso-
and Classic Hodgkin Lymphoma ciated. Endemic BL occurs in equatorial Arica and in
B-cell lymphoma, unclassifable, with eatures inter- Papua, New Guinea, and is associated with EBV inec-
mediate between DLBCL and classical Hodgkin lym- tion in 95% to 100% o patients. The peak incidence
phoma (cHL) is also known as grey-zone lymphoma is at 4 to 7 years and the male-to-emale ratio is 2–3:1.
(GZL). These neoplasms are very rare and not precisely Jaw and acial bones lesions are present in about 50%
defned as o this writing. The median age o patients o patients. Mesentery, gonads, and CNS are other
is around 40 years, with males more commonly common sites o presentation.
aected. Mediastinal GZL (MGZL) is most common, Sporadic BL occurs worldwide, accounts or 1% to
and patients present with a large anterior mediastinal 2% o lymphomas in the United States and is associ-
mass. Nonmediastinal GZL (NMGZL) oten presents ated with EBV inection in 25% to 40% o patients.
in older patients and tends to be a more advanced- Patients are usually in their third decade o lie, but
stage disease with higher IPI score.63 there is also an incidence peak in the elderly. The male-
Morphologically, cases o GZL tend to be tumor to-emale ratio is 2–3:1. Clinical presentation most
cell–rich and can be urther divided into two subtypes: requently involves the ileocecal region, and less com-
cases in which the neoplastic cells morphologically monly the bone marrow, ovaries, kidneys, breasts or
resemble Hodgkin and Reed-Sternberg cells, and cases CNS.
morphologically resembling DLBCL/PMBL. Cases BL can also occur in the clinical setting o immu-
morphologically resembling cHL usually show CD45 nosuppression, including HIV inection (urther
(LCA) positivity and strong expression o pan–B-cell inormation in Chapter 52), post transplant, or con-
markers such as CD20, CD22, CD79a, PAX5, OCT2, genital immune defciency. In HIV-inected patients,
and BOB1. Cases morphologically resembling DLBCL/ BL appears oten when CD4+ T-cell counts are still in
PMBL may show loss o some pan–B-cell markers or the normal range or low, but not extremely low, and
CD45 but demonstrate positivity or CD15 and CD30. the risk o developing BL persists in spite o highly
A B C
FIGURE 9–9 Burkitt lymphoma. A. The neoplastic cells are intermediate in size, similar to that o benign histiocyte nuclei, with
multiple small nucleoli. A “starry-sky” pattern is also seen in this eld. B and C. The neoplastic cells are negative or BCL2 (B) and
are over 99% positive or Ki-67 (C). (A, hematoxylin-eosin, ×1000; B-C, immunohistochemistry, ×400.)
active antiretroviral therapy. EBV inection occurs in actor 3 (TCF3) or its own negative regulator ID3 occur
25% to 40% o cases. A nodal presentation is most in approximately 70% o sporadic and immunode-
common, with occasional bone marrow involvement. fciency-related BL and 40% o endemic cases. TCF3
CNS dissemination can occur as well.67 Burkitt leuke- promotes survival and prolieration in lymphoid cells
mia variant tends to involve the CNS at diagnosis or by activating the B-cell receptor/phosphatidylinositol
CHAPTER 9
early in the disease course. 3-kinase (PI3K) signaling pathways and modulating
In general, all variants o BL show similar morpho- the expression o cyclin D3, which is also mutated in
logic eatures. At low power, clear tingle-body mac- 30% o BL.1,25,67
rophages in the background o deep-blue lymphoma
cells impart a “starry-sky” appearance. The neoplastic Burkitt-Like Lymphoma With 11q Aberration
cells are typically intermediate in size and relatively
homogeneous, with basophilic cytoplasm containing Burkitt-like lymphoma with 11q aberration (BLL-11q)
small vacuoles and round nuclei. The neoplastic cells is a lymphoma that closely resembles BL but lacks
in sporadic cases might be more pleomorphic; the neo- MYC rearrangement and has some other distinctive
plastic cells in immunodefciency cases can show plas- eatures. Notably, these neoplasms carry a chromo-
macytic eatures. The nuclear chromatin is granular some 11q alteration characterized by proximal gains
with small nucleoli and recurrent mitoses. and telomeric losses. Compared with BL, BLL-11q
All BL types are o mature B-cell lineage and o have more complex karyotypes, lower levels o MYC
GCB origin, expressing surace Ig, pan–B-cell antigens, expression, a certain degree o cytologic pleomor-
CD10, and BCL6.22 Burkitt lymphomas have a very phism, sometimes a ollicular pattern, and requently a
high prolieration rate, approaching 100%, using an nodal presentation. This malignancy may be closer to
antibody specifc or Ki-67 (Table 9–3, Fig. 9–9) and HGBCL or DLBCL than to BL.1,25,68
are negative or BCL2. MYC translocations are typical
o BL; 80% o cases carry the t(8;14)(q24;q32), with the STAGING AND INITIAL EVALUATION
other cases having one o two variant translocations,
t(2;8)(p11;q24) or t(8;22) (q24;q11). Common to each
o these translocations is involvement o chromosome
General Workup
region 8q24, the site o the MYC, which is deregulated. The Ann Arbor Staging system, developed in 1971 or
Via these translocations, MYC is juxtaposed with Hodgkin lymphoma, is used to stage patients with
the IGH or IGK or IGL. Mutations in the transcription NHL (Table 9–4). O interest, there does not appear
Table 9–4 Ann Arbor Staging System or NonHodgkin Lymphomasa
Stage I Involvement o a single nodal group or extranodal site (IE)

Stage II Involvement o two or more nodal groups on the same side o the diaphragm or localized involvement o an
extranodal site or organ (IIE) and one or more nodal groups on the same side o the diaphragm
Stage III Involvement o nodal groups on both sides o the diaphragm, which may be accompanied by localized
involvement o an extranodal region or site (IIIE) o spleen (IIIS) or both (IIISE)
Stage IV Diuse or disseminated involvement o one or more distant extranodal sites
a
Temperature >38 °C, weight loss more than 10% o body weight in the last 6 months, and night sweats preceding diagnosis are dened as “B” symptoms and
designated by the sufx B. Others are designated by the sufx A.
to be any meaningul dierence in the outcomes o is usually high normal metabolic activity within the
patients with stage III or IV disease, and thus the pur- brain, CNS lymphomas are oten positive on FDG-PET
pose o staging is to identiy the patients with localized scans, showing greater metabolic activity than the adja-
NHL who may beneft rom a reduced course o sys- cent brain. However, additional imaging with magnetic
temic therapy and eventual additional local therapy.69 resonance imaging (MRI) is indicated or confrmation.
A careul history and physical examination, includ- Focal bone marrow FDG uptake with or without
ing fndings o systemic symptoms (including B symp- increased diuse uptake is more sensitive than bone
toms), is essential. Perormance status and comorbid marrow biopsy (BMB) or infltration in aggressive
conditions should be assessed. Physical examination B-cell lymphoma and is highly specifc. O note, the
should include a complete survey o all external lymph pattern o uptake within the bone marrow spaces on
node groups including cervical, supraclavicular, axil- FDG-PET is important because a diuse pattern is
lary, epitrochlear, inguinal, and popliteal areas. Exami- commonly seen with activation (eg, with underlying
nation o abdomen or organomegaly is necessary, and anemia or inection, or ater chemotherapy or growth
in men the testes should be examined. A complete neu- actor treatment), and caution should be taken in inter-
rologic examination must also be perormed. Labora- preting this as diuse bone marrow involvement by
tory evaluation includes a complete blood count with tumor. In contrast, ocal or nodular uptake within
dierential diagnosis; lactate dehydrogenase (LDH) osseous structures is suspicious
level; kidney and liver unction tests; albumin, cal- However, low-volume involvement (<10%–20%)
cium, and uric acid levels; pregnancy testing in women and discordant lymphoma may be missed by PET/
CHAPTER 9
o childbearing age; testing or hepatitis B (especially CT imaging, but these positive BMB/negative PET/
indicated beore rituximab therapy, as the virus may CT fndings are lower than 10% (Figure 9-12). There-
reactivate during or ater treatment); hepatitis C; and ore, BMB is no longer required when a PET/CT scan
HIV.70 Serum protein electrophoresis can be considered demonstrates bone or marrow involvement indicating
in some cases.
Let ventricular unction should be assessed by
echocardiogram or multigated acquisition scan. Fertil-
ity-preserving treatments, such as sperm cryopreserva-
tion or males and reerral to a ertility specialist or
emales, should be discussed with eligible patients.70
Imaging Studies and Bone Marrow Evaluation or

Initial Staging
Based on the recent consensus recommendations
or staging and restaging o lymphoma developed
by the clinical and imaging working groups o the
International Conerence on Malignant Lymphomas,
uorodeoxyglucose positron emission tomography/
computed tomography (FDG-PET/CT) scan is recom-
mended as standard practice or staging patients with
DLBCL. Indeed, PET/CT is more sensitive, especially
or extranodal disease, and improves staging accu-
racy and subsequent response assessment69 (Figures
9-10 and 9-11). Moreover, several studies showed that
high baseline total metabolic tumor volume negatively
impacts outcome in DLBCL patients.71
Limitations o PET/CT scan or staging o aggressive
lymphoma include the act that uptake o FDG is not
specifc to tumors and that inection and inammatory
processes are common alse-positive fndings on PET
scans. As a result, an unexpected FDG-avid lesion that
will result in a signifcant change in management should
be confrmed by biopsy. The presence o high normal
background activity in an organ—or example, in the FIGURE 9–10 Positron emission tomography scan showing
kidneys or testes—may also make it difcult to iden- right cervical lymph nodes involved by diuse large B-cell
tiy abnormal FDG sites in that region. Although there lymphoma.
stage IV, but is appropriate in case o negative PET, kidney/adrenal involvement; low risk (0–1 actors),
when its results would change prognosis and treat- intermediate risk (2–3 actors), and high risk (≥4 ac-
ment, especially when a shortened number o immu- tors). In addition, extranodal disease with involvement
nochemotherapy cycles is proposed or as workup o o testicular, uterine, breast, epidural, and skin is a risk
unclear cytopenia.72 actor or CNS. Moreover, the ollowing aggressive
I bone marrow aspiration and biopsy are per- B-cell lymphoma subtypes, such as BL, double-/triple-
ormed, bilateral iliac crest assessment is preerred hit lymphoma/HGBCL, double-expressor lymphomas,
because sensitivity o detection is higher than with HIV-associated lymphoma, non-GCB DLBCL, intra-
unilateral biopsy.73 vascular DLBCL, CD5+ DLBCL, PCDLBCL-LT, and
IgM-secreting DLBCL,75 present increased risk o CNS
involvement.76,77
Specifc Considerations Evaluation o clinical or radiologic suspicion o pri-
Assessment o CNS Disease mary or secondary CNS lymphoma requires lumbar
puncture (unless contraindicated), MRI o the brain
Examination o the cerebrospinal uid (CSF) should be and biopsy o the lesion (preerably a stereotactic
strongly considered or patients with risk actors such biopsy). It is important to withhold corticosteroids
as: elevated CNS-IPI74 (age >60 years, Eastern Cooper- beore biopsy, because they can induce rapid tumor
ative Oncology Group [ECOG] Perormance Status ≥2, shrinkage and prevent an appropriate diagnosis.25
extranodal disease >1 site, stage III/IV, elevated LDH, Moreover, in case o suspected PCNSL, a vigorous
CHAPTER 9
search or additional disease sites, such as testicular
ultrasound or men older than 60 years, ull ophthal-
mologic examination including slit-lamp eye exami-
nation, spine MRI, PET/CT, and BMB should be done
concurrently, because therapy or CNS and systemic
disease will need to account directly or both.78
Involvement o the Gastrointestinal Tract

Lymphomas o the GI tract, especially in the stomach,
require endoscopy or diagnosis unless other disease
sites can be ound to biopsy. It is especially important
that multiple biopsies o dierent areas o the stomach
be obtained because sampling error is requent. There
is no utility to gastrectomy or other surgical manage-
ment or extranodal disease.
Intravascular Large B-Cell Lymphomas

Standard staging workup usually has a high proportion
o alse-negative results because o a lack o detect-
able tumor masses. Random skin biopsies o normal-
appearing skin and transbronchial lung biopsy can be
necessary. Evaluation or CNS disease is recommended
because o the high risk o CNS relapse.25,81
Laboratory abnormalities are requent, particularly
high serum LDH and soluble IL-2 receptor levels.26
FIGURE 9–11 Extranodal lymphoma on FDG-PET/CT. The PROGNOSTIC FACTORS

patient presented with mediastinal lymphoma; this is easily
seen on a maximum intensity projection image rom FDG- Pretreatment
PET/CT. However, an additional ocus is present in the right
kidney; although not conrmed by biopsy, the renal lesion Prognostic actors in patients with aggressive NHL can
disappeared ater chemotherapy, and the stage was changed be broadly grouped into pretreatment (tumor-related)
rom stage I to stage IV. and treatment-related characteristics. Tumor-related
A B
CHAPTER 9
FIGURE 9–12 Bone and bone marrow uptake on FDG-PET/CT. A. Typical pattern o marrow activation, commonly seen ater
chemotherapy or with growth actor treatment. This is diuse but homogenous. In contrast (B), another patient had negative
bilateral iliac crest biopsies but had ocal activity in a destructive lesion involving the right humerus. Directed biopsy o this
site was positive or bone involvement.
genetic characteristics o importance, as noted earlier, to be the most important, with patients over the age o
include GCB or non-GCB origin genetic profle and the 60 years having lower response rates and higher rates
presence o MYC and BCL2 and/or BCL6 transloca- o relapse.82
tions (double-hit lymphomas). The IPI score remains a widely used prognostic
Other tumor-related characteristics reported to model, despite its not accounting or any tumor-specifc
be o prognostic value include a complex karyotype biologic eatures. With rituximab plus chemotherapy–
shown by conventional cytogenetics, high proliera- based disease management, the progression-ree sur-
tion rate (high Ki-67 expression), and BCL2 and/or vival (PFS) and overall survival (OS) rates or DLBCL
MYC expression shown by immunohistochemical patients with IPI, age-adjusted IPI, National Compre-
staining.1 In addition, a study ound that P53 altera- hensive Cancer Network (NCCN)-IPI and Revised IPI
tions correlated with poorer survival and augmented (R-IPI) are shown in Tables 9–5, 9–6, and 9–7.83,84 Com-
the negative prognostic eect o MYC rearrangement, pared with the IPI, the NCCN-IPI better discriminates
expression, or concurrent MYC/BCL2 expression in low- and high-risk subgroups, by refned categoriza-
DLBCL.80 tion o age and LDH, and the identifcation o disease
High serum LDH level is a measure o anaerobic involvement at specifc extranodal sites.84 The NCCN-
metabolism and/or cell turnover and tumor bulk and IPI was shown to better discriminate between patients
is associated with a lower probability o complete with poor and avorable OS compared with the IPI/R-
remission and poorer long-term survival in patients IPI.85 However, even i these data are inormative, they
with aggressive NHL. Other pretreatment prognostic are not reliably predictive o outcomes or an individual
actors include serum β2-microglobulin level, stage, patient and are not validated in routine practice or
number o disease sites, bulky disease, presence o choice o therapy. Nearly hal o patients will have a
bone marrow involvement, poor perormance status, poor-risk R-IPI, and o these patients, approximately
and age.81 O these pretreatment actors, age appears hal will be cured.
Table 9–5 International Prognostic Index and NCCNIPI
Factors IPI NCCN-IPI

Age, years >60 1 >40 to ≤60 1
>60 to <75 2
≥75 3
Serum LDH >normal 1 LDH ratio >1 to 3 1
LDH ratio >3 2
Perormance status 2-4 1 ≥2 1
Extranodal disease >1 site 1 BM, CNS, Liver/GI tract or lung 1
Stage, Ann Arbor III-IV 1 III-IV 1
BM, bone marrow; CNS, central nervous system; GI, gastrointestinal; IPI, International Prognostic Index; LDH, lactate dehydrogenase; NCCN, National Comprehensive
Cancer Network.
Table 9–6 Survival Rates o IPI, AgeAdjusted IPI, and NCCNIPI or Patients With Difuse Large BCell
Lymphoma
International Prognostic Index, Age Adjusted and NCCN-IPI
CHAPTER 9
Group Risk Factors RFS Survival
Score 2 Years (%) 5 Years (%) 2 Years (%) 5 Years (%)
All ages 0–1 79 70 84 73
2 66 50 66 51
3 59 49 54 43
4–5 52 40 34 26
Age adjusted ≤60 0 88 86 90 83

1 74 66 79 69
2 62 53 59 46
3 61 58 37 32
Age adjusted >60 years 0 75 46 80 56

1 64 45 68 44
2 60 41 48 37
3 47 37 31 21
NCCN-IPI risk group Score 5-year PFS (%) 5-year OS (%)

Low 0–1 91 96
Low-intermediate 2–3 74 82
High-intermediate 4–5 51 64
High ≥6 30 33
IPI, International Prognostic Index; NCCN, National Comprehensive Cancer Network; OS, overall survival; PFS, progression-ree survival; RFS, relapse-ree survival
Table 9–7 Survival Rates or Patients With Difuse Large BCell Lymphoma
Revised IPI No. o Factors Present % o Patients 4-Year PFS 4-Year OS

Very good 0 10 94 94
Good 1-2 45 80 79
Poor 3-5 45 53 55
IPI, International Prognostic Index; OS, overall survival; PFS, progression-ree survival.
Prognostic Factors in Primary Central with aggressive B-cell lymphoma be evaluated or a
Nervous System Lymphoma clinical trial at each treatment stage.
Age and LDH level are important prognostic actors in

patients with HIV-negative primary CNS lymphoma; Frontline Therapy
however, the most important actor is perormance
status at the time o treatment. Elevated LDH, CSF Large B-Cell Lymphomas
protein, and tumor mass location(s) are also contribu- R-CHOP remains the backbone o therapy or untreated
tors to prognosis.86 Many patients can improve their DLBCL. However, the total number o cycles and addi-
CHAPTER 9
condition by use o corticosteroids and thus be candi- tion o radiation depends on stage at presentation and
dates or intensive chemotherapy-based regimens that tumor bulk. Abundant eorts to improve R-CHOP,
are potentially curative. including increased dose density with 14-day cycles,
the use obinutuzumab in place o rituximab, or inten-
Therapy-Associated Prognostic Factors sifcation o therapy to, or example, dose-adjusted
(DA) etoposide, prednisone, vincristine, cyclophos-
An important posttreatment prognostic indicator is phamide, and doxorubicin (EPOCH) have been made,
tumor response to induction chemotherapy. In patients but have generally ailed to show signifcant clinical
with aggressive NHL, dramatic response to induction benefts.90–92 Notably, the phase 3 trial Alliance/CALGB
with early complete remission (by the third cycle o 50303 showed that DA-EPOCH-R was more toxic and
therapy) is associated with a superior outcome. FDG- did not improve PFS and OS compared with R-CHOP.
PET has been ound to be highly sensitive or the detec- However, the subgroup analysis showed improvement
tion o aggressive NHL in posttreatment residual masses, o PFS or patients with high IPI (3–5) when treated
but its ability to detect interim therapy response is con- with DA-EPOCH-R.
troversial.87 Moskowitz et al ound that DLBCL patients
with persistent FDG avidity ater our cycles o ritux-
Treatment Option by Stage
imab plus CHOP (R-CHOP) had an 86% alse-positive
rate (PET/CT positive, biopsy negative or persistent Early-Stage Aggressive Non-Hodgkin B-Cell
disease).88 Similar data have been shown by many oth- Lymphoma
ers, highlighting the need or biopsy confrmation o a Therapy o early (localized) stage I and II includes che-
positive PET/CT scan beore therapeutic decisions. moimmunotherapy with R-CHOP administered alone
Patients who ail to achieve at least a good partial or combined with radiation therapy (RT; combined
response to induction chemotherapy have primary modality therapy [CMT]). The choice o chemoim-
reractory disease and an unavorable prognosis. munotherapy alone versus CMT and number o cycles
Another important indicator o prognosis is duration o systemic therapy are inuenced by adverse eects,
o remission obtained ater induction chemotherapy, comorbidities, response to therapy, and personal pre-
because patients with relapses occurring at less than erence. For instance, or patients in whom RT may
one year have a worse outcome.89 cause substantial early toxicity (notably i there is
involvement o the oronasopharynx or pelvis) or late
toxicity (in young women whose breasts would be in
APPROACH TO THERAPY the RT feld), treatment with chemoimmunotherapy
alone can be avored. Inversely, the lower total dose o
There is a diversity o clinical practice surrounding the doxorubicin o an abbreviated course o chemotherapy
preerred treatment approach or patients with aggres- associated with CMT may be preerred or a patient
sive B-cell lymphoma, notably related to its wide with marginal cardiac unction.
pathologies, molecular variations, and clinical behav- The ollowing trials studied the optimal therapy o
iors. At MDACC, our preerence is that all patients early-stage DLBCL, which has to be tailored according
to adverse eatures, size o lesion(s) and response to Alternatively, the NCTN Study S1001 proposed
therapy. PET-directed therapy to improve outcomes and
The FLYER trial showed that in patients with avor- decrease toxicities. Ater three cycles o R-CHOP,
able prognosis (aged 18–60 years, with stage I-II dis- patients with nonbulky (<10 cm), stage I/II, untreated
ease, normal serum LDH, ECOG perormance status DLBCL had an interim PET ater cycle 3. Patients with
0–1, and without bulky disease [max tumor diameter negative PET scan results (Deauville 1–3, interim [i]
<7.5 cm]), our cycles o R-CHOP plus two cycles o PET-negative) proceeded with one additional cycle
rituximab was noninerior to six cycles o R-CHOP o R-CHOP. Patients with positive PET scan results
(Table 9-8), with relevant reduction o toxic eects. (Deauville 4–5, iPET-positive) were initiated 36 Gy o
Ater a median ollow-up o 66 months, 3-year PFS IFRT, plus an additional boost to FDG-avid area up to 9
was 96% with our cycles o R-CHOP versus 94% Gy, within 5 weeks o the third cycle o R-CHOP. This
with six cycles o R-CHOP.95 was ollowed by ibritumomab tiuxetan three to six
Moreover, in the SWOG S0014 trial, patients with weeks ater completing IFRT. NCTN S1001 demon-
limited-stage disease and at least one adverse risk ac- strated that 89% o patients maintained excellent out-
tor as defned by the stage-modifed IPI (nonbulky stage comes ater our ounds o R-CHOP with PET-directed
II disease, age >60 years, WHO perormance status o therapy. Only 11% o patients were iPET-positive
2, or elevated serum LDH) treated with three cycles and required radiation, but they also had excellent
o R-CHOP plus one cycle o rituximab ollowed by outcomes. Together with the FLYER trial in younger
40–46 Gy o involved-feld radiation therapy (IFRT) patient, this NCTN trial may establish a new standard
CHAPTER 9
showed 2-year PFS o 93% and 4-year PFS o 88%. approach to limited-stage disease or the majority o
This study highlighted a pattern o continuing relapse patients.96
likely related likely to biologic dierences between
limited- and advanced-stage lymphoma.28,94 Advanced-Stage Aggressive Non-Hodgkin Lymphoma
In addition, some studies, such as RICOVER-60/ For patients with advanced-stage lymphoma, six cycles
RICOVER-noRTh (6 cycles o R-CHOP plus 2 cycles o o immunochemotherapy are the standard o care, as
rituximab ollowed by IFRT o 36 Gy to sites o initial established by dierent trials. In the MInT study, with
bulky [≥7.5 cm] disease and extralymphatic involve- patients aged 18–60 years with maximal IPI I in stage
ment) report that adding RT to chemoimmunotherapy II–IV disease, or who had stage I disease with bulk,
may improve outcomes or patients with bulky dis- received six cycles o R-CHOP. Bulky and extranodal
ease; however, this is not well proven.95 sites received additional radiotherapy. Ater a median
Table 9–8 Most Commonly Used Chemotherapeutic Regimens in Aggressive BCell Lymphomas
Regimen Dose/Route Days Interval

Frontline
R-CHOP
Cyclophosphamide 750 mg/m2 IV 1 21 days
2
Doxorubicin 50 mg/m IV 1
Prednisone 100 mg PO 1–5
Vincristine 1.4 mg/m2 IV 1
2
Rituximab 375 mg/m IV 1
Salvage (rst salvage, pre-autologous SCT)
R-ICE
Rituximab 375 mg/m2 IV 1 14–21 days
2
Iosamide 5 g/m IV CI 2
Mesna concurrent with iosamide 5 g/m2 IVCI 2 over 24 h, then 2 g/m2 2–3
over 12 h
Carboplatina Maximum 800 mg 2
Etoposide 100 mg/m2 IV 2–4
GCSF 5 μg/kg/day SC 7–14
a
Calculate carboplatin dose using Calvert equation: AUC = 5 g/mL/min; dose = 5 × [25+Clcr] capped at 800 mg.
ollow-up o 34 months, the 3-year event-ree survival CNS prophylaxis in patients with aggressive B-cell
(EFS) was 79% and 3-year OS was 93%.97 lymphoma.
The CNS-IPI represents a robust risk model but
does not integrate high-risk CNS biomarkers such
Treatment Options by Cell o Origin
as rearrangement o MYC and BCL2 (DHL), at-risk
Multiple studies have shown that patients with the extranodal sites such as testicles, or subtypes such as
ABC disease subtype have signifcantly poorer out- IVDLBCL. A retrospective population-based database
comes with standard up ront similar therapy, com- o patients with DLBCL treated with R-CHOP dem-
pared with GCB disease. For instance, in a study o 344 onstrated the ollowing two-year CNS relapse risk
patients with DLBCL treated with R-CHOP that used estimates: CNS-IPI low risk, 0.8%; intermediate risk,
the Lymph2Cx assay on the parafn-embedded tissue 3.9%; and high risk, 12.0%.76
to identiy COO, the 5-year PFS was 48% versus 73%, There is no prospective study integrating all the
and 5-year OS was 56% versus 78%, respectively in previously described risk actors or CNS disease.
ABC disease compared with GCB disease.38,98 However, it can be considered reasonable to give CNS
Eorts to improve up ront therapy in ABC-DLBCL prophylaxis to the ollowing patients: any patient
have combined biologic agents, including ibrutinib,99 with CNS-IPI score o at least 4, any patient with tes-
bortezomib,100 or lenalidomide101 with R-CHOP ticular or breast involvement, any patient with DHL/
with varying success. These agents were chosen or THL, any patient with HIV-associated aggressive B-cell
their synthetic lethality specifc to the ABC disease, NHL; BL; intravascular DLBCL; plasmablastic lym-
CHAPTER 9
driven by dysregulation and constitutive activation phoma; PEL; CNS-IPI score o at least 2 and adrenal/
o B-cell receptor signaling, leading to downstream kidney/uterine/skin involvement; or double-expressor
activation o the NF-κB) pathway and uncontrolled lymphoma (DEL) and/or ABC/non-GCB. Consider as
gene transcription and cellular survival and proliera- well CNS prophylaxis or patients with CD5+ DLBCL
tion.98 Alternatively, the Smart Start trial with ritux- and IgM-secreting DLBCL.76,105
imab, ibrutinib, and lenalidomide alone and combined Considering the most recent evidence, systemic CNS
with chemotherapy in patients with ABC-DLBCL prophylaxis with 2 to 4 cycles high-dose methotrex-
achieved impressive results with 1-year PFS o 92.5% ate (HDMTX) 3–3.5 g/m2 is the preerred option with
and 1-year OS o 96.5%. Instead, the more intensive early integration i easible, typically on days 10 to 15 o
R-ACVBP regimen (rituximab, doxorubicin, cyclo- R-CHOP.106,107 Nephrotoxicity is typically the main lim-
phosphamide, vindesine, bleomycin, and prednisone, iting actor aecting easibility o this approach, espe-
ollowed by consolidation with methotrexate, has cially in older patients. Also, hepatotoxicity can rarely
demonstrated superiority to R-CHOP, but vindesine occur with HDMTX and is contraindicated in patients
is not available in the United States.102 Nevertheless, with eusions, because this can be a drug reservoir, thus
rontline R-CHOP is still considered the standard o enhancing toxicity. Further, given that HDMTX can also
care regardless o COO type. Patients with non-GCB cause neutropenia, growth actor support should be con-
DLBCL should be reerred or trials investigating novel sidered i HDMTX is to be integrated with R-CHOP.
therapies. Given the high requency o leptomeningeal disease in
high-risk CNS-IPI patients, intrathecal (IT) chemother-
apy (MTX and/or cytarabine 4–8 doses, at least once per
CNS Prophylaxis
cycle o systemic chemotherapy) may be an alternative i
The incidence o CNS relapse among patients HDMTX is contraindicated or integrated in more intense
with DLBCL is only around 5% in unselected chemotherapy regimens such as EPOCH-R and R-Hyper-
cohorts.103 However, in high-risk patients, such as CVAD/MA (cyclophosphamide, vincristine sulate, doxo-
those with adrenal/kidney involvement, estimates as rubicin, dexamethasone/methotrexate and cytarabine) or
high as 36% have been reported (25% at time o diag- as a result o patient preerence.76 There is an unmet need
nosis, 75% at time o relapse).104 Patients with CNS or prospective studies validating prognostic models inte-
relapse may have indications o occult disease at diag- grating the diverse clinical, biochemical, molecular, and
nosis. Indeed, CSF diagnostic sensitivity is low. Nev- histologic eatures o aggressive B-cell lymphomas and
ertheless, the overall consequence o CNS relapse is new less toxic CNS prophylaxis therapies.
oten devastating, and or most patients, the median
OS is typically only a ew months, highlighting the
Tumor Lysis Syndrome Prophylaxis
need to accurately identiy at-risk patients, screen or
CNS disease, and develop sae and eective treatment/ Tumor lysis syndrome (TLS) is a potentially lie-
prophylaxis strategies.76 threatening oncologic emergency characterized by
There are several approaches or risk stratifcation, metabolic abnormalities, which may lead to renal
prophylaxis methods, and diagnostic tools related to insufciency and cardiac arrhythmias. Cairo-Bishop
risk classifcation includes biological evidence o labo- Testicular Involvement

ratory TLS (≥2 o the ollowing changes within 3 days
beore or 7 days ater cytotoxic therapy: uric acid Patients with testicular involvement in DLBCL have
≥476 μmol/L or ≥25% increase rom baseline, potas- increased risk o CNS and extranodal disease and ail-
sium ≥6.0 mmol/L or ≥25% increase rom baseline and ure in contralateral testis. To prevent these events, it is
phosphate ≥2.1 mmol/L or ≥25% increase rom base- standard practice to treat them similarly to that in the
line, calcium ≤1.75 mmol/L or 25% decrease o base- study IELSG-10, with six cycles o R-CHOP, CNS pro-
line); prolieration (particularly BL), bulk, and stage o phylaxis, preerably with systemic MTX (alternatively
aggressive B-cell NHL; and renal impairment and/or with 4 cycles o IT MTX), and RT to the contralateral
involvement at the time o TLS diagnosis.108 The best testis (30 Gy) or all patients and RT to regional lymph
treatment is prevention, based on disease-specifc esti- nodes (30 to 36 Gy) or stage II disease.114 Unilateral
mated risk o TLS. Low-risk disease is defned as an orchiectomy is usually perormed or diagnostic pur-
approximate risk o less than 1% o developing TLS, poses, but orchiectomy alone or RT alone is not a su-
and requires intravenous uids, allopurinol, and daily fcient treatment, even or stage I disease.
laboratory tests. Intermediate-risk disease is defned as
a risk o approximately 1% to 5% o developing TLS, T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
and requires intravenous uids, allopurinol or rasburi-
case, and laboratory tests every 8 to 12 hours. Finally, Outside a clinical trial, THRLBCL should be treated
high-risk disease is defned as a risk o greater than 5% similarly to other stage-matched DLBCLs. There is
CHAPTER 9
o developing TLS, and requires intravenous uids, conicting evidence regarding prognosis. However,
rasburicase, cardiac monitoring, and laboratory tests some studies report that THRLBCL ollows a natural
every 6 to 8 hours.108,109 history similar to those o other DLBCLs and responds
For urther inormation about the prevention and similarly to therapy.115 Nevertheless uture therapies
management o TLS, please see Chapter 61, Oncologic may target the relationship o the tumor cells with
Emergencies. their inammatory microenvironment.116
SPECIAL TYPES AND SITUATIONS Primary Diuse Large B-Cell Lymphoma o the
OF LARGE B-CELL LYMPHOMAS Central Nervous System
The treatment o HIV-negative patients with primary
Diuse Large B-Cell Lymphoma, Not diuse large B-cell lymphoma o the central nervous
Otherwise Specifed system (PCNSL) is limited to drugs that can cross the
blood-brain barrier, unlike R-CHOP. The most impor-
Double-Expressor DLBCL
tant drug is HDMTX, in general at doses ≥3.0 g/m2.
Despite the inerior outcomes seen with R-CHOP However, there is no uniorm consensus regarding the
therapy, there are limited data evaluating alternative optimal components o induction and consolidative
treatment strategies or DEL. Indeed, several retrospec- therapy. Outside a clinical trial, the choice o a regimen
tive studies showed potentially improved outcome or is based on a patient’s organ unction, age, and comor-
patients treated with DA-EPOCH-R.110,111 However, bidities, as well as local institutional preerences.
unplanned subset analyses rom several trials, includ- The combination o chemoimmunotherapy using 5
ing the CALGB 50303 trial, have not ound a dierence to 7 cycles o rituximab, HDMTX, procarbazine, and
with more intensive treatment or patients with DEL, vincristine (R-MPV) is considered one o the standards
although they were not powered to look or dier- o care.117 In this approach, patients have historically
ences specifcally in this subset.92 received consolidation with reduced-dose whole-brain
Interestingly, in a retrospective study, patients with radiation therapy (rdWBRT) o 23.40 Gy i they are
DEL stage I/II treated with R-CHOP–like therapy, with in complete remission, although there is controversy
or without radiation, did not show signifcantly inerior regarding the role o RT. Lower doses o radiation have
PFS or OS compared with patients with non-DEL.112 decreased the long-term neurotoxicity seen in prior stud-
Further prospective clinical trials are needed to bet- ies.118 In the previously mentioned approach with R-MPV
ter delineate the optimum treatment approach in this and rdWBRT, patients receive consolidation with two
patient population. In the absence o defnitive data cycles o high-dose cytarabine ater completion o RT.
to guide decision making, both R-CHOP and more Patients who could complete this whole therapy pre-
intensive induction regimens such as DA-EPOCH-R sented a 2-year PFS o 77% and 3-year OS o 87%.117
are reasonable approaches or DEL.113 Because o the Based on dierent trials, efcacy o consolidative
increased risk o CNS disease, evaluation or prophy- high-dose chemotherapy (HDCT)/autologous stem
laxis is recommended. cell transplant (ASCT) is similar to WBRT, but the latter
approach carries a higher incidence o neurotoxicity. important variable in the choice o therapy. Indeed, or
For instance, in the second phase o the IELSG32 trial, limited stage, surgery resection alone was curative in
patients who had responsive or stable disease ater two o our patients. However, advanced DLBCL-CI
induction with HDMTX/cytarabine-based therapy had a poor prognosis.126 Because o the rarity o the
assigned to the HDCT/ASCT arm presented a 2-year disease and the multiple types o presentation, reerral
PFS o 80% and a 2-year OS o 85%; patients assigned to a center with experience with DLBCL-CI multidis-
to the WBRT arm with 36 Gy presented a 2-year PFS ciplinary management is recommended.
o 69% (P = .17) and a 2-year OS o 71% (P = .12). As
expected, hematologic toxicity was more common in EBV-Positive Mucocutaneous Ulcer
patients treated with HDCT/ASCT, and neurotoxicity
EBVMCU presents an oten-benign course, includ-
was more common in patients who received WBRT.119
ing requent spontaneous regressions and excellent
PCNSL with leptomeningeal lymphoma can be
responses to conservative treatments such as reduc-
treated with additional IT MTX.
tion o immunosuppression. I these measures are
Patients may present with intraocular lymphoma
unsuccessul, some series reported patients responding
(IOL) either as part o primary IOL (without CNS
to systemic therapy such as bendamustine rituximab,
involvement) or as part o PCNSL with ocular dis-
R-CHOP, or RT.127,128
semination, which happens in 15% to 25% o cases.120
Standard treatment o such cases remains unclear but
Lymphomatoid Granulomatosis
includes MTX-based systemic chemotherapy with
CHAPTER 9
ocular external beam radiotherapy and intravitreal Given the rarity o LYG, no standard treatment con-
chemotherapy with MTX. Intravitreal rituximab is sensus exists, and treatment has varied widely rom
oten used to decrease the requency o methotrexate observation to systemic corticosteroids, intereron-
injections or or MTX-resistant IOL.121 -2b, intravenous gamma globulin, anti-CD20 mono-
For urther inormation about AIDS-related B-cell clonal antibody therapy such as rituximab, and/or
lymphomas, please see Chapter 52, The Acquired chemotherapy such as DA-EPOCH-R.58
Immunodefciency Syndrome–Related Cancers.
Large B-Cell Lymphoma With IRF4
Primary Cutaneous DLBCL, Leg Type Rearrangement
R-CHOP with or without IFRT 36–40 Gy or solitary Patients with ollicular neoplasms oten have indolent
or localized disease is considered the frst line o treat- disease and an excellent prognosis ater tumor exci-
ment in these lymphomas.122,123 According to some sion; chemotherapy may not be needed. Patients with
series, PCDLBCL-LT have increased risk or CNS purely diuse neoplasms also have a good prognosis
involvement at the time o diagnosis or at relapse, and but require chemotherapy. Further studies are needed
CNS prophylaxis may be warranted.124 to determine whether chemotherapy can be reduced
or whether a watch-and-wait strategy can be used or
EBV-Positive DLBCL, Not Otherwise Specied patients with localized disease ater excision.26,129
Patients with EBV+ DLBCL–NOS should be managed Primary Mediastinal (Thymic) B-Cell Lymphoma
ollowing comparable guidelines as patients with EBV-
negative DLBCL. EBV+ DLBCL–NOS, though, has a Because PMBL is uncommon and has been only
worse prognosis than EBV-negative DLBCL in the era recently described, there is a paucity o prospective
o chemoimmunotherapy. There is an opportunity to treatment data and a lack o randomized studies. 64
study and develop targeted therapy such as CD30 anti- A rituximab and anthracycline–containing rontline
body therapy in the treatment o patients with EBV+ regimen is commonly used at most centers in the
DLBCL–NOS.52,125 United States. Notably, DA-EPOCH-R without RT,
as described in the phase 2 study o Dunleavy et al
DLBCL Associated With Chronic Infammation showed an excellent outcome with a 5-year EFS
o 93% and a 5-year OS o 97%.130 Alternatively,
DLBCL-CI is very rare and can exhibit variable presen- R-CHOP with RT can be considered equivalent in
tation and clinical course, including an indolent behav- terms o lymphoma-related outcome, but it carries
ior or some cases. Moreover, there is a paucity o data the risks associated with RT.131 Nevertheless, a ret-
regarding optimal management, which can include rospective study o the BC Cancer Lymphoid Cancer
excisional surgery (such as pleuropneumonectomy Database showed that a PET-guided approach could
with or without resection o adjacent involved tissues), reduce the use o RT by over 60% without compro-
systemic therapy such as R-CHOP, RT, or a combina- mising cure rates.132 Randomized studies are required
tion o these. In a Japanese series, clinical stage was an to validate the optimal approach.
Intravascular Large B-Cell Lymphomas Primary Eusion Lymphoma

These lymphomas have a high incidence o CNS There are no prospective studies o PEL. However, in a
relapse. In the phase 2 PRIMEUR-IVL, IVDLBCL retrospective study, modifed EPOCH resulted in 3-year
patients without apparent CNS involvement at diag- cancer-specifc survival o 47%.138 Nevertheless, such out-
nosis received three cycles o R-CHOP, ollowed by comes o EPOCH or CHOP-like are still unsatisactory,
two cycles o rituximab with HDMTX, then three and an eort to urther improve outcomes is needed.139
additional cycles o R-CHOP, with IT (methotrexate For urther inormation about AIDS-related B-cell
15 mg, cytarabine 40 mg, and prednisolone 10 mg) lymphomas, please see Chapter 52, The Acquired
administered our times during the R-CHOP phase. Immunodefciency Syndrome–Related Cancers.
Overall, the 2-year PFS was 76% and the cumulative
incidence o secondary CNS involvement was 3%.133 High-Grade B-Cell Lymphoma
This regimen warrants urther investigation but pres-
ents promising clinical outcome. High-Grade B-Cell Lymphoma, With MYC and BCL2
and/or BCL6 Rearrangements
There is a lack o prospective data to help establish
ALK-Positive Large B-Cell Lymphoma an optimal induction regimen. Multiple retrospective
Because o the rarity o this malignancy, the data are studies have suggested that intensifcation o upront
limited to retrospective studies. In the case series o Pan therapy such as DA-EPOCH-R, R-CODOX-M/IVAC
et al, most patients received CHOP, CHOEP, EPOCH, (cyclophosphamide, doxorubicin, vincristine, metho-
CHAPTER 9
or Hyper-CVAD, and some also underwent RT and trexate/iosamide, etoposide, high-dose cytarabine,
HDCT/ASCT. However, patients with ALK+ LBCL also called “Magrath regimen”), and R-Hyper-CVAD
showed a dismal outcome, with a 5-year OS o 34% may be superior to R-CHOP, notably with longer
and a median survival o 1.83 years. However, patients PFS.31,140 At MDACC, our approach to double-hit
with stage I–II disease and/or patients younger than 35 DLBCL currently includes DA R-EPOCH outside o
years o age had a signifcantly better OS.62 Whenever a clinical trial. CNS prophylaxis is warranted. Retro-
possible, these patients should be included in a clinical spective data suggest that there is no improvement o
trial. OS with consolidative ASCT in the frst remission in
patients who were treated with intensive induction
Plasmablastic Lymphoma regimens.141 Because o the inerior prognosis o DHL,
participation in a clinical trial is highly recommended.
Overall, EPOCH is widely used to treat PBL, with Interestingly, in a retrospective study with DHL
complete response rate (CRR) o 71%. 134 Alterna- stage I/II patients treated with R-CHOP–like therapy,
tively, a retrospective study with 16 patients showed with or without radiation, double-hit status was not
that adding bortezomib to EPOCH could lead to a signifcantly associated with inerior PFS or OS. It is
CRR o 94% and a 5-year OS o 63%.135 However, possible that early-stage DHLs have a dierent biol-
added toxicity was an issue. Alternative regimens ogy and a more avorable outcome not requiring more
include CODOX-M/IVAC and Hyper-CVAD. Patients intensive therapies.112
may beneft rom HDT/ASCT in their frst remis-
sion.136 Nevertheless, urther studies are required, High-Grade B-Cell Lymphoma, Not Otherwise
and patients should be enrolled in a trial whenever Specied
possible. HGBL–NOS is associated with a short survival period
For urther inormation about AIDS-related B-cell and substantial extranodal involvement. High-intensity
lymphomas, please see Chapter 52, The Acquired chemotherapy such as DA-EPOCH-R, R-CODOX-M/
Immunodefciency Syndrome–Related Cancers. IVAC, or R-Hyper-CVAD may improve outcome com-
pared with R-CHOP, as shown in the retrospective
HHV8-Positive Diuse Large B-Cell Lymphoma study o Li et al. CNS prophylaxis is recommended.
Consolidative RT or localized disease can be consid-
Patients with HHV8-positive DLBCL may be treated ered. Participation in a clinical trial is suggested.142
with similar regimens as patients with HIV-positive
large B-cell lymphoma, such as EPOCH or CHOP,
with rituximab in case o CD20 positivity.137 There is B-Cell Lymphoma, Unclassiable
a lack o data regarding optimal management o this B-Cell Lymphoma, Unclassiable, With Features
uncommon malignancy. For urther inormation about Intermediate Between DLBCL and Classical Hodgkin
AIDS-related B-cell lymphomas, please see Chapter 52, Lymphoma
The Acquired Immunodefciency Syndrome–Related There is no standard o care regarding the management
Cancers. o patients with GZL. The prospective study o Wilson
et al, with 24 untreated MGZL patients treated with MA [3%]).145 Nevertheless, R-EPOCH is less toxic than
6 to 8 cycles o DA-EPOCH-R, showed a 59-month R-CODOX-M/IVAC or R-Hyper-CVAD and might be
EFS o 62% and a 59-month OS o 74%.143 However, an acceptable alternative or patients without evidence
there is no study proving the superiority o R-CHOP o CNS disease, who are unable to tolerate more inten-
to R-EPOCH, and R-CHOP is a valid therapy.63 Con- sive regimens. However, adequate CNS prophylaxis,
solidative RT can be considered or bulky or localized notably with HDMTX, should be evaluated.
disease.63,144 Patient with low-risk disease (ECOG 0–1, normal
LDH, stage I–II, and mass <10 cm) may be treated with
Burkitt Lymphoma a shorter course o chemotherapy.146–148
AIDS-related BL should be treated with similar
The optimal therapy o BL has yet to be defned regimens as or HIV-negative patients with BL. Anti-
in a prospective, randomized trial, but R-CHOP is retroviral therapy can be saely administered with
not an adequate therapy. However, i a patient can- chemotherapy.149 For urther inormation about AIDS-
not be enrolled in a clinical trial, we use aggressive related B-cell lymphomas, please see Chapter 52,
combination chemotherapy such as DA-EPOCH-R, The Acquired Immunodefciency Syndrome–Related
R-CODOX-M/IVAC, or R-Hyper-CVAD with CNS Cancers.
prophylaxis (Table 9-9). However, in a multi-insti-
tutional retrospective study, the risk o CNS recur-
Burkitt-Like Lymphoma With 11q Aberration
rence diered according to chemotherapy regimen
CHAPTER 9
and was signifcantly higher or patients treated with BLL-11q is rare and its optimal management is unde-
DA-EPOCH with intrathecal chemotherapy (12% at fned, although it is most oten treated like typical
3 years vs CODOX-M/IVAC [4%] or Hyper-CVAD/ BL.68,150 Further studies are needed.
Table 9–9 RHyperCVAD Regimen Used in Mantle Cell Lymphoma and Highly Aggressive
Lymphomasa
Regimen Dose/Route Days Interval

Hyper-CVAD/Methotrexate/ 21–28 days
Ara-C
Cycles 1, 3, 5, 7
Rituxan 375 mg/m2 IV by slow inusion 1
2
Cyclophosphamide 300 mg/m /dose over 3 h q 12 h × 6 doses 1–3
Mesna 600 mg/m2/day CIV over 24 h daily 1–3
(Start 1 h prior to cyclophosphamide and complete by
12 h ater last dose o cyclophosphamide)
Doxorubicin 25 mg/m2/day CIV over 24 h daily 4–5
(Begin at 12 h ater last dose o cyclophosphamide)
Vincristine 1.4 mg/m2 IV (max 2 mg) 4 and 11
(Give 12 h ater last dose o cyclophosphamide and on
day 11)
Dexamethasone 40 mg PO daily 1–4 and 11–14
Cycles 2, 4, 6, 8
Methotrexate 200 mg/m2 IV over 2 h then 800 mg/m2 IV over 22 h 1
Solumedrol 50 mg IV q 12 h × 6 doses 1–3
Ara-C 3 g/m2 IV over 2 h every 12 h × 4 doses 2–3
Leucovorin 50 mg IV ollowed by 15 mg IV q 6 h × 8 doses (start 12 h
ater completion o methotrexate)
Intrathecal therapyb
Ara-C 100 mg 2
Methotrexate 12 mg (6 mg i Ommaya reservoir) 7
a
Dose reductions or renal insufciency, age, and previous toxicity are required. Intrathecal chemotherapy is more requent or proven CNS disease.
b
Mantle cell lymphoma is not typically treated with intrathecal therapy.
Therapy in Older Adult Patients salvage chemotherapy in patients with relapsed, che-
motherapy-sensitive NHL. Patients were randomly
As has been repeatedly shown, patients with aggressive
assigned to receive our more cycles o DHAP (ritux-
NHL over the age o 60 years have a worse prognosis,
imab, cisplatin, dexamethasone, high-dose cytara-
notably because o comorbid conditions, lower treat-
bine) versus high-dose therapy with stem-cell support,
ment tolerance, and administration o inadequate ther-
showing an EFS rate o 46% in the high-dose arm but
apy. We suggest screening or clinical trials with novel
only 12% in the DHAP-alone arm.154
therapies. Outside a clinical trial, we recommend ull-
Conventional salvage therapies include rituximab
dose R-CHOP with growth actor support or patients
combined with standard chemotherapeutics such as
older than 60 years. In the REMARC study, lenalidomide
iosamide, etoposide, taxanes, and platinum com-
maintenance versus placebo given to 60- to 80-year-
pounds. Among the most commonly used are R-DHAP,
old patients with DLBCL ater completion o R-CHOP
R-ICE (iosamide, carboplatin, and etoposide) (Table
therapy increased the PFS but not the OS, and at the
9-8), R-GDP (gemcitabine, dexamethasone, and cispla-
cost o increased toxicity.151 Alternatively, attenuated
tin), TTR (paclitaxel, topotecan, and rituximab), and
immunochemotherapy regimen (R-miniCHOP) can be
R-ESHAP (etoposide, methylprednisolone, cytarabine,
considered in adult patients older than 80 years.152
and cisplatin). The best chemotherapy regimen would
provide the highest response rates with the most
Patients With Cardiac Disease tolerable toxicity. There remains no clear evidence
Patients with cardiac disease showing a contraindica- regarding the superiority o one regimen over another
CHAPTER 9
tion to doxorubicin can be treated with an alternative in randomized studies. Moreover, ailure to collect
regimen. There is a paucity o data to guide the choice peripheral stem cells is around 10% and does not
o therapy. In a retrospective study with R-CEOP (eto- seem, in the frst relapse, to be dierent rom one regi-
poside substituted or doxorubicin), patients treated men to another. In particular, the CORAL trial ound
with R-CEOP presented a 5-year OS o 49% versus no dierence between R-DHAP and R-ICE. Overall,
64% or patients treated with R-CHOP.153 only 50% o the patients could proceed to HDCT/
ASCT, mainly because o an insufcient response to
second-line treatment. The rate o collection ailure o
Therapy o Reractory or Relapsed stem cells was 10% in both arms.155
Aggressive Non-Hodgkin B-Cell In relapsed disease, the prognostic impact o COO
Lymphoma remains less clear. Although the Bio-CORAL study
suggested that GCB DLBCL treated with R-DHAP had
General Management o Large B-Cell
an improved 3-year PFS compared with those treated
Lymphomas and High-Grade B-Cell Lymphomas with R-ICE, multiple other studies have ailed to repro-
First Relapse duce these results, including in patients who went on
Approximately 10% o patients treated or aggressive to receive consolidative ASCT.156 The topic o ASCT i
NHL ail to achieve a complete remission ater induc- discussed in urther detail in Chapter 18, Autologous
tion therapy; their disease is termed primary reractory Hematopoietic Progenitor Cell Transplantation.
(see Fig. 8–20). A larger portion o patients with aggres- Patients who respond to second-line treatment,
sive NHL, up to one-third o all patients, will relapse but who are unable to mobilize stem-cell treatment,
ater initially responding to chemotherapy, usually should be considered or alternative options such as
within the frst two years. chimeric antigen receptor T-cell therapy (see Chapter
In the SCHOLAR-1 study, which was done beore 17, Cellular Therapy or Lymphomas) or donor trans-
chimeric antigen receptor (CAR)-T cell therapy, patients plant (see Chapter 19, Allogeneic Transplantation).
with reractory DLBCL had an ORR o 26% (CRR o 7%)
to the next line o therapy, and the median OS was 6.3
Noncandidates or Transplant
months. Overall, 20% o patients were alive at 2 years.89
Beore proceeding to urther therapy, the relapse Overall, most such patients cannot tolerate the plat-
needs to be histologically proven and restaging inum-containing salvage regimens described above,
completed. Participation in a clinical trial is highly and other salvage regimens are unlikely to achieve a
recommended. complete and/or sustained remission. The choice o
therapy depends on dierent actors, including per-
ormance status, organ unction, pathologic eatures
Intention to Proceed to Transplant o the disease, and the patient’s preerences. We avor
Outside a clinical trial, the standard o care is salvage participation in a clinical trial, or when a clinical trial is
therapy and HDCT ollowed by ASCT in chemo- not available, we suggest either ibrutinib (ORR 40%157)
sensitive patients. Notably, the PARMA trial exam- or lenalidomide with or without rituximab (ORR
ined autologous bone marrow transplantation versus 28.6%–33%158,159) or ABC-subtype lymphomas.
Other acceptable options or second-line salvage rituximab can be attempted i there was a long dura-
therapy include bendamustine rituximab (ORR 62.7%, tion o the frst remission.165 Patients with recent prior
CRR 37.3%, median PFS 6.7 months),160 lenalidomide whole-brain RT may be at high risk or methotrexate-
with or without rituximab or rituximab-gemcitabine- induced encephalopathy.
oxaliplatin (ORR 61%, CRR 44%).161 In case o reractory disease or short duration o
remission ater HDMTX, alternative therapies including
Second Relapse and More lenalidomide and rituximab (ORR 32.0%, median PFS
7.8 months166), ibrutinib (ORR 52%, CRR 19%, median
Optimal treatment or patients who experience ailure PFS 4.8 months167), HD cytarabine and etoposide (ORR
o at least two dierent systemic therapies is unknown, 47%168), and rituximab and temozolomide (ORR 53%,
and selection o treatment depends on prior therapies, median OS 14 months169) should be considered.
perormance status, available resources, institutional Responding patients may beneft rom consolida-
preerences, and patient wishes. We recommend par- tion with high-dose chemotherapy (especially with
ticipation in a clinical trial. Some patients will choose preparative regimens including thiotepa), ollowed by
palliation o symptoms, which may include chemo- ASCT.
therapy or immunotherapy as described above.
Outside o a clinical trial, we recommend CAR–T
Primary Mediastinal B-Cell Lymphoma
cell therapy, i good perormance status and acceptable
Relapsed/reractory PMBL should be managed like
organ unction.
aggressive B-cell lymphoma. However, some cases
CHAPTER 9
Currently, CAR–T cell therapy is FDA approved

with localized disease can be salvaged with RT only.
ater ailure o two lines o systemic therapy; however,
Moreover, in the CHECKMATE-436 trial, patients with
several trials enroll patients ater ailure o one systemic
relapsed reractory (rr) PMBL that ailed at least two
therapy. CAR–T cell therapy is explained in urther
lines o therapy presented an ORR o 70% and CRR
details in Chapter 17, Cellular Therapy or Lymphomas.
43% with brentuximab vedotin, and nivolumab.170
When CAR–T cell therapy is not available, we oer
Alternatively, in the trial KEYNOTE-170, a similar
allogenic HCT or patients who are medically eligible
population presented an ORR o 45% when treated
(see Chapter 19, Allogeneic Transplantation).
with pembrolizumab.171
For patients ineligible or trials, CAR–T cell therapy,
or transplant, who have ailed two lines o systemic
therapy, polatuzumab-vedotin-BR is FDA approved ALK-Positive Large B-Cell Lymphoma
and presents signifcant activity (ORR 45%, CRR 40%, There is a paucity o data regarding optimal manage-
median OS 12.4 months).162 ment o rr-ALK+LBCL, and participation in a clinical
In addition, the combination o taasitamab trial is recommended. Outside a clinical trial, there
(MOR208), an Fc-enhanced humanized anti-CD19 have been reports o short response with ALK inhibi-
monoclonal antibody, with lenalidomide showed an tors such as crizotinib172 or nivolumab.173 Outcome is
ORR o 60% and CRR o 43% in the L-MIND trial.163 generally poor.
Alternatively, brentuximab vedotin can be consid-
ered or CD30-positive DLBCL (ORR 44%, CRR 15%, B-Cell Lymphoma, Unclassiable, With Features
median PFS 4 months).164 Intermediate Between DLBCL and Classic Hodgkin
Lymphoma
Optimal therapy o rr-GZL is unknown and partici-
Special Types o Aggressive B-Cell Lymphomas pation in a clinical trial is recommended. Because o
Transormed Follicular Lymphoma some common biological eatures with PMBL, there
Patients with a history o ollicular lymphoma with are reports o activity o checkpoint inhibitors174 and
subsequent transormation to DLBCL, who had prior brentuximab vedotin.163
doxorubicin-based treatment, should be treated with
salvage therapy or recurrent DLBCL. Burkitt Lymphoma
Prognosis is poor or patients with rr-BL,175 and par-
Recurrent Primary Central Nervous System and Ocular ticipation in a clinical trial is highly recommended.
Lymphoma Outside a clinical trial, or patients with relapse lon-
The treatment o recurrent primary CNS lymphoma is ger than 6 months ater completion o appropri-
limited because o the inability o many drugs to pen- ate frst-line therapy, a second-line therapy such as
etrate the CNS. Moreover, the choice o therapy will R-ICE should be considered. I a complete response is
depend on the perormance status, organ reserve, and achieved, consider HDT/ASCT or allo-SCT. However,
patient preerences. Outside a clinical trial, retreatment patients who do not receive appropriate rontline ther-
with high-dose methotrexate (ORR 91%, median apy may respond to a dose-intensive regimen such as
PFS ater frst relapse 61.9 months) with or without R-CODOX-M/IVAC, or R-Hyper-CVAD.
RESPONSE AND FOLLOW-UP and is not recommended or treatment decisions as

part o routine clinical practice.176
Defnitions o Response
Response to therapy is assessed according to criteria Restaging
based on the anatomic and metabolic changes that Fluorodeoxyglucose-PET has proven very useul in
occur in disease-involved nodal and extranodal sites.69 assessing responses to therapy and is now considered
A recent consensus statement was issued by lead- standard o care or initial post-therapy restaging in
ing clinical investigators to attempt standardization FDG-avid lymphomas.69 Despite this recommenda-
o response criteria to be used in clinical trials. There tion, FDG-PET/CT should not be used or long-term
remains controversy about what constitutes an abnor- ollow-up imaging ater initial response is confrmed
mal PET scan, and it is generally recommended that (Fig. 9–13).
uptake be compared with the mediastinal blood pool
and liver as internal controls and that the results be
scored based on these results (Table 9–10). Surveillance
The use o interim PET/CT is controversial, notably Follow-up o patients with aggressive NHL ater
because o alse-positive and inter-reader variability, complete remission and cessation o therapy is
CHAPTER 9
Table 9–10 Response Denitions or Clinical Trials
Response Denition Nodal Masses Spleen, Liver Bone Marrow

CR Disappearance o all (a) FDG-avid or PET positive Not palpable, nodules Inltrate cleared on repeat
evidence o disease beore therapy; mass o disappeared biopsy; i indeterminate
any size permitted i PET is by morphology,
negative immunohistochemistry
(b) Variably FDG-avid or PET should be negative
negative; regression to
normal size on CT
PR Regression o ≥50% decrease in SPD o up to ≥50% decrease in Irrelevant i positive beore
measurable disease 6 largest dominant masses; SPD o nodules (or therapy; cell type should
and no new sites no increase in size o other single nodule in be specied
nodes greatest transverse
(a) FDG-avid or PET positive diameter); no
prior to therapy; one increase in size o
or more PET positive at liver or spleen
previously involved site
(b) Variably FDG-avid or PET
negative; regression on CT
SD Failure to attain CR/ (a) FDG-avid or PET positive
PR or PD prior to therapy; PET
positive at prior sites o
disease and no new sites
on CT or PET
(b) Variably FDG-avid or PET
negative; no change in size
o previous lesions on CT
Relapsed Any new lesion or Appearance o a new lesion(s) >50% increase rom New or recurrent
disease increase by ≥50% >1.5 cm in any axis, ≥50% nadir in the SPD involvement
or PD o previously increase in longest diameter o any previous
involved sites rom o a previously identied lesions
nadir node >1 cm in short axis
Lesions PET positive i FDG-
avid lymphoma or PET
positive prior to therapy
CR, complete remission; CT, computed tomography; FDG, [ 18F] uorodeoxyglucose; PD, progressive disease; PET, positron emission tomography; PR, partial remission;
SD, stable disease; SPD, sum o the product o the diameters.
Reproduced with permission rom Cheson BD, Pstner B, Juweid ME, et al: Revised response criteria or malignant lymphoma, J Clin Oncol. 2007 Feb 10;25(5):579-586.
A B
CHAPTER 9
FIGURE 9–13 Residual mass, not residual lymphoma. Ater completing chemotherapy, this patient had a residual sot tissue
abnormality in the retroperitoneum. A. This was previously positive on FDG-PET, but now does not have activity above back-
ground levels and is considered negative. B. Biopsy o this mass was negative, and it was stable on ollow-up studies. Previ-
ously, this would be considered a partial response (PR) or unconrmed complete response (CRu). Under the revised criteria,
considering the FDG-PET ndings, this is considered a complete response (CR).
typically done every 3 to 6 months or 2 years, then fndings may represent a premalignant lesion, such as
annually until year 5, although there is signifcant a thyroid or colonic adenoma, or an incidental second
controversy about optimal use o surveillance imag- malignant tumor (Fig. 9–15).
ing. A large retrospective evaluation o the utility
o surveillance imaging to detect recurrence, com-
pared with patient-reported complaints, ound that NEW DIRECTIONS
most DLBCL recurrences were identifed based on
symptoms and not imaging alone and that outcomes Over the last 30 years, remarkable advances have been
were not dierent between imaging and symptom- made in the diagnosis, characterization, and treatment
identifed recurrences. 177 The emergence o blood- o patients with aggressive NHL. It is our strong rec-
based minimal residual disease detection techniques ommendation that all patients be considered or clini-
may ultimately make the debate about the utility o cal trials to move the feld orward.
imaging moot. The multitude o the dysregulated circuits, the
overall complexity and heterogeneity o aggressive
Relapse or Recurrence B-cell lymphomas (which may also involve nonge-
netic mechanisms), and the interplay with the micro-
The presence o a new lesion, either by anatomic environment underscore the need or more precise
criteria or on FDG-PET scan, is highly suspicious or patient stratifcation to improve personalized medi-
relapsed or progressive disease. However, a biopsy cine. Moreover, advancements in bioinormatics and
to confrm imaging fndings is essential. FDG-PET is gene-editing technologies in translational medicine
nonspecifc, and uptake may occur in both benign will lead to signifcant progress in this area in the near
and malignant tumors, in inammatory or inectious uture.
lesions, and with normal physiologic processes. Sar- In addition, signifcant advances may come rom
coidosis and ungal inections may mimic lymphoma, the use o circulating tumor DNA (ctDNA), which
and biopsy is oten necessary to exclude recurrence proved to be a reliable surrogate or simultaneously
(Fig. 9–14). A single persistent or new ocus o activ- tracking multiple somatic mutations in aggressive
ity, with paradoxical response at other sites o disease, B-cell lymphomas, with high specifcity and sensi-
requires urther evaluation with a biopsy, because tivity.178 This approach was superior to radiographic
A B
CHAPTER 9
FIGURE 9–14 Examples o alse-positive FDG-PET. Restaging study is suspicious or recurrent lymphoma. A. With predomi-
nantly osseous involvement; however, biopsy revealed non-necrotizing granulomas thought to be caused by sarcoidosis. Two
months later, nearly all o the FDG-avid sites resolved without any therapy. B. A second patient presented over 10 years ater
successul treatment or lymphoma with new lymphadenopathy and lung opacities that were positive on FDG-PET. Biopsy
revealed ungal lymphadenitis.
imaging or the detection o minimal residual disease

and was independently predictive o clinical outcome
in a study. Moreover, ctDNA genotyping allows the
identifcation o distinct patterns o clonal evolution,
which makes it a valuable tool in the setting o trans-
ormation or relapse, by inorming individualized
therapy.179 Furthermore, the discovery o genes and
pathways that are recurrently disrupted in DLBCL
reveals vulnerabilities in the lymphoma cells that are
oten uniquely associated with distinct lymphoma
subtypes and could thus be exploited or the design
o more eective, targeted therapeutic approaches. It is
expected that additional novel therapeutic targets will
be identifed as more mutational events become unc-
tionally dissected.180
There is an unmet need to improve the prognosis
o relapsed/reractory disease, to decrease the relapse
rate o rontline therapy, decrease toxicity, and to tai-
lor treatments or rarer malignancies. Improved novel,
immune, and cellular therapies such as CAR–T cell
therapies will likely be moved rom the last line o
FIGURE 9–15 Incidental signicant nding on FDG-PET/CT.
therapy to the second line and rontline, and use o
An enlarging metabolically active lung nodule is seen. Biopsy
revealed non–small-cell lung cancer, and the patient went on standard cytotoxic therapy might become progres-
to have lobectomy or stage I lung cancer. sively obsolete.

J Our preerence is that all patients with aggressive J In the CHECKMATE-436 trial, patients with relapsed
B-cell lymphoma be evaluated or a clinical trial at reractory PMBL who ailed at least two lines o ther-
each treatment stage at MDACC. apy presented an ORR o 70% and CRR o 43% with
J Therapy o early-stage, avorable prognosis, non- brentuximab vedotin and nivolumab.2 Considering
bulky (maximal tumor diameter <7.5 cm) DLBCL the biology o PMBL, these immune therapies pres-
can include a shorter course o R-CHOP without ent an appropriate option.
consolidative RT, i complete response is achieved J For patients ineligible or trials, CAR–T cell therapy,
at completion o systemic therapy. or stem-cell transplant, who have ailed two lines o
J There is a lack o prospective data to help estab- systemic therapy, polatuzumab-vedotin-BR is FDA
lish an optimal induction regimen o HGBL, with approved and presents signicant activity (ORR
MYC and BCL2 and/or BCL6 rearrangements (dou- 45%, CRR 40%, median OS 12.4 months). In addi-
ble-hit lymphoma [DHL]). Our approach currently tion, the combination o taasitamab (MOR208),
includes DA R-EPOCH with CNS prophylaxis, out- an Fc-enhanced humanized anti-CD19 monoclo-
side a clinical trial. However, in a retrospective nal antibody, with lenalidomide showed an ORR o
study with DHL, stage I/II patients treated with 60% and CRR o 43% in the L-MIND trial or a similar
R-CHOP–like therapy with or without radiation, population.3
CHAPTER 9
double-hit status was not signicantly associated J Novel, immune, and cellular therapies such as
with inerior PFS or OS. Early-stage DHL may have CAR–T cell therapies will likely be moved rom latter
dierent biology and a more avorable outcome, lines o therapy o aggressive B-cell lymphomas to
not requiring more intensive therapies.1 More second line, and possibly rontline, and use o stan-
studies are required. dard cytotoxic therapy might become progressively
obsolete.
cross-Canada study o pesticides and health. Cancer Epidemiol

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lenalidomide in relapsed or reractory diuse large B-cell
10 Mantle Cell Lymphoma
Preetesh Jain
Michael Wang
KEY CONCEPTS
 Advances in the eld o mantle cell lymphoma (MCL) have  Patients with MCL who exhibit high-risk eatures at initial
signicantly changed our understanding o its pathobi- diagnosis such as high-risk MCL international prognostic
ology. With the treatment modalities currently available, index (MIPI) score, blastoid and/or pleomorphic histology,
the response rates and survival have improved but this high Ki-67% (≥50%), TP53 aberrations, MYC gene rear-
lymphoma still remains incurable. Heterogeneity in clini- rangement, complex genomics (CCND1, CDKN2A, NSD2,
cal presentation o patients poses a therapeutic dilemma KMT2D, SMARCA4, and NOTCH1 or NOTCH2 mutations) and
among the clinicians. Broadly, two distinct clinical variants complex karyotype generally portend a poor prognosis
are recognized—an indolent non-nodal leukemic phase, and requent relapses.
which is generally SOX-11–negative, and another nodal or  Long-term ollow-up o intensive chemoimmunotherapy
extranodal SOX-11–positive conventional MCL. studies demonstrated durable responses and remissions
 Pathogenic relevance o actors such as overexpression o in a subset o patients with MCL. However, the advent
SOX-11 in lymphoma cells, prolierative lymph node micro- o newer agents or rontline therapy, such as ibrutinib,
environment, clonal and subclonal evolution, presence o acalabrutinib, and their combinations with rituximab
mutations in epigenetic modiers, and presence o CCND1 and venetoclax, are very promising and under active
genes in addition to other cell cycle–associated genetic investigation.
aberrancies are closely associated with survival, growth,  The ocus o treating MCL is rapidly changing toward
prolieration and maintenance o MCL clones in tumor investigation o “chemotherapy-ree” agents such as
microenvironment and maintain minimal residual disease. BTK inhibitors, venetoclax, and rituximab. Most recently,
 An improved understanding o B-cell receptor kinase the FDA approval o anti–CD19-chimeric antigen recep-
signaling pathways, such as Bruton tyrosine kinase (BTK) tor therapy (CAR-T)—brexucabtagene autoleucel—has
pathway is identied as a critical pathway or therapeutic been a landmark advancement in treating patients with
targeting o MCL B-cells. MCL.
Mantle cell lymphoma (MCL) is a distinct category

o B-cell non-Hodgkin lymphoma (B-NHL). These INCIDENCE AND POSSIBLE
patients generally exhibit an aggressive, albeit PREDISPOSING RISK FACTORS
heterogeneous, clinical course but smoldering or
indolent orms o MCL are also recognized. In this MCL comprises about 3% to 10% o adult-onset
chapter, we will provide a comprehensive update on NHL in Western countries, with an incidence o
various aspects o MCL—actors associated with the approximately our to eight cases per million persons
etiopathogenesis, clinical and diagnostic eatures, per year, and its incidence is rising, with an estimated
advances in risk stratication, management o MCL, 3320 cases1 diagnosed in 2016.2–4 Its incidence appears
current challenges, and management approach at to be rising in older adult patients (age ≥65 years) and
MDACC to treat MCL. in non-Hispanic whites.5 The median age at initial
227
presentation in Western countries is 68 or 71 years old. o MCL is likely caused by the extent to which these
Furthermore, the incidence o MCL in Asian countries actors are involved in an individual patient.
is variable6,7 (1%–6%) and appears to be lower than Based on these developments, two orms o MCL
in Western countries, and MCL initially presents at are recognized in the World Health Organization clas-
a lower median age o 60 years in Asian countries.8,9 sication o B-NHL in 2016.26 Figure 10–1 depicts the
Overall, the incidence o MCL is higher in whites.10 A development o the two orms o MCL.23
male predilection o MCL with a male/emale ratio o
more than 2:1 is common.11 Precise reasons or male
predisposition is unknown. Nodal or Extranodal
Few possible predisposing risk actors or MCL This is a conventional orm o MCL with unmutated
include12 possible associations with European strains o IGHV, SOX-11–positive, aggressive MCL. Naïve B-cells
the Borrelia burgdorferi when it involves skin as acroder- do not undergo germinal center reaction.27 SOX11 has
matitis chronica atrophicans,13 living/working on arm been reported to block B-cell dierentiation, suggesting
houses,14 polymorphisms in IL-10 to 1082A>G,15 and that it has a direct role in MCL pathogenesis, a higher
twoold increase risk o hematologic malignancies in degree o genomic instability, and increased requency
rst-degree relatives o patients with MCL.14,16 Autoim- o ATM, TP53, CDKN2A, and KMT2D mutations.
mune diseases (10% o MCL can be associated with
autoimmune diseases),17 and B-cell–mediated autoim-
mune diseases posed a negative impact on the survival Non-Nodal, Leukemic and SOX-11–
CHAPTER 10
o patients with MCL.18 Similar to ndings rom studies Negative, Mutated IGHV
in small lymphocytic lymphoma/chronic lymphocytic This orm develops with a generally, indolent or
leukemia (SLL/CLL), antigenic drive is hypothesized smoldering clinical course. The smoldering variant
to have a role in the development o MCL. This is is thought to develop rom an antigen-experienced,
probably related to the nding o a biased and highly memory B-cells.28,29 These patients have a generally
restricted immunoglobulin (IGHV) gene repertoire19 stable genome. Compared with conventional MCL,
with stereotyped variable heavy chain (VH) comple- the non-nodal variant has ewer copy number altera-
mentary determining region (CDR3s) and recogni- tions and ewer structural variants.30 With leukemic
tion o superantigens20 by the B-cell receptor (BCR) o clinical presentation, it can masquerade as CLL and
clonal MCL B-cells. The role o micro-RNA (miR-155, CD200 can be positive.31 TLR2 and CCND1 muta-
miR18b, and miR-17-92) and epigenetic perturbations21 tions are overrepresented. A high number o DNA
(aberrant methylation especially or NFkB and HDAC1 methylation changes27 and/or presence o TP53
and methylation status) in MCL etiopathogenesis is mutations in these patients may negatively aect the
also being explored. Further, patients with MCL are at prognosis.
higher risk o developing second primary cancers (mel- In addition, biopsies rom patients may reveal the
anoma, thyroid, nonepithelial skin cancers, SLL/CLL, presence o cyclin D1+ cells in the inner mantle zone
and other hematologic malignancies).22 o lymphoid ollicles (this is termed in situ mantle cell
neoplasia).26,32 Instances o patients with this variant
are rare, with an indolent course and low risk o pro-
DECODING THE gression to overt MCL. These patients must be recog-
ETIOPATHOGENESIS OF MCL nized to avoid inadvertent systemic therapy.
In the last decade, our understanding on the

development, origin, and growth o MCL cells has MAJOR PATHOGENETIC FEATURES
signicantly improved. Various actors23 such as SOX- OF MCL
11 (SRY [sex-determining regions-Y] box transcription
actor 11) nuclear transcription actor, cell cycle
Cyclin D1 Overexpression
dysregulation, genomic instability, microenvironment,
resistance to apoptosis, and epigenetic perturbations Constitutive overexpression o cyclin D1 with trans-
are involved.24 Most MCL cases are postulated to location t(11;14) (q13;q32) is considered the hallmark
derive rom naïve pre–germinal center B-cells o the oncogenic step in almost all MCL. This translocation
mantle zone, which do not demonstrate somatic is not specic to MCL and can be seen in multiple
hypermutation o IGHV genes, whereas a subset o myeloma. The juxtaposition o DNA coding sequence
MCL may originate rom marginal zone or peripheral or cyclin D1 at 11q13 with the immunoglobulin heavy
blood memory B-cells. O note, MCL is a distinct chain joining region at 14q32 promotes cell cycle transi-
lymphoma but demonstrates a close resemblance to tion rom G1 to S phase and promotes cell prolieration.
SLL/CLL.25 The heterogeneity in the clinical course Overexpressed cyclin D1 activates cyclin-dependent
Chapter 10 Mantle Cell Lymphoma 229
Leukemic non-nodel MCL (SOX11-): indolent behavior, delayed treatment
Cyclin Peripheral blood

deregulation
MCL IGHV-M
SOX11-
Reciprocal
translocation
Marginal
Pre B cell Zone Germinal 17p loss, TP53 mutation
center
Chromosomal complexity Blastoid MCL
IGH-CCND1 9p21 loss
IGH/K/L-CCND2
ISMCN
ATM, NOTCH1/2 Mutations
Cryptic Insertion
Germinal
center
CHAPTER 10
Marginal
IG-enh IGH/L-CCND1 Zone
IGH-CCND2
IGH/L-CCND3 MCL IGHV-U
SOX11+
Blastoid MCL
ISMCN
Conventional MCL (SOX11+): Aggressive behavior, high genomic instability
FIGURE 10–1 Possible model or development o mantle cell lymphoma (MCL). Two major clinical orms: one is a common
conventional orm, which is aggressive in its clinical course and is characterized by SOX-11–positive and unmutated immuno-
globulin heavy chain variable region (IGHV) and another is an indolent orm o MCL, which is generally leukemic, non-nodal,
SOX-11–negative, and exhibits germinal center reaction eature with somatic hypermutation o IGHV. In situ mantle cell neo-
plasia (ISMCN) is the presence o MCL clones in the inner mantle zone without disrupting the nodal architecture. The addition
o other aberrant molecular changes such as TP53 and CDKN2A deletions are shown to alter the clinical course toward an
aggressive blastoid or pleomorphic type o MCL. (Reproduced with permission rom Navarro A, Beà S, Jares P, et al: Molecular
Pathogenesis o Mantle Cell Lymphoma, Hematol Oncol Clin North Am 2020 Oct;34(5):795-807.)
kinases 4 and 6, which in turn phosphorylate and inac- where the MCL cases show cyclin D1 rearrangement
tivate Rb (tumor suppressor gene) and promote G1 to with IgK or IgL, are observed. Conventional karyotype
the S phase, leading to rapid cell prolieration. Cyclin or usion or break-apart fuorescent in situ hybridiza-
D1 also interacts with chromatin remodeling, histone- tion (FISH) probes ail to detect these variant transloca-
modiying enzymes and transcription actors and tions. Occasionally, cyclin D1 may not be detectable
modulates transcriptome. Perinucleolar localization o by immunohistochemistry but is detectable by FISH,
t(11;14)33 or the CCND1 allele is important because and this is related to the presence o cyclin D1b iso-
these areas are rich in RNA polymerase II, leading to orm39 or a mutation in C-terminal domain on cyclin
activation o cyclin D1 transcription.34 Truncated orm D1.
o cyclin D1 (deletion aecting the 3′ untranslated
region o cyclin D1) stabilizes the cyclin D1 transcript,35
and this results in increased cyclin D1 mRNA levels.
Cyclin D1-Negative MCL
Increase in the truncated orm o cyclin D1 is associated Rarely, cyclin D1 is negative by immunohistochemistry
with poor clinical outcome.36 and t(11;14) is not detectable by FISH. Cyclin D2 or
cyclin D3 gene rearrangements or an upregulation o
cyclin E can be observed.40,41 In a third o these rare
Cryptic Pyclin D1-Positive MCL cases, Ig light chain enhancer hijacking is observed as
Rarely, variant cyclin D1 translocations such as trans- the initial oncogenic aberration. Generally, these cases
location t(2;11) (p11;q13)37 and t(11;22) (q13;q11.2),38 are associated with SOX-11 positivity, exhibit a similar
gene expression prole, and clinical course to that o observed in approximately 30% to 50% o MCL cases.
conventional MCL, but very rare cases with cyclin E ATM is involved in the detection o DNA damage and
dysregulation are associated with blastoid morphology plays an important role in the regulation o cell cycle
and an aggressive clinical course.41 progression.
Other Cell Cycle Dysregulations Apoptosis Resistance

CDKN2A Deletions In MCL, resistance53 to apoptosis may occur as a
result o overexpression o B-cell lymphoma 2 (BCL2),
CDKN2A gene encodes or p16 (INK4A; a cyclin- upregulation o the PI-3 kinase/AKT prosurvival sig-
dependent kinase inhibitor that specically inhibits naling pathway, and/or activation o nuclear actor-κB
CDK4 and CDK6 keeping RB1 active) and or p14 (NF-κB) and/or mutations in TP53. Gain-o-unction
(ARF; a E3 ubiquitin-protein ligase that stabilizes TP53 truncating mutations in NOTCH1 and NOTCH2 genes
by interacting with MDM2 preventing its degrada- are also relevant in mediating apoptosis resistance in
tion).42 Deletion o INK4a/ARF locus on 9p21 occurs in MCL.54,55 NOTCH activation may also induce overex-
about 20% to 25% MCL and is associated with aggres- pression o MYC.
sive histology MCL.43
Epigenetic Perturbations and Other Molecular

CDK4 Amplication
CHAPTER 10
Alterations
Gains in 12q or copy number gains in 12q are associated
Integrated genomics approaches have revealed that
with promotion o cell cycle dysregulation and an
complex genomic variants30,56 and higher degree o
aggressive (blastoid) histology MCL.44 Inhibition o
DNA methylation is associated with higher proliera-
CDK4 can possibly overcome ibrutinib resistance.45
tion and aggressive behavior o MCL cells.27 Common
mutations that aect the epigenetic pathways in MCL
SOX-11 Overexpression include KMT2D,57 NSD2,58 and mutations in SWI-
SOX-11 is a neural transcription actor that plays a SNF chromatic remodeling complex59; SMARCA4,
critical role in the pathogenesis o MCL. Overexpres- SMARCA2, and ARID2 mutations are associated with
sion o SOX-11 is observed in conventional MCL and resistance to ibrutinib-venetoclax in MCL. Other
in 25% to 50% o Burkitt lymphoma.46 SOX-11 over- mutations such as MEF2B and UBR560 are inrequent
expression in MCL is shown to infuence MCL cells in MCL and infuence transcription and post-tran-
via various mechanisms—constitutive activation o scription processes. Other aberrant somatic muta-
PAX-5, thereby blocking the dierentiation o B-cells tions include MAP2K14, NOTCH2, BIRC3, KMT2D,
to plasma cells by impairing BLIMP147; augmented CARD11, SMARCA4, and BTK.61 Activation o PI3K/
BCR signaling48; suppression o Bcl-6 to avoid germinal AKT and the integrin-β1 signaling pathway62 has been
center transit o MCL cells, which exhibit unmutated shown as another mechanism o acquired ibrutinib
IGHV49; promotion o angiogenesis via platelet-derived resistance. O note, mutation prole in case o ibru-
growth actor α50; and migration and adhesion o MCL tinib resistance or venetoclax resistance in MCL is
cells to stromal cells via upregulation o CXCR4 and dierent rom that o CLL because BTKC481S muta-
ocal adhesion kinases, leading to enhanced PI3K/AKT tions were inrequent in MCL58 (10%–15%) and BCL2
signaling and promoting cell adhesion–mediated drug mutations were also inrequent in venetoclax-resis-
resistance.51 tant MCL.63 Altered splicing o the HNRNPH1 gene
associated with RNA processing is also observed in
patients with MCL. 64
TP53 Mutations
TP53 gene (tumor protein 53) is a tumor suppresser gene Microenvironmental Impact and BCR Signaling
located at 17p13.1, which, when inactivated, deleted, Kinases
or mutated, can unleash genomic instability, cell cycle
upregulation, inhibition o apoptosis, and promotion o The tissue microenvironment cellular composition
cell growth. TP53 mutations predict an aggressive dis- and cytokine milieu play a vital role in MCL cell
ease course and inerior outcomes52 in MCL. growth and survival and promote drug resistance. In
contrast to peripheral blood, the lymph node micro-
environment in patients with MCL is unique, having
ATM Mutations
a dierential expression o genes involved in BCR sig-
Ataxia telangiectasia mutated (ATM) tumor suppressor naling and canonical NF-κB pathways.65 This eature
gene is located on 11q22-q23 and ATM mutations are in MCL provides activation signals to MCL cells and
is involved in drug resistance. In addition, because and parts o the gastrointestinal tract (lymphomatous
the M2 polarized macrophages (CD163+), which are polyposis)73,74 are common. Extranodal involvement
tumor-associated macrophages, play an important o the kidneys and central nervous system (CNS) is
role in promoting MCL cell survival via colony-stimu- rare.75,76 The pure asymptomatic, non-nodal leukemic
lating actor-1, 66 thereore, inhibition o colony-stim- phase, in which the absolute monoclonal lymphocyte
ulating actor-1 receptor might be clinically useul. count is higher than 5000 cells/µL is inrequent and
Targeting various components o BCR signaling67,68 may masquerade as CLL. The asymptomatic indolent
and interactions with stromal cells can overcome or smoldering nodal/extranodal77 or leukemic non-
treatment resistance and eradicate dormant residual nodal presentation26,78 is seen in about 10% to 20% o
cells.69 Additional studies on the cytokine-chemokine cases and generally does not require immediate sys-
milieu and its interaction with MCL cells and stromal temic treatment, and can simply be saely observed.79
cells in tissue microenvironment are under investiga- Conversely, most patients with MCL (~80%) pres-
tions. Finally, an immune “cold” microenvironmental ent with symptomatic lymphadenopathy or extrano-
signature was shown to be associated with ibrutinib dal disease requiring systemic therapy. Appropriate
resistance in MCL.70 diagnostic workup o patients with MCL is the initial
Furthermore, using RNA sequencing, we showed critical step to determine the diagnosis and the prog-
that a dysregulated metabolic programming exists nosis. Figure 10–2 outlines our clinical approach to the
in MCL cells and contributes to ibrutinib resistance. patient with MCL.
Inhibition o oxidative phosphorylation in MCL The initial workup includes history and physi-
CHAPTER 10
cells can provide an opportunity to inhibit ibrutinib- cal examination, assessment o perormance status,
resistant MCL cell growth in patient-derived mouse comorbidities, and B symptoms. Laboratory workup
models.71 must include a complete blood cell count with dier-
ential count, comprehensive metabolic panel, serum
lactate dehydrogenase (LDH) levels, β2 microglobulin
CLINICAL WORKUP AND levels, and hepatitis panel. Bone marrow aspiration/
DIAGNOSIS OF MCL biopsy and involved tissue biopsy is routinely per-
ormed at initial diagnosis. Immunophenotype on
Clinical maniestations o MCL are summarized in peripheral blood/bone marrow/involved tissue biopsy
Table 10–172 and commonly present as symptomatic is critical. The typical MCL immunophenotype26 is
progressive generalized lymphadenopathy, cytopenia, CD5, CD20, CD19, sIgM/sIgD, FMC-7 + B-cells with
and bone marrow inltration. Enlarged spleen, tonsils, monoclonal kappa/lambda light chains, dim/negative
Table 10–1 Clinical Presentations in MCL Patients
Clinical Presentation Clinicopathologic Features

Smoldering MCL77 Asymptomatic and with absence o B symptoms (drenching night sweats, unintentional weight loss
o >10% o normal body weight over a period o ≤6 months or less, ever >38 °C), main indicator or
smoldering MCL
Normal serum LDH, β2 microglobulin levels
White blood cell count <30,000 K/µL
Low MIPI (mantle cell lymphoma international prognostic index) score
Ki-67% on lymphoma cells in nonmarrow tissue biopsy o <30%
Nonblastoid/pleomorphic cytomorphologic pattern in tissue biopsy
Maximum lymph node diameter <3 cm, spleen size <20 cm
PET scan showing the maximum standardized uptake value <6
Absence o TP53 or NOTCH1/2 mutations by DNA sequencing
Absence o deletion 17p or MYC translocation/amplication by FISH testing, absence o complex
karyotype
Asymptomatic Monoclonal B lymphocytosis (with typical MCL immunophenotype and nonblastoid morphology) in
purely leukemic peripheral blood with or without splenomegaly
nonblastoid MCL
Conventional MCL Symptomatic bulky nodal/extranodal disease
(most common) Classic or blastoid/pleomorphic cytomorphology
At initial diagnosis or at clinical progression
Reproduced with permission rom Jain P, Wang M: Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management, Am J Hematol
2019 Jun;94(6):710-725.
PATHOLOGIC DIAGNOSIS INITIAL EVALUATION
ESSENTIAL: ESSENTIAL:
• Hematopathology review of all slides with at least one tumor • Physical exam: attention to node-bearing areas, including Waldeyer’s
paraffin block. Hematopathology confirmation of classic versus ring, size of liver and spleen, and patient’s age
aggressive variant of MCL (blastoid/pleomorphic). Re-biopsy • Performance status (ECOG)
if consult material is non-diagnostic. • B symptoms (fever, drenching night sweats, unintentional weight loss)
• Adequate immunophenotype to confirm diagnosis1 • CBC with differential, LDH, BUN, creatinine, albumin, AST, total bilirubin,
° Paraffin panel: alkaline phosphatase, serum calcium, uric acid
- Pan B-cell marker (CD19, CD20, PAX5), CD3, CD5, CD10, • Screening for HIV 1 and 2, hepatits B and C (HBcAb, HBaAg, HCVAb)
and cyclin D1 • Beta-2 microglobulin (B2M)
- Ki-67 (proliferation rate) • Chest x-ray, PA and lateral
or • Bone marrow bilateral biopsy with unilateral aspirate
° Flow cytometry immunophenptyping: kappa/lambda light chains, • CT neck, chest, abdomen and pelvis with contrast
CD5, CD10, CD19, CD20, CD23, FMC-7, CD200, and CD43 • PET/CT without contrast
OF USE IN CERTAIN CIRCUMSTANCES: • Lifestyle risk assessment4
• Molecular genetic analysis OF USE IN SELECTED CASES:
° Somatic hyper-mutation for IGHV gene rearrangement and • Upper GI/barium enema/endoscopy • Lumbar puncture
mutation status • Plain bone radiographs and bone scan • Stool guaiac
° TP53 ° NSD22 ° CDKN2A3 • CT head or MRI brain • Colonoscopy
° NOTCH1 ° BTK ° KMT2D3 • Discuss fertility preservation options • Urine pregnancy test
2
° NOTCH2 and sperm banking for patients of child
• Immunohistochemistry for SOX-112 bearing potential
• FISH to detect t(11;14(q13;q32)/CCND1-IgH, TP53, and MYC • Referral(s) as indicated:
STRONGLY RECOMMENDED: ° Cardiology to screen for cardiac related comorbidities
• Fine needle aspiration (FNA) or core biopsy for tissue banking ° Genetics to screen for family history of hematologic or other cancers
CHAPTER 10
by protocol ° Dermatology to screen for secondary cancer risk

FISH = fluorescence in situ hybridization
FIGURE 10–2 Outlines o our approach in the initial evaluation o a patients with a newly diagnosed mantle cell lymphoma
(MCL). Immunophenotype: CD5++, CD20++, CD43++, CD23–/+/+, cyclin D 1+. Note: Some cases o MCL may be CD5–, CD10++,
or CD23. I the diagnosis is suspected, cyclin D 1 staining or FISH to demonstrate t(11;14, q13, q32) should be perormed. Cur-
rently approved. Currently not available or routine testing. Ongoing reassessments o liestyle risks (smoking, physical activity,
and nutrition should be a part o routine clinical practice).
CD23, dim/negative CD200, and strong cyclin D1 tissue biopsies or prognosis. Imaging studies should
expression. Immunohistochemical analysis o involved be obtained or staging and include assessment with
nodal/extranodal tissues shows a strong nuclear stain- whole-body positron emission tomography-com-
ing or cyclin D1 (BCL-1 or PRAD-1), and generally puted tomography (PET-CT) scan or CT scan only.
MCL cells are positive or SOX-11. Cytogenetic assess- Serial imaging studies will demonstrate response to
ment or karyotype or FISH showing translocation treatment (Lugano lymphoma response criteria).81
t(11;14) (q13; q32) is an important diagnostic hallmark A pregnancy test, magnetic resonance imaging o
o MCL (90%). At MDACC, i the BM involvement is the brain, electrocardiogram, echocardiogram, and
higher than 10% by MCL cells then we also perorm endoscopic evaluation o the gastrointestinal tract
somatic mutation o IGHV genes, percent deviation (essential to conrm stage I-II disease) should be con-
rom germline IGHV sequence, and type o VH gene ducted depending on the clinical presentation and/
usage. Targeted DNA sequencing rom involved tis- or requirement by the clinical trial protocol (i appli-
sues or somatic mutations such as TP53, NOTCH1/2, cable). Cardiac status should be evaluated by a cardi-
BIRC3, CDKN2A, NSD2, BTK, and ATM genes is very ologist beore starting Bruton tyrosine kinase (BTK)
useul. inhibitor therapy. Consider stem cell transplantation
Comprehensive histopathologic assessment o (SCT) consultation or high-risk patients. Lumbar
involved tissue biopsy is required. Morphology at puncture is perormed in cases with clinically sus-
initial diagnosis can change at disease progression/ pected CNS involvement. In addition to morphology,
relapse to an aggressive morphology (blastoid/pleo- immunophenotype should be perormed rom any
morphic), ie, transormed MCL (t-MCL). Figure 10–3 fuid assessments (cerebrospinal fuid and/or ascitic
shows the morphologic spectrum o MCL. The his- or pleural fuid).
tology can vary rom classic morphology (nodal, Finally, exploratory investigations in MCL would
mantle zone, interstitial, diuse) to an aggressive include serial plasma samples and genomic evaluation
histology (blastoid or pleomorphic). MCL cell size o tissue biopsies at diagnosis and relapse, analysis
can vary rom small to medium with irregular nuclei o minimal residual disease (MRD) and copy number
to lymphoblast-like cells (medium to large) that are changes, as well as or chromosomal aberrations and
blastoid or pleomorphic. It is mandatory to obtain the clonal evolution assessment. Multiomic assessment
Ki-67%80 o MCL cells rom the involved nonmarrow with single-cell sequencing is perormed at MDACC.
A C
FIGURE 10–3 (A–C) Representative hematoxylin and eosin

B (H&E) images (400×) o classic MCL and aggressive MCL; blas-
toid, pleomorphic variants rom lymph node biopsies. A. Classic
morphology MCL cells. Monotonous population with slightly or
CHAPTER 10
markedly irregular nuclear contours and moderately dispersed
chromatin. This variant can demonstrate a nodular or difuse
architectural pattern. B. Blastoid morphology with homoge-
nous pattern, round nuclei, and ne thin chromatin resembling
lymphoblasts is shown; black arrows point to typical blastoid
MCL cells. C. Pleomorphic morphology, heterogeneous distri-
bution, small-to-large MCL cells with anaplastic nucleus, irregu-
lar but requent and prominent nuclei, resembling large B-cell
lymphoma (black arrows point to typical blastoid MCL cells).
(Reproduced with permission rom Jain P, Zhang S, Kanagal-
Shamanna R, et al: Genomic proles and clinical outcomes o
de novo blastoid/pleomorphic MCL are distinct rom those o
transormed MCL, Blood Adv 2020 Mar 24;4(6):1038-1050).
Diferential Diagnoses CD5-negative MCL,84 cyclin D1–negative MCL,40,85

CD200+ MCL,31 SOX-11–negative MCL,28,86 and
MCL can be distinguished rom other masquerad- CD23–positive MCL.87 In some cases, biopsies may
ing lymphoid malignancies such as SLL/CLL,25 ol- reveal presence o cyclin D1+ cells in the inner mantle
licular lymphoma, marginal zone lymphoma, and zone o lymphoid ollicles (termed as in situ mantle cell
B-cell–prolymphocytic leukemia. Translocation neoplasia),26,32 which should not lead to a diagnosis o
t(11;14) (q13;q32) can be observed in a raction o MCL.
patients with multiple myeloma (20%–25%), SLL/
CLL (2%–5%), and plasma cell leukemia and B-cell–
prolymphocytic leukemia (20% with t (11;14) and
cyclin D1+ cells, and these are considered as the PROGNOSTIC FACTORS IN MCL
leukemic phase o MCL 82). Cyclin D1 expression is
also observed in a subset o patients with myeloma, Determining the prognosis is o vital importance.
hairy cell leukemia, and splenic lymphoma, and Various parameters that can reliably predict patient
SOX-11 expression can be seen in Burkitt lymphoma prognosis are summarized in Table 10–2. We have
(20%–25%), hairy cell leukemia, and lymphoblastic implemented the inclusion o these risk actors
lymphoma. to select therapy in the ongoing clinical trials at
MDACC. We believe that in the uture, the selection
o therapy will be based on risk actors. Thus ar, the
Atypical MCL relevance o prognostic actors is well established
Variations rom the typical immunophenotype o in patients treated with chemoimmunotherapy.
MCL are included under this category. These varia- We also anticipate that with the advent o newer
tions are largely based on fow cytometric evaluation therapies, the prognostic impact o risk actors may
o the involved tissues and include CD10+ MCL,83 change.
Table 10–2 Summary of Prognostic Markers in Newly Diagnosed Patients With MCL
Currently Used May Be Included Under Initial Workup i Available in Clinical Practice
Perormance status Complex karyotype 103
Advanced age with comorbidities MYC translocation or overexpression104
MIPI risk categories88 Unmutated IGHV status28
Blastoid/pleomorphic cytomorphology Additional somatic hypermutations - NOTCH1 and NOTCH2 mutations,55
Ki-67% >30%90 CCND1, NSD2 (WHSC1)55a, SWI/SNF (SMARCA4)a, BIRC3, KMT2D/MLL2,
TP53 mutations, TP53 by FISH or overexpression o BTKa,58 CDKN2Aa, MAP3K14a, CARD11a
TP53 by immunohistochemistry52 MCL35 RNA expression assay113
Tumor metabolic volume by PET-CT scans
MRD testing by ow cytometry, PCR or IgH, t(11;14), IgH clonocseq or
by ctDNA
miRNA18b91
a
Gene mutations associated with ibrutinib-venetoclax resistance in patients with relapsed MCL.
As o this writing, the ollowing actors are compared with classic histology MCL. We described
used in routine clinical practice to determine high patients with de novo aggressive-histology MCL who
CHAPTER 10
risk in MCL patients: high-risk MIPI (mantle cell had superior survival (48 months) compared with
lymphoma international prognostic score), blastoid patients with t-MCL (14 months). These aggressive
or pleomorphic histology, high Ki-67% (≥30%) histologies coexist with additional high-risk eatures,
score, and TP53 mutations. In addition, in relapsed especially with CNS involvement (5%). In addition,
patients, t-MCL and/or complex karyotype and/or high-risk genomic prole is requently observed in
early progression within 12 to 24 months ater starting aggressive-histology MCL92 (reviewed in detail in reer-
rst-line chemoimmunotherapy or detection o ence 93). Because most o the patients with aggressive-
additional somatic mutations in addition to TP53 such histology MCL also exhibit high Ki-67%, patients with
as CDKN2A, KMT2D, NSD2, NOTCH1/2, BIRC3, or either one or both o these risk actors are considered
SMARCA4 are highly indicative o high-risk MCL. as high-risk MCL.
The MIPI risk scoring is commonly used. The sim- Finally, TP53 gene mutations are well established in
plied MIPI score is based on a weighted sum (o per- MCL.94,95 Reported requency o TP53 mutations at ini-
ormance status, age, LDH levels higher than upper tial diagnosis is about 15% to 25%, and the requency
limit o normal and white blood cell count) and divides o these mutations increases up to 45% at relapse.96
the patients into low-, intermediate-, and high-risk High tumor burden o TP53 mutations indicates a
categories.88 The score can be used as a continuous worse prognosis.97 A Nordic group52 has reported that
variable. Patients with MIPI scores less than 5.70 were the requency o TP53 mutations at initial diagnosis
classied as low risk, patients with MIPI scores o at was 11%, and these patients have a poor response to
least 5.70 but lower than 6.20 as intermediate risk, and standard rontline chemoimmunotherapy. The median
patients with MIPI score o at least 6.20 as high risk. OS was 1.8 years in TP53 aberrant versus 12.7 years in
The 5-year overall survival (OS) rate in low-, intermedi- patients without TP53 aberrancy. TP53 gene mutations
ate- and high-risk MIPI categories was 81%, 63%, and may coexist with other aberrations such as NOTCH1
35%, respectively, and this was validated in the context mutation (71%), deletion o CDKN2A (del9p21) (31%),
o European randomized clinical trials with chemoim- and deletion o TP53 (del17p13) (31%). The presence o
munotherapy.89 The prognostic value o the simplied both TP53 deletion (detected by FISH) and TP53 muta-
MIPI risk score is urther improved by adding the value tions (by DNA sequencing) was associated with the
o Ki-67%, and this modied MIPI score is also called worst survival. In addition, we have demonstrated that
biologic MIPI or MIPIb.90 In general, a Ki-67% more TP53 mutations may coexist with NSD2 mutations in
than 30% is considered as the high-risk category and a three o our patients with ibrutinib-resistant t-MCL.58
cuto value o more than 50% is used at MDACC. The
5-year survival percentage in low-, intermediate-, and
high-risk MIPIb categories was 81%, 83%, and 37%, Other Important Prognostic Factors
respectively. Further modications o MIPI—combined
SOX-11
MIPI (MIPIc) with binary Ki-67% and MIPI score and
MIPIb with expression o miR-18b91—are reported. Absence o SOX-11 expression with mutated IGHV
The presence o aggressive-histology MCL, ie, blastoid identied a subset o patients with MCL with a avor-
or pleomorphic variants, exhibit an inerior prognosis able prognosis.28,98 The clinical relevance o SOX-11
in nodal MCL in the era o newer therapies remains poor outcome and increased risk o relapse on subse-
unclear.99 IGHV somatic mutation status and the type o quent lines o therapies.120 Visco et al.121 demonstrated
VH gene usage type are important variables. Patients that among the 188 patients who received intensive
with mutated MCL (>3% deviation rom the germ- chemoimmunotherapies (with/without consolidative
line sequence)100 exhibit a better outcome compared SCT), patients with early disease progression (<24
with patients with unmutated IGHV; however, the months rom diagnosis; n = 90) had signicantly shorter
systematic studies on IGHV mutation status in MCL OS (rom the time o disease progression ater rst-line
are lacking, especially in the context o newer thera- therapy to death rom any cause) compared with late
pies.28 Complex karyotype, dened as having three progressors (n = 98) (median survival 12 months and
or more chromosomal abnormalities in addition to not reached, respectively; P < .001). Patients with early
t (11;14) or additional chromosomal abnormalities ailure had an increased risk o death.
detected by conventional karyotype,101 also coexist
with TP53 mutations and generally exhibit poorer out-
MRD-Positive Status
comes.102,103 Miscellaneous actors associated with re-
quent relapses and disease resistance include CDKN2A This is proposed as an important prognostic actor to
(locus 9p21) deletions43,59; MYC gene rearrangements; predict relapses. The optimal technique to detect MRD
and amplication o MYC,104–108 NOTCH1,54 and/or in MCL is investigational—either fow cytometry
NOTCH255 mutations; NSD2 mutations55,109; CCND1 rom bone marrow (i involved at baseline), periph-
mutations110; and KMT2D57 SWI/SNF (SWitch/sucrose eral blood polymerase chain reaction (PCR) or IgH or
CHAPTER 10
nonermentable) chromatic remodeling complex IgH clonoseq by next-generation sequencing, or track-
mutations (including SMARCA4 gene); these are asso- ing ctDNA (circulating tumor DNA or liquid biopsy).
ciated with ibrutinib-venetoclax resistance,59 BIRC3 MRD estimation and optimization in MCL is inves-
(Baculoviral IAP repeat containing three mutations are tigational. In a phase 3 randomized trial,122 patients
seen in 10%–15% o patients with MCL). BIRC3 dele- (n = 240) who had received our cycles o rituximab
tions o 11q21–q23 are common alterations in MCL, – dexamethasone, cisplatin, ara-C (R-DHAP) induc-
and in addition to ATM, BIRC3 is also located in this tion ollowed by auto-SCT were randomly assigned
region (11q22.2). BIRC3 aberrations in MCL may result to observation versus rituximab maintenance groups.
in decreased response to ibrutinib because o a ailure The rituximab maintenance group received 375 mg/
to suppress the alternate NF-κB pathway mediated by m2 rituximab once every 2 months or 3 years. This
MAP3K14, which is proposed as a therapeutic target study demonstrated that rituximab maintenance can
in BIRC3-mutated lymphomas.111 Elevated absolute improve survival ater SCT. Achieving MRD-negative
monocyte count is also prognostic.112 status improves outcome and may obviate the need
Gene prolieration signature (MCL35 assay) is pre- or maintenance therapy ater SCT. MRD assessment
dictive o prognosis. Using a NanoString RNA expres- in MCL has not been systematically implemented in
sion–based molecular assay (MCL35113–115), a 17-gene clinical practice; however, a ew studies123 have shown
prolieration signature was validated to predict prognosis the clinical signicance o MRD-positive disease sta-
in patients with MCL treated with rst-line chemoimmu- tus and risk o predicting uture relapses.124–126 Kolstad
notherapy. In another study, a six-gene signature (AKT3, et al has shown that preemptive rituximab treatment
BCL2, BTK, CD79B, PIK3CD, and SYK) was predictive o has shown benet in turning MRD-positive status post
poor outcome,116 but exhibited higher sensitivity to ibruti- auto-SCT to MRD-negative status; however, 69% o
nib.117 Micro-RNA (miRNA) prole is investigational.29,118 patients relapsed ater rituximab therapy. Detailed dis-
Patients with an overexpression o miR-18b91 were identi- cussion o methodology o MRD and various studies
ed as a high risk in the MCL3 prospective clinical trial. in MCL with MRD is beyond the scope o this chapter
The impact o complete metabolic response ater treat- and is discussed elsewhere.127
ment completion is also known to correlate with a better
clinical outcome119; however, this aspect requires urther
Progression on BTK inhibitors
validation or MCL in prospective studies. Detailed dis-
cussion o mechanistic relevance o each prognostic actor The approval o the BTK inhibitor ibrutinib is a major
in the context o MCL is beyond the scope o this chapter. advance in MCL128; however, progression an outcome
o patients who progress on ibrutinib has become
Post-Treatment Prognostic Factors a therapeutic challenge as these patients generally
exhibit poor outcomes. The pattern and mechanisms
Early Disease Progression
o resistance o ibrutinib in MCL are under active
Disease relapse or progression within 12 to 24 months investigation. The median survival ater progression
ater receiving rst-line therapy such as intensive che- on ibrutinib was 2.9 months in 114 patients with
moimmunotherapy (with/without) SCT can portend a MCL.129 In a cohort o 80 patients with relapsed MCL
at MDACC who discontinued ibrutinib,58 the out- inhibitors, venetoclax and anti–CD19-CAR-T), and
comes o patients who progressed on ibrutinib (n = 41) patients who have CNS disease continue to remain a
were very poor, with a median survival o 9 months huge therapeutic challenge.
(range 6–10). Response rates to subsequent treatments At MDACC, we approach patients with MCL using
were about 30% with chemoimmunotherapy, benda- the ollowing ve clinical categories: (1) smoldering
mustine, lenalidomide, or bortezomib. Furthermore, MCL; (2) previously untreated patients (age <65 or age
development o anti–CD19-CAR-T has demonstrated ≥65 years) in all risk categories; (3) previously treated
excellent results in managing BTK inhibitor–reractory relapsed MCL–BTK inhibitor-naïve; (4) previously
MCL130; however, longer ollow-up o this modality is treated relapsed MCL–BTK inhibitor reractory; and
awaited. (5) triple-relapsed-reractory MCL.
TREATMENT OF PATIENTS WITH Smoldering MCL

MCL For patients with excellent perormance status (0), no
B symptoms or asymptomatic, nonbulky disease (<5
Various actors should be considered beore selecting cm) with normal LDH levels, low Ki-67% (<30%),
therapy. These include patient related actors: per- and nonaggressive cytomorphology, we do not rec-
ormance status, age, comorbidities, disease status ommend systemic therapy and these patients can
(smoldering nodal MCL vs leukemic non-nodal vs con- simply be observed.77 These patients can also exhibit
CHAPTER 10
ventional nodal MCL presentation), organ dysunc- an asymptomatic, non-nodal leukemic phase or local-
tion, prior therapies (i relapsed), toxicities rom prior ized gastrointestinal involvement. We counsel these
therapy, eligibility or SCT, nancial constraints, and patients about the risks and benets o observation
availability o a clinical trial. Feasibility or clinical trial alone.140 It is also important to distinguish smoldering
or reerral to a specialized center that treats patients MCL rom MCL in situ neoplasia because in situ neo-
with MCL should always be explored. A recent study plasia does not qualiy to be reerred to as MCL.
rom the United Kingdom showed that patients who Observation as an initial strategy in MCL is
received treatment at specialized centers had better described by eight dierent studies. Most recently, a
outcomes compared with those treated at nonspecial- series o 94 patients by Kumar et al141 was reported.
ized centers.131 The median time o observation alone was 23 months
Chemoimmunotherapy still remains a standard and non-nodal clinical presentation was associated
rontline treatment in most centers. Chemotherapy- with longer time to initiate treatment. Although
associated toxicities, prolonged myelosuppression, patients with high Ki-67% (>30%) tend to receive
inection-associated mortality, therapy-related myelo- immediate therapy versus observation alone, among
dysplasia, and second cancers remain a serious concern. the patients who were under observation alone, the
Considerable advances are made in the treatment time to rst treatment was similar, irrespective o
or patients with MCL. Currently, the ocus is headed Ki-67%. This nding indicated that extent o clinical
toward chemotherapy-ree treatments in the ront- symptoms and clinical eatures, rather than Ki-67% or
line and relapsed settings. In the relapsed setting, BTK TP53 status, should determine whether patients can
inhibitors, venetoclax, and FDA approval o brexu- be observed. In another study rom British Colum-
cabtagene autoleucel are major achievements. Initially, bia,79 440 patients were reviewed (75 with observa-
BTK inhibitors were shown as eective in canine lym- tion alone or ≥3 months, 365 with early treatment).
phoma models.132 This seminal study drove human tri- Overall, 80% o patients underwent observation or
als with BTK inhibitors in lymphoma.133 Our group led more than 12 months, including 10 patients who were
the initial clinical trial o ibrutinib in relapsed MCL.128,134 observed or more than 5 years. The median ollow-
Subsequently, we also led the FDA approval or acala- up in the observation group was 48 months, and the
brutinib.135 Venetoclax is also investigated in reractory median time to rst treatment was 35 months (range
MCL.63,136,137 Furthermore, we characterized ibrutinib58 5–79). The median OS was signicantly longer in the
acalabrutinib,138 and venetoclax-reractory139 MCL observation group compared with the early treatment
patients and their genomic eatures to possibly explore group (72 vs 52.5 months; P = .04). Patients with non-
mechanisms o resistance. Finally, our group led the nodal clinical presentation or those with negative TP53
pivotal Zuma-2 study and the FDA approval o brexu- by immunohistochemistry had longer survival in the
cabtagene autoleucel (anti–CD19-CAR-T) in relapsed observation group. Another study using the National
or reractory MCL. Cancer Database reported that among 8029 patients
Despite these advances, more research and newer with MCL, 492 were deemed as wait-and-watch-
clinical trials are needed in MCL. High-risk patients, alone. Younger age, male gender, and lack o comor-
patients who are triple resistant (reractory to BTK bidities were predictive o OS.142
A group rom Spain reported the initial results o The use o Hyper-CVAD with alternating Mtx/
ibrutinib with rituximab in indolent MCL (n = 40).143 ara-C ollowed by consolidation auto-SCT, was
They demonstrated that in patients with indolent initially reported rom MDACC in 1998.147 We
MCL, ibrutinib with rituximab therapy led to deep conducted a phase 2 clinical trial with R-HCVAD/
MRD-negative responses (87%). At MDACC, we are methotrexate-ara-C regimen in 97 patients. Ater
conducting a phase 2 study with single-agent ibrutinib a median ollow-up o 13.4 years,148 the overall
in high-risk smoldering MCL (NCT03282396). High- response rates (ORR) and complete remission (CR)
risk smoldering MCL reers to patients who have clini- rates were 97% and 87%, respectively. The ailure-
cally smoldering MCL but exhibit high-risk eatures, ree survival in young patients was 30% ater 10 years
with TP53 mutations and/or high Ki-67% (≥30%). In and appeared to reach a plateau. In another study,
this study, we are investigating whether the use o bortezomib was added to R-HCVAD/methotrexate-
ibrutinib in smoldering MCL instead o observation ara-C, 149 but the response rates did not improve over
alone can prolong the time to rst treatment in high- R-HCVAD alone.
risk patients with MCL. The R-HCVAD regimen was also tested in two mul-
Limited-stage disease, ie, stages I/II, is uncommon. ticenter phase 2 studies—one rom Italy150 (n = 60) and
These patients can all into the smoldering MCL cat- another rom SWOG151 (n = 49). The ORRs were 83%
egory; however, there are patients who have limited- and 86%, respectively. Because o severe hematologic
stage disease but signicant symptoms and they need toxicities, 40% to 60% o patients could not tolerate
treatment—either local radiation or systemic therapy the treatment and could not complete the regimen.
CHAPTER 10
alone. Management o limited disease is detailed in More commonly, a Nordic regimen is utilized in
reerence 144. clinical practice.152,153 In a phase 2 trial with R-maxi
CHOP alternating with R-high dose ara-C was used
Previously Untreated Patients (Age <65 or and showed 97% response rate; however, 9% o
patients had development o second cancers over
Age ≥65 Years)—All Risk Categories long-term ollow-up. One phase 2 French study154 used
Factors to consider beore selecting rontline therapy three cycles o R-CHOP and three cycles o R-DHAP
are age, perormance status, eligibility or SCT, risk ollowed by auto-SCT in 60 patients, with 90% to
categories especially or high-risk patients, and avail- 94% ORR. With a median ollow-up o 67 months,
able clinical trials. Limited-stage, nonbulky disease the 5-year OS was 75%. In a phase 3 trial rom the
may benet rom the addition o radiation to chemo- European MCL network,155 R-CHOP/R-DHAP ol-
therapy; however, this strategy has not been conrmed lowed by auto-SCT was compared against R-CHOP
in large randomized studies.145 Chemoimmunother- alone ollowed by auto-SCT. Time to treatment ail-
apy with or without autologous SCT and with or ure was signicantly longer with R-CHOP/R-DHAP.
without maintenance therapy is the most commonly In one recent retrospective analysis o young patients
used standard-o-care rontline treatment; however, with MCL (n = 1254),146 consolidation auto-SCT
at MDACC, clinical trials or chemo-ree therapies are was shown to be associated with improved progres-
the rst choice. In Table–3,72 we have summarized the sion-ree survival (PFS) but not OS in a multivariate
ndings rom major rontline clinical trials in patients analysis. Considering the durable remissions with
with MCL. auto-SCT, many physicians preer that young MCL
patients receive auto-SCT ater intensive induction
Previously Untreated Young Patients (Age chemotherapy. In addition, rituximab maintenance
or 3 years ater our cycles o R-DHAP ollowed by
<65 Years)—All Risk Categories auto-SCT led to signicant improvement in survival
At MDACC, the standard o protocol treatment or outcomes compared with observation alone.122
physically it, transplant-eligible patients is inten- Bendamustine was combined with rituximab
sive chemoimmunotherapy with rituximab with (BR) ollowed by rituximab and high-dose ara-C
HCVAD (hyperractionated cyclophosphamide, and auto-SCT in 23 patients.156 The median ollow-
vincristine, doxorubicin, dexamethasone) as part up was 13 months, and the PFS was 96%, with a
A and methotrexate-ara-C as part B (R-HCVAD/ median OS not reached. MRD-negative status ater
methotrexate-ara-C). We do not recommend con- chemotherapy alone was 93%. We do not have data
solidation with SCT ater R-HCVAD. At other cen- on whether BR induction is a better choice beore
ters, intensive chemoimmunotherapy is ollowed by auto-SCT compared with R-CHOP. In a randomized
auto-SCT and rituximab maintenance in high-risk SWOG study, BR was compared with R-HCVAD
MCL. 146 The choice o chemoimmunotherapy regi- beore auto-SCT, but the study was stopped prema-
men is based on easibility, physician choice, and turely because the stem cell mobilization ailure was
patient choice. 29% ater R-HCVAD.157
Table 103 Summary of Pivotal Published Studies in the Frontline Setting in MCL
Median
Number o Median Remission
Protocol Used Patients Follow-up ORR (CR), % Duration/PFS Median OS Comments
R-HCVAD/Mtx- 97 13.4 y 97 (87) 4.8 y 10.7 y In young (<65 y; n =
ara-C148,229,230 65) patients, median
(no auto-SCT) FFS 6.5 y and OS 13.4
whereas in older adult
(>65 y; n = 32), median
FFS 3 y and OS 4.9 y
6.2% rate o
myelodysplasia and
acute myeloid leukemia
Blastoid/pleomorphic
histology (n = 15) not
associated with survival
FFS plateaued ater 10 y
R-maxi-CHOP/R- 160 11.4 y 96 (54/89*) 8.5 y 12.7 y 145 patients received
CHAPTER 10
HiDAC (with auto-SCT, and median

auto-SCT), PFS and OS were 11 y
Nordic and NR
regimen152,153,231 9.4% rate o second
cancers (n = 20 with
15 solid tumors and 5
myeloid cancers)
Plateau in survival curves
not reached, 50%
patients relapsed ater
12 y
R-CHOP + 234 6.1 y 97 (61) vs 98 4.3 vs 9.1 y NR vs 9.8 y Time to treatment ailure
auto-SCT 232 (63) longer in ara-C group
R-CHOP/R-DHAP (9.1 vs 4.3 y)
+ auto-SCT155 OS was not signicantly
diferent
2.4% secondary leukemia
and 4.3% other cancers
with ara-C group
R-DHAP (4 cycles) 120 each 50 mo 89 (77) 4 y % (83% vs 4 y % (89% Maintenance rituximab
+ auto-SCT ater 4b 64%) vs 80%) ater R-DHAP induction
followed by R-DHAP therapy, ollowed by
rituximab R-BEAM consolidation
maintenance therapy, prevented
vs observation relapses and was
alone122 associated with a low
risk o major inection
BR vs R-CHOP 46 vs 48 45 mo 93b (40) vs 91 35.1 vs 22.1 NR in both Response rates were
(StiL)159 (30) mo reported rom both
indolent and MCL
patients
Trend o longer time to
next treatment with BR
but OS was similar in BR
vs R-CHOP
Long-term ollow-up and
detailed subset analysis
is not reported
Table 103 Summary of Pivotal Published Studies in the Frontline Setting in MCL (Cont.)
Median
Number o Median Remission
Protocol Used Patients Follow-up ORR (CR), % Duration/PFS Median OS Comments
b
BR vs R-CHOP 37 vs 37 65 mo 97 (31) vs 91 5 y 40% vs 82% vs Higher second cancers in
(BRIGHT)160,161 (25) 14% 85% BR group
alive at Detailed subset analysis is
5y not reported
Lesser toxicities with BR
c c
Bortezomib- 243 vs 244 82 mo 92 (53) vs 89 25 vs 14.4 mo 91 vs 56 Improved overall survival
R-CHOP (42) mo with bortezomib-R-
vs R-CHOP CHOP in patients with
alone164 high Ki-67% (>30%)
42% died in bortezomib
group vs 57% in
R-CHOP alone group
Similar incidence o
second cancers
CHAPTER 10
Lenalidomide- 38 64 92 (64) 5 y 64% 5 y 77% 6 patients (16%) had
Rituximab167,168 second primary cancers
(mostly skin cancers)
42% grade ≥3
neutropenia
Th2 to Th1 cytokine/
chemokine switch ater
3 cycles o induction
showing immune
modulation and efect
on inammation
a
CR 89% ater auto-SCT
b
In both indolent and MCL patients
c
140 and 128 patients were included at 82-month ollow-up.
The table excludes data in relapsed-reractory MCL and unpublished studies on rontline BTK inhibitors at the time o this writing.
NR is not reached, ORR is overall response rate, CR is complete response rate, yrs. Years, R-HCVAD/Mtx-ara-C (rituximab with hyperractionated cyclophosphamide,
vincristine, doxorubicin, dexamethasone alternating with highdose methotrexate and cytosine arabinoside), R-DHAP (rituximab – dexamethasone, cisplatin, ara-C), StiL
(study group indolent lymphoma).
Reproduced with permission rom Jain P, Wang M: Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management, Am J Hematol
2019 Jun;94(6):710-725.
Clinical Trials at MDACC or Young MCL the patients had grade 3 or higher atrial brillation or
bleeding.158 Longer ollow-up o this study is pending.
We have a portolio o clinical trials or rontline
This regimen is included in the 2020 NCCN guide-
therapy in young, physically t patients with MCL. We
lines or treating MCL (NCT02427620).
have incorporated orally available targeted therapies in
the rontline setting to minimize or obviate the need Window-2 Trial
or chemotherapy except in high-risk patients. These Ibrutinib and rituximab induction is ollowed by vene-
clinical trials include the ollowing. toclax and risk-stratied use o R-HCVAD-Metho-
trexate/ara-C. For high-risk patients (4 cycles) and or
Window-1 Trial moderate risk, only two cycles o chemotherapy are
Ibrutinib with rituximab (IR) induction (Part A) ol- approved, whereas the low-risk patients do not receive
lowed by short-course our cycles o R-HCVAD- chemotherapy (NCT03710772).
Methotrexate/ara-C (Part B) were used in 131 patients.
Ater a median ollow-up o 22 months, the ORR on Other Important Trials in Young MCL Patients in
part A o therapy was 100% (88% CR and 12% PR)
the Frontline Setting
and ater completion o both parts A and part B, ORR
was 100% (94% CR). Overall, the median PFS and OS TRIANGLE Study
were not reached (3 year, 85% and 97%, respectively) The TRIANGLE study is a phase 3 trial in young,
and nine patients had relapse ater treatment and 21 transplant-eligible patients in Europe. It is a three-arm
patients let the study or various reasons. None o randomized trial with six cycles o R-CHOP/R-DHAP
+ auto-SCT versus six cycles o R-CHOP + ibrutinib/R- combination was noted.164,165 the European MCL net-
DHAP + auto-SCT + 2 years o ibrutinib maintenance work demonstrated that rituximab maintenance or
versus six cycles o R-CHOP + ibrutinib/R-DHAP + two years or beyond ater induction with R-CHOP
2 years o ibrutinib maintenance. Results o this trial signicantly improved PFS (5 years) and OS (9.8
would indicate whether ibrutinib and ara-C–based years) versus no maintenance (PFS 1.9 years and OS
induction is ecacious and can improve the previous 7 years). 166 Maintenance rituximab ater BR has not
results with chemoimmunotherapy alone in induction shown benet.
beore auto-SCT (NCT02858258). Lenalidomide was also investigated in older adults
with MCL. A combination o lenalidomide with ritux-
E4151 Study imab was investigated in 38 elderly patients. The
This phase 3 randomized study by a United States 5-year ollow-up o this study showed that the major-
intergroup is evaluating maintenance rituximab in ity (75%) o these patients completed more than 3
patients who achieve MRD-negative CR ater induc- years o treatment. In a subset o patients (8/10), MRD
tion therapy and who are then randomly assigned to was negative at the last ollow-up assessment.167,168
auto-SCT + MR versus MR alone. This study may pro- However, lenalidomide-based regimens are currently
vide insight into the role o consolidation SCT ater less avored in MCL, largely because o the avail-
achieving MRD-negative CR (NCT03267433). ability o better, well-tolerated BTK inhibitors and
the concern about second cancers with lenalidomide.
Previously Untreated Elderly Patients The combination o lenalidomide with chemotherapy
CHAPTER 10
was also investigated. Lenalidomide with BR in one

(Age ≥65 Years)—All Risk Categories study169 (n = 51) reported that 42% o patients expe-
Older adult patients usually exhibit comorbidities rienced grade 3–4 inections and 16% o patients
and thereore may not be eligible or SCT; their toler- developed second cancers. Lenalidomide in combina-
ability to chemotherapy is generally poorer compared tion with bortezomib and dexamethasone170 showed
with young and physically t patients. Older adult a 2-year PFS o 70%, but 51% o patients experienced
patients (n = 32) had signicantly inerior ailure- grade 3–4 neutropenia.
ree and OS compared with patients younger than
65 years in the long-term ollow-up o R-HCVAD/ Clinical Trials at MDACC or Previously Untreated
Mtx-ara-C.148 In general, bendamustine with ritux- Older Adults With MCL
imab (BR) combination is used in the routine clinical
practice or older patients with MCL, largely because We have incorporated orally available targeted
o its less intensive schedule. The BR regimen was therapies in the rontline setting to minimize or obviate
tested in two dierent phase 3 randomized trials: one the need or chemotherapy. Our clinical trials include
in Germany159 and another in North America.160,161 the ollowing.
In 2013, Rummel and colleagues159 reported that BR
signicantly improved PFS in patients with MCL Ibrutinib With Rituximab in Nonblastoid/Pleomorphic
compared with R-CHOP,159 and showed that BR MCL
was less toxic compared with R-CHOP. A nine-year Our group has conducted a phase 2 clinical trial171 with
ollow-up o this study conrmed these ndings. 162 a combination o ibrutinib and rituximab in 50 patients
Similar results demonstrating superiority o BR over (NCT01880567). Ibrutinib was administered as 560
R-CHOP or improved PFS were reported ater a mg orally daily or 28 days (one cycle) and was con-
5-year ollow-up o the BRIGHT study. 161 The inci- tinued until disease progression or discontinuation or
dence o second cancers was 19% in the BR group any reason. Rituximab was given on days 1, 8, 15, and
versus 11% in the R-CHOP group in the BRIGHT 22 plus or minus 1 day by IV injection at a xed dose
study. One o the caveats o the BRIGHT study was o 375 mg/m2 (Cycle 1, ollowed by rituximab on day
that this included a combination o patients—indo- 1 o every cycle starting in Cycles 3–8). Ater Cycle 8,
lent and MCL. BR was also studied in combination rituximab was given on day 1 o every other cycle or
with low-dose ara-C 163 (R-BAC-500; n = 57; BR + up to two years. The ORR was 98% (60% CR, 38%
ara-C 500 mg/m 2 on days 2–4 4 weekly), the ORR PR, 2% stable disease). With a median ollow-up o
and CR were 91%, with 50% o patients develop- 28 months, the median PFS and OS were not reached.
ing grade 3–4 neutropenia. R-BAC ollowed by vene- Four patients progressed during the study and two
toclax as consolidation in high-risk elderly MCL is patients died. Overall, 19 patients (39%) discontinued
evaluated (NCT03567876). therapy. Atrial brillation was noted in seven patients
Promising OS was noted in a combination o (3 had new onset and our had prior history o atrial
bortezomib with R-CHOP compared with R-CHOP brillation), and bleeding was noted in three patients.
alone, but an increase in hematologic toxicity with The combination o IR was an excellent rontline
treatment option or older adult patients; however, older adult age group. Conventionally, ater rst-line
patients taking this combination are strongly recom- ailure, patients were treated with salvage regimens
mended to closely ollow up with a cardiologist. Lon- such as R-ICE or R-DHAP or with bortezomib (ORR
ger ollow-up o this study is pending. 25%–50% with a CR o 4%–8%),175–177 temsirolimus
(ORR 22%),178 lenalidomide (ORR 28% with single
SYMPATICO Study agent and 57% with rituximab),179,180 or their com-
This is an ongoing global multicenter phase 3 study binations with rituximab.181 These modalities in the
with a combination o ibrutinib and venetoclax relapsed setting demonstrated modest response rates,
(NCT03112174). The ecacy o a combination o but intolerance is a major issue.182
ibrutinib with venetoclax in transplant-ineligible, pre-
viously untreated patients with MCL who are 65 years Treatment Options in Relapsed BTK-Naïve MCL
or older (n = 50) and patients under the age o 65 who
have TP53-mutated MCL is tested (n = 25). O note, Lenalidomide With Rituximab (LR)
patients with blastoid variant and those with CNS In a phase 1/2 study,181 the LR combination was tested
involvement are excluded. in 52 patients. Forty-our patients were enrolled in a
phase 2 cohort with an ORR o 57% and CR o 36%.
Zanubrutinib-Rituximab Versus BR Study The median PFS was 11.1 months and the median OS
This is an ongoing randomized phase 3 study com- was 24.3 months.
paring ZR with BR in transplant-ineligible patients.
CHAPTER 10
Patients either between 65 and 69 years o age or 70 Ibrutinib
years or older with comorbidities precluding auto-SCT This is an irreversible, covalent inhibitor o BTK (a
are eligible (NCT04002297). TEC kinase) and binds to cysteine 481 on the ATP
binding site o the BTK kinase domain. Ibrutinib has
ECOG-E1411 Study o-target eects on other TEC kinases (BMX, ITK, and
The ECOG-E1411 study is a our-arm randomized BLK), which are distributed in various tissues, leading
phase 2 trial in patients age 60 years or older. Arm 1 to o-target eects such as bleeding, cardiac arryth-
is BR induction ollowed by rituximab maintenance, mias (mainly atrial brillation),183,184 and ventricular
arm 2 is BR + bortezomib ollowed by rituximab arrhythmias.185,186 Inhibition o BTK leads to abroga-
maintenance, arm 3 is BR ollowed by lenalidomide + tion o MCL cell survival, prolieration, and growth.187
rituximab maintenance, and arm 4 is BR + bortezomib Ibrutinib also leads to redistribution lymphocytosis
ollowed by lenalidomide + rituximab maintenance. ater interering with the chemokine-receptor inter-
This study will provide inormation on ideal mainte- actions and homing o MCL cells.145 Lymphocyto-
nance strategy with lenalidomide (NCT 01415752). sis ater ibrutinib is not considered a sign o disease
progression.
MCL-R2 Older Adult Trial Initial results rom single-agent ibrutinib in patients
This is a phase 3 randomized trial to assess the e- with relapsed MCL (n = 111) were reported in 2013.128
cacy o ara-C induction and lenalidomide mainte- The median age o patients was 68 years, with a
nance. This study is evaluating whether the addition median o three prior lines o therapies. The ORR was
o lenalidomide to rituximab maintenance is useul in 68% and CR was 21%. Grade 3 or 4 adverse events
older adult patients with MCL (NCT01865110). included 16% neutropenia, 11% thrombocytopenia,
10% anemia, and 5% bleeding. On the longer ol-
Miscellaneous Studies low-up o 26.7 months,134 the CR rate improved to
These studies are investigating various combinations 23%, and 22% o patients continued treatment or
o newer BTK inhibitors, with venetoclax and/or more than 2 years. Two-year PFS and OS were 31%
obinutuzumab with/without chemotherapy. and 47%, respectively, and the median duration o
response was 17.5 months. Six percent o patients had
Previously Treated Relapsed MCL—BTK grade 3 or 4 bleeding events (none atal), 11% had
atrial brillation (grade 3 in 6%), and second cancers
Inhibitor–Naïve developed in 5%.
The success story o BTK inhibitors and venetoclax Ibrutinib was also compared with temsirolimus
in MCL in the last 5 to 7 years is a landmark eat. (m-TOR inhibitor) in a randomized study (RAY
Ibrutinib,133,172 acalabrutinib,135 and zanubrutinib173 are study188) and ibrutinib was superior to temsirolimus. A
approved BTK inhibitors136,174 in patients with relapsed three-year ollow-up o this study demonstrated that
MCL. Their main advantages are oral availability, survival and saety data were better with ibrutinib.
excellent ecacy, better tolerability, and saety prole Long-term ollow-up rom a pooled analysis o 370
compared with chemotherapy and easibility or the ibrutinib-treated patients with relapsed MCL with
a median ollow-up o 41.5 months was reported.172 assessment) at week 16. In all patients, MRD-negative
Seventeen percent o patients continued to receive response was 67% by fow cytometry and 38% by PCR.
treatment or more than 4 years. The median PFS and The median PFS was not reached, with a 12-month PFS
OS were 12.5 and 26.7 months, respectively. A higher o 75%. Interestingly, among the patients with TP53
number o prior lines o therapy was associated with mutation (n = 12), 50% achieved CR. Grade 3–4 diar-
shorter PFS in the multivariate analysis. Ibrutinib ater rhea was noted in 71%, and neutropenia was noted
ailure o rst-line therapy has a superior response rate in 33% o patients. Resistance mechanisms or the
77% (37% CR) and longer duration o response (36 combination demonstrated that the mutations in the
months) compared with ibrutinib administered ater SWI/SNF chromatin-remodeling complex was associ-
ailure o multiple lines o therapies. Among blastoid ated with drug resistance.59 In addition, ibrutinib was
MCL, the response rate was inerior compared with also investigated in combination with palbociclib. In
nonblastoid histology (50% vs 68%). In addition, a phase 1 trial, the ORR was 67% and CR was 37%,
OS was shorter in blastoid versus nonblastoid MCL whereas the two-year PFS was 59%.201
(12.8 vs not reached, respectively). O note, 14% o O interest is the activity o ibrutinib to penetrate
patients were TP53-mutated and demonstrated ine- the blood-brain barrier; it has been investigated in
rior response rates (55%), shorter PFS (4 months), CNS lymphomas, and ibrutinib has a potential or ur-
and shorter OS (10.3 months). Patients with wild- ther testing in MCL involving CNS.202–205
type TP53 showed a 70.2% response rate, PFS o 12 In relapsed MCL, various combinations o ibrutinib
months, and OS o 33.6 months. Atrial brillation with chemotherapy—ibrutinib with venetoclax, and
CHAPTER 10
occurred in 11% o patients (any grade; 5% grade 3) obinutuzumab and ibrutinib with anti-CD19-CAR-T
but none o the patients discontinued ibrutinib owing therapy (because o a potential to improve CAR-T
to atrial brillation.189 Ibrutinib can induce platelet ecacy by the o-target eects o ibrutinib), and
dysunction186,190,191 and impaired thrombus ormation, ibrutinib with palbociclib (a CDK4/6 inhibitor)201 are
contributing to bleeding tendency, and concomitant being investigated. In the Australian TARMAC study
anticoagulant and antiplatelet agents must be careully (NCT04234061), ibrutinib is administered beore
evaluated in patients taking ibrutinib.192 Cardiovascu- CAR-T in patients with relapsed MCL.
lar eects, arrythmias193,194 (mainly atrial brillation), Few challenges with ibrutinib include disease pro-
and hypertension are critical to watch or in patients gression and ibrutinib discontinuation caused by side
taking ibrutinib. These cardiac adverse events are eects, patient choice,58,129 ibrutinib-reractory MCL,
likely associated with inhibition o other TEC kinases and the mechanisms o ibrutinib resistance.61 Unlike
present in cardiac myocytes.183,195,196 CLL/SLL, BTK C481S mutation is inrequent in ibru-
We conducted a phase 2 study at MDACC using a tinib-resistant MCL.58,206 At MDACC, we are work-
combination o IR in relapsed MCL (with a median o ing to urther understand the mechanisms o ibrutinib
three prior therapies). A 4-year ollow-up o this study resistance105 and strategies to overcome ibrutinib resis-
showed that the CR improved rom 44%197 to 58%198. tance in MCL.207,208
The median PFS was 43 months and the median OS
was not reached. High-risk patients, high Ki-67% Acalabrutinib
(>50%) and/or patients with aggressive histology had A more selective, FDA-approved and orally admin-
inerior survival outcomes. The addition o lenalido- istered agent, acalabrutinib is a covalent, irrevers-
mide to IR was investigated in the PHILEMON study, ible inhibitor o BTK and binds to C481S in the ATP
a European phase 2 multicenter trial.199 In 50 previ- binding pocket. Minimal o-target kinase activity o
ously treated patients with relapsed MCL, the ORR acalabrutinib is a distinct advantage over ibrutinib.209
was 76% (56% CR) ater a median ollow-up o 17.8 Acalabrutinib preserves Src amily kinase (collagen to
months; 38% o patients had grade 3–4 neutropenia on platelet adhesion) activity and thus avoids the unstable
this combination. platelet thrombus ormation seen with ibrutinib ther-
Finally, ibrutinib was investigated in a combination apy.210 These activities may explain the low incidence
with venetoclax in relapsed MCL (AIM study rom o atrial brillation and less risk o bleeding compared
Australia). This combination o ibrutinib and veneto- with ibrutinib; however, randomized studies with
clax was based on preclinical data showing synergy head-to-head comparison o acalabrutinib and ibruti-
between the two.200 The I+V regimen was ibrutinib nib may reveal the actual risk o these adverse events.
(560 mg daily) with venetoclax (weekly dose escala- In the pivotal multicenter phase 2 trial in relapsed
tion up to 400 mg daily dose). Among 23 patients with MCL (n = 124), patients had a median o two lines
relapsed MCL, 75% had high-risk MIPI score and 50% o prior therapy.135 Ater a median ollow-up o 15.2
had TP53 mutations. The median ollow-up dura- months, the ORR was 81% with 40% CR, and at the
tion was 15.9 months. The combination174 resulted 26-month ollow-up analysis,211 the median PFS was
in an ORR o 71% with 62% CR (with PET-based 19.5 months, and the median OS was not reached.
About 40% o patients continued on acalabrutinib. majority (85%) o patients in this study were resistant
Three patients experienced grade 3 bleeding events, to BTK inhibitors, and the median PFS was 3.2 months.
and none had atrial brillation. Headache and diarrhea At MDACC, we reported our experience in 24 patients
were observed in 38% and 30% patients, respectively. with heavily treated MCL (median 5 prior lines o
Various combinations o acalabrutinib with ritux- therapy). The majority o patients had high-risk dis-
imab and/or acalabrutinib-venetoclax, acalabrutinib- ease and 67% were reractory to BTK inhibitors. Ater
lenalidomide, or a combination o acalabrutinib with a median ollow-up ater venetoclax o 17 months,
venetoclax and rituximab are investigated. Longer the ORR was 50% (21% CR). The median PFS was
ollow-up and the analysis o outcomes ater acalabru- 8 months. Using whole-exome sequencing, we dem-
tinib progression138 are important to ully explore the onstrated that non-BCL2 mutations (SMARCA4, TP53,
potential o acalabrutinib in MCL. CDKN2A, KMT2D, CELSR3, CCND1, and NOTCH2)
were noted ater progression on venetoclax. BCL2
Zanubrutinib mutations were inrequent (only one-third o patients).
Zanubrutinib is a newly FDA-approved selective and Venetoclax is actively investigated with various com-
irreversible BTK inhibitor. In the phase 1 trial,212 with binations in MCL, with BTK inhibitors in the rontline
a median ollow-up o about 16 months in 37 patients and in the relapsed-reractory setting.
with relapsed MCL, the response rate was 87%, with
30% CR with single-agent zanubrutinib, whereas in LOXO-305
eight previously untreated patients, the response rate
LOXO-305 is the latest and novel, reversible, nonco-
CHAPTER 10
was 87.5% with 37% CR. In a phase 2 study213 o 86
patients rom China, zanubrutinib demonstrated 84% valent, and orally administered BTKi that inhibits both
ORR and 68% CR in relapsed MCL (median two prior wild-type and C481-mutated BTK in preclinical stud-
lines). The median ollow-up was 18 months and ies. LOXO-305 has minimum o-target kinase and
the median PFS was 22 months. In 15 TP53-mutated nonkinase inhibitory activity. This molecule is cur-
patients, ORR was 80% versus 87% in TP53 wild- rently undergoing a phase 1 clinical trial in B-cell lym-
type, and the median PFS was 14.2 versus 22.1 months phoid malignancies.216
in TP53 wild-type patients. O note, because o mini- In the phase 1 trial, in 38 relapsed-reractory MCL
mal o-target eects, none o the patients exhibited patients, the median number o prior lines o therapy
grade 3 or higher bleeding or cardiac arrythmias. was two (range 2–8), and 92% o patients were treated
Tirabrutinib214 and orelabrutinib215 are other irre- with a prior BTK inhibitor. Among the 35 ecacy-
versible BTK inhibitors with higher selectivity against evaluable patients with MCL treated across all dose
BTK and better side eect proles compared with levels, the ORR was 51%, including nine CRs. Among
ibrutinib. These are under clinical investigation. the subset o 20 ecacy-evaluable patients with MCL
who started at 200 mg daily, the ORR was 65% includ-
ing seven CRs, six PRs, our SDs, one PD, and two NEs.
Previously Treated Relapsed MCL–BTK Because o lesser o-target eects, LOXO-305 has bet-
Inhibitor Reractory ter saety data compared with ibrutinib. Fatigue and
diarrhea were common adverse events noticed in less
As our experience with BTK inhibitors is growing,
than 20% o patients. Final data were reported at the
we are seeing patients with BTK inhibitor–reractory
2020 American Society o Hematology meeting. The
MCL. Newer therapies are urgently required to treat
phase 2 dose was 200 mg orally daily. LOXO-305 and
these complex patients.
its combinations hold great promise or patients with
BTK inhibitor–reractory MCL.
Venetoclax
This drug is an orally available, selective inhibitor o R-BAC Regimen
the anti-apoptotic BCL-2 protein. Initial experience In a multi-institutional retrospective report rom 36
with venetoclax in MCL was demonstrated in a phase patients whose disease ailed prior BTK inhibitors, this
1 study.136 Twenty-eight relapsed-reractory MCL regimen demonstrated 83% ORR and 60% CR, and
patients (none BTK inhibitor reractory; median age, 31% bridged to allo-SCT. The median OS was 12.5
72 years and median o 3 prior lines o treatments) months.217
were enrolled, and patients achieved an ORR o 75%,
CR o 21%, and a median PFS o 14 months. Veneto-
Stem Cell Transplantation
clax has very promising activity in MCL. One retro-
spective study137 described venetoclax monotherapy in Autologous SCT is conventionally used as a con-
20 patients with relapsed MCL (median o 3 prior lines solidation strategy ater completing intensive che-
o therapy). The ORR was 53% and CR was 18%. The moimmunotherapy. Some retrospective and ew
prospective studies have described their experience experience in the community, and its availability at
with SCT in MCL, although the data o SCT in BTK specialized centers are the major limitations.
inhibitor-reractory MCL are not well described. In a
multicenter retrospective analysis,218 70 patients with Newer Cellular Therapies
relapsed MCL who received allo-SCT were described.
Patients with chemosensitive disease demonstrated Lisocabtagene maraleucel (JCAR-017)222 is a CD19-
superior outcomes compared with patients who had directed 4-1BB CAR-T product undergoing clinical tri-
PR or no response. Allogenic SCT can be useul in als in MCL. In the phase 1 study, median ollow-up
high-risk, transplant-eligible TP53-mutated relapsed was 18 months (n = 17) and the ORR was 71% (CR
MCL. Allo-SCT can provide long-term disease con- 53%). Grade 3 or higher toxicities were 6% cytokine
trol in about 30% o patients with MCL.219,220 Ibruti- release syndrome and 12% neurotoxicity. Other newer
nib beore allo-SCT can be ecacious as a bridging cellular therapies include CD19 CAR-NK cells,223 allo-
therapy, as reported in a study o 22 patients.221 Pre- geneic CAR-T, and humanized binding domain in
transplant disease response is important in predicting CD19 CAR-T cells (Hu19-CD828Z).224 Most recently,
response to allo-SCT in MCL. As o this writing, the clinical trials have also started investigating the com-
role o allo-SCT in relapsed MCL is limited because o bination o BTK inhibitors with anti–CD19-CAR-T.
its availability, mortality, morbidity, and the advent o Other antigens relevant in MCL and being investigated
relatively sae and ecacious brexucabtagene autoleu- are CD20, CD22, ROR1, BAFF,225 and CD79b,226 or bi-
cel an anti–CD19-CAR-T therapy. specic antibodies (CD3-CD20).
CHAPTER 10
Chimeric Antigen Receptor T-Cell (CAR-T) Therapy Triple-Reractory Relapsed MCL

CAR-T therapy is the most recent and most potent Recently, in our clinical experience, we have also
landmark development or highly reractory patients observed a very-high-risk subset in patients with
with MCL. The recent FDA approval o anti–CD19- MCL that we call “triple-reractory MCL,” reerring
CAR-T, brexucabtagene autoleucel (KTE-X19), was the to patients who have progressed on BTK inhibitors,
highlight o the year 2020 and was recently approved venetoclax, and CAR-T therapy. Treatment options
by the FDA or adult patients with relapsed or rerac- or these patients are highly limited. Currently, newer
tory MCL. clinical trials are required to address the issue o tri-
The ZUMA-2 study is a single-arm, international, ple resistance. In the coming years, we will be able to
multicenter, open-label, phase 2 trial in which 68 observe the pattern o resistance observed in triple-
patients with relapsed MCL received CAR-T therapy. resistant MCL patients.
All patients had progressed on BTK inhibitors and
they had a median o 3 prior lines o therapy (range
CNS Prophylaxis in MCL
1–5). Forty-two patients were primary reractory to
BTK inhibitors, and 18 patients (26%) had relapsed This is controversial and no denitive guidelines exist.
ater an initial response to BTK inhibitor. The patients The practice varies at dierent centers, especially in
underwent leukapheresis and lymphocyte-depleting patients with aggressive-histology MCL. Few retro-
chemotherapy ollowed by CAR-T inusion at a target spective studies76,227,228 demonstrated that some baseline
dose o 2 × 106 CAR-T cells/kg. Patients who had high- characteristics o patients with MCL (blastoid MCL,
risk MCL were included : 17 (25%) had blastoid his- very high LDH levels, high Ki-67%) correlate with a
tology, six with TP53 mutations, and 32 had Ki-67% higher requency o CNS involvement. The outcomes
o at least 50%. The ORR was 93% and the CR was o CNS-MCL are very poor. In one study with 57
67%. With a ollow-up o 12 months, 57% patients patients who developed CNS involvement by MCL,76
remained in remission. Furthermore, the ORR was 20% had prior intrathecal chemotherapy and 18% had
higher than 93% in blastoid, TP53-mutated, and high prior R-HCVAD; thereore, complete prevention o
Ki-67% patients. The PFS and OS were not reached. CNS involvement by routine intrathecal chemotherapy
Most common grade 3 or higher adverse events were may not be attainable. However, patients with blastoid
cytopenias (69%) and inections (32%), and grade 3 MCL are advised to undergo prophylactic intrathecal
or higher cytokine release syndrome in 15%, whereas chemotherapy by some physicians. In addition, because
neurotoxicity was noted in 31% patients. A longer ibrutinib has been shown to penetrate the blood-brain
ollow-up on this study is required to urther evalu- barrier202,205 and is increasingly used in MCL, the role
ate the durability o responses achieved by this modal- o CNS prophylaxis in ibrutinib-treated MCL patients
ity. The process with CAR-T is less complicated and remains unknown. As o this writing, we do not admin-
well tolerated compared with similar data rom tradi- ister intrathecal chemotherapy in patients i they have
tional allo-SCT. Conversely, the cost o CAR-T, limited received ibrutinib-based therapies, and/or have had
R-HCVAD therapy; however, in specic clinical situ- understanding o MCL, leading to improvement in risk
ations such as patients with high-risk MCL receiving stratication, urther advances in the eld, and help
only chemotherapy, paraspinal disease, or paranasal in accurately predicting the prognosis. In addition,
involvement, we consider intrathecal chemotherapy. newer therapies have signicantly improved survival
outcomes and response rates. The evolution o BTK
inhibitors, venetoclax and anti-CD19 CAR-T, have
SUMMARY demonstrated phenomenal results and are shiting the
ocus to investigate these therapies in the rontline set-
The eld o MCL is changing rapidly. Advances in our ting. We hope that this momentum o advancement in
understanding o the pathobiology, molecular events, understanding MCL will continue and we may nd a
and tissue microenvironment have improved our cure or it in the coming years.

J To obtain ull risk actor assessment with relevant in patients with MCL. About 30% o MCL can have
investigations and collect various parameters delayed clearance o the GI tract, and residual disease
at initial diagnosis (outlined in Fig. 10–2). This is in the GI tract disqualies patients to achieve CR.
CHAPTER 10
important or determining prognosis and uture J The ocus in the treatment o MCL is gradually shit-
considerations on clinical trials. ing rom rontline chemotherapies to “chemo-ree”
J To obtain inormation on the high-risk eatures at therapies such as BTK inhibitors and venetoclax
initial diagnosis: high-risk MIPI score, blastoid/pleo- as their initial therapy. We recommend enrolling
morphic histology, high Ki-67% at least 30%, and patients in clinical trials and exploring the option or
TP53 mutation status. This inormation is highly rel- recently approved anti–CD19-CAR-T (brexucabta-
evant because it can afect the clinical outcome. gene autoleucel) therapy in relapsed patients and/
J To obtain a detailed cardiology assessment and or patients who progressed on BTK inhibitors and/or
cardiology clearance beore starting BTK inhibitors patients who are high risk and relapsed ater standard
on any patient with MCL. Cardiac arrythmias, hyper- therapies.
tension, and bleeding tendencies can be lie threat- J Explore the option or enrollment in clinical tri-
ening or older adult patients with MCL. als and reer the patient to specialized centers or
J To obtain gastrointestinal tract (upper and lower) MCL treatment in the US or elsewhere. We have the
endoscopies with random biopsies, along with PET- center o excellence in MCL at MDACC. For urther
CT scan and bone marrow assessment (ow cytom- enquiries, please contact miwang@mdanderson.
etry, cytogenetics, molecular testing) to conrm CR org and/or pjain@mdanderson.org.
ACKNOWLEDGMENTS consultancy or advisory role or Pharmacyclics, Cel-

gene, Janssen, AstraZeneca/Acerta Pharma, More-
Funding or various MCL studies at MD Anderson Health, Loxo Oncology, Kite, a Gilead Company,
Cancer Center was provided in part by the generous Oncternal, InnoCare and Pulse Biosciences; research
philanthropy donated to the MD Anderson Cancer unding rom Pharmacyclics, Janssen, AstraZeneca/
Center B-Cell Lymphoma Moon Shot Program; R21 Acerta Pharma, BioInvent, Novartis, Kite, a Gilead
CA202104 (Michael Wang, PI); and philanthropy unds Company, Juno, Celgene, Loxo Oncology, Oncternal,
rom The Gary Rogers Foundation and the Fox Family InnoCare and VelosBio; expert testimony or Astra-
Foundation. Zeneca/Acerta Pharma; and travel support rom Jans-
sen, Pharmacyclics, Celgene, Targeted Oncology, and
OMI.;P.J. – none.
CONFLICTS OF INTEREST
DISCLOSURES
MW – honoraria rom Pharmacyclics, Janssen, Astra-
Zeneca/Acerta Pharma, Targeted Oncology, and OMI;
20. Fichtner M, Spies E, Seismann H, et al. Complementarity

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mediated but not ADP-mediated platelet aggregation. Leuke- unction in NHL patients receiving ibrutinib is absent in patients
mia. 2015;29(4):783-787. receiving acalabrutinib. Blood Adv. 2017;1(26):2610-2623.
191. Dobie G, Kuriri FA, Omar MMA, et al. Ibrutinib, but not zanu- 211. Wang M, Rule S, Zinzani PL, et al. Long-term ollow-up o aca-
brutinib, induces platelet receptor shedding o GPIb-IX-V com- labrutinib monotherapy in patients with relapsed/reractory
plex and integrin alphaIIbbeta3 in mice and humans. Blood Adv. mantle cell lymphoma. Blood. 2018;132(suppl 1):2876-2876.
2019;3(24):4298-4311. 212. Tam CS, Trotman J, Opat S, et al. Phase 1 study o the selective
192. Caron F, Leong DP, Hillis C, et al. Current understanding o BTK inhibitor zanubrutinib in B-cell malignancies and saety
bleeding with ibrutinib use: a systematic review and meta- and ecacy evaluation in CLL. Blood. 2019;134(11):851-859.
analysis. Blood Adv. 2017;1(12):772-778. 213. Song Y, Zhou K, Zou D, et al. Treatment o patients with
193. Lampson BL, Yu L, Glynn RJ, et al. Ventricular arrhyth- relapsed or reractory mantle cell lymphoma with zanubruti-
mias and sudden death in patients taking ibrutinib. Blood. nib, a selective inhibitor o Bruton’s tyrosine kinase. Clin Cancer
2017;129(18):2581-2584. Res. 2020;26(16):4216-4224.
194. Guha A, Derbala MH, Zhao Q, et al. Ventricular arrhythmias 214. Rule SA, Cartron G, Fegan C, et al. Long-term ollow-up o
ollowing ibrutinib initiation or lymphoid malignancies. J Am patients with mantle cell lymphoma (MCL) treated with the
Coll Cardiol. 2018;72(6):697-698. selective Bruton’s tyrosine kinase inhibitor tirabrutinib (GS/
195. Leong DP, Caron F, Hillis C, et al. The risk o atrial brillation ONO-4059). Leukemia. 2020;34(5):1458-1461.
with ibrutinib use: a systematic review and meta-analysis. 215. Song Y, Song Y, Liu L, et al. Saety and ecacy o orelabruti-
Blood. 2016;128(1):138-140. nib monotherapy in Chinese patients with relapsed or rerac-
196. Dickerson T, Wiczer T, Waller A, et al. Hypertension and inci- tory mantle cell lymphoma: a multicenter, open-label, phase II
dent cardiovascular events ollowing ibrutinib initiation. Blood. study. Blood. 2019;134(suppl 1):755.
2019;134(22):1919-1928. 216. Mato AR, Flinn IW, Pagel JM, et al. Results rom a rst-in-
197. Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with human, proo-o-concept phase 1 trial in pretreated B-cell
rituximab in relapsed or reractory mantle cell lymphoma: a single- malignancies or Loxo-305, a next-generation, highly selective,
centre, open-label, phase 2 trial. Lancet Oncol. 2016;17(1):48-56. non-covalent BTK inhibitor. Blood. 2019;134(suppl 1):501.
198. Jain P, Romaguera J, Srour SA, et al. Four-year ollow-up o a 217. McCulloch R, Visco C, Eyre TA, et al. Ecacy o R-BAC in
single arm, phase II clinical trial o ibrutinib with rituximab relapsed, reractory mantle cell lymphoma post BTK inhibitor
(IR) in patients with relapsed/reractory mantle cell lymphoma therapy. Br J Haematol. 2020;189(4):684-688.
(MCL). Br J Haematol. 2018;182(3):404-411. 218. Le Gouill S, Kröger N, Dhedin N, et al. Reduced-intensity
199. Jerkeman M, Eskelund CW, Hutchings M, et al. Ibrutinib, conditioning allogeneic stem cell transplantation or relapsed/
lenalidomide, and rituximab in relapsed or reractory mantle reractory mantle cell lymphoma: a multicenter experience.
cell lymphoma (PHILEMON): a multicentre, open-label, single- Ann Oncol. 2012;23(10):2695-2703.
arm, phase 2 trial. Lancet Haematol. 2018;5(3):e109-e116. 219. Robinson SP, Boumendil A, Finel H, et al. Long-term outcome
200. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmaco- analysis o reduced-intensity allogeneic stem cell transplanta-
logical and protein proling suggests venetoclax (ABT-199) as tion in patients with mantle cell lymphoma: a retrospective
optimal partner with ibrutinib in chronic lymphocytic leuke- study rom the EBMT Lymphoma Working Party. Bone Marrow
mia. Clin Cancer Res. 2015;21(16):3705-3715. Transplant. 2018;53(5):617-624.
201. Martin P, Bartlett NL, Blum KA, et al. A phase 1 trial o ibrutinib 220. Lin RJ, Ho C, Hilden PD, et al. Allogeneic haematopoietic cell
plus palbociclib in previously treated mantle cell lymphoma. transplantation impacts on outcomes o mantle cell lymphoma
Blood. 2019;133(11):1201-1204. with TP53 alterations. Br J Haematol. 2019;184(6):1006-1010.
221. Dreger P, Michallet M, Bosman P, et al. Ibrutinib or bridging 227. Chihara D, Asano N, Ohmachi K, et al. Ki-67 is a strong predic-
to allogeneic hematopoietic cell transplantation in patients tor o central nervous system relapse in patients with mantle
with chronic lymphocytic leukemia or mantle cell lymphoma: cell lymphoma (MCL). Ann Oncol. 2015;26(5):966-973.
a study by the EBMT Chronic Malignancies and Lymphoma 228. Ferrer A, Bosch F, Villamor N, et al. Central nervous sys-
Working Parties. Bone Marrow Transplant. 2019;54(1):44-52. tem involvement in mantle cell lymphoma. Ann Oncol.
222. Wang M, Gordon LI, Palomba ML, et al. Saety and preliminary 2008;19(1):135-141.
ecacy in patients (pts) with relapsed/reractory (R/R) mantle cell 229. Romaguera JE, Fayad L, Rodriguez MA, et al. High rate o
lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) durable remissions ater treatment o newly diagnosed aggres-
in TRANSCEND NHL 001. J Clin Oncol. 2019;37(suppl 15):7516. sive mantle-cell lymphoma with rituximab plus hyper-CVAD
223. Liu E, Marin D, Banerjee P, et al. Use o CAR-transduced natu- alternating with rituximab plus high-dose methotrexate and
ral killer cells in CD19-positive lymphoid tumors. N Engl J Med. cytarabine. J Clin Oncol. 2005;23(28):7013-7023.
2020;382(6):545-553. 230. Romaguera JE, Fayad LE, Feng L, et al. Ten-year ollow-up ater
224. Brudno JN, Lam N, Vanasse D, et al. Saety and easibility o intense chemoimmunotherapy with Rituximab-HyperCVAD
anti-CD19 CAR T cells with ully human binding domains in alternating with Rituximab-high dose methotrexate/cytara-
patients with B-cell lymphoma. Nat Med. 2020;26(2):270-280. bine (R-MA) and without stem cell transplantation in patients
225. Qin H, Dong Z, Wang X, et al. CAR T cells targeting BAFF- with untreated aggressive mantle cell lymphoma. Br J Haematol.
R can overcome CD19 antigen loss in B cell malignancies. Sci 2010;150(2):200-208.
Transl Med. 2019;11(511):eaaw9414. 231. Geisler CH, Kolstad A, Laurell A, et al. Nordic MCL2 trial
226. Ormhøj M, Scarò I, Cabral ML, et al. Chimeric antigen update: six-year ollow-up ater intensive immunochemother-
receptor T cells targeting CD79b show ecacy in lym- apy or untreated mantle cell lymphoma ollowed by BEAM or
phoma with or without cotargeting CD19. Clin Cancer Res. BEAC + autologous stem-cell support: still very long survival
2019;25(23):7046-7057. but late relapses do occur. Br J Haematol. 2012;158(3):355-362.
CHAPTER 10
11 Nodal Peripheral T-Cell Lymphoma
Ranjit Nair
Francisco Vega
Swaminathan P. Iyer
KEY CONCEPTS
 Nodal peripheral T-cell lymphomas (PTCLs) are catego-  Understanding o the genomic landscape has recently
rized into three basic subtypes: systemic anaplastic large- helped to identiy better prognostic markers. Whereas the
cell lymphoma (sALCL) anaplastic lymphoma kinase presence o ALK or DUSP-22 in sALCL is associated with
ALK (+) and ALK (-), angioimmunoblastic T-cell lymphoma; avorable prognosis, expression o GATA-3 or GATA-3 target
and peripheral T-cell lymphoma not otherwise specifed genes in PTCL-NOS is associated with a worse prognosis.
(PTCL-NOS).  Except or ALK (+) ALCL and ALK (-) ALCL with DUSP22 rear-
 The prognosis or patients with nodal PTCLs remains sub- rangement, patients with PTCL generally have a chemo-
optimal compared with its aggressive B cell counterparts resistance, short-term remission, and early relapse when
despite the use o aggressive chemotherapy. The introduc- treated with cyclophosphamide, doxorubicin, vincristine,
tion o novel agents such as CD30(+) antibody–drug con- and prednisone (CHOP) or CHOP-like chemotherapy.
jugates and histone deacetylase inhibitors have brought  Combination therapies using novel agents holds the
unprecedented enthusiasm in bench to bedside research uture to improve clinical response and outcomes in both
or this disease. rontline and relapsed or reractory disease. Whereas
 It is recently recognized that angioimmunoblastic T– BV-CHP (brentuximab vedotin plus cyclophosphamide,
cell lymphoma has its cell o origin rom CD4+ T-ol- doxorubicin, prednisone) is currently the standard o care
licular helper (TFH) cells and as a result a third o the treatment in patients with CD30(+) PTCLs, Cyclophospha-
PTCL-NOS are more aptly diagnosed as angioimmuno- mide, doxorubicin, vincristine, and prednisone (CHOP),
blastic T-cell lymphoma because o the expression o with or without the addition o etoposide, is commonly
TFH markers. used in those with CD30(-) PTCLs.
Peripheral T-cell lymphoma (PTCL) comprises a rare CHOP-like combination chemotherapies. Although
and heterogeneous group o mature T- and natural many patients initially respond to induction chemo-
killer (NK)-cell neoplasms with diverse clinical pre- therapy, responses are oten brie, and many patients
sentation, response to treatment, and prognosis.1 relapse or become reractory to treatment. The intro-
PTCLs have historically been a challenging disease duction o agents based on the novel targets such as
because o their rarity, oten grouped by their shared CD30 and brentuximab vedotin (BV) has given us tre-
immunophenotype o neoplastic T-cells, despite the mendous hope recently leading to the only Food and
biologically dierences and lack o standard treat- Drug Administration (FDA)–approved chemother-
ment approaches.2 Getting a second opinion and apy combination or frst-line treatment. Signifcant
reviews by expert hematopathologists improve the advances in our understanding o this disease biol-
accuracy o subtyping, and reerral to academic or ogy have also led to revisions in the classifcation o
specialty centers is recommended. Even though mature T-cell and NK-cell neoplasms and introduction
there is no current standard o care or patients o provisional entities. According to the 2016 World
with PTCL, frst-line approaches still revolve around Health Organization classifcation (WHO) classifca-
anthracycline-based therapy with cyclophosphamide, tion o lymphoid neoplasms, based on morphologic,
doxorubicin, vincristine, and prednisone (CHOP) or immunophenotypic, molecular, and clinical eatures,
253
TABLE 111 Summay o 2016 Wold Health Oganization Classication o Matue TCell and Natual
Kille Cell Neoplasmsa
Leukemic Nodal Extranodal Cutaneous

T-cell prolymphocytic PTCL-NOS Extranodal NK-/T-cell lymphoma, Subcutaneous panniculitis-like
leukemia AITL nasal type T-cell lymphoma
T-cell large granular Follicular T-cell Enteropathy-associated T-cell Mycosis ungoides
lymphocytic lymphomab lymphoma Sezary syndrome
leukemia Nodal peripheral Monomorphic epitheliotropic Primary cutaneous CD30(+) T-cell
Chronic T-cell lymphoma intestinal T-cell lymphomab lymphoprolierative disorders
lymphoproliferative with TFH Hepatosplenic T-cell lymphoma Lymphomatoid papulosis
disorder of NK cells phenotypeb Systemic EBV (+) T-cell lymphoma Primary cutaneous anaplastic
Aggressive NK-cell Anaplastic large-cell o childhoodb large-cell lymphoma
leukemia lymphoma, ALK (+) Hydroa vacciniorme–like Primary cutaneous gδ T-cell
Adult T-cell leukemia/ Anaplastic large-cell lymphoprolierative disorderb lymphoma
lymphoma lymphoma, ALK (-)b Breast implant–associated Primary cutaneous CD8(+)
anaplastic large-cell aggressive epidermotropic
lymphomab cytotoxic T-cell lymphoma
Indolent T-cell Primary cutaneous CD4(+)
lymphoproliferative disorder small-/medium T-cell
CHAPTEr 11
of the GI tractb lymphoproliferative

disorderb
a
Provisional entities are listed in bold.
b
Changes rom the 2008 classication.
AITL, angioimmunoblastic T-cell lymphoma; ALK, anaplastic lymphoma kinase; EBV, Epstein-Barr virus; GI, gastrointestinal; NK, natural killer cell; PTCL-NOS, peripheral
T-cell lymphoma not otherwise specied.
there are total 19 subtypes o mature T-cell and NK- T-cell lymphoma, is starting to outnumber the PTCL-
cell neoplasms and eight provisional entities that are NOS cases.7,8
currently recognized (Table 11–1). PTCLs, although There is signicant geographic variation in the inci-
uncommon in young individuals, can be diagnosed dence and prevalence o the dierent type o PTCL,
as early as childhood, and rates continue to increase which is attributed to a combination o genetic and
until about age 70 years.3The most common subtype environmental actors. AITL tends to be more re-
o nodal PTCL, aside rom mycosis ungoides (MF), is quent in Europe (28.7% o all PTCLs) ollowed by
PTCL not otherwise specied (PTCL-NOS) ollowed Asia (17.9%) and North America (16.0%).9 PTCL-NOS
by systemic anaplastic large-cell lymphoma (sALCL), is more common in in Western countries than Asian
and angioimmunoblastic T-cell lymphoma (AITL). countries (30% vs 20%–25% o PTCL). sALCL tends
T-cell acute lymphoblastic leukemia/lymphoma are to be more common the United States (24% o PTCL)
derived rom T-cell precursors (eg, thymocytes) is not and with less incidence in Europe and Asia.10 Other
included in the mature lymphoma group and hence PTCL subtypes—adult T-Cell Lymphoma/Leukemia
will not be discussed in this chapter.4,5 (ATLL) and extranodal natural killer/T-cell lymphoma
(ENKL)—occur at higher requencies in Asia and Cen-
tral and South America than in Western countries,
EPIDEMIOLOGY paralleling the distribution o human T-lymphotropic
virus 1 (HTLV1) and the Epstein-Barr virus (EBV)
PTCL represent approximately 10% to 15% o non- respectively. Enteropathy-associated T-cell lymphoma
Hodgkin lymphomas (Fig. 11–1). These are urther (EATL) is seen more in Northern Europe, where celiac
subclassied as nodal, extranodal, leukemic, and disease is more prevalent.6,11
cutaneous T-cell lymphomas. The most common his-
tologic subtype is PTCL-NOS ollowed by AITL and
sALCL anaplastic lymphoma kinase (ALK) (+) and INCIDENCE AND OUTCOMES
ALK (-). These three accounts or approximately two-
thirds o the T-cell lymphomas.6 With better diagnostic According to the US Surveillance Epidemiology and
markers and molecular criteria, the combined entity o End Registry, the age-adjusted incidence o PTCL is
three nodal lymphomas expressing signatures typi- ewer than one case per 100,000 people in the United
cal or T-ollicular helper (TFH) cells, including AITL, States, with approximately over 10,000 new cases
nodal PTCL with a TFH phenotype, and ollicular diagnosed each year.3 In recent years, although the
Chapte 11 Nodal Peripheral T-Cell Lymphoma 255
CLL and SLL

Follicular lymphoma
Plasma cell neoplasms
DLBCL
All cancers Marginal zone lymphoma
PTCL
3% Mantle cell lymphoma
Lymphoplasmacytic lymphoma
Hairy cell leukemia
Mycosis fungoides
Burkitt lymphoma/leukemia
Others
FIGUrE 11–1 Distribution o subtypes o mature non- Hodgkin lymphoid neoplasms. CLL, chronic lymphocytic leukemia.
DLBCL, diuse large B- cell lymphoma; PTCL, peripheral T-cell lymphoma; SLL, small lymphocytic lymphoma. (Data rom Teras
LR, DeSantis CE, Cerhan JR, et al: 2016 US lymphoid malignancy statistics by World Health Organization subtypes, CA Cancer J
CHAPTEr 11
Clin 2016 Nov 12;66(6):443-459.)
incidence rates o many B-cell lymphomas have begun d. RHOA pathway

to decline or plateau at best, the incidence rates or e. Phosphoinositide 3-kinase (PI3K) pathway
T-cell lymphomas have continued to rise globally. . Epigenetic regulation
This is likely a consequence o the aging population, g. AP-1–mediated transcriptional programs
improved health care access, and improved diagnostics 2. Extrinsic or microenvironmental changes
tools. Worldwide there is still no consensus on rst- 3. Virus-mediated (eg, EBV, HTLV-1–induced T-cell
line or salvage therapies or patients because o the rar- neoplastic transormation)16
ity o the disease and the lack o randomized clinical
trials, which translates to worse overall survival (OS)
among patients with nodal PTCL (36%–56% 5- year ANGIOIMMUNOBLASTIC T-CELL
survival). In contrast, the outcomes or MF are overall
better (79%–92% 5- year survival rate).3
LYMPHOMA
AITL is characterized by its cellular derivation rom
CD4+ TFH cells, which is the eector T-cell sub-
PATHOGENESIS AND HISTOLOGY set, and the diagnostic criteria remain unchanged in
the 2016 WHO classication. TFH cells are a critical
The exact pathogenesis o PTCL is largely elusive, and
peripheral checkpoint or B-cell activation and dier-
the putative cellular derivation o the dierent patho-
entiation within a germinal center.17 Dysregulated TFH
logical subtypes remains poorly characterized. There
cell that triggers the transormation to AITL is pro-
have been signicant attempts with gene expression
posed to be the cell o origin (COO) with subsequent
proling (GEP; RNA sequencing, microarray analysis,
disruption o immunologic tolerance and uncontrolled
micro-RNA proling, mutation analysis, copy number
constitutively activated immune system presenting as
alterations) and epigenetics analysis to help identiy
autoimmune phenomenon.18 The tumor cells retain
new biomarkers and mutations.12–15 PTCLs are derived
characteristic phenotype o TFH cells with the expres-
rom mature T-cells, and deregulation at T-cell dier-
sion o markers PD-1 (programmed death-1), BCL6,
entiation or maturation level is a critical event in lym-
CXCL13, CD10, ICOS, SAP, and CXCR5, CD279 (PD-
phomagenesis. The pathogenic events in general can
1, PDCD1) CD40L, and NFATC1. A subset o what
be classied into three categories:
used to be classied as PTCL-NOS on molecular analy-
1. Intrinsic or recurrent molecular events in the piv- sis expresses TFH-associated markers and shares recur-
otal intracellular signaling pathways rent genetic abnormalities with AITL. This has been
a. TCR/CD3 pathway given provisional category in WHO 2016 called nodal
b. Notch pathway T-cell lymphomas with a TFH phenotype. Another
c. Janus kinase (JAK)/signal transducer and activa- category called ollicular T-cell lymphoma has also
tor o transcription (STAT) pathway been added to this group, which primarily involves the
ollicles and could resemble its B cell counterpart–the The PTCL-NOS diagnosis is known to have the
ollicular lymphoma (see Table 11–1). GEP has shown highest rate o dilemma and discordance rate among
that the malignant TFH cell oten carry mutations pathologists. This refects the heterogeneity and the
in the genes encoding methyl cytosine dioxygenase presence o dierent PTCL subtypes at dierent stages
TET2 (47%–73%), isocitrate dehydrogenase 2 (IDH2) o disease progression.6 One third o PTCL-NOS case
(20%–40%), DNA methyltranserase 3A (DNMT3A) are more aptly diagnosed as AITL because o the expres-
(33%), or RHOA-G17V mutation (∼60%).19 CXCL13 sion o TFH markers. The lymph nodes usually appear
produced by AITL cells has a known association with diusely eaced with pleomorphic cells, which are
hypergammaglobulinemia and autoimmune hemo- medium-sized or large cells with irregular nuclei con-
lytic anemia because this protein stimulates B-cell taining prominent nucleoli and many mitoses. There
expansion and plasmacytic dierentiation in the tumor is oten presence o hyperplastic endothelial venules
microenvironment.20,21 EBV-positive clonal/oligoclo- with an admixture o eosinophils, plasma cells, small
nal B-lymphoblastoid cells are present in majority o lymphocytes, B cells, histiocytes, and activated mac-
AITL cases, but their exact pathogenetic role is elusive. rophages. A morphologic variant o PTCL-NOS that is
Given that EBV virtually aects only B-cell population, known to have a avorable prognosis called lympho-
it is postulated to rather play a protumorigenic role epithelioid cell lymphoma (Lennert’s lymphoma) pres-
in the microenvironment than a primary role in the ents with more abundant epithelioid histiocytes and
lymphomagenesis. neoplastic cells that portray a CD8-positive cytotoxic
Microscopically (Fig. 11–2A–D), there is a polymor- (TIA1, granzyme B, and/or perorin) phenotype.26
CHAPTEr 11
phic immune inltrate in lymph node specimens with In PTCL-NOS, there is variable loss o expression
eacement o germinal centers and prominent neo- o T-cell–associated antigens, more requently CD5 or
vascularization, with a rich microenvironment com- CD7 and rarely CD2 or CD3. In majority o the cases,
posed not only o tumor cells but also o small reactive T-cells express CD4, αβ-TCR (TCR-β positive), or
lymphocytes, histiocytes, eosinophils, an expanded both than in minority with CD8 and/or gδ phenotype.
ollicular dendritic cell meshwork, and prominent CD30 is less commonly expressed, and its prognostic
endothelial venules.22 In addition to the tumor cells impact is currently unclear. Hal o PTCL-NOS cases
expressing TFH cell markers, T-cell receptor gene rear- are EBV-positive, an observation shown to be asso-
rangements (TCRs) are present in about 80% o the ciated with a poor survival.7 Other markers that are
tumor cells, and trisomy o chromosomes 3 and 5 are rarely expressed include B-cell markers such as CD20,
the commonly observed cytogenetic abnormality. EBV CD19, CD79a, or PAX5. A recent genome-wide next-
positivity is universally present in the large B immu- generation sequencing analysis o PTCL-NOS led to
noblasts in the lymph node but not in the neoplastic the identication o recurrent translocations involving
T-cells.23 rearrangements o the TP63 gene (a TP53 amily mem-
ber) with TBL1XR1 and ATXN1 genes (10% cases).27
Peripheral T-Cell Lymphoma Not These gene usions encode proteins that inhibit the
p53 pathway and are associated with adverse clinical
Otherwise Specifed outcomes. Screening a large series o cases or TP63
PTCL-NOS is a heterogeneous entity and includes a rearrangements by fuorescence in situ hybridization
watershed area o dierent mature T-cell neoplasms showed similar requencies in ALK (-) ALCL (12.5%)
that do not have a characteristic immunophenotype and primary cutaneous ALCL (10.5%).27
or do not meet the criteria o a specic PTCL entity.
Despite the absence o a distinct COO or recurrent
cytogenetic abnormality, GEP studies have dened
Systemic Anaplastic Large-Cell Lymphoma
two novel molecular clusters in this group with dis- sALCL shows ALK expression in more than 30% o
tinct eatures using PTCL-GATA3 and PTCL-TBX21. cases.28 The translocation leads to the expression o
The cluster with high expression o GATA3-related the constitutively active NPM-ALK kinase, trigger-
target genes (CCR4, IL18RA, CXCR7, and IK) had ing downstream signaling pathways that regulate cell
poorer outcomes with the 5-year OS o nearly hal o growth, survival, and malignant transormation.29,30
the TBX21 cluster (19% vs 38%). Within the TBX21 This leads to a downward cascade involving STAT3/5,
subgroup, expression o cytotoxic CD8+ T-cells is CEBPB, and AP1.31–33 In sALCL, GEP studies o tumor
associated with adverse outcomes.24 Immunohisto- cells to identiy COO have largely been largely unsuc-
chemistry (IHC) algorithms are currently being iden- cessul. A recent gene set enrichment analysis points to
tied to distinguish these two subtypes in paran a Th17 origin, which is a lineage o interleukin (IL)-17–
tissue using antibodies to key transcriptional actors producing CD4+ T helper cell program.34,35 Whether
(GATA3 and TBX21) and their target proteins (CCR4 this Th17 expression is rom an already known recur-
and CXCR3).25 rent chromosomal rearrangements involving the ALK
gene with nucleophosmin (NPM1) (t(2;5)(p23q35)) is entity in the 2016 WHO classication. The prognosis
unclear.36 GEP indicates that ALK (+) ALCL and ALK (-) is intermediate between ALK (+) ALCL and PTCL.
ALCL display similar genome signatures, thus suggest- One third o ALK (-) ALCL harbors the DUSP22-IRF4
ing a common COO.35 ALK (-) subtype was a provi- locus on a 6p25.3 rearrangement and has a avorable
sional entity in the WHO 2008 and is now a recognized prognosis with survival comparable to ALK (+) ALCL
A D
CHAPTEr 11
B E
FIGUrE 11–2 Microscopic histopathology o peripheral T-cell lymphoma. Angioimmunoblastic T-cell lymphoma (AITL): AITL
(A; hematoxylin and eosin [H&E] stain), immunohistochemistry (IHC) or CD21 (B), ICH or PD1 (C), and in situ hybridization or
Epstein-Barr virus (EBV)-encoded RNA (D). Systemic anaplastic large-cell lymphoma (sALCL): sALCL (E; H&E), IHC or CD30
F G
CHAPTEr 11
FIGUrE 11–2 (Continued) (F), and IHC or anaplastic lymphoma kinase 1 (ALK1) (G). (Used with permission rom Dr. Francisco
Vega, MDACC.)
counterpart. About 8% to 12% cases demonstrate the paracortex are oten seen. Uncommon morphologic
TP53 homolog TP63 on 3q28 and are associated with variants include small-cell, monomorphic, lymphohis-
an aggressive clinical behavior and poor outcomes tiocytic, neutrophil-rich, clear cell, signet ring cell, giant
(5-year OS rate, 17%).37 The subset o ALK(-) ALCL cell–rich, Hodgkin-like, and sarcomatoid variants. On
that does not carry none o the above rearrangements is IHC, CD30 is universally and strongly expressed in a
termed triple-negative ALCL (ALK, TP63 and DUSP22 membrane and Golgi pattern, with requent expression
negative) and carries an intermediate prognosis (5-year o TIA1, granzyme B, perorin, EMA, and low expres-
OS rate, 33%), poorer than ALK(+) ALCL and DUSP22- sion o CD8 and CD56. Cells are negative or B-cell
rearranged ALCL but better than TP63-rearranged surace markers (CD19, CD20, CD22). There is heter-
ALCL and similar to ALK(-) ALCL as a whole.37 ogenous expression o T-cell antigens and in some cases
The majority o the cases o ALCL display a clas- is dened as a null group none o the lineage-specic
sical morphology under the microscope characterized markers are detected. Whereas the majority o ALCL
by the presence o large cells with abundant cytoplasm have clonally rearranged TCR genes, roughly 10% in
(see Figure 11–2E–G). The common or classic type is the null group have no rearrangement o TCR.10,38,39
characterized by sheets o large pleomorphic tumor
cells and the presence o hallmark cells with eccen-
tric kidney-shaped nucleus (with multiple prominent CLINICAL COUrSE
nucleoli) and a prominent and pale Golgi region (para-
nuclear halo). Variations o multinucleated cells, Reed- The clinical presentation o mature T-cell lympho-
Sternberg–like cells, and doughnut cells that oten mas is extremely variable and largely depends on the
preerentially involve the lymph node sinuses and subtype (Table 11–2). PTCL-NOS, AITL, and ALCL
TABLE 112 FiveYea Outcomes by Difeent Peipheal TCell Lymphoma Subtypes
ITCP: 5-Year FFS (%) ITCP: 5-Year OS (%) BCCA: 5-Year FFS (%) BCCA: 5-Year OS (%)
AITL 18 32 13 36
PTCL-NOS 20 32 29 35
ALK (-) ALCL 36 49 28 43
ALK (+) ALCL 60 70
AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; FFS, ailure-ree survival; ITCP, International T-Cell
Project; OS, overall survival; PTCL-NOS, peripheral T-cell lymphoma not otherwise specied.
all oten present with generalized lymphadenopathy Anaplastic Large-Cell Lymphoma

and B symptoms and can involve extranodal sites,
including the skin, gastrointestinal tract, liver, spleen, ALK (+) ALCL is clinically distinctive with a more
and bone marrow. Patients commonly present with common incidence in younger patients (median age,
advanced-stage disease (stages III and IV; AITL, 89%; 34 years).10,44,45 Both ALK (+) and ALK (-) have re-
PTCL-NOS, 69%; ALK (+) ALCL, 65%; ALK (-) ALCL, quent B symptoms, and one in ve aected patients
58%).10 It is common or PTCL to be mistaken or has involvement o the bone marrow, skin, sot tis-
other types o lymphoma, which oten can lead to a sues, bone, bone marrow, liver, and lungs. In adults,
delay in diagnosis because o suboptimal rates o con- breast involvement has been described, with most
cordant pathological diagnosis.40 Inrequently, patients cases being ALK (-) ALCL and requently seen in
present with or develop during the course eatures o association with breast implants. The outer shell o
hemophagocytic lymphohistiocytosis (HLH) and can the implant (smooth vs textured) is implicated in the
have a high atality rate. In one series, 23% patients risk o Breast implant–associated - ALCL with no risk
had PTCL was associated with lymphoma-associated reported in patients who had smooth implants.46–48 Pri-
hemophagocytic syndrome, PTCL-NOS accounted or mary cutaneous ALCL are morphologically similar but
the majority.41 a clinically distinct subtype o ALCL without systemic
involvement at the time o diagnosis. They lack the
expression o ALK and do not have gene rearrange-
Angioimmunoblastic T-Cell Lymphoma ments involving the ALK gene.49,50
CHAPTEr 11
Patients with AITL are typically middle-aged to older
adults. There is a nearly equal incidence between
both genders. The majority o patients present with DIAGNOSIS AND STAGING
an aggressive clinical course characterized by gener-
alized lymphadenopathy, B symptoms (evers, unin- The diagnosis o PTCL is oten challenging because o
tentional weight loss, drenching night sweats), bone the spectrum o clinical maniestations, heterogenous
marrow involvement, and hepatosplenomegaly. pathological appearance, and oten overlap with more
There are anecdotal reports o a patients presenting common nonmalignant conditions, both clinically and
with a smoldering course with waxing and waning pathologically. The workup o all patients who may
lymphadenopathy. This is one o the commonest have PTCL includes excisional lymph node biopsy i
lymphomas that masquerades as other pathologic easible, which is the gold standard test. The patho-
entities, posing a diagnostic challenge and present- logic diagnosis is based on characteristic morphologic
ing with atypical symptoms. This includes symp- eatures and immunohistochemical patterns in correla-
toms o immunodeciency, opportunistic inections, tion with the clinical signs and symptoms on presen-
skin rash, and hemolytic anemia. 42 Skin rash can be a tation. Several actors add to a diagnostic gap in this
presenting symptom, usually pruritic. Rash is seen in lymphoma, including its rarity and need or detailed
20% to 50% o patients with AITL, ranging rom urti- immunophenotypic markers. Current guidelines sup-
carial lesions to nodular tumors. Hematologic abnor- port the use o diagnostic panels to improve diagnostic
malities (eg, Coombs-positive hemolytic anemia and accuracy and oten require an expert hematopatholo-
polyclonal hypergammaglobulinemia) can be seen in gist. The initial workup o patients with PTCL should
up to 45% o cases.9 include physical examination; complete blood counts;
and chemistry, including lactate dehydrogenase
(LDH), β2-microglobulin, bone marrow aspirate, and
Peripheral T-Cell Lymphoma Not
biopsy. Serologic tests or human immunodeciency
Otherwise Specifed virus, HTLV11, hepatitis B and C can aid in identiying
The median age o the patients with PTCL-NOS the subtypes o PTCLs. Positron emission tomography
is 60 years. The male-to-emale ratio is 2 to 1, and (PET) with 2-deoxy-2-[fuorine-18] fuoro-D-glucose
it has an aggressive clinical course .Although the should be considered at diagnosis, and urther imaging
majority o patients have nodal sites o involvement should be done with PET or computed tomography
(87%), extranodal disease can be present in 62%.43 scan or treatment monitoring at mid-treatment and
Biochemical abnormalities include the presence the end o therapy in all cases. One should have a low
o circulating tumor cells (10%); elevated serum threshold to workup i there is any suspicion o HLH
β2-microglobulin (36%), C-reactive protein (50%), and should consider tests including EBV polymerase
or calcium (5%) levels; hypogammaglobulinemia chain reaction (PCR), erritin, brinogen, triglycerides,
(9%); monoclonal serum immunoglobulin (4%); and cytokine 12 prole, including soluble interleukin-2
hemolytic anemia (3%); and hemophagocytic syn- receptor (IL-2sR). In men and women o childbear-
drome (3%).43 ing potential, the possibility o inertility should be
discussed, and reerral or ertility preservation consul- had low-risk IPI scores and had an excellent 5-year
tation and therapy should be considered. OS (75%). However, the remainder o the patients
with PTCL mostly had IPI scores greater than 2, and
the 5-year OS rate were 25%, underscoring the high
PrOGNOSIS unmet need in this group.39,43
The specic subtypes o aggressive PTCL along with

the molecular markers discussed so ar can provide
Expression o CD30
inormation on the prognosis, with ALK (+) ALCL hav- CD30 is a transmembrane glycoprotein belonging
ing the best prognosis. Clinical actors are also devel- to the tumor necrosis actor receptor superamily. It
oped such as B-cell lymphoma to risk stratiy patients is expressed normally in activated B and T lympho-
called the International Prognostic Index (IPI), which cytes and in pathological states on many PTCL sub-
is based on age, perormance status (PS), LDH, stage, types, including sALCL, in which it is characteristically
and extranodal involvement.6 This was developed in uniorm and high. Ligation o CD30 activates down-
aggressive B lymphomas and is less popularly used stream nuclear actor κB (NF-κB) signaling pathways
in T-cell lymphomas because o its limited ability to to promote cell growth and survival. Because signal-
identiy PTCL patients with their risk o treatment ailing through CD30 can be oncogenic in some T-cell
ure. They were validated in smaller studies, and the lymphomas, with limited expression in normal cells,
prognostication was not so satisactory or the nodal it is one o the ideal targets. The CD30-directed anti-
CHAPTEr 11
entities. Hence, scores based on the biologic eatures body–drug conjugate BV has changed the approach to
o the tumors are currently being explored. An Italian PTCL, essentially drawing a therapeutic line between
cooperative group proposed a revision o the IPI or CD30(+) and CD30(-) groups.
PTCL-NOS, the Prognostic Index or T-cell lymphoma
(PIT) score, which includes age, PS, LDH, and bone
marrow involvement.51 The National Comprehensive
CD30 + Peripheral T-Cell Lymphoma
Cancer Network (NCCN)-IPI, which subspecied ea- BV is an antibody–drug conjugate with the CD30-spe-
tures with respect to age, serum LDH, and inclusion o cic monoclonal antibody attached by a linker peptide
specic extranodal sites (central nervous system, bone to the chemotherapeutic agent monomethyl auristatin
marrow, liver, gastrointestinal tract, lung), seemed to E (MMAE). Upon binding to CD30, BV undergoes
separate prognostic groups slightly better on a visual endocytosis and is taken up by the lysosomal com-
scale. Both the PIT and the NCCN- IPI are able to dis- plexes. Under low pH conditions, the proteases cleave
criminate the risk groups better in PTCL- NOS and the linker and release MMAE to cytoplasm. Single-
ALCL than in AITL.51,52 Although these clinical models agent BV was approved or patients with sALCL ater
are useul in estimating the prognosis, they have not ailure o one or more previous multiagent chemother-
impacted treatment approaches, and better tools incor- apy regimens. A phase I study evaluating BV in combi-
porating immunophenotypic and molecular markers nation with CHP (CHOP without vincristine) in newly
are much needed. diagnosed patients with CD30(+) T-cell lymphomas
showed an overall response rate (ORR) o 86%, with
complete response rate (CRR) o 57%. The toxicities
CLINICAL MANAGEMENT were manageable; adverse events (AEs) o grade 3 or
higher commonly included neutropenia (21%), throm-
Despite the advancements in the knowledge o the bocytopenia (14%), peripheral sensory neuropathy
biology o PTCLs, the clinical course varies exten- (12%), and anemia (7%). The long term 5-year ollow-
sively depending on PTCL subtype and therapeutic up in 38 patients who achieved CR showed progres-
intervention. It is imperative that the choice o ront- sion-ree survival (PFS) o 57% and OS o 79%.
line treatments to be critically appraised based on the A large, randomized, phase III study (ECHELON-2)
subtype and the expression o CD30. Except or ALK comparing BV-CHP with CHOP BV plus CHP dem-
(+) ALCL and ALK (-) ALCL with DUSP22 rearrange- onstrated superior response rates, higher rates o PFS,
ment, patients with PTCL generally have a chemo- higher and OS without added toxicity or BV-CHP.54
resistance, short-term remission, early relapse when This is an important practice changing milestone in
treated with chemotherapy with CHOP or CHOP-like PTCL history, and BV-CHP is currently the standard
chemotherapy.53 Historically, most o our knowledge o care treatment in patient with CD30 (+) PTCLs.
on the treatment outcomes rom the International CD30 is universally expressed in ALCLs, both ALK (+)
T-Cell Project (ITCP) and the British Columbia Cancer and (-). In non-sALCL subtypes, CD30 expression is
Agency (BCCA) series (see Table 11–1). In the BCCA estimated to be approximately 58% to 64% in PTCL-
group, the majority o patients with ALK (+) disease NOS and 43% to 63% in AITL.55,56 The ECHELON-2
study required the expression o CD30 to be at least PTCL-TBX21

10% or greater in the neoplastic cells to be included +
PTCL-TBX21
in the study. About 75% o the patients in the ECH-
+
ELON-2 study had advanced-stage disease, 30% were –
65 years o age or older, and 70% had sALCL (48%
CXCR3 (IHC;≥20%) PTCL-GATA3
ALK (-)). Twenty-two percent o patients were ALK
+
(+) were required to have IPI scores o 2 or greater. –
Others in the study included patients with PTCL-NOS
GATA3 (IHC;≥50%) PTCL-GATA3
(16%), AITL (12%), ATLL (<2%), and EATL (<1%).
+
The ORR and CRR were signicantly higher with BV- –
CHP than CHOP (ORR, 83% vs 72%; CR rate, 68% vs
CCR4 (IHC;≥50%)
56%). The study met the primary endpoint showing
signicant improvement o PFS with BV-CHP. With a –
median ollow-up period o 36.2 months, the median Unclassifiable
PFSs were 48.2 months versus 20.8 months (BV-CHP
vs CHOP; hazard ratio [HR], 0.71, 95% condence FIGUrE 11–3 Cell o origin or peripheral T-cell lymphoma
interval [CI], 0.54–0.93; P = .011). There was also a sig- (PTCL) not otherwise specifed. IHC, immunohistochemistry.
nicant improvement in OS with HR (0.66; 95% CI,
0.46–0.95; P = .0244 or BV-CHP versus CHOP). The
CHAPTEr 11
OS benet was predominantly seen in sALCL but not levels o LDH. The positive eect o etoposide on
in PTCL-NOS (HR, 0.83; 95% CI, 0.38–1.80) and AITL EFS was conrmed when patients with ALK(+) ALCL
(HR, 0.87; 95% CI, 0.29–2.58). The treatment-related were considered (3-year EFS, 91.2% vs 57.1%; P =
AE rates were similar between the two groups: AEs .012); the comparison showed a similar numerical
o grade 3 or greater occurred in 66% o the BV group trend when the other subtypes were taken together
versus 65% o the CHOP group. Febrile neutropenia (3-year EFS, 60.7% vs 48.3%; P = .057).58,59 In older
occurred in 18% versus 15% and any grade peripheral adult patients, the addition o etoposide is consid-
neuropathy in 52% versus 55%. Serious AE occurred ered debatable and can oten cause toxicity; its use
in 39% vs 38%; treatment discontinuation because o should be evaluated on a case-by-case basis. Many
AEs occurred in 6% and 7% o patients in BV-CHP centers use it to achieve deeper remissions rates in
and CHOP arms, respectively. Treatment-related AEs anticipation or consolidation with high-dose che-
leading to death were similar in both cohorts (3% vs motherapy with hematopoietic stem-cell transplant
4%). The study clearly breaks the traditional norm (HDC SCT). More intensive induction regimens (eg,
in PTCL trials and established CD30-based treat- inusional EPOCH, hyper-CVAD [hyperraction-
ment or rontline treatment o patients with T-cell ated cyclophosphamide, vincristine, doxorubicin,
lymphomas. However, it remains to be noted that and dexamethasone]) provide comparable clinical
AITL and PTCL-NOS subgroups were suboptimally outcomes, but no prospective studies have directly
represented, so the study is not powered to compare compared the regimens. Moreover, these intensive
ecacy between histologic subtypes along with the regimens are associated with increased AEs.60 CHOP
potential benet o BV in non- ALCL CD30(+) PTCL is generally administered every 3 weeks, similar to
subtypes.54 In November 2018, the FDA approved Cyclophosphamide, Doxorubicin, Vincristine, Eto-
BV with CHP or patients with previously untreated poside and Prednisone (CHOEP), in which the addi-
sALCL or other CD30-expressing PTCLs, including tional etoposide is administered on days 1 through 3
AITL and PTCL-NOS (Fig. 11–3). every 3 weeks58 (Fig. 11–4).
CD30-Negative T-Cell Lymphoma UPFrONT CONSOLIDATION AND

For the vast majority o both cases o AITL and PTCL- MAINTENANCE
NOS that are CD30 (-), CHOP-based chemotherapy
remains the standard o care. Although more inten- The majority o patients receiving rontline chemo-
sive therapies have been attempted, these did not therapy (see Fig. 11–4), except or those with ALK
are better than those treated with CHOP therapy. 57 (+) ALCL, ail to achieve long- term remissions in
Both the registry study rom Sweden and the German PTCL. 61 Studies have looked at the role o consoli-
High-Grade Non-Hodgkin Lymphoma Study Group’s dation with radiation therapy (RT) and HDC SCT
ad-hoc analysis showed improved event-ree survival in eligible patients; however, it is worth noting that
(EFS) with the incorporation o etoposide in CHOP, there is a lack o adequately powered randomized
especially i age is younger than 60 years, and normal controlled trials to make a strong recommendation.
CD30 (-) Observation

CHOP +/- Etoposide
AITL Versus
PTCL
CD30(+) HDC/ SCT for
BV-CHP fit patients.
Observation
*ALK(+) &
ALK(-) BV-CHP if high risk IPI,
ALCL Consider HDC/ SCT
for fit patients.
FIGUrE 11–4 Frontline treatment algorithm or peripheral T-cell lymphoma (PTCL). AITL, angioimmunoblastic T-cell lym-
phoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; BV, brentuximab vedotin; CHOP, cyclophos-
phamide, doxorubicin, vincristine, and prednisone; CHP, cyclophosphamide, doxorubicin, and prednisone; HDC SCT, high-dose
chemotherapy with stem-cell transplantation; IPI, International Prognostic Index.
*Universal expression o CD30
CHAPTEr 11
In early stage and low IPI group, RT is generally an group); however, the study was not designed to look at
accepted mode o consolidation based on retrospec- the eect o transplant.54 An exploratory analysis was
tive analyses and anecdotal experience.62–64 There urther reported o the patients in CR ater BV + CHP
are many limitations to these studies, including their who received SCT and those who did not showed a
small sample size, selection bias o dierent che- numerical PFS benet in avor o SCT.72 The Center or
motherapies used, and inclusion o primary rerac- International Blood and Marrow Transplant Research
tory disease. The current national guideline- (the retrospectively evaluated HDC SCT, and the results
NCCN guidelines) recommend consolidative RT suggested better outcomes when consolidation was
in all patients with stage I or II PTCL disease who oered earlier in the disease course and limited utility
achieve remission ater standard anthracycline-based in multiply relapsed disease.69 Although there is a role
chemotherapy. or consolidative HDC SCT in the primary treatment
In advance stage with high IPI, studies have sup- o nodal PTCLs, urther studies are needed based on
ported HDC SCT as a consolidation treatment in clinical and genetic stratication, particularly patients
patients with all major subtypes o PTCL with noted with high-risk eatures. Allogeneic transplant carries
signicant benet in the rst remission compared a high transplant-related mortality (TRM) rate and is
with subsequent remission (Table 11–3).65–71 In the generally not considered in rst remission. Improve-
ECHELON-2 trial, at the discretion o the investiga- ments in TRM may permit the role o upront allo-
tor, patients underwent consolidative HDC SCT (22% geneic SCT in appropriately designed clinical studies
patients in the BV +CHP group and 17% in the CHOP with high-risk characteristics. 73
TABLE 113 Outcome o HighDose Chemotheapy Autologous StemCell Tansplantation in Fist

remission in Peipheal TCell Lymphoma om Landmak Studies
Reference Patients (n) Frontline Treatment PFS and EFS OS

66
Mercadal et al (2008) 41 High-dose CHOP/standard ESHAP 4-year PFS, 30% 4-year OS, 39%
Corradini et al68 (2006) 62 (1) 32 patients received APOx2 + ALK-positive ALK-positive
DHAPx2 ollowed by HDT/ASCT lymphomas: lymphomas:
(2) 30 patients received MACOP-B or 12-year EFS, 54% 12-year OS, 62%
8 weeks with intensication with
a 3-day course o mitoxantrone
and ara-C, ollowed by HDT/ ASCT
d’Amore et al65 (2012) 166 Biweekly CHOEP or six cycles 5-year PFS, 44% 5-year OS, 51%
Reimer et al68 (2009) 83 CHOP 3-year PFS, 36% 3-year OS, 48%
71
Rodriquez et al (2007) 74 CHOP-based regimen 5-year PFS, 63% 5-year OS, 68%
ALK, anaplastic lymphoma kinase; APO, doxorubicin, vincristine, prednisone; CHOEP, cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone; CHOP,
cyclophosphamide, doxorubicin, vincristine and prednisone; EFS, event-ree survival; ESHAP, etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C),
and cisplatin; MACOP-B, methotrexate-doxorubicin-cyclophosphamide-vincristine-prednisone- bleomycin; OS, overall survival; PFS, progression-ree survival
rELAPSED Or rEFrACTOrY can in turn acilitate subsequent consolidation with

DISEASE HDC SCT. 82
The role o these novel agents to improve disease-
A substantial number o patients with nodal PTCL related outcomes is actively being investigated in the
either relapse or ail to achieve remission, as shown rontline induction, disease salvage, and high-dose
in the 153-patient BCCA series, and have poor out- consolidation or in a maintenance setting. Mature clin-
comes with short survival times.74 For patients who ical data are needed to show their impact on survival
are t and eligible, intensive salvage chemotherapy curves.
options are considered with the intention to consoli-
date with HDC SCT. The ORR or the various sal-
vage regimens is in the 40% to 50% range; only a ew EMErGING HOrIZONS
patients manage to achieve CR, and the window to
get these patients to HDC SCT is oten short. In the Clinical trials remain an integral part o the care o
BCCA series, the median PFS and OS ater the rst patients with PTCL, and participation is thereore
relapse or disease progression were only 3.1 and 5.5 highly encouraged. Understanding o the molecu-
months, respectively, without HDC SCT. Moreover, lar and epigenomic markers has provided targetable
the patients who did receive chemotherapy at relapse mutations and pathways and has the potential to
had longer OS, but the dierence was only 3 months transorm the current treatment landscape to more
compared with those who did not (6.5 vs 3.7 months, personalized care or patients. Overall, there is a need
CHAPTEr 11
respectively). or eective treatments or most PTCL subtypes, and
Multiple studies suggest that outcomes o patients this requires increased understanding o the biology
who have chemotherapy-sensitive disease have bet- o PTCL to improve diagnosis and provide biomark-
ter outcomes with HDC SCT. However, there is a ers or assessment o response or relapse. Several
lack o randomized controlled studies, and most data novel therapeutic agents are under investigation in
on the role o HDC SCT and the types (autologous relapsed or reractory PTCL, which has shown to
vs allogeneic) come rom phase II and retrospective result in deeper responses, potentially improving
studies, which have inherent bias because o patient outcomes; however, this discussion is beyond the
selection, heterogenous pathology, and inclusion o scope o this chapter. Using these agents, single-agent
patients with more avorable PTCL subtypes. In addi- therapy or palliative intent or combination therapies
tion, most studies include patients who went on to ollowed by HDC SCT consolidation is actively being
receive HDT SCT.69—72 Patients who achieve a CR investigated. These investigational agents include
with salvage regimens could be consolidated with an ALK inhibitors (crizotinib and ceritinib), alisertib
HDC autologous SCT, but those with a PR should be (selective inhibitor o aurora A kinase), panobino-
considered or allogeneic HCT or additional salvage stat (pan-HDAC [histone deacetylase] [class ½/4]
therapy. inhibitor), bortezomib (proteasome inhibitor), deni-
Another major challenge in PTCL is that at the leukin dititox (IL-2–diphtheria toxin usion pro-
time o relapse, many patients are not eligible or tein), lenalidomide(immunomodulatory, synthetic
intensive chemotherapies because o age, comor- thalidomide derivative), alemtuzumab (humanized
bidities, perormance status, or personal preerences. anti-CD52 monoclonal antibody), mogamulizumab
In these patients, many new drugs are being inves- (deucosylated, humanized, monoclonal antibody
tigated to extend the duration o response. The US targeting CC chemokine receptor 4), duvelisib
FDA has approved our drugs with novel mecha- and tenalisib (phosphoinositide-3 kinases δ and g
nisms o action or the treatment o patients with inhibitors), cyclosporine (immunomodulatory), and
relapsed or reractory nodal T-cell lymphoma based Selinexor (oral selective inhibitor o nuclear export).3
on ORR. These include pralatrexate, romidepsin, Innovative therapies such as chimeric antigen recep-
belinostat, and BV.75—81 Response rates with prala- tor (CAR) T-cell therapy (an adoptive T-cell therapy
trexate, romidepsin, and belinostat range rom 25% approach that uses genetically engineered T cells
to 54% in relapsed or reractory PTCL populations, transduced to express an articial receptor against
and the ORR is as high as 86% (CR, 57%) with BV a target antigen on the tumor) are among the most
or patients with ALCL (Table 11–4). The actual promising immunotherapies or cancer. They have
impact on survival outcome or the single agents produced remarkable response rates in patients with
remains unclear. There have been attempts made to B-lymphoid malignancies and are currently in phase ½
incorporate these novel agents into the salvage che- trials in patients with PTCL. These approaches have
motherapy backbone with the intention o providing the potential to move rapidly to the rontline clinical
higher CR rates without an increase in toxicity. This investigation; many o these are currently underway.
TABLE 114 Tageted Agents and the Pivotal Tials That Led to Appoval o Peipheal TCell
Lymphoma
Patients
Study Drugs Mechanism o Action (n) ORR CR PFS or EFS Median OS
PROPEL Pralatrexate Novel selective 109 29% 11% 3.5 14.4 months
antiolate agent PTCL-NOS: months
Competitively inhibits 32
dihydroolate sALCL: 35
reductase and AITL: 8
thymidylate synthase
Thereby disrupts
the DNA/RNA
synthesis required
or lymphoma cell
prolieration
BELIEF Belinostat Potent IV (class 129 25.8% 10.8 1.6 7.9 months
1/2/4), epigenetic- PTCL-NOS: AITL: months
modiying HDAC 23% 18%
CHAPTEr 11
inhibitor AITL: 46%

ALK (-) ALCL:
15%
Phase II Brentuximab (R/R ADC directed against 58 86% 57% 20 months Not reached
systemic ALCL CD30, a cell-surace 1 year: 70%
ater treatment antigen 3 years: 63%
ailure o at 4 years: 64%
least one prior
therapy)
Phase II Romidepsin Epigenetic-modiying 130 25% 15% 4 months 11.3 months
agent that alters PTCL-NOS:
chromatin, 29%
specically as a AITL: 30%
potent IV class 1 ALK (-) ALCL:
HDAC inhibitor 24%
Intereres with the
acetylation pattern
o chromatin on
histone lysine
residues
Prevents gene
transcription
and disrupts
protein unction
in malignant
lymphoma cells
ADC, Antibody-drug Conjugates; AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large-cell lymphoma; ALK, anaplastic lymphoma kinase; Phase II BELIEF
(CLN-19) Study; CR, complete remission; EFS, event-ree survival; FFS, ailure-ree survival; HDAC, histone deacetylase; ORR, overall response rate; OS, overall survival;
PFS, progression-ree survival; Phase II, PROPEL; PTCL-NOS, peripheral T-cell lymphoma not otherwise specied; R/R, Relapsed / Reractory; sALCL, systemic anaplastic
large-cell lymphoma.
CONCLUSIONS to maintain this remission. As the eld moves toward

individualized therapies, large cooperative eorts are
PTCL is a heterogenous group o rare lymphomas with needed to advance the research to understand the di-
poor prognoses and a lack o large, randomized trials erent molecular subtypes and develop genome-driven
to dictate treatment options. The immediate goal o clinical trials. Several new therapies, including CAR
therapy is to achieve a rapid and complete response T-cell therapies, are likely to make a positive impact
and ollow dierent treatment consolidation strategies on survival outcomes in the next ew years.

J Excisional lymph node tissue biopsy is strongly rec- Group and the analysis o the Swedish Lymphoma
ommended or the diagnosis o PTCL and is consid- Registry. There was a trend toward improved EFS in
ered the gold standard test. Many centers perorm avor o CHOEP in the other subsets as well, which
core biopsy to provide pathological diagnosis in was not statistically signicant.
clinical presentations with time-sensitive require- J For patients older than 60 years, intensive regimens
ments. Fine-needle aspiration is considered subop- are associated with increased toxicity without the
timal or establishing the diagnosis. benet o improvement in outcomes. There was
J The presence o neoplastic T-cell inltrate is deter- no benet o CHOP-14 compared with CHOP-21,
mined based on morphology, aberrant T-cell phe- and adding etoposide CHOP chemotherapy was
notype (loss o expression o antigens normally more toxic in the older adult group; hence, BV-CHP
expressed by T-cells or expression o antigens nor- and CHOP continues to be the standard in older
mally not associated with normal T-cells). Dem- adult patients with CD30(+) and CD30(-) PTCL,
onstration o T-cell clonality o PTCL is routinely respectively.
evaluated with a PCR-based method using genomic J Because o the high relapse rates in PTCL, high-
DNA; however, the absence o an identiable T-cell dose chemotherapy with autologous SCT should
clone does not denitively rule out a diagnosis o strongly be considered or consolidation ater the
PTCL.
CHAPTEr 11
rst remission except in the ALK (+) subtypes.
J For patients 60 years o age or younger with normal J The US FDA has approved our drugs with novel
LDH, especially or ALK (+) sALCL, addition o etopo- mechanisms o action or the treatment o patients
side to CHOP may be more efcacious than CHOP with relapsed or reractory PTCL. These include pra-
according to the subgroup analysis rom large, pro- latrexate in 2009, romidepsin in 2011, BV (or sALCL)
spective, randomized clinical trials rom The Ger- in 2011, and belinostat in 2014.
man High-Grade Non-Hodgkin Lymphoma Study
20. Dupuis J, Boye K, Martin N, et al. Expression o CXCL13 by

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CHAPTEr 11
12 Cutaneous Lymphomas
Auris Huen
KEY CONCEPTS
 Cutaneous lymphomas are a heterogenous group o B-  The treatment o patients with CTCL is guided by stage
and T-lymphocyte inltration to the skin with varying clini- and distribution o the skin involvement. The initial treat-
cal behaviors and prognoses. ment approach to skin-limited disease is embodied by the
 Mycosis ungoides (MF) is the most common sub- use o skin-directed treatment modalities.
type o cutaneous T-cell lymphoma (CTCL) with typical  Two newly approved treatment options or patients with
indolent course, but a subset o patients can progress relapsed reractory MF and SS include brentuximab vedo-
to more advanced stages involving nodal and blood tin and mogamulizumab, which target skin and blood
compartments. compartments o disease, respectively.
 Sézary syndrome (SS) is a leukemic variant o CTCL with a  Primary cutaneous B-cell lymphomas should be distin-
more aggressive course. In many patients, skin biopsy is guished rom secondary metastasis o B-cell lymphoma
nondiagnostic because it does not reveal malignant cells, to the skin and are typically associated with an indolent
and diagnosis is made by peripheral blood ow cytometry disease course and a avorable prognosis.
or Sézary cell count.
Cutaneous lymphoma is an umbrella diagnosis consist- carries diering clinical presentation, histopathologic
ing o multiple subtypes involving malignant mature eatures, prognoses, and treatment approaches. The vari-
B- or T-lymphocyte inltration in the skin. It should be ous subtypes o cutaneous B and T-cell lymphomas can
distinguished rom secondary metastasis o systemic be separated into aggressive and less aggressive orms
lymphoma to the skin where involvement in the skin is (Table 12–2). Mycosis ungoides (MF), pagetoid reticulo-
considered advanced stage. Cutaneous T-cell lymphoma sis, and CD30+ lymphoprolierative disorders are consid-
(CTCL) is considered a rare entity consisting o approxi- ered relatively indolent diagnoses. For B-cell lymphomas,
mately 4% o all cases o non-Hodgkin lymphoma.1 In marginal zone and ollicle center cell lymphomas are
the majority o patients with CTCL, the disease course avorable subtypes. In indolent cutaneous lymphoma,
is typically indolent; however, in a subset o patients, the skin lesions can wax and wane or years and sometimes
prognosis is less avorable, and progression to advanced- even sel-resolve without treatment. In more aggressive
stage disease with nodal, blood, and visceral compart- subtypes such as Sézary syndrome (SS), primary cutane-
ments can develop. The cutaneous B-cell lymphomas are ous gδ T-cell lymphoma (pcGDL), and primary cutane-
less common than their T-cell counterparts, also with a ous CD8+ epidermotropic cytotoxic T-cell lymphoma,
avorable prognosis in the majority o patients.2,3 diuse large-cell lymphoma, eg type (DLBCL leg type),
In 2008, the World Health Organization (WHO) patients characteristically develop rapidly progressive
established the classication o cutaneous lymphomas. skin lesions and systemic involvement pertaining to a
This classication was updated in 2016 and again by the poor prognosis.4,5 It is critical to determine the patient’s
WHO–European Organization or Research and Treat- subtype to accurately provide prognosis and treatment.
ment o Cancer (EORTC) and provides the basis or sub- Appropriate classication o the patient’s disease can pre-
categorization o this disease (Table 12–1).2 Each subtype vent overtreatment o indolent orms o disease.
269
TABLE 121 World Health OrganizationEuroean Organization or Research and Treatment o
Cancer 2018 Classifcation o Cutaneous Lymhomas
Cutaneous T-Cell Lymphomas Frequency (%) 5-Year DSS (%)

Mycosis ungoides (MF) 39 88
MF variants
Folliculotropic MF 5 75
Pagetoid reticulosis <1 100
Granulomatous slack skin <1 100
Sézary syndrome 2 36
Adult T-cell leukemia/lymphoma <1 NDA
Primary cutaneous CD30+ lymphoprolierative disorder
Primary cutaneous anaplastic large-cell lymphoma 8 95
Lymphomatoid papulosis 12 99
Subcutaneous panniculitis-like T-cell lymphoma 1 87
Extranodal NK/T-cell lymphoma, nasal type <1 16
Chronic active EBV inection <1 NDA
Primary cutaneous peripheral T-cell lymphoma, rare subtypes
Primary cutaneous g/d T-cell lymphoma <1 11
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma <1 31
CHApTER 12
Primary cutaneous CD4+ Small/medium pleomorphic T-cell

lymphoprolierative disorder (P) 6 100
Primary cutaneous acral CD8+ T-cell lymphoma (P)
Primary cutaneous peripheral T-cell lymphoma, NOS <1 100
2 15
Primary cutaneous marginal zone lymphoma 9 99
Primary cutaneous ollicle center cell lymphoma 12 95
Primary cutaneous difuse large B-cell lymphoma, leg type 4 56
EBV+ mucocutaneous ulcer (P) <1 100
Intravascular large B-cell lymphoma <1 72
DSS, disease-specic survival; EBV, Epstein-Barr virus; MF, mycosis ungoides; NDA, no data available; NOS, not otherwise specied; P, provisional.
Modied with permission rom Willemze R, Cerroni L, Kemp W, et al: The 2018 update o the WHO-EORTC classication or primary cutaneous lymphomas, Blood 2019
Apr 18;133(16):1703-1714.
TABLE 122 Lymhoma Subtyes
A. T-Cell Lymphoma Subtypes

Indolent Aggressive
Mycosis ungoides Sézary syndrome
Folliculotropic mycosis ungoides Primary cutaneous natural killer/T-cell lymphoma, nasal type
Pagetoid reticulosis Primary cutaneous aggressive CD8+ T-cell lymphoma
Granulomatous slack skin Primary cutaneous g/δ T-cell lymphoma
Primary cutaneous anaplastic large-cell lymphoma Primary cutaneous peripheral T-cell lymphoma, unspecied
Lymphomatoid papulosis Primary cutaneous CD8+ aggressive epidermotropic cytotoxic
T-cell lymphoma
Primary cutaneous CD4+ small/medium pleomorphic
T-cell lymphoprolierative disorder
B. B-Cell Lymphoma Subtypes
Indolent Aggressive
Marginal zone Difuse large B-Cell
Leg type
Follicle center cell Intravascular lymphoma
Other
Chater 12 Cutaneous Lymphomas 271
A CUTANEOUS TUMOR TYpES

Patients with cutaneous lymphoma typically pres-
ent with patches, plaques, and tumors on the skin.
Patches are characterized by fat, nonpalpable ery-
thematous involvement in the skin. I lesions become
thickened and palpable, they are considered plaques.
More advanced stages are associated with tumors in
the skin that are more indurated or ulcerated. (Fig.
12–1). Other less common cutaneous ndings asso-
ciated with CTCL include leonine acies, palmar
plantar hyperkeratosis (Fig. 12–2), poikiloderma, and
B
A
CHApTER 12
C
FIGURE 12–1 Patches (A), plaques (B), and tumors (C) of FIGURE 12–2 Leonine facies (A) and palmar plantar kerato-
mycosis fungoides. derma (B) of Sézary syndrome.
EVALUATION OF pATIENTS WITH

CUTANEOUS LYMpHOMA
Patients with cutaneous lymphoma are ideally evalu-
ated by a multidisciplinary team with expertise in the
disease consisting o dermatologists and oncologists,
with support rom pathologists and radiation oncolo-
gists.8,9 Patients typically present with skin lesions as
the initial presenting sign. Multiple skin biopsies are
sometimes needed or the diagnosis o cutaneous lym-
phoma, especially in patients with thin lesions, oten
requiring immunohistochemistry markers and clon-
ality studies or diagnosis. Skin lesion examination
assessing extent o skin involvement and complete
clinical history is vital to aid in classication o disease
into subtypes. Quantiying cutaneous involvement o
CTCL involves determining body surace area (BSA)
and the modied severity-weighted assessment tool
CHApTER 12
(SWAT), which adds the infuence o the lesion type.

The modied SWAT is the most recognized method
o measuring cutaneous involvement with CTCL and
FIGURE 12–3 Hypopigmented mycosis fungoides. is oten used clinically and in clinical trials or skin
assessment. The patient’s hand size is used to estimate
about 1% BSA (Table 12–3). Patches are weighted
with actor o 1, plaques are weighted with actor o 2,
hypopigmentation.6,7 (Fig. 12–3) These ndings are and tumors are weighted with actor o 4 to determine
unique to certain subtypes o CTCL and are discussed the modied SWAT. This weighted model takes into
in individual sections. consideration changes in skin lesions type and more
TABLE 123 Samle Form or Body Surace Area (BSA) Calculation and Modifed SeverityWeighted
Assessment Tool (mSWAT)
Area BSA for Region (%) BSA Patch (%) BSA Plaque (%) BSA Tumor (T)
Head 7
Neck 2
Anterior trunk 13
Posterior trunk 13
Buttocks 5
Genitalia 1
Upper arms 8
Forearms 6
Hands 5
Thighs 19
Lower legs 14
Feet 7
TOTALa 100
a
Total BSA involvement:
Percent BSA patch: ___
Percent BSA plaque: ___
Percent BSA tumor: ___
Total BSA: ___
mSWAT = (% BSA patch × 1) + (% BSA plaque × 2) + (% BSA tumor × 4) = ___
Modied with permission rom Olsen EA, Whittaker S, Kim YH, et al: Clinical end points and response criteria in mycosis ungoides and Sézary syndrome: a consensus
statement o the International Society or Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force o
the European Organisation or Research and Treatment o Cancer, J Clin Oncol 2011 Jun 20;29(18):2598-2607.
accurately refects the severity o the patient’s cutane- increased dendritic cell such as antigen-presenting cell
ous involvement.10 (APC) ligands B7 and CD40 and their costimulatory
Taking a complete medication history or recently ligands CD28 and CD40L in MF lesions.14 Other stud-
started medications and history o recent exposures to ies show elevated Toll-like receptor (TLR) expression
viral or inectious organisms can help rule out pseu- by keratinocytes and expression o human leukocyte
dolymphoma. All patients with B-cell cutaneous lym- antigen class II alleles in patients with MF.16 Stimulation
phoma should undergo screening or systemic disease, rom Staphylococcus aureus enterotoxins may contribute
including computed tomography (CT) with contrast o to MF. Studies have ound high rates o colonization o
the chest, abdomen, and pelvis and blood work with a the bacteria in erythrodermic patients with MF and SS
complete blood count (CBC).11 In patients with CTCL, and improvement in their disease with treatment o
laboratory workup should include CBC, comprehen- inection.17 Viral etiologies such as Epstein-Barr virus
sive metabolic prole, lactate dehydrogenase (LDH), (EBV) and cytomegalovirus (CMV) have been inves-
and screening or inectious triggers such as syphilis, tigated.18,19 Patients receiving immunosuppressive
human immunodeciency virus(HIV), hepatitis B and treatment or in immunocompromised state has been
C, and in select patients, human T-cell leukemia/lym- reported to be vulnerable to development o cutaneous
phoma virus-1 (HTLV-1) i applicable. Flow cytometry lymphoma and have a more aggressive course.20–24
or aberrant T-cells in the peripheral blood should Several genetic alterations have been linked to MF,
also be assessed in all patients with erythrodermic including dysregulation in the nuclear actor κ light
and advanced-stage CTCL.9 In patients with indolent chain enhancer o activated B-cells (NF-κB) as well
CHApTER 12
CTCL such as MF, early-stage disease with patch-only as aberrant gene methylation and histone deacety-
involvement, no imaging or bone marrow studies are lation.25,26 Alterations in p16 and p53 tumor suppressor
typically perormed unless the patient reports systemic genes have also been associated with MF tumors.27,28
symptoms or has laboratory abnormalities. In patients MF can be associated with a composite lymphoma
with thicker plaques, tumors, and erythroderma, ull where a second unrelated lymphoma can occur con-
staging evaluation, including CT or positron emission currently.29–32 An increased risk or other cancers has
tomography–CT (PET-CT) should be done.3 Lymph also been linked to MF, which can precede, appear con-
nodes greater than 1.5 cm by palpation or imaging currently, or appear subsequent to its diagnosis.33,34
should be evaluated or potential disease involvement
with core or excisional biopsies. Fine-needle aspiration
o lymph nodes should be avoided so that the lymph
node architecture and eacement o the sample can be Patients are typically adults (median age at diagnosis,
evaluated.12 ~55–60 years), but it can occur rarely in children.35,36
They typically present with erythematous patches on
the skin, which in some patients progress over years
CUTANEOUS T-CELL LYMpHOMAS to plaques and tumors. The majority o patients pres-
ent with early-stage disease with 30% o patients
presenting with tumors and erythroderma at diagno-
Mycosis Fungoides sis.37 The lesions avor a “double-hidden” distribution
The most common subtype o CTCL is MF, which in non–sun-exposed areas beneath underwear. The
accounts or approximately 50% to 60% o cases o patches are oten described as nely scaly with “ciga-
cutaneous lymphoma and typically carries an indolent rette paper” in appearance because o loss o elastic
course. In the United States, the annual age-adjusted bers and atrophy o the epidermis.3 The plaques are
incidence is reported at 7.5 cases per million and is typically dark red in appearance and can have variable
considered a rare diagnosis.13 Patients present with amounts o scale. Tumors are oten ulcerated and have
patches and plaques, which are oten mistaken or a variable growth rate. Patients with advanced-stage
other dermatoses such as atopic dermatitis or psoria- disease may develop tumors while also having patches
sis or years beore the correct diagnosis is made. The and plaques. The stage o disease does not only pertain
median delay in diagnosis o 36 months was recently to the percentage skin involvement but also the lesion
reported in a large series o patients. This is largely due type.
to challenges in evaluating early-stage disease clini- Other less common skin ndings in patients with
cally with mimickers and on histopathologic review.14 MF include unique variants reported in the literature.
No denite cause or association leading to the These include leonine acies, especially in patients
development o MF has been identied. However, it is with olliculotropic variant o the disease and in SS
believed that it is triggered by chronic antigenic stimu- patients. Alopecia can also be seen in olliculotropic
lation, leading to expansion o clonal skin homing T patients.38 Hypopigmentation on the skin has also
lymphocytes to the skin.15 This theory is supported by been associated with the hypopigmented variant o
MF. Loose foppy skin most prominent in skin olds is support the diagnosis in early ambiguous cases o MF.46
associated with granulomatous slack skin variant. Poi- (Table 12–4).
kiloderma is associated with poikiloderma vasculare et In cases in which there are increased large cells
atrophicans.3,39,40 exceeding 25% o the inltrate, MF is considered to
have large-cell transormation (LCT) and carries a
Histopathology more aggressive course. In patients with LCT, some
can express CD30, which is associated with a better
The typical aberrant cell in MF is the mature small to prognosis compared with those who are CD30 nega-
medium-sized T lymphocytes. They have a “cerebri- tive.47 LCT should only be considered in a patient with
orm” appearance. There is a hallmark epidermotropic preexisting MF. I no prior disease is known, consider-
eature with intraepidermal inltration o these lym- ation or alternative diagnosis such as lymphomatoid
phocytes. Clustering o these cells are called Pautrier’s papulosis or anaplastic large-cell lymphoma should be
microabscesses. The immunophenotype o classic MF made.
is typically characterized by α/β T-helper central mem-
ory lymphocytes with CD3+, CD4+, CD8-, CD45Ro+,
Variants
TIA-1- phenotype.3 In plaques and tumors, the CD4
to CD8 ratio is greater than 4:1. In many cases, there There are numerous MF variants reported in the litera-
is loss o CD7 and CD26 on the cell surace.41 In rare ture. The most common variants include olliculotropic
cases, CD8+, CD4-/CD8-, g/δ, and cytotoxic pheno- MF, granulomatous slack skin, and hypopigmented
CHApTER 12
types have been reported.42,43 Detection o monoclonal MF. Folliculotropic MF is an entity in which the malig-
rearrangement o α/β or g/δ T-cell receptor (TCR) can nant lymphocytes have anity or the pilosebaceous
be used as a tool to support the diagnosis o MF, which units. Typically, mucin deposits are also seen, and
can be challenging in early stages o the disease.44 A there is associated ollicular mucinosis. Clinically,
clonal TCR has been reported in 40% to 90% o cases these patients present with acneiorm lesions along
o MF.14 TCR clonality is most commonly determined with scalp involvement and alopecia. Patients with ol-
using polymerase chain reaction technique, but next- liculotropic MF were also ound to have increased risk
generation sequencing has been ound to improve o disease progression and lower overall survival (OS)
sensitivity in detecting a predominant malignant compared with those with conventional MF (82% vs
clone.45 A scoring system devised by the International 91% at 10 years; 41% vs 91% at 15 years).48 This is
Society Cutaneous Lymphoma incorporating clinical, likely attributed to decreased response to skin-directed
histologic, and molecular biological characteristics to therapy because o disease sanctuary in the ollicles.49
TABLE 124 Algorithm or the Diagnosis o Early Mycosis Fungoides proosed by the International
Society or Cutaneous Lymhoma
Criteria Scoring Systema

Clinical basic 2 points or basic plus two additional criteria
Persistent or progressive patches or thin plaques 1 point or basic plus one additional criterion
Additional
Non–sun-exposed location 2 points or basic plus two additional criteria
Size or shape variation
Poikiloderma
Histopathologic basic
Supercial lymphoid inltrate 1 point or basic plus one additional criterion
Additional
Epidermotropism without spongiosis 1 point or clonality
Lymphoid atypia
Molecular
Clonal T-cell receptor gene rearrangement
Immunopathologic 1 point or one or more criteria
<50% CD2+, CD3+, and/or CD5+ T-cells
<10% CD7+ T-cells
Epidermal/dermal discordance o CD2, CD3, CD5, or CD7
a
A total o 4 points is required or the diagnosis o mycosis ungoides based on any combination o points rom the clinical, histopathologic, molecular, and
immunopathologic criteria.
Modied with permission rom Pimpinelli N, Olsen EA, Santucci M, et al: Dening early mycosis ungoides, J Am Acad Dermatol 2005 Dec;53(6):1053-1063.
Granulomatous slack skin is a rare indolent vari- to stage IIB. Stage III corresponds to erythroderma in
ant o MF in which there are granulomatous T-cell the skin dened as more than 80% skin involvement,
inltrates in the skin and destruction o elastic bers, and stage IV pertains to patients with signicant blood
resulting in loose skin olds. Given that the inltration and lymph node involvement.
o malignant cells is typically deep into the dermis and
subcutis, localized radiation can be used or local con-
trol o the disease. Systemic treatment is needed or Prognosis
advanced-stage disease.40 The majority o patients (~70%) present with early-
Hypopigmented MF is a unique variant o MF seen stage disease (stage IA–IIA).37 In patients with stage IA,
in younger patients. The median age o onset is 28 to similar lie expectancy as age, sex, and race-matched
35 years with an overall avorable prognosis. This is control populations are predicted.53 Patients with
predominantly a CD8+ phenotype; however, CD4+ plaques have a poorer prognosis than those with patch
variants have been reported. Phototherapy is an eec- disease, even in early-stage disease. The degree o skin
tive treatment modality in this variant.50,51 disease involvement rom stage T1 to T4 is associated
with decreased OS and progression-ree survival with
Staging the risk or disease progression at 5 years estimated or
T1 disease at 10%, T2 at 22%, T3 at 48%, and T4 at
MF is staged using the International Society o Cutane- 56%.54
ous Lymphoma (ISCL) and EORTC proposed TNMB Prognostic actors in patients with MF include
CHApTER 12
system evaluating all compartments o involvement. advanced age at diagnosis, LCT, elevated serum LDH
T reers to tumor and is staged by increasing skin and β2 microglobulin, and olliculotropic disease.
involvement and worsening lesion types (Table 12–5). Poorer prognosis is also associated with presence
Patients with tumors and erythroderma are considered o T-cell clonal population in the blood o patients.55
to have advanced-stage skin disease. The lymph node Other actors considered to pertain to poor prognosis
stage is determined by N0 to N3 grading correspond- include high Sézary cell count, loss o T-cell markers
ing to increasing eacement o the lymph node by the such as CD5 and CD7, and chromosomal abnormali-
lymphoma cells. The blood staging or patients with ties in the circulating T-cells.9,37,54
MF is similar to that o patients with SS using fow
The Cutaneous Lymphoma International Progno-
cytometry to evaluate the degree o aberrant cells in
sis Index (CL-IPI) has been proposed as a prognostic
the peripheral blood.12 Using fow cytometry analysis
index tool or patients with MF, enabling prediction
or CD4+/CD7- or CD4+/CD26- cells, the highest B2 o OS in early- and late-stage patients. Signicant
stage pertains to those with CD4:CD8 ratio o 10 or adverse prognostic actors in the early-stage group
greater, CD4+/CD26- o 30% or greater o total lym- are male gender, age older than 60 years, presence o
phocytes or CD4+/CD7- o 40% or greater o total plaques, olliculotropic disease, and stage N1/Nx. For
lymphocytes (or ≥1000 aberrant cells).52 The overall the advanced-stage group, adverse prognostic actors
stage can be summarized as stage IA and IB corre- are male gender, age older than 60 years, stages B1/B2,
sponding to skin-limited involvement o less than 10% N2/N3 and visceral involvement.56
and 10% or greater o skin patches and plaques, respec-
tively. In patients with tumors on the skin, this relates
Treatment
TABLE 125 Staging o Mycosis Fungoides and The goals o treatment or MF are similar to those
Sézary Syndrome o other indolent lymphomas in maintaining remis-
sion and treating symptoms, but cure o disease is
Stage T N M B rare. Treatment is guided by patient age and comor-
bidities, extent and progression rate o skin disease,
IA 1 0 0 0 or 1
and involvement o other compartments.53 Figure
IB 2 0 0 0 or 1 12–4 summarizes the approach to patients with MF
IIA 1 or 2 1 or 2 0 0 or 1 separated by stage o disease. In patients with early-
IIB 3 0–2 0 0 or 1 stage disease (stage IA to IIA) with skin-limited dis-
IIIA 4 0–2 0 0 ease, skin-directed treatment is used rontline. Early
IIIB 4 0–2 0 1 aggressive intervention with chemotherapy and radi-
ation or MF has not been shown to improve progno-
IVA1 1–4 0–2 0 2
sis compared with topical therapy.57 Most studies in
IVA2 1–4 3 0 0–2 early-stage disease are retrospective, single-arm stud-
IVB 1–4 0–3 1 0–2 ies with ew patients, making comparative ecacy
B, blood; M, metastasis; N, node; T, tumor. challenging.
IA: IB/IIIA: IIB: III: IV:

limited disease, T1 generalized, T2 tumors, T3 erythroderma, T4 extracutaneous disease
Topical steroids, retinoid gel ECP ± bexarotene, IFN
Single-agent monoclonal antibodies/HDAC

Nitrogen mustard
(brentuximab, mogamulizumab, romidepsin)
Single-agent chemotherapy
Phototherapy ± bexarotene, IFN
(pralatrexate, gemcitabine, doxorubicin)
TSEBT ± NM, bexarotene or IFN Combination chemotherapy
Clinical Trial
FIGURE 12–4 Summary of treatment approach in cutaneous T-cell lymphoma. ECP, extracorporeal photopheresis; HDAC, his-
tone deacetylase inhibitor; IFN, interferon; NM, nitrogen mustard; TSEBT, total-skin electron-beam radiation.
In patients with advanced stages o disease (stage in up to 13% o patients in this study.64 Additionally,
CHApTER 12
IIB–IVB), the disease is oten treatment reractory, and topical steroids also decrease erythema, pruritus, and
the prognosis is poor. The duration o response or scale in patients with CTCL.65 Given the relatively ease
systemic treatment options such as immunotherapy o availability o topical steroids, it has become the
and targeted therapy is relatively short, and in select avored initial treatment modality.
younger patients, allogeneic stem cell transplantation
should be considered when remission is achieved.58,59 Nitrogen Mustard
Clinical trials should be considered in patients with Nitrogen mustard (mechlorethamine) is an alkylat-
relapsed or reractory disease. ing chemotherapy agent that directly induces DNA
damage to malignant cells. When applied to the skin,
Skin-Directed Therapies an immune-mediated antitumor mechanism or by
Topical Corticosteroids interruption o Langerhans and epidermal cell inter-
Topical corticosteroid treatment is oten used as ront- action has been proposed. A retrospective trial was
line treatment in patients with early-stage disease as conducted o 203 patients receiving topical nitrogen
well as in combination with other treatment modali- mustard as an aqueous solution o 10 to 20 mg/100
ties.60 The mechanism o action in cutaneous lym- mL in an earlier cohort and ointment ormulation in
phoma is proposed to be that o apoptosis, intererence similar concentration in a later cohort o patients.
lymphocyte adhesion to the endothelium, and down- Overall response rates (ORRs) and complete response
regulation o NF-κB with downstream suppression rates were 93% and 65% respectively or T1 stage
o cytokine and growth actor production.61,62 Mid- to patients 72% and 34% or stage T2 patients. The
high-potency steroid creams and ointments have been median time to complete response was 12 months,
studied in small series demonstrating eectiveness in and the duration o response was also 12 months, with
the treatment o MF. In a large retrospective review o some patients achieving long-term remission o over 8
163 patients treated with topical corticosteroid mono- years.66 Nitrogen mustard has been used in the treat-
therapy or MF, 73% o patients responded to treatment ment o patients with cutaneous lymphoma or several
with 33% achieving a complete response. Most patients decades as a compounded medication until the avail-
in the study were treated with clobetasol 0.05% cream ability o a new gel-based product (Valchlor, mechlor-
or ointment along with a lower potency steroid such as ethamine 0.016%), which is commercially available.
hydrocortisone or the skin olds.63 In a prospective trial When evaluated in a multicenter trial in comparison
o 79 patients treated with mid- to high-potency steroid with the ointment ormulation, the gel ormulation
twice daily or 2 to 3 months, 94% o stage T1 patients resulted similar response rates o 58.5% versus 47.7%
and 82% o stage T2 patients achieved a response with in the ointment ormulation. The time to response was
complete remission (CR) rate o 63% and 25% in stage superior in the gel ormulation, achieving response 16
T1 and T2, respectively. However, a sustained result weeks sooner than the comparator.67 The main side
or was not maintained upon drug discontinuation. eects include local skin reactions similar to those seen
Side eects o topical steroid use include skin atrophy in an irritant contact dermatitis or allergic contact der-
with prolonged use, striae, and possible hypothalamic– matitis in up to 16% o patients and resulting pruritus,
pituitary–adrenal axis suppression, which were observed which should be managed by holding the medication
and using topical steroids or antihistamines. There is production, and decreasing Langerhans cells in the
also reported increased risk or skin cancers in some skin. Complete response has been reported in up to
series.68,69 71% o patients with early-stage disease, but it is less
eective with thicker plaques and tumors. It can be
Imiquimod used in combination with other systemic agents such
Imiquimod is a topical imidazoquinolinone immuno- as INF-α or retinoids.75–77 Side eects associated with
modulator with activity as an agonist or the TLR 7 PUVA include nausea rom the psoralen, erythema,
demonstrating antiviral and antitumor eects. When burning, and pruritus, all improve with dose or inter-
applied topically, the innate immune system is acti- val adjustment. Squamous cell carcinomas have been
vated inducing production o intereron-α (INF-α) and reported in patients treated with PUVA, likely related
interleukin (IL)-12 and blocking IL-4 and IL-5.70 In a to cumulative dose.78
small prospective study o six patients, 50% response NB-UVB has been shown to inhibit neoplastic T-cell
was observed in patients with MF treated with the 5% unction and prolieration through APC inhibition and
imiquimod cream three times weekly or 12 weeks. increased production o keratinocyte cytokines. UVB
An initial infammatory response was observed at has a shorter wavelength than UVA and thereore does
the application site only in those responding to treat- not penetrate the skin as well or thicker lesions. It has
ment and should not be mistaken or disease progres- greater activity toward skin patches over plaques with
sion.71 Other smaller case reports and series have been one series o 23 patients reporting 100% complete
reported eectiveness o the drug.72 Application site response to treatment or skin patches compared with
CHApTER 12
reaction is the most common adverse eect, with ery- 60% in patients with plaques. It is an eective modal-
thema and peeling o skin reported in up to 100% o ity or treatment o hypopigmented MF.79 Other stud-
patients ollowed by edema, pruritus, and a burning ies demonstrate complete response to NB-UVB ranging
sensation. Flulike symptoms are reported in up to 4% rom 54% to 91%.80 It is generally well tolerated. Side
o patients treated with imiquimod. Imiquimod can eects to treatment are related to UV-induced burn-
induce psoriasis or psoriasis-like skin dermatitis in sus- ing, pruritus, and erythema. Cumulative UV-induced
ceptible individuals possibly because o a shit toward skin aging can develop but less than with PUVA. NB-
the T-helper (Th) 1 pathway and the IL-23 and IL-17 UVB can also be used in combination with retinoids
axis and is avoided or CD8+ predominate MF at our successully.81,82
institution because o possible risk or worsening dis-
ease rom stimulation o INFs.73 Radiation
Radiation is one o the most eective treatment
Topical Bexarotene modalities or the treatment o patients with MF
The topical ormulation o bexarotene is a 1% gel also and other cutaneous lymphomas. Local radiation to
approved or treatment o patients with MF. This topi- tumors and thicker plaques has complete response
cal gel can be applied up to our times daily, but most rates o more than 90%. Typically, using single or two
patients are only able to tolerate twice daily applica- ractions o low-dose radiation (8 Gy) is sucient to
tions due to skin irritation. Patients achieved an ORR eect complete responses in most patients.83,84 How-
o 63% and a clinical complete response rate o 21% ever, a longer duration o response appears to be asso-
and median time to response was 20 weeks.74 ciated with higher doses.85 Total-skin electron-beam
therapy (TSEBT) treats the entire surace o the skin
Phototherapy radiation and with more penetration than photo-
Phototherapy is the use o ultraviolet (UV) light or the therapy. Electrons can be controlled more eectively
treatment o cutaneous disorder. Patients are treated than photons, which help spare deeper tissues rom
at predetermined most eective narrowband wave- exposure. TSEBT is typically reserved or patients
length (311 nm) with UVB light and UVA light expo- with skin-limited disease with more signicant disease
sure at 320 to 400 nm. Patients are treated two or three burden involving plaques and tumors. Conventional
times weekly at increasing time intervals to increase doses o TSEBT (30–36 Gy delivered over 8–10 weeks)
dosing exposure as tolerated to avoid toxicity. Unin- has been reported to have ORRs o 100% and com-
volved sites o the skin are shielded. When remission is plete response seen in 60% o patients with patches,
achieved, treatment is tapered down or maintained at plaques, and tumors. Higher CR was observed in
less requent intervals. In patients receiving UVA, oral patients with T2 (patches and plaques; 75%) versus T3
8-methoxypsoralen is taken 60 to 90 minutes beore (tumors; 43%).86 Cumulative toxicity with repeated
treatment to sensitize the skin to the UV rays and thus doses o TSEBT prevent requent retreatment with
is called PUVA. No sensitizer is needed or narrow- this modality. Lower dose TSEBT (10–20 Gy) has been
band UVB (NB-UVB). PUVA light has been reported ound to be highly eective and results comparable to
to induce tumor apoptosis, suppression o cytokine the conventional doses.87,88
Toxicity associated with TSEBT includes erythema, at ollow-up visits. Further adjustments o thyroid
desquamation, xerosis, anhidrosis, skin atrophy or and lipid medications should be perormed at regular
necrosis, alopecia, and nail dystrophy. These eects intervals.91
are dose dependent with signicantly ewer side Acitretin is a retinoid also evaluated or treatment o
eects associated with low-dose versus conventional patients with CTCL. Unlike bexarotene, it binds to the
doses (5–10 Gy, 16%; 10–20 Gy, 35%; 20–30 Gy, 34%; RAR receptor and thereore has a dierent side eect
and >30 Gy, 62%).88 Risk or radiation dermatitis or prole. In a retrospective review o 32 patients with
recall should be considered in patients receiving radi- CTCL, acitretin in varying doses o 10 to 50 mg/day
ation-sensitizing medications such as methotrexate, used as monotherapy or combination therapy with
doxorubicin, or gemcitabine. second CTCL treatment modality achieved ORR o
59% with one patient achieving CR (although only six
patients received treatment as monotherapy). It was
Systemic Therapies noted that many patients who responded to treatment
Retinoids with acitretin also previously responded to treatment
The retinoids are structural and unctional derivatives with bexarotene. Adverse eects include dyslipidemia,
o vitamin A (retinol). They exert their mechanism o xerosis, alopecia, cheilitis, and depression.96 In another
action by control o gene expression, aecting cell pro- more recent retrospective review o 128 patients,
lieration, dierentiation, and apoptosis. In the treat- acitretin alone or in combination with another agent
ment o patients with cancer, retinoids are considered was ound to have an 77% ORR with 44% complete
CHApTER 12
biologic response modiers, inducing response with- responses seen. It was noted that acitretin was more
out immune suppression. In T-cell lymphoma cells, ret- eective as a rst-line option compared with use
inoids have been ound to induce apoptosis and DNA in patients who are more reractory.97 Isotretinoin,
ragmentation in aected T lymphocytes.89,90 Several another RAR receptor ligand, has also been studied in
systemic and topical retinoids have been studied or patients with CTCL. Dosages ranged rom 0.2 to 2 mg/
treatment o patients with CTCL. Retinoids bind to kg/day have demonstrated ORR ranging rom 43% to
two distinct amilies o nuclear receptors regulating 100%.91 Its use in patients with CTCL is limited by
gene expression called retinoic acid receptors (RARs) the burden o the iPLEDGE program’s monthly labo-
and retinoic X receptors.91 ratory surveillance requirements to have access to the
Bexarotene is a synthetic retinoid binding to reti- medications.
noid X receptor. It is available as an oral capsule and Overall, all retinoids appear to have activity in
approved or treatment o patients with CTCL in the CTCL, but no direct comparative trial has established
United States. Patients in the advanced-stage (stage a denite superior agent in this patient population. A
IIB–IVB) group were treated with 300 mg/m2/day with limiting actor or use o this class o medications in
clinical responses o 45% and 2% complete response.92 younger patients is that signicant precaution must be
In early-stage patients (stage IA–IIA), responses at 300 taken to prevent pregnancy while patients are taking
mg/m2/day were ORR o 54% and complete response these medications to avoid birth deects. At our insti-
o 7%.93 Dose response was observed in the clinical tution, this class o medications is used in patients pro-
trial with highest response noted in patients receiving gressing through topical therapy, in those with diuse
more than 300 mg/m2/day; however, at our institu- distribution o cutaneous disease limiting topical appli-
tion, most patients are unable to tolerate more than cation o medications, or or maintenance o response
300 mg/day because o toxicity. Bexarotene has also ater radiation or chemotherapy in patients with more
been studied in small combination trials with systemic advanced-stage disease.
chemotherapy, INFs, phototherapy, and radiation and
appears to be well tolerated.94,95 Intererons
Unique side eects associated with oral bexaro- INF-α and INF-g are two types o INFs used in the
tene include central hypothyroidism and hyperlip- treatment o patients with CTCL. In the human body,
idemia occurring in the majority o patients, which INFs are peptides produced by the innate immune
should monitored in patients taking the medication. system with antiviral and antitumor properties. The
All patients should have baseline thyroid unction malignant T-cells in CTCL are typically skin-hom-
and lipid panel assessment beore starting treatment. ing T-cells releasing IL-4, IL-5, and IL-10 cytokines,
All patients are started on an HMG-CoA reductase along the T-helper 2 (Th2) phenotype. It is observed
inhibitor “statin” such as atorvastatin 40 mg/day and that this shit toward Th2 activity propagated by the
levothyroxine 25 to 50 mcg/day at the start o bexar- tumor cells allows or immune suppression and block-
otene treatment. Free serum thyroxine (not thyroid- ing o the antitumor response in patients with CTCL.
stimulating hormone) levels should be monitored IFN-α and -g augment CD8+ T-cells and natural killer
and used or thyroid supplementation adjustment (NK) cells and suppresses the Th2 activity incited by
lymphoma cells.98 In patients with CTCL, IFN-α-2b has attenuate the fulike symptoms associated with the
been studied at varying doses ranging rom 2 million drug. These symptoms typically decrease in severity
units three times per week to 18 million units per day. over time. Patients should have monitoring o the CBC
ORRs noted ranged rom 20% to 80% with 0% to up and liver unction tests, holding the drug i moderate or
to 67% complete responses noted.99 Although higher severe abnormalities occur. INF-g is typically given at
doses have been reported in the literature, IFN-α-2b is 50 to 100 µg/m2 three times weekly. These medications
typically dosed as 3 to 6 million units given subcutane- should be used with caution in patients with preexist-
ously three times per week with titration per tolerance. ing autoimmune, mood, or cardiovascular disorders.98
In a prospectively enrolled study evaluating low (3 mil-
lion units) versus high (dose escalation up to 36 mil- Brentuximab Vedotin
lion units) intramuscular injections o INF-α daily or 10 Brentuximab vedotin (BV) is an anti-CD30 conjugate
weeks, several patients in the high-dose arm required monoclonal antibody linked to a toxin monomethyl
dose reduction because o toxicity.100 A pegylated ver- auristatin E (MMAE). The antitumor eect o the drug
sion o IFN-α-2b is commercially available and allows is assumed to be targeting CD30 and bringing the
or weekly dosing. Evidence suggests the pegylated or- MMAE toxin to the malignant cells; however, diu-
mulation is also eective in patients with CTCL.98,101 sion o the toxin to the surrounding supportive micro-
Side eects associated with IFN-α-2b include fulike environment may also play a role in its mechanism o
symptoms (ever, atigue, chills, myalgias) in the major- action.104 The drug was investigated or use in CTCL
ity o patients. Other adverse eects include anorexia, in a large, randomized, phase III trial o 131 patients
CHApTER 12
weight loss, depression, cough, and hair loss.100 comparing BV with physician choice o methotrexate
IFN-g’s activity in T-cell lymphoma is less well under- or bexarotene. For treatment o patients with MF, the
stood. Fewer studies have been perormed or treatment ORR was 65% with 10% achieving complete response
o patients with CTCL. INF-g was studied in a phase II in the BV-treated arm compared with 16% in the bex-
prospective trial with 16 patients reporting objective arotene or methotrexate arm. When combined with
partial response in 31% o patients.102 In another study all patients in the study, which includes patients with
rom Japan, 15 patients with MF were treated with INF-g primary cutaneous anaplastic large-cell lymphoma
at 2 million units daily or 5 days or 4 weeks. The ORR (pcALCL), ORR was 67% compared with 20% in the
was 60% with a durable disease response. The median comparator arm. BV appears to have comparable, i not
duration o response was not reached at 170 days. The higher, activity in patients with advanced-stage disease
drug was overall well tolerated, and fulike illness was compared with early-stage patients. In the phase III
the main adverse eect.103 Although not ormally com- trial, ORR was 69% in the advanced-stage group com-
pared, it is the author’s impression that INF-g appears to pared to 53% in the early-stage group. Patients quali-
be better tolerated than INF-α and may be considered in ed or the trial i their skin biopsies had at least 10%
patients who are intolerant to the α type. o tumor cells expressing CD3≈0.105 Two additional
At our institution, nonpegylated INF-α is typically phase II open-label studies also demonstrate similar
started at lower dosages o 1.5 to 3 million units three activity in CTCL patients but, unlike the phase III trial,
times weekly and increased to 6 million units as tol- accepted patients with lower CD30 expression106,107
erated. The medication is sel-injected at night by (Table 12–6). Based on ndings o these two studies,
the patient with acetaminophen as premedication to it is unclear i any presence o CD30 expression or
TABLE 126 Summary o Clinical Trials o Brentuximab Vedotin in patients with Mycosis Fungoides
and Sézary Syndrome
Evaluable
Reference Phase Trial Design Patients (n) CD30 Eligibility ORR CR
Duvic et al (2015) II Open label, single 28 CD30+ (no lower limit but 15 (54%) 2 (7%)
center expression graded)
Kim et al (2015) II Open label, 30 Negligible to 100% CD30 21 (70%) 1 (3%)
investigator expression levels
initiated,
multicenter
Prince et al (2017) III Randomized open 48 CD30+ (10% tumor cells 31 (65%) 5 (10%)
label, multicenter, expressing CD30)
international
CR, complete remission; ORR, overall response rate.
Data rom reerence 105, 106, 107.
higher expression translates to an increase in BV activ- related to the drug. Mogamulizumab treatment beore
ity. Anecdotal report o BV activity in a CD30-negative allogeneic transplantation has also been associated
MF patient has been reported.108 with increased risk or grat-versus-host disease.115
The dose-limiting toxicity or BV is peripheral sen-
sory neuropathy, which was ound in 45% o patients Histone Deacetylase Inhibitors
with 5% developing severe grade 3 neuropathy. Other Two histone deacetylase (HDAC) inhibitors, romidep-
less common side eects include nausea (36%), diar- sin and vorinostat, are approved or the treatment o
rhea (29%), atigue (29%), vomiting (17%), alopecia patients with CTCL. HDACs are enzymes that regulate
(15%), and pyrexia (17%). Rash was also noted in 11% the cell cycle, apoptosis, and protein olding through
o patients.105 Patients should be monitored closely or acetylation and deacetylation. The equilibrium o this
signs o peripheral neuropathy, and dose modication process is dysregulated in cancer cells.116,117 HDAC
or suspension should be considered. Lower dose (<1.8 inhibitors are small molecules that prevent removal o
mg/kg) or alternate interval (dosing as needed) strate- acetyl groups, blocking the eects o HDACs. HDACs
gies have been proposed to improve tolerability o BV are also implicated in oncogenic pathways by upregu-
in patients with CTCL but have not yet been validated lation o signal transducer and activator o transcription
in trials.109 (STAT) amily o proteins, which has been implicated
in the pathogenesis o CTCL and T-cell proliera-
Mogamulizumab tion.118 Notably, STAT 5 is important or expression o
Mogamulizumab is a humanized monoclonal antibody antiapoptotic proteins such as bcl-2, cell cycle genes
CHApTER 12
against chemokine receptor type 4 (CCR4) approved such as cyclin-D and c-myc, and oncogenic miR-155
in the United States or patients with relapsed or microRNA. STAT 6 is associated with Th2 phenotype
reractory MF or SS ater at least one prior systemic seen in CTCL. HDAC inhibitors upregulate STAT 4,
therapy. The cytokine CCR4 is normally involved in which promotes Th1 and suppresses STAT 6, restoring
the tracking o T-cells to the skin.110 It is expressed the imbalance.116
by multiple subtypes o malignant T-cells and are most Vorinostat is an oral HDAC inhibitor that has been
notably ound in adult T-cell leukemia/lymphoma. It shown to have activity in CTCL. ORRs o 30% was
is also expressed in CTCL and other peripheral T-cell noted in a phase IIb multicenter trial. Despite achieving
lymphomas, especially in advanced-stage disease with response, the median time to progression was only 4.9
blood involvement.111 The drug was evaluated in a months, which is quite brie. Patients report signicant
randomized phase III trial comparing the drug with gastrointestinal (GI) toxicity when taking this medica-
vorinostat in 372 patients with MF and SS. Mogamuli- tion with almost hal o treated patients experiencing
zumab was associated with 28% ORR compared with nausea and diarrhea. Other adverse eects include
5% in the vorinostat arm. Notably, the best response atigue (46%) and anorexia (26%). O note, pulmonary
was in the blood compartment, where the response embolism was observed in 5% o patients.119 The drug
was 68% in the mogamulizumab arm compared with was quite eective in improving pruritus in 32% o
19% in patients treated with vorinostat. Skin response patients and is oten used in lower doses at our institu-
o 42% was also superior in the mogamulizumab arm tion or this purpose.
compared with 16% or vorinostat.112 Romidepsin is given as an intravenous inusion. In a
Mogamulizumab is generally well tolerated with large phase II trial in patients with CTCL, romidepsin
mild inusion-related reaction as the most common at 14 mg/m2 weekly or 3 weeks o a 4-week cycle dem-
toxicity. The drug has also been associated with caus- onstrated an ORR o 34% with 4 o 71 patients achiev-
ing a drug eruption, reported in 20% o patients, ing complete responses. Unlike vorinostat, the median
which can be conused with disease progression, espe- duration o response was longer at 13.7 months.120
cially in patients with erythroderma.113,114 Skin biopsy Romidepsin has been reported to have activity in
should be perormed in patients who appear to have tumor-stage MF and its olliculotropic variant with
skin progression despite improvement in other com- 45% and 60% ORR observed in the respective patient
partments or who initially have response to the drug groups in a phase II trial.121 In a second phase II trial, 96
but develop a fare to help rule out drug hypersensitiv- patients were treated, resulting in similar response o
ity. In patients who have CD4+ CTCL, the presence o 34% and median duration o response o 15 months.
signicant numbers o CD8+ T-cells in the skin biopsy Time to response o 8 weeks is also relatively aster
may suggest reactive dermatitis rather than lymphoma than other treatment options.122 Adverse eects appear
progression. Most drug hypersensitivity associated similar to those o vorinostat, which include GI symp-
with mogamulizumab can be managed with topical toms o nausea and vomiting, anorexia, and diarrhea
steroids and holding the drug. Ater improvement, as most common. Fatigue is also a commonly reported
many patients can tolerate restarting the medication. side eect o the drug seen in almost 50% o patients.
Photosensitivity has also been reported in the literature In our institution, romidepsin is considered in patients
with advanced-stage CTCL with blood involvement practice has been to give patients olic acid on the
or tumor-stage disease. days o the week they are not receiving methotrexate.
Adverse reactions to methotrexate include inections,
Alemtuzumab liver enzyme abnormality, nausea, dyslipidemia, and
Alemtuzumab is a monoclonal antibody targeting myelosuppression.133
CD52 on the surace o lymphocytes. This depletes the Pralatrexate is a more potent antimetabolite than
peripheral blood o T- and B-cells, including malignant methotrexate with higher anity or dihydroolate
T-cells.123 It is eective in patients with MF with blood reductase.130,134 In patients with CTCL, lower doses
involvement and in patients with SS. ORRs range rom o pralatrexate weekly or 3 weeks in a 4 week cycle
38% to 100%.124–126 Low-dose alemtuzumab is also was ound to be the optimal dose between tolerabil-
ound to be ecacious in patients with CTCL at 10 ity and ecacy. At this dose level, the ORR was 45%
mg subcutaneously three times per week.127 The treat- with two patients achieving complete responses.135 All
ment is associated with signicant immunosuppres- patients should receive vitamin B12 and olate supple-
sion, which requires prophylaxis or opportunistic mentation while on treatment. In some patients, the
inections.128,129 addition o leucovorin greatly reduced the incidence o
mucositis when treated with pralatrexate.136
Chemotherapy
In patients with CTCL, chemotherapy agents are Gemcitabine
typically reserved or those with aggressive systemic Gemcitabine is a pyrimidine analog that incorporates
CHApTER 12
involvement o disease or when other options or treat- into DNA causing disruption o DNA replication. In a
ment are exhausted. As previously mentioned, early phase II prospective study o gemcitabine in 30 pre-
aggressive intervention with chemotherapy and radia- vious treated patients with MF and 14 patients with
tion or MF has not been shown to improve progno- peripheral T-cell lymphoma, an ORR o 70% was
sis when compared with topical therapy.57 Moreover, observed with 11% achieving complete response.137
chemotherapy has a shorter time to next treatment Specic to CTCL, gemcitabine at 1000 mg/m2 as mono-
compared with single-drug treatment with INF-α or therapy achieved an ORR o 68% in 25 patients. Eight
HDAC inhibitors. The median time to next treatment percent o patients achieved complete responses.138
or single or multiagent chemotherapy is only 3.9 The most common adverse eect o gemcitabine is
months, and it can be associated with more toxicity.58 myelosuppression, which is seen in 56% o patients.
Gemcitabine was ound to have an ORR o 75% as
Antimetabolites rontline therapy or patients with CTCL, but the
Methotrexate and pralatrexate are competitive dihy- median duration o response was only 10 months.139
droolate reductase inhibitors that are cell cycle Increase hepatitis transaminases, atigue, radiation
S–specic chemotherapeutic agents. They exert anti- recall, and mucositis was also reported.138
infammatory and antitumor eects by blocking the
metabolism o olic acid. Recently, methotrexate has
Pegylated Liposomal Doxorubicin
been ound to block protein and DNA methylation,
Pegylated liposomal doxorubicin is a dierent ormu-
resulting in control o gene regulation through this
lation o doxorubicin in which the drug is encapsu-
mechanism. Increase in Fas death receptor protein
lated in liposomes and stabilized by the attachment o
expression has also been noted in patients treated with
polyethylene glycol to the liposomal surace, resulting
methotrexate.130
in improved accumulation in tumor tissues. In a phase
Oral methotrexate at doses up to 100 mg per week
II trial in patients with advanced-stage MF, a 41% ORR
have been reported or treatment o patients with
was observed. Signicant side eects include hand–
CTCL. Clinical practice is closer to 25 mg per week.130
oot reaction and other skin reactions, hypersensitivity
Most studies evaluating the use o methotrexate in
reaction, and GI toxicity.140 Other studies demonstrat-
CTCL are small, and the response criteria are not well
ing response rates o 56% to 88% have been reported
dened. One retrospective study o 29 patients report
in other trials.141–143
an ORR o 58% in patients with erythrodermic MF
with 41% achieving CR.131 In another review o 69
patients, 33% ORR was seen in patients with plaque Combination Chemotherapy
MF.132 Surprisingly, a much lower response was noted Combination chemotherapy with CHOP (cyclophos-
in the phase III ALCANZA trial when methotrexate phamide, doxorubicin, vincristine, prednisone) or
(or bexarotene) was used as a comparator to BV in CHOP-based treatments or CTCL was ound to have
CD30 positive CTCL patients.105 Patients receiving ORR o 40% with 25% complete response, but the
low-dose oral methotrexate do not typically require median duration o response is only 5.7 months and
leucovorin rescue at the low doses used, but our with more toxicity.144
Other Modalities aggressive cytotoxic NK or T-cell lymphomas o the

Extracorporeal Photopheresis skin by history. Treatment is primarily radiation or
Extracorporeal photopheresis (ECP) was developed excision because supercial treatment modalities are
when patients with CTCL were treated with leuka- insucient or controlling the deeper extension o the
pheresis and their blood was treated with PUVA. In disease in the skin. 3 Successul treatment with pho-
early investigative research, evidence o anti-idiotypic totherapy in combination with INF-α-2b has been
response to malignant TCRs were discovered when reported.154
these cells were exposed to UVA light and 8-methox-
salen, a photosensitizer. Patients receiving ECP rst
undergo leukapheresis; then the buy coat is treated CD30 LYMpHOpROLIFERATIVE
with methoxsalen photosensitizer and irradiated with DISORDERS
UVA (320- to 400-nm wavelength). The mechanism
o action was initially considered to be due to DNA Lymphomatoid papulosis (LyP) and primary cutane-
crosslinking and apoptosis. However, upon reinu- ous anaplastic large-cell lymphoma (pcALCL) are
sion o the treated and likely apoptotic cells, there was two entities on the spectrum o CD30 lymphopro-
conversion o circulating monocytes to immature den- lierative disorders that are associated with good
dritic cells, presentation o tumor-loaded dendritic cells prognoses. 155 On one end o the spectrum is LyP,
to cytotoxic T-cells, and expansion o the cytotoxic which are clinically small (<1 cm), red, grouped pap-
T-cells against the malignant clone.145–147 ECP is estab- ules or nodules that spontaneously resolve within
CHApTER 12
lished as a rontline treatment o patients with blood 1 to 2 months. This condition is considered to be
involvement o CTCL.145 In a meta-analysis, ECP was benign, but in 10% to 20% o patients, it can appear
ound to have a response rate o 55% and CR rate o along with another type o lymphoma, most com-
18% with higher response seen in patients with lower monly in MF. It is also reported in patients with
disease burden.145,146 Multimodality treatment using other hematologic malignancies such as Hodgkin
ECP in combination with other immunomodulatory lymphoma or pcALCL. 156,157 Although clinically simi-
treatments may enhance its eects.148 lar, histopathologic eatures can be divided into ve
main subtypes, all with CD30 as prominent eature.
Stem Cell Transplantation Type A is the “conventional” and most common
Hematopoietic allogeneic stem cell transplanta- type; it is described as a wedge-shaped inltrate
tion may induce durable remission in patients with with large atypical anaplastic cells admixed with
advanced CTCL likely because o the donor T-cell and histiocytes, eosinophils, and neutrophils. Type B
NK cell grat-versus-tumor eect. Long-term response is MF-like and resembles a wedge-shaped inltrate
durations o more than 5 years have been reported ater with CD4+ bandlike epidermotropic cells. Type C is
transplant; however, transplant-associated toxicity and indistinguishable rom pcALCL by histopathologic
mortality can occur in up to 30% o patients because o eatures alone and diagnosis is made by correlation
inections and grat-versus-host disease.59,149,150 Lower with clinical history. Type D is similar to aggressive
intensity nonmyeloablative conditioning regimens epidermotropic CD8+ cytotoxic T-cell lymphoma.
may be associated with less toxicity and still maintain Epidermotropism is very prominent as is CD8 and
grat-versus-tumor response.151 In comparison, autolo- CD30 positivity, but the clinical course is indolent
gous transplantation is associated with requent and like other LyPs. Type E has angiocentric or angiode-
early relapses.152 structive eatures and may be mistaken or vasculitis
or NK T-cell lymphoma. Lesions can be monitored
or resolution. In patients with widespread involve-
pAGETOID RETICULOSIS ment, improvement has been reported with pho-
totherapy, methotrexate, or bexarotene.158–160 More
Sometimes also reerred to as Woringer-Kolopp dis- recently, treatment with BV is associated with high
ease, this indolent orm o CTCL presents as local- response rates.161
ized psoriasiorm plaques, usually in the extremities, Primary cutaneous ALCL is oten histologically
avoring the acral sites. The lesions may clinically be indistinguishable rom LyP. Unlike systemic ALCL,
mistaken or warts or other benign lesions o the skin. pcALCL does not express anaplastic lymphoma
Histopathologic eatures include epidermal hyper- kinase and i positive suggests a secondary ALCL in
plasia and typically CD8+ cytotoxic neoplastic cells the skin. This condition typically presents as single
with marked exocytosis o cells in the epidermis. A ulcerated tumor or cluster o tumors. In contrast to
CD4- and CD8- case has also been reported in the LyP, there is rarely spontaneous resolution, but the
literature without poor prognosis observed.153 It is prognosis is good with the estimated 5-year sur-
important to dierentiate this condition with more vival rate at more than 90%.155 Frontline treatment
or localized disease is radiation. For more extensive multimodality therapy in combination with retinoid
disease, systemic treatment with BV has demon- or INF produces high overall responses o 75% with a
strated superiority over methotrexate or bexarotene 30% complete response.167 Mogamulizumab can also
in the recent ALCANZA study. Overall response or be considered in this group o patients given its high
pcALCL in the BV arm was 75% compared with 33% blood compartment response o 68% in the MAVORIC
in the comparator arm.105 trial.112 Supportive care is crucial in the care o patients
with SS because o the high risk or skin inections and
severe pruritus associated with the disease. See the
CD4 SMALL-MEDIUM Supportive Care section or review.
pLEOMORpHIC
LYMpHOpROLIFERATIVE DISORDER
gδ T-CELL LYMpHOMA
CD4 small-medium pleomorphic lymphoprolierative
disorder is an indolent condition previously listed as gδ T-cell Lymphoma (GDTCL) is a rare aggressive pri-
“CD4 small-medium pleomorphic lymphoma” but mary cutaneous lymphoma presenting as ast-grow-
downgraded to lymphoprolierative disorder in 2016 ing nodules and tumors with ulceration. Unlike MF
by the WHO. It maniests clinically as a solitary lesion tumors, in which there is a preceding history o lesions
on the upper body, ace, or neck without systemic that have been present or years, lesions in GDTCL
typically develop over weeks to months. The median
CHApTER 12
involvement. Histologic eatures include CD4+ lym-
phocytes with αβ phenotype and absence o CD30 survival associated time with this condition is 15
and background o reactive cells. These patients are months, and it carries a poor response to conventional
successully treated with radiation or surgery. Radia- chemotherapy.2 Histologic eatures include CD4-CD8-
tion may be preerred in some sites to avoid excessive double-negative phenotype with strong expression o
scarring rom surgery.162,163 cytotoxic markers granzyme B and TIA-1.168 Treatment
with combination chemotherapy is typically used, but
there are insucient data to dictate a preerred course
o management.
SÉZARY SYNDROME A subset o patients demonstrating gδ TCR staining
but behaving in a more indolent ashion has also been
SS is a leukemic variant o CTCL in which patients reported. In one series, average survival rom onset o
present with new-onset erythroderma, lymphade- symptoms was 7.3 years. A proposed hypothesis is
nopathy, and aberrant cells in the peripheral blood that expression o CD4, CD30, or βF1 in some o the
compartment. Unlike patients with erythrodermic MF cases was associated with good prognosis.169
who progressively develop worsening blood involve-
ment at advanced stages o disease, patients with SS
typically do not report a history MF-like lesions pre-
ceding the diagnosis. Histopathologic ndings on
pRIMARY CUTANEOUS CD8+
skin biopsy can be nondiagnostic in 30% o patients CYTOTOXIC AGGRESSIVE
with known erythrodermic CTCL, and the diagno- EpIDERMOTROpIC T-CELL
sis is made by fow cytometry analysis o peripheral LYMpHOMA
blood.164 A matching T-cell clone in the skin and blood
compartment helps support the diagnosis in ambigu- Primary cutaneous CD8+ cytotoxic aggressive epider-
ous cases. SS is associated with a poor prognosis and motropic T-cell lymphoma is a rare cutaneous lym-
aggressive disease course with 5-year survival rate esti- phoma with a poor prognosis; median OS was 12
mated to be 36% in the updated 2018 WHO-EORTC months with 5-year OS o 32% in one series.170 His-
classication o cutaneous lymphomas.2 Genetic varia- tologic eatures include CD8+ lymphocyte ull-thick-
tion in CDKN2A and CDKN2B genes have been linked ness exocytosis into the epidermis in pagetoid pattern.
to shorter survival periods in patients with SS.165 The Expression o at least one cytotoxic marker (TIA-1)
expression o FOX-P3 by SS cells has also been associ- and granzyme B was noted in almost all biopsies. Clin-
ated with a poor prognosis.166 Unique clinical eatures ically, patients present with plaques on the skin with
o this variant include hyperkeratosis o the palms and ulceration related to the cytotoxic granules released by
soles, nail dystrophy, and ectropion. the malignant cells. Treatment with standard CTCL
Treatment o patients with SS is similar to the man- treatment is ineective in most cases, and the scarce-
agement o patients with advanced-stage MF with ness o data on this entity prevents the development
blood compartment involvement. Frontline treat- o treatment recommendations and management
ment incorporating the use o ECP in the setting o guidelines.
SUBCUTANEOUS pANNICULITIS lymphocytes. The immunohistochemistry prole is

T-CELL LYMpHOMA CD20+, Bcl-2 +, CD5-, and Bcl-6 -.3 Monoclonal Ig
genes are present in only hal o cases. In patients with
Subcutaneous panniculitis T-cell lymphoma (SPTCL) the lymphoplasmacytic variant o pcMZL, association
is a rare orm o CTCL presenting as deep painul with Borrelia burgdorferi has been reported and should
infammatory nodules, resulting in atrophic plaques in be screened.174 Although no denitive link has been
involved sites. There is usually no surace change to established between other inections such as Helico-
the skin. The median age at diagnosis is in the third bacter pylori, hepatitis C virus, or Epstein-Barr virus,
or ourth decade o lie, occurring in younger emale we screen all patients to rule out treatable inections.
patients. The αβ subtype has an indolent course pre- Treatment or pcMZL and pcFCL is similar and entails
senting histologically as a lobular lymphocytic pannic- low-dose radiation, intralesional corticosteroids, intra-
ulitis with tumor cells rimming around the at lobules. lesional INF, or rituximab. Systemic rituximab or che-
The malignant lymphocyte is typically CD4-, CD8+, motherapy is reserved or widespread or progressive
βF1 + and expresses cytotoxic granules. A history o systemic involvement.
autoimmune disorder was ound in 25% o patients,
with the most common being systemic lupus ery-
thematosus. Because lupus panniculitis also presents
Difuse Large B-Cell Lymphoma, Leg Type
as a lobular panniculitis and dicult to distinguish Primary cutaneous diuse large B-cell lymphoma, leg
CHApTER 12
rom SPTCL, patients should be screened or lupus type (PCDLBL-LT), is a rare entity o primary cutaneous
at diagnosis.171 Patients who develop hemophago- B-cell lymphoma with more aggressive course, result-
cytic lymphohistiocytosis with this condition have ing in a relatively lower 5-year disease-specic sur-
a poorer prognosis. A more aggressive course is also vival rate o 56%.2 Despite the name o the condition,
seen patients with the gδ phenotype.172 A variety o PCDLBL-LT can develop outside o the lower extremi-
treatment options have been reported benet, but ties and may be associated with improved survival.175A
corticosteroids with immunosuppressive therapy are unique histologic eature is the predominance o cen-
requently used as the initial treatment. The 5-year troblasts staining MUM-1 + along with CD20+, CD3-,
disease-specic survival rate is about 85%.173 and Bcl-2+.176 Patients are typically treated with com-
bination chemotherapy and radiation, with one review
series demonstrating an improved 2-year survival rate
in patients treated with rituximab plus anthracycline-
pRIMARY CUTANEOUS B-CELL based chemotherapy.175
LYMpHOMAS
Primary Cutaneous Marginal Zone SUppORTIVE CARE
Lymphoma and Primary Cutaneous
Follicle Center Lymphoma Pruritus
The cutaneous B-cell lymphomas are less common Pruritus is a cause o signicant morbidity in patients
than their T-cell counterparts. We will discuss the with cutaneous lymphoma. In a retrospective analy-
three most common types in this review. Because they sis, a high prevalence o severe pruritus was ound in
are so rare, all patients should be screened or sys- patients with advanced-stage MF (83%) and SS (94%).177
temic B-cell lymphoma. Primary cutaneous marginal In patients with CTCL, multiple cytokines such as IL-4
zone lymphoma (pcMZL) and primary cutaneous and IL-5 have been upregulated, consequently leading to
ollicle center lymphoma (pcFCL) are both indolent recruitment o eosinophils. Eosinophils in the blood can
subtypes o B-cell lymphoma in the skin associated drive skin infammation and pruritus.178 More recently,
with an excellent prognosis. The 5-year disease-spe- IL-31 has been ound to be upregulated in patients
cic survival rates are 99% or pcMZL and 95% or with CTCL and to correlate with itch.179 Patients with
pcFCL.2 PcFCL presents as reddish-brown papules and CTCL-associated pruritus are best treated with treat-
nodules with preerence or the head and neck. His- ment o the underlying lymphoma; however, many
tologic eatures include nodular or diuse inltrates patients have treatment-reractory disease or are slow
o lymphocytes, which are CD20+, Bcl-6 +, with to respond to lymphoma treatment. Although pruritus
monoclonal rearrangement o Ig genes detected. In caused by CTCL does not typically respond to antihis-
contrast, pcMZL preers the trunk and upper extremi- tamines, multiple other nontraditional treatments or
ties. Histologic eatures include patch, nodular, or pruritus can be tried. Gabapentin is an anticonvulsant
diuse lymphocytic inltrates without germinal cen- that dampens the release o neurotransmitters, promot-
ters with central nodular dark area o small reactive ing itch. Doses up to 2400 mg in divided doses daily
can be used.180 Other options, such as aprepitant, nal- and urther breakdown rom scratching. In addi-
oxone, mirtazapine, and thalidomide, have been sug- tion, host immunosuppression and decrease in cell-
gested.178,180 In very pruritic patients, phototherapy may mediated immunity put patients at risk or skin
be helpul in select patients. inection and colonization with bacteria and herpes
virus. 181–183 S. aureus inections are common and can
Inections promote worsening o disease. 17,184,185 Treatment o
Patients with cutaneous lymphoma have decreased skin inections has been reported to improve disease
natural barrier to inection because o the disease severity.181,186

J Patients with cutaneous lymphoma should be results or lymphoma but rather reactive dermatitis
ideally evaluated by a multidisciplinary team con- on histopathology.
sisting o dermatologists, oncologists, radiation J In patients with skin-limited indolent cutaneous
oncologists, and pathologists at a reerral center lymphoma, the rontline treatment is skin-directed
with expertise in the disease. therapy. Early aggressive intervention with chemo-
CHApTER 12
J Imaging using CT or PET-CT should be perormed therapy and radiation or MF has not been shown to
in patients with thicker plaques, tumors, or eryth- improve prognosis compared with topical therapy.
roderma to rule out systemic involvement o CTCL. J Mogamulizumab is highly efective or blood com-
No imaging is typically needed or patients with partment disease especially, in patients with SS,
early patch-stage disease unless there are systemic but has lower response rates in the skin and lymph
symptoms or rapid progression o disease. node compartments.
J Peripheral blood ow cytometry should be obtained J BV may be efective or patients with MF with low
on all erythrodermic patients to rule out SS. Many expression o CD30.
patients with SS do not have positive skin biopsy
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CHApTER 12
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T-plastin, FoxP3 and other tumor-associated markers by leu- 179. Nattkemper LA, Martinez-Escala ME, Gelman AB, et al.
kemic T-cells o cutaneous T-cell lymphoma. Leuk Lymphoma. Cutaneous T-cell lymphoma and pruritus: the expression
2008;49(6):1190-1201. o IL-31 and its receptors in the skin. Acta Derm Venereol.
167. Raphael BA, Shin DB, Suchin KR, et al. High clinical 2016;96(7):894-898.
CHApTER 12
response rate o Sezary syndrome to immunomodulatory 180. Demierre MF, Taverna J. Mirtazapine and gabapentin or reduc-
therapies: prognostic markers o response. Arch Dermatol. ing pruritus in cutaneous T-cell lymphoma. J Am Acad Dermatol.
2011;147(12):1410-1415. 2006;55(3):543-544.
168. Guitart J, Weisenburger DD, Subtil A, et al. Cutaneous gδ 181. Emge DA, Bassett RL, Duvic M, Huen AO. Methicillin-resis-
T-cell lymphomas: a spectrum o presentations with over- tant Staphylococcus aureus (MRSA) is an important pathogen
lap with other cytotoxic lymphomas. Am J Surg Pathol. in erythrodermic cutaneous T-cell lymphoma (CTCL) patients.
2012;36(11):1656-1665. Arch Dermatol Res. 2020;312(4):283-288.
169. Vin H, Talpur R, Tetzla MT, Duvic M. T-cell receptor-g in 182. Segal RJ, Watson W. Kaposi’s varicelliorm eruption in mycosis
gamma-delta phenotype cutaneous T-cell lymphoma can be ungoides. Arch Dermatol. 1978;114(7):1067-1069.
accompanied by atypical expression o CD30, CD4, or TCRβF1 183. Mallo-García S, Coto-Segura P, Suárez-Casado H, et al. Fatal
and an indolent clinical course. Clin Lymphoma Myeloma Leuk. outcome due to bacterial superinection o eczema herpeti-
2014;14(6):e195-e200. cum in a patient with mycosis ungoides. Dermatol Online J.
170. Guitart J, Martinez-Escala ME, Subtil A, et al. Primary cuta- 2008;14(6):21.
neous aggressive epidermotropic cytotoxic T-cell lymphomas: 184. Krejsgaard T, Willerslev-Olsen A, Lindahl LM, et al. Staphy-
reappraisal o a provisional entity in the 2016 WHO classica- lococcal enterotoxins stimulate lymphoma-associated immune
tion o cutaneous lymphomas. Mod Pathol. 2017;30(5):761-772. dysregulation. Blood. 2014;124(5):761-770.
171. Bosisio F, Boi S, Caputo V, et al. Lobular panniculitic inl- 185. Jackow CM, Cather JC, Hearne V, et al. Association o eryth-
trates with overlapping histopathologic eatures o lupus rodermic cutaneous T-cell lymphoma, superantigen-positive
panniculitis (lupus proundus) and subcutaneous T-cell lym- Staphylococcus aureus, and oligoclonal T-cell receptor V beta
phoma: a conceptual and practical dilemma. Am J Surg Pathol. gene expansion. Blood. 1997;89(1):32-40.
2015;39(2):206-211. 186. Lewis DJ, Holder BB, Duvic M. The “Duvic regimen” or
172. Kao GF, Resh B, McMahon C, et al. Fatal subcutaneous pannic- erythrodermic fares secondary to Staphylococcus aureus
ulitis-like T-cell lymphoma gamma/delta subtype (cutaneous in mycosis ungoides and Sézary syndrome. Int J Dermatol.
gamma/delta T-cell lymphoma): report o a case and review o 2018;57(1):123-124.
the literature. Am J Dermatopathol. 2008;30(6):593-599.
13 Hodgkin Lymphoma
Collin K. Chin
L. Jefrey Medeiros
Fredrick B. Hagemeister
Hun J. Lee
KEY CONCEPTS
 Nodular lymphocyte–predominant Hodgkin lymphoma to be a better regimen or unavorable earlystage and
(HL) usually presents in early stages. Therapy depends advancedstage disease. BEACOPP is associated with a
on disease extent, but localized radiotherapy is the usual higher risk o neutropenia and hospitalization and in the
choice or earlystage disease. Rituximab is also an eec United States is administered to only selected patients.
tive agent, but it should be given in combination with  Brentuximab vedotin (BV) has been studied as adjuvant
chemotherapy. therapy or earlystage disease, as a single agent and in
 Staging by positron emission tomography is standard, and combinations or relapsed and reractory disease, as pro
marrow biopsy is generally unnecessary. Response ater phylaxis ater autologous stem cell transplant (ASCT), and
two cycles o therapy is a standard to assess response, and in combinations or initial treatment o classical Hodgkin
the Lugano (Deauville score) response criteria should be disease. The drug causes some peripheral neuropathy
ollowed. Patients with DS 1 or 2 should be considered as but is generally tolerable, and the A (BV)AVD regimen
having a metabolic complete response. Those with DS 4 or provides better progressionree survival results or most
5 should be considered to have likely had ailure o ther patients with advanced disease than ABVD.
apy, and those with persistent positivity ater our cycles  PD1 (programmed death1) inhibitors (nivolumab, pem
o therapy are at a high risk o ailure. German Hodgkin brolizumab) are also eective single agents or relapsed
Lymphoma Study Group criteria and the International disease and in combinations improve responses or
Prognostic Score should be calculated or all patients to relapsed and untreated disease even in patients who have
assess outcomes o therapy. previously received BV. The most eective combinations
 Standard o care or avorable earlystage classical HL is using this and other targets are still under investigation.
two cycles o ABVD (doxorubicin, bleomycin, vinblastine,  Highdose therapy ollowed by ASCT remains the stan
and dacarbazine) and 20Gy involved site radiation ther dard o care or patients with relapsed HL. However, proo
apy (ISRT). For unavorable earlystage disease, it is our o adequate response, usually by PET and in most patients
cycles o ABVD and 30 Gy ISRT. The ABVD regimen remains by biopsy, is necessary beore this therapy. Patients with
the preerred regimen or most patients with advanced reractory disease should be oered alternate therapies,
disease treated in the United States even though BEACOPP and novel agents and therapies, including Tcell and other
(bleomycin, etoposide, doxorubicin, cyclophosphamide, immunotherapy, are under investigation or this small
vincristine, procarbazine, and prednisone) has proven group o patients.
Hodgkin lymphoma (HL) was recognized in the rst 185 countries.2 In a recent report, the incidence o HL
hal o the 19th century by Thomas Hodgkin and Sam- was 3.0 per 100,000 person-years in the United States;
uel Wilks.1 HL usually arises in lymph nodes, preer- it is higher in Western countries than in Asian coun-
entially in the cervical area, and the majority o HLs tries.3 Biological and clinical studies have shown that
maniest clinically in young adults in their third and HLs include two disease entities: nodular lymphocyte–
ourth decades o lie. In 2018, 79,990 new cases o predominant HL (NLPHL) and classical HL (cHL). The
the disease were described, and 34,984 persons were two entities dier in their clinical eatures and behav-
reported to have died o the illness worldwide rom iors. Within cHL, our subtypes have been described:
291
nodular sclerosis (NS), mixed cellularity, lymphocyte The management o patients with HL continues to
rich, and lymphocyte depleted. These our subtypes evolve. Beore the widespread use o modern poly-
dier in their clinical eatures, growth pattern, pres- chemotherapy, large-eld radiation therapy (RT) was
ence o brosis, and requency o Epstein-Barr virus able to cure patients with cHL. However, reliance on
(EBV) inection but share the immunophenotype o radiation alone required extensive radiation portals to
tumor cells. treat nearly the entire lymphatic system with radiation
In 2019, it was estimated that 8110 Americans doses up to 44 Gy. With long-term ollow-up, many
would be diagnosed with HL, and as o January1, patients developed cardiac toxicity and second malig-
2019, there were 234,890 survivors o the disease.4 nancies. Thereore, eorts have been made to reduce
HL has been traditionally dened as a hematopoi- the long-term toxicities o treatment or HL while
etic neoplasm composed o diagnostic Hodgkin and maintaining excellent cure rates. With modern chemo-
Reed-Sternberg (HRS) cells within a reactive cell back- therapy, multiple randomized studies have shown that
ground. An HRS cell is large, 30 to 60 μm, containing radiation portals can be saely reduced rom extended-
a bilobed vesicular nucleus, with each lobe containing eld radiation therapy (EFRT) to involved-eld radia-
a prominent round eosinophilic nucleolus surrounded tion therapy (IFRT) and, now, even smaller elds o
by a clear zone or halo; it also has abundant cytoplasm. radiation, including involved-node radiation.
However, HRS cells oten comprise less than 1% o the Currently, the treatment o patients with cHL
involved tumor tissue and are absent in NLPHL. HRS is stratied by risk groups—early-stage avorable,
cells are believed to be derived rom germinal center early-stage unavorable, and advanced-stage dis-
CHAPTEr 13
(GC) B cells that have unavorable immunoglobulin ease—according to the clinical stage and the presence
V gene mutations, whereas lymphocyte-predominant or absence o adverse clinical eatures. This chapter
(LP) cells, which were previously termed lymphocytic reviews advances in the management o HL, including
and histiocytic (LH) cells, are thought to originate rom recent publications about strategies o management o
antigen-selected GC B cells.5 patients with the rarer diagnosis o NLPHL.
IMMUNOPHENOTYPIC FINDINGS IN CLINICAL SUBTYPES OF HODGKIN

HODGKIN LYMPHOMAS LYMPHOMA
NLPHL is immunophenotypically distinct rom other Over the past decade, investigators have made signi-
types o HL. LP cells usually express leukocyte com- cant progress in the diagnosis, classication, staging,
mon antigen (LCA; CD45), immunoglobulin J chain, prognosis, and treatment o HL. In past years, the true
B-cell antigens (CD19, CD20, CD22, CD79A, and lineage o the neoplastic cells in HL was unknown;
BCL-6), and epithelial membrane antigen (EMA) and hence, the term Hodgkin disease was used. It is now
are negative or CD15 and CD30 (Figs. 13–1C and D). recognized that almost all cases o HL are o B-cell lin-
These results suggest that the LP cells are B cells that eage; hence, the name was changed to HL. However,
arise rom the GC. LP cells are negative or T-cell anti- the classication o HL has remained relatively stable
gens but are oten surrounded by a rosette o small, over the past 40 years, and the World Health Orga-
reactive T cells that may be positive or pan-T-cell nization (WHO) classication o lymphoid neoplasms
antigens and CD57 (Fig. 13–1E). EBV is almost always was updated in 2016 (Table 13–1).1 The current WHO
absent in the LP cells o NLPHL. classication recognizes that NLPHL is distinct rom
Immunophenotypic ndings in classical HL dier the other types that can be grouped together under the
rom those observed in NLPHL. Overall, the mature rubric o cHL.1
B-cell origin o the HRS cells is not readily apparent
because HRS cells have a very unusual phenotype and
have expression o genes that are seen on many hema- Nodular Lymphocyte–Predominant
topoietic cell types. The neoplastic cells are positive Hodgkin Lymphoma
or CD15 and CD30 and negative or LCA (CD45)
Clinical Features
(Fig. 13–2) and EMA.1 B-cell antigens, such as CD20,
CD79A, PAX-5/BSAP, and MUM1/IRF4, are expressed Approximately 5% o patients with HL have NLPHL.
in a subset o cases. CD20 expression is oten weak. This disease is usually localized and most oten involves
T-cell antigens are usually not expressed by the neo- cervical or axillary lymph nodes.1,7 The disease aects
plastic cells. BCL-2 is positive in up to hal o cases patients o all ages, males more oten than emales,
and has been correlated with poorer prognosis.6 EBV and is clinically indolent (Table 13–2). Systemic symp-
is relatively common in cHL, but its requency varies toms such as ever, weight loss, and nights sweats (also
greatly among dierent types. known as B symptoms) are inrequent. Patients with
Chapte 13 Hodgkin Lymphoma 293
A B
D
C
CHAPTEr 13
E
FIGUrE 13–1 Nodular lymphocyte–predominant Hodgkin

lymphoma. A. At low-power magnifcation, the neoplasm is
vaguely nodular. B. At high-power magnifcation, large lym-
phocytic and histiocytic (LH) cells, resembling popped kernels
o corn, are identifed in a background o reactive lympho-
cytes and histiocytes. C and D. Immunohistochemical stain
or CD20. C. At low-power magnifcation, this immunostain
highlights the nodular pattern and shows numerous B cells
in the nodules. D. At high-power magnifcation, large LH cells
and small reactive B cells are positive or CD20. E. Immunohis-
tochemical stain or CD3. Scattered small reactive T cells are
present and ocally surround the LH cells (so-called rosetting).
NLPHL are characterized as having a more indolent treatment ailure [FFTF]) and overall survival (OS) were
course with delayed relapse compared with those with 88% and 96%, respectively, slightly better than in cHL
cHL, analogous to low-grade non-HLs.7 Patients with (82% and 92%, respectively).
NLPHL are at a 5% to 6% risk o developing diuse
large B-cell lymphomas (DLBCLs) or T-cell/histiocyte-
Histologic Features
rich large B-cell lymphomas.1
The German Hodgkin Lymphoma Study Group NLPHL is characterized by eacement o nodal archi-
(GHSG) has reported a large retrospective study o tecture by variably sized, vague nodules composed o
394 patients with NLPHL. Patients were predomi- numerous small lymphocytes, histiocytes, and char-
nantly men (75%), only 9% had B symptoms, and acteristic neoplastic LP cells (see Fig. 13–1A).1,9 These
79% had early-stage disease.8 With a median ollow- cells are typically large, with pale cytoplasms and
up o period 50 months, tumor control (reedom rom polyploid vesicular nuclei containing inconspicuous
A B
C
CHAPTEr 13
FIGUrE 13–2 Typical immunohistochemical fndings in

classic Hodgkin lymphoma. The Hodgkin cells are positive
or CD15 (A) and CD30 (B). The Hodgkin cells (C) are negative
or leukocyte common antigen (CD45RB).
TABLE 131 Wold Health Oganization TABLE 132 Compaison o Clinical Featues o
Classifcation o Hodgkin Lymphoma Nodula LymphocytePedominant (NLPHL) and
Classical Hodgkin Lymphoma (HL)
Nodular lymphocyte predominant
Classical Hodgkin lymphoma Clinical
- Nodular sclerosis Feature NLPHL Classical HL
- Lymphocyte rich Frequency 5% 95%
- Mixed cellularity
- Lymphocyte deplete Age Unimodal: equal Bimodal: peak in
distribution in children and second and third
adults decades o lie
Male (%) 70 50
nucleoli resembling kernels o popped corn—hence
the nickname popcorn cells (see Fig. 13–1B). However, Sites involved Lymph nodes Mediastinum,
LP cells can exhibit a range o cytologic appearances. with sparing cervical lymph
mediastinum nodes
These cells can be round or have relatively prominent
nucleoli. Eosinophils, neutrophils, and plasma cells are Stage at I II or III
usually absent in NLPHL, and there is no associated diagnosisa
necrosis or brosis. B symptoms <20 40
Cases o NLPHL can also have diuse areas. (%)
When diuse areas are large, their presence oten Clinical course Indolent, late Aggressive, curable
correlates with more aggressive disease. To refect relapses
this change in clinical behavior, many pathologists a
Most common stage at time o diagnosis.
diagnose such cases as NLPHL with progression to similar in diuse cases o LRHL, but nodularity is mini-
T-cell/histiocyte-rich large B-cell lymphoma, also mal or absent. Immunohistochemical studies o LRHL
described as T-cell–rich B-cell lymphoma (TCRBCL). show that the large neoplastic cells have an immuno-
Other pathologists use the term NLPHL with large phenotype similar to that o all cHL cases, positive or
diuse areas and suggest that the diuse areas may CD15 and CD30 and negative or LCA (CD45) (Figs.
represent the beginning stages o progression to 13–3C–E).
DLBCL. The boundary between NLPHL with di-
use areas and TCRBCL remains blurred. Most cases
previously designated as diuse LPHL, as dened Nodular Sclerosis Hodgkin Lymphoma
previously, are now classied dierently. 10 With
appropriate workup, these cases are usually classi- Clinical Features
ed as NLPHL with large diuse areas, lymphocyte- NS is the most common orm o cHL, representing
rich cHL, or TCRBCL. 60% to 70% o all cases in Western countries; it is also
Gene expression proling o NLPHL to determine the most common type o cHL in patients younger
the origin and pathogenesis o LP cells ound sig- than 50 years o age. Whites are aected more oten
nicant similarities between NLPHL, TCRBCL, and than others, and nodular sclerosis HL (NSHL) is much
cHL.11 Overall, LP cells are thought to derive rom less requent in Asian countries.2,3 The age-adjusted
antigen-selected GC B cells.5 LP cells also demonstrate incidence rate o NSHL has been stable since 1993 to
deregulation o numerous apoptosis regulators and 2008 in the United States according to the National
CHAPTEr 13
putative oncogenes and a partial loss o their B-cell Cancer Institute (NCI) Surveillance, Epidemiology, and
phenotype. In addition, there is constitutive activa- End Results (SEER) data.2 The male-to-emale ratio is
tion o nuclear actor-κB (NF-κB), the Janus kinases/ approximately equal. NSHL has a marked predilection
signal transducers and activator o transcription (JAK/ or involving mediastinal, supraclavicular, and cervical
STAT) pathway, and aberrant extracellular-regulated lymph nodes. A mediastinal mass is very common,
kinase signaling. and the thymus may be involved.
Histologic Features
Lymphocyte-Rich Classical Hodgkin NSHL is characterized by a triad o ndings: (1) a nod-
Lymphoma ular pattern, (2) broad bands o brosis that outline the
Lymphocyte-rich cHLs (LRHLs) have been recog- nodules, and (3) characteristic mononuclear cell vari-
nized that resemble NLPHL histologically but are cHL ants known as lacunar cells (Fig. 13–4). A lacunar cell
immunophenotypically.1,7 In a study o NLPHL by the has abundant clear cytoplasm with a sharply demar-
European Task Force on Lymphoma, a large number cated cell membrane. In ormalin-xed tissue, a char-
o tumors that had been classied as NLPHL were acteristic artiact occurs. The cell cytoplasm retracts,
reviewed; the diagnosis was conrmed in only hal leaving a clear space or lacuna surrounding the cell,
o these cases. Most o those excluded were reclas- hence the origin o the name. The typical lacunar cell
sied as LRHL.9 The requency o this type o HL is has a polylobate nucleus with one or multiple small
not well known but is most likely low (<5%). Clini- nucleoli. However, lacunar cells can show great mor-
cally, patients with LRHL have disease that is similar phologic variability and can be round with prominent
to that seen in patients with other subtypes o cHL or nucleoli, or they may resemble large noncleaved cells.
have clinical ndings intermediate between NLPHL A heterogeneous mixture o reactive cells may be
and cHL. Unlike patients with NLPHL, late relapse is seen in HL, including small lymphocytes, histiocytes,
uncommon in patients with LRHL. eosinophils, neutrophils, and plasma cells in variable
Histologically, these tumors are rich in small lym- numbers.
phocytes and histiocytes. Granulocytes and plasma NSHL has been graded as 1 or 2 by the Brit-
cells are usually inrequent. Necrosis is usually not ish National Lymphoma Investigation (BNLI) group
present. Lymphocyte-rich cHL may be either nodular according to numbers o neoplastic cells and reactive
or diuse. The nodular type closely resembles NLPHL. cells present; this grading system has been adopted
Vague nodules o numerous small lymphocytes are in the WHO classication.1,12 Grade 2 cases o NSHL
present, and the nodules may have a small, com- show numerous neoplastic (lacunar) cells and deple-
pressed GC (Figs. 13–3A and B). The neoplastic cells tion o reactive lymphocytes. Lymphocyte-depleted
are present in the mantle zones o the nodules. These and syncytial variants (Fig. 13–5) o NSHL have been
neoplastic cells usually resemble Reed-Sternberg and described; these cases are the outermost examples o
typical mononuclear variant cells (so-called Hodg- grade 2 NSHL. This syncytial variant o NSHL is com-
kin cells) rather than LP cells. The cell composition is posed o sheets o neoplastic cells and necrosis.
A B
C D
CHAPTEr 13
FIGUrE 13–3 Lymphocyte-rich classical Hodgkin lym-

phoma, nodular variant. A. At low-power magnifcation, the
neoplasm has a nodular pattern and is rich in reactive small
lymphocytes (resembling nodular lymphocyte–predominant
Hodgkin lymphoma). B. At high-power magnifcation, large
neoplastic cells (so-called Hodgkin cells) are identifed in
the mantle zone o the ollicle (note reactive germinal cen-
ter to the let o feld). C and D. Immunohistochemical stain
or CD20. C. The nodules contain numerous small reactive B
cells. D. The Hodgkin cells are negative or CD20. E. Immuno-
histochemical stain or CD30. The Hodgkin cells are positive.
Mixed-Cellularity Hodgkin Lymphoma o patients with MCHL have clinical stage III or stage
IV disease and B symptoms.
Clinical Features
The mixed-cellularity variant o HL (MCHL), the sec-
ond most common type, aects 15% to 25% o all Histologic Features
patients with the disease and is the most common Mixed-cellularity HL is characterized by a large num-
orm in patients older than 50 years o age.1,13 Men ber o Reed-Sternberg cells and Hodgkin cells in a
are aected more oten than women. According to background o numerous eosinophils, plasma cells,
NCI SEER data, MCHL is relatively more common in histiocytes, and granulocytes in varying proportions
Arican Americans and Hispanic Americans than in (Fig. 13–6).1 The lymph node architecture is usually di-
whites in the United States. A substantial percentage usely replaced. Partially involved lymph nodes show
A A
B B
CHAPTEr 13
FIGUrE 13–4 Nodular sclerosis Hodgkin lymphoma. A. The
neoplasm is nodular, and the nodules are surrounded by FIGUrE 13–5 Syncytial variant o nodular sclerosis Hodgkin
dense fbrous bands. B. The large neoplastic cells (lacunar lymphoma. A. Nodularity and a fbrous bond can be appreci-
cells) lie within lacunar spaces, and many are multinucleated ated in this feld. B. The nodules are composed o many neo-
in this feld. Reactive cells are present in the background. plastic cells with depletion o small lymphocytes.
A B
FIGUrE 13–6 Mixed-cellularity Hodgkin lymphoma. A. Classic Reed-Sternberg cell (center o feld) and mononuclear Hodgkin
cells can be appreciated in a background o reactive lymphocytes, histiocytes, and eosinophils. B. Immunostain or Epstein-Barr
virus latent membrane protein type 1. The neoplastic cells are positive.
selective paracortical inltration. Disorderly brosis

may be seen, but the broad brous bands and capsular
brosis characteristic o NSHL are absent.
Two variants o MCHL can be relatively more di-
cult to diagnose. In the interollicular variant, which
most likely represents partial involvement o lymph
nodes by HL, the tumor is located in the interollicular
region and is oten associated with reactive ollicular
hyperplasia and marked plasmacytosis. In the epi-
thelioid histiocyte-rich variant, numerous epithelioid
histiocytes and granulomas are present; these can be
so numerous as to obscure the neoplastic cells. The
importance o these variants o MCHL lies in their
unusual histologic ndings.
Lymphocyte-Depleted Hodgkin
Lymphoma
FIGUrE 13–7 Lymphocyte-depleted Hodgkin lymphoma.
Clinical Features Large neoplastic cells in the background o loose, nonpolar-
CHAPTEr 13
ized fbrosis and lymphocyte depletion.

Lymphocyte-depleted HL (LDHL) is the least common
type, representing 1% o all cases.13 In the NCI SEER
study, it was shown that the age-adjusted incidence cells and pleomorphic variants may be ound in sheets.
rate or LDHL has decreased. This decrease is most Mitotic gures are usually numerous.
likely explained by the recognition by pathologists
that many tumors previously classied as LDHL are,
in act, non-HLs (eg, anaplastic large-cell lymphoma). CLINICAL EVALUATION
Improved classication is the result o application o
immunohistochemical and molecular methods to the Staging o Patients
study o these tumors.
The Ann Arbor system or staging patients with HL
Patients with LDHL are usually older, and LDHL is
at the time o initial presentation orms the basis or
rare in individuals younger than 40 years o age. There
the treatment o disease and has allowed comparison
is a slight male predominance. Whites and Arican
o results achieved by dierent investigations or more
Americans are equally aected. Most patients have
than two decades. Important modications o the Ann
advanced clinical stage and B symptoms. Patients com-
Arbor system were developed at the Cotswold Con-
monly have a large contiguous mass o matted lymph
erence in 1989 (Table 13–3).14 Since then, the staging
nodes or diuse visceral involvement. The diuse
evaluation has been in evolution. A recent recom-
brosis type o LDHL commonly has a subdiaphrag-
mendation or the staging procedure in lymphoma
matic distribution. Lymphocyte-depleted HL has the
described the importance o positron emission tomog-
poorest prognosis o all types o HL.
raphy (PET)–computed tomography (CT) scan or
fuorodeoxyglucose (FDG)-avid lymphomas, o which
Histologic Features HL is one example.15 For HL and other FDG-avid lym-
The LDHL category includes two variants originally phomas, PET-CT improves the accuracy o staging
recognized by Lukes and Butler: diuse brosis and compared with CT scans or nodal and extranodal
reticular (Fig. 13–7). The diuse brosis variant o sites.16 PET-CT leads to change in stage in 10% to 30%
LDHL is characterized by an extensive prolieration o o patients, more oten upstaging, although alteration
disordered, hypocellular brosis. Diagnostic HRS cells in treatment occurs in ewer patients with no demon-
can be dicult to nd and may be spindled within strated impact on overall outcome. However, PET-CT
dense collagen. Reactive infammatory cells are rela- is critical as a baseline measurement beore therapy to
tively ew. The reticular variant o LDHL has numer- increase the accuracy o subsequent response assess-
ous HRS cells and bizarre variants that have been ment.17 In addition, contrast-enhanced CT should be
termed pleomorphic variants. These cells may exhibit included or a more accurate measurement o nodal
marked variations in nuclear number and shape, oten size i required or clinical trials. The University o
with giant nucleoli. Normal small lymphocytes are Texas MD Anderson Cancer Center (MDACC) diag-
inrequent compared with the other subtypes o HL. nostic and treatment algorithms or HL are shown in
Necrosis is common and may be extensive. The HRS Figure 13–8.
TABLE 133 Ann Abo Staging System with Cotswold Modifcations o Hodgkin Lymphoma
Stage I Involvement o a single lymph node region or lymphoid structure (eg, spleen, thymus, Waldeyer
ring) or a single extralymphatic site
Stage II Involvement o two or more lymph node regions on the same side o the diaphragm; localized
contiguous involvement o only one extralymphatic organ or site and lymph node region on the
same side o the diaphragm (IIE); the number o anatomic regions involved should be indicated
by a subscript (eg, II3)
Stage III Involvement o lymph node regions on both sides o the diaphragm (III), which may also be
accompanied by spleen involvement (IIIS) or by localized contiguous involvement o only one
extralymphatic organ or site (IIIE) or both (IIISE)
Stage IV Diuse or disseminated involvement o one or more extranodal organs or tissues, with or without
associated lymph node involvement
Modiying Features
A No symptoms
B Fever (>38°C), drenching night sweats, unexplained weight loss o >10% body weight within the
preceding 6 months
X Bulky disease: greater than one third widening o the mediastinum, >10 cm maximum diameter o
CHAPTEr 13
a nodal mass
E Involvement o a single extranodal site that is contiguous or proximal to the known nodal site
CS Clinical stage
PS Pathologic stage (as determined by laparotomy)
Clinical presentation Primary treatment

ABVD for two cycles and 20 Gy
Favorable without any evidence of the following: of involved-site RT
- Elevated ERS ≥50 mm/hr for stages I and IIA
- Elevated ESR rate ≥30 mm/hr for stages IB and IIB
If RT crosses breast or cardiac:
- Nodal regions ≥3
ABVD for three cycles; then stop
- Extranodal disease
if PET negative (DS ≤4); if PET
Classical HL positive, (DS = 5), give additional
stage I–II, without bulky cycle of ABVD and 30 Gy of IFRT
disease
Unfavorable with any evidence of the following: ABVD for four cycles and 30 Gy
- Elevated ERS ≥50 mm/hr for stages I and IIA of involved-site RT
Classical - Elevated ERS ≥30 mm/hr for stages IB and IIB
HL - Nodal regions ≥3
stage I–II If RT crosses breast or cardiac:
- Extranodal disease ABVD for six cycles without RT
Classical HL ABVD for six cycles and 30 Gy

A stage I–IIB, bulky disease of involved-site RT
FIGUrE 13–8 MD Anderson Cancer Center treatment algorithms or Hodgkin lymphoma (HL). A. Therapy or stage I-II HL.
B. Therapy or advanced stage IIB and stage III-IV classical HL and lymphocyte-predominant HL. C. End-o-therapy response
assessment and management o classical HL and lymphocyte-predominant HL. D. Therapy or relapsed or reractory HL.
A + AVD, brentuximab vedotin, Adriamycin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, dacar-
bazine; ASCT, autologous stem cell transplantation; AVD, Adriamycin, vinblastine, and dacarbazine; BV, brentuximab vedotin;
DHAP, high-dose cytarabine, cisplatin, and dexamethasone; DS, Deauville score; ESR, erythrocyte sedimentation rate; GND,
gemcitabine, Navelbine, and Doxil; ICE, iosamide, carboplatin, and etoposide; IPS, International Prognostic Score; IFRT,
involved-feld radiotherapy; IGEV, iosamide, gemcitabine, vinorelbine, and prednisone; PD-1, programmed death-1;
PET-2, positron emission tomography assessment ater two cycles o therapy; R-ABVD, rituximab, doxorubicin, bleomycin,
vinblastine, and dacarbazine; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RT, radiation
therapy.
Clinical presentation Primary treatment
Classic Hodgkin disease, advanced ABVD for two cycles; then PET-2
stages, IIB, III, and IV response assessment; if PET-2
negative (DS ≤3), continue with
AVD for four cycles; if PET-2 positive.
(DS ≥4), transition to salvage therapy
and ASCT
In high-risk disease (IPS ≥4)

A + AVD for six cycles with PET-2
response assessment; if PET-2
positive (DS = 5), transition to
salvage therapy and ASCT
Residual bulk after induction:

IFRT to residual mass
Lymphocyte-predominant Hodgkin
Involved-site RT
disease, stages I and II
Lymphocyte-predominant Hodgkin - R-CHOP for six cycles or R-ABVD for

disease, stages III and IV six cycles
CHAPTEr 13
Change to salvage
Yes treatment followed
by ASCT
Biopsy
Yes Biopsy
positive?
PET/CT of previously PET-CT Observation or

positive areas positive? No
consider RT
C No Observation
Patient Salvage
presentation therapy
• Brentuximab
Vedotin
• Clinical trial
Yes
Complete ASCT with or without Progressive
response locoregional RT disease post
AHSCT? No
Post first-line therapy, Consider: Monitor clinically
chemotherapy alone Relapsed Clinical trials (see C)
or first-line therapy or - ICE
combination: Refractory - DHAP
as chemotherapy disease - IGEV
with indicated - GND
RT Less than Consider change to
complete a different regimen
D response including BV or anti–PD-1
FIGUrE 13–8 (Continued)
sedimentation rate (ESR); pulmonary unction testing

Patient Evaluation
with carbon monoxide diusing capacity; evaluation
The initial evaluation o patients with HL has both o cardiac ejection raction; chest radiography; CT o
prognostic and therapeutic signicance (see Fig- the neck, chest, abdomen, and pelvis; and PET-CT
ure 13–8). Routine studies that should be perormed (Table 13–4).
include a complete blood cell count with dierential; Bone-marrow biopsy has been a standard test or
electrolytes; blood urea nitrogen; creatinine; liver lymphoma staging. However, the high sensitivity o
unction tests; lactate dehydrogenase; albumin; preg- PET-CT or bone-marrow involvement has recently
nancy tests in women o childbearing age; erythrocyte led to questioning the use o bone-marrow biopsy as
TABLE 134 recommended Pocedues o Staging o Hodgkin Lymphoma
History and Examination Identifcation o B Symptoms

Radiologic and other assessments - Chest radiograph
- CT scans, including the neck, chest, abdomen, and pelvis wholebody PET scan
- Echocardiogram or MUGA scan
- Pulmonary unction tests
- HIV serology
- Pregnancy test in women o childbearing age
Hematologic procedures - CBC with dierential
- ESR
Biochemical procedures - Liver unction tests
- Serum albumin
- Lactate dehydrogenase
Procedures or use under special - Ultrasound scanning
circumstances - MRI
CBC, complete blood count; CT, computed tomography; ESR, erythrocyte sedimentation rate; HIV, human immunodeciency virus; MRI, magnetic resonance imaging;
MUGA, multigated acquisition; PET, positron emission tomography.
CHAPTEr 13
a staging procedure in several common histologies, number o involved nodal regions; (7) elevated ESR; (8)
including HL.15 In one study o patients with HL, 18% anemia; and (9) low serum albumin level.19,20
had ocal skeletal lesion on PET-CT, but only 6% had International organizations have dened various
positive bone-marrow biopsies, all with advanced-stage systems that calculate the risk o recurrence o disease
disease on PET-CT.18 Patients with early-stage disease or, in some cases, death, ater treatment or HL. The
rarely have marrow involvement in the absence o a European Organization or the Research and Treat-
suggestive PET nding, and those with advanced-stage ment o Cancer (EORTC) has dened CS I and CS II
disease rarely have marrow involvement in the absence patients as having an unavorable risk o development
o disease-related symptoms. Although the issue is o recurrence i any o the ollowing actors apply: (1)
controversial and some institutions perorm bone-mar- age older than 50 years, (2) no B symptoms present
row biopsy or initial staging evaluation o HL, almost with an ESR greater than 50 mm/hr or B symptoms
all patients would not have been allocated to another with ESR greater than 30 mm/hr, (3) a large mediasti-
treatment based on bone-marrow biopsy results. Thus, nal mass, (4) stage II, or (5) at least our nodal regions
bone-marrow biopsy is no longer indicated or the rou- involved.21 The GHSG has assigned CS I and CS II
tine staging o patients with cHL. Magnetic resonance patients to the category o unavorable disease with
imaging has also not superseded CT scanning o the any o the ollowing adverse actors: (1) large medi-
chest and abdomen in the evaluation o HL. It is largely astinal mass, (2) at least three nodal regions involved,
restricted to the assessment o specic situations such (3) no symptoms present with ESR greater than 50
as bony involvement and spinal cord compression and mm/hr or B symptoms with ESR greater than 30 mm/
in lieu o CT scans in pregnant patients. hr, or (4) localized extranodal inltration (so-called E
lesions) (Table 13–5).22 In advanced disease, the Inter-
national Prognostic Score (IPS) was developed on the
Prognostic Factors basis o an analysis o 5141 patients, most o whom
For clinically early-stage (CS) disease (CS I or CS II), were initially treated with an anthracycline-containing
several prognostic actors have been identied through chemotherapy regimen. Seven actors were identied,
retrospective studies o patients with HLs, largely as shown in Table 13–6.23
based on patients treated with radiotherapy alone.
Adverse eatures include (1) advanced age, which cor-
relates with the presence o occult abdominal disease
Response Assessment
and with poor results o salvage therapy; (2) male Beore 1999, the criteria used to assess response to
gender; (3) MC histologic type, which is associated therapy were not routinely standardized. The Inter-
with the presence o occult abdominal disease; (4) B national Working Group ormulated guidelines or the
symptoms, also associated with the presence o occult assessment o response to therapy in 1999.24 The cri-
abdominal disease; (5) large mediastinal mass, dened teria were based on CT scan and gained international
as a mass measuring greater than one-third o the chest recognition. However, with the introduction o the PET
diameter on a standard chest radiograph; (6) a larger scan, the guideline has been updated twice, in 2007 and
TABLE 135 Pognostic Classifcation o the Euopean Oganization o the reseach and Teatment
o Cance (EOrTC) and Geman Hodgkin Lymphoma Study Goup (GHSG) Goups o Clinical Stage I/II
Hodgkin Lymphoma
Unavorable (presence o any o the ollowing)

EORTC - Age 50 years or younger
- ESR >50 mm/hr without B symptoms; ESR >30mm/hr with B symptoms
- Four or ewer nodal sites o involvement
- Bulky mediastinal mass
Unavorable (presence o any o the ollowing)
GHSG - ESR >50 mm/hr without B symptoms; ESR >30 mm/hr with B symptoms
- Three or ewer nodal sites o involvement
- Bulky mediastinal mass
- Extranodal involvement
ESR, erythrocyte sedimentation rate.
TABLE 136 Intenational Pognostic Scoe o TABLE 137 Five-Point Deauville Citeia
Hodgkin Lymphoma
CHAPTEr 13
Score 1: no uptake
Hemoglobin <10.5 g/dL Score 2: uptake ≤ mediastinum
Age 45 years or younger Score 3: uptake > mediastinum but ≤ liver
Male sex Score 4: moderately increased uptake > liver
Lymphocyte count <600/mL or <8% o WBC count Score 5: markedly increased uptake > liver or new lesions
Serum albumin <4g/dL related to lymphoma
WBC count ≤ 15,000/mL Score X: new areas o uptake unlikely to be related to
lymphoma
Stage IV disease (Ann Arbor system)
WBC, white blood cell.
Data rom Moccia AA, Donaldson J, Chhanabhai M, et al: International Prognostic
Score in advancedstage Hodgkin’s lymphoma: altered utility in the modern era,
J Clin Oncol. 2012 Sep 20;30(27):33833388.
in 2014.15,25 Based on the high negative predictive value TrEATMENT

(95%–100%) and positive predictive value (>90%) o
PET scan in the response evaluation or HL, current rec- Nodular Lymphocyte–Predominant
ommendations or response evaluation clearly state that Hodgkin Lymphoma
PET-CT is more accurate than CT or end-o-treatment
(EOT) assessment.26 Previous guidelines or reviewing Because o the rarity o this disease, it is dicult to
PET scans were based on somewhat imprecise visual perorm randomized prospective clinical trials. How-
interpretation as to whether a scan was positive or neg- ever, several well-designed single-arm phase II trials
ative and whether it was intended or EOT evaluation and large retrospective analyses have been recently
using mediastinal blood pool as the comparator.27 More reported.
recent guidelines recommend using a 5-point scale
assessment (Deauville criteria; Table 13–7) or clinical Early-Stage Disease
trials including interim analysis and EOT assessment.
A score o 1 or 2 is considered to represent complete Although radiation as a single modality or treatment
metabolic response (CMR). A score o 4 or 5 is con- would be considered inerior treatment or patients
sidered to be treatment ailure at the EOT evaluation. with early-stage cHL, multiple studies have observed
Inherent are diculties in the interpretation o a score excellent outcomes using RT or early-stage NLPHL.
o 3, in which the uptake is higher than mediastinal In a retrospective review o results or early-staged
but less than or equivalent to liver uptake. Recent data NLPHL rom the HD-4 and HD-7 trials perormed by
suggest that patients with a score o 3 at the EOT have the GHSG, the 2-year FFTF and OS rates ater treatment
a good prognosis and should be considered as having with IFRT were 92% and 100%, respectively, com-
CMRs.28,29 However, in response-adapted trials explor- pared with 100% and 94%, respectively, or EFRT.30
ing treatment deescalation, a more cautious approach Investigators rom our center (MDACC) also reported
may be preerred. excellent outcomes with RT alone or stage IA and IIA
patients.31 With a median ollow-up o 8.8 years, only results between those with NLPHL and cHL, with
one o 20 patients who received limited-eld RT experi- 50-month FFTF rates o 77% and 75%, respectively.
enced relapse. The best outcome was noted in stage IA Chemotherapy regimens used in the GHSG trials were
patients, who had a 5-year relapse-ree survival rate o COPP (cyclophosphamide, vincristine, procarbazine,
95%. The Harvard study group reported a retrospective and prednisone), COPP/ABVD, and BEACOPP (bleo-
analysis o long-term outcomes o 113 patients with mycin, etoposide, doxorubicin, cyclophosphamide,
early-stage NLPHL.32 Ten-year progression-ree survival vincristine, procarbazine, and prednisone), combina-
(PFS) and OS rates were 64% and 100%, respectively, tions that contain higher doses o alkylating agents
with limited-eld RT, and 81% and 95%, respectively, than ABVD. The BCCA also reported a matched-con-
with EFRT. O note, 86% o patients who received che- trol analysis o patients with NLPHL and cHL treated
motherapy alone had relapse o disease. with ABVD or ABVD-like chemotherapy.36 Although
These observations suggest that (1) chemotherapy not statistically signicant, there was a trend toward an
alone is not indicated or patients with NLPHL, (2) inerior PFS or patients with NLPHL compared with
RT alone should be the standard o care or patients that or cHL (44% and 77% at 15 years, respectively;
with early-stage NLPHL without bulky disease or B P = .096). These studies have suggested that alkylating
symptoms, and (3) limited-eld RT is appropriate to agents may provide some therapeutic advantage or
reduce toxicity and mortality ater more extensive this disease. We have reported the results o R-CHOP
RT. In these retrospective analyses, no improvement (rituximab plus cyclophosphamide, doxorubicin, vin-
was seen with combined-modality treatment (chemo- cristine, and prednisone) in therapy o patients with
CHAPTEr 13
therapy and RT) compared with RT alone. However, advanced-stage NLPHL.37 Five- and 10-year PFS rates
review o data rom therapy o early-stage NLPHL at or patients treated with R-CHOP were 88% and
the British Columbia Cancer Agency (BCCA) have 59%, respectively. With a median ollow-up period o
suggested a potential improvement in the outcomes 6.7 years, no transormation to DLBCL or TCRBL has
by adding a brie course o ABVD (doxorubicin, bleo- been observed. Currently, NCCN guidelines list thera-
mycin, vinblastine, and dacarbazine) beore RT.33 peutic options including CVP (cyclophosphamide, vin-
Ten-year PFS and OS rates were 65% and 84%, respec- cristine, and prednisone), CHOP, and ABVD with or
tively, ater RT alone, and 91% and 93%, respectively, without rituximab or patients with advanced disease.
or combined-modality treatment. As with retrospec-
tive studies, cautious interpretation is needed because Relapsed and Transormed Disease
o possible selection bias, variable staging procedures,
availability o supportive care, and dierences in dura- Patients with NLPHL may have late relapse or develop
tion o ollow-up or these dierent treatments. transormation to B-cell lymphoma, or which stan-
Because o high CD20 expression in NLPHL, ritux- dard treatment has to be yet dened. However, ritux-
imab monotherapy was evaluated or the treatment imab has been evaluated or treatment o patients with
o patients with early-stage NLPHL. The GHSG and relapsed NLPHL. In a study o 14 patients reported
Stanord groups have reported analyses o prospec- by the GHSG, rituximab therapy induced an ORR o
tive studies o therapy o patients with NLPHL with 100%, a complete response (CR) rate o 57% and a
this drug.34,35 Overall response rates (ORRs) were high median time to progression o 33 months.38 The Stan-
(100% in both studies); however, responses were not ord group examined the benet o limited versus
durable. Currently, National Comprehensive Cancer extended rituximab therapy in rontline and relapsed
Network (NCCN) guidelines recommend IFRT alone settings.34 Eighteen patients with relapsed NLPHL
or early-stage NLPHL without B symptoms. B symp- were enrolled in this study; the ORR with rituximab
toms and bulky disease are uncommon presentations monotherapy was 100%, and the 5-year PFS was
or NLPHL and should be treated with combined- 71.4% with rituximab maintenance therapy, consisting
modality treatment as or cHL. o our weekly inusions every 6 months or 2 years.
These results suggest that rituximab monotherapy is
Advanced-Stage Disease eective in relapsed NLPHL.
Transormation at time o relapse can be a challeng-
Because at least 70% to 80% o patients with NLPHL ing disorder. In a retrospective study by the BCCA, 95
are diagnosed with early-stage disease, dening the patients with NLPHL were seen over a 40-year time
optimal treatment regimen or advanced-stage disease period.39 Median time o ollow-up was 6.5 years,
is challenging. However, chemotherapy is the main- and 14% o patients experienced transormation. The
stay o treatment or those with stage II or IV disease. median time to transormation was 8.1 years, with a
The GHSG recently compared the outcomes o 4:1 ratio o DLBCL to TCRBCL. In the 10 patients with
patients with NLPHL and cHL enrolled in prospec- transormed lymphoma, the 10-year PFS and OS rates
tive trials.7 There was no signicant dierence in FFTF were 52% and 62%, respectively.
The rarity o the disease makes it dicult to pro- alone with combined-modality strategies. In the
spectively evaluate the role o autologous stem cell GHSG HD-7 trial, patients were randomly assigned to
transplantation (ASCT) or patients with relapsed or receive either 30 Gy o EFRT alone or two cycles o
reractory NLPHL. However, patients who relapse ABVD ollowed by the same RT.44 Although response
with transormation should be managed according rates did not dier between the two treatment arms,
to algorithms or DLBCL. An MDACC retrospective the 7-year FFTF rate was signicantly better in the
study reviewed the outcomes or 26 patients who combined-modality arm (88% vs 67%). The results
underwent ASCT. At the time o transplantation, o the randomized EORTC H8F trial were similar. In
many had transormation to TCRBCL. At the time o this trial, treatment arms consisted o three cycles o
ASCT, 85% were in remission, with 25% in CR. At a MOPP (mechlorethamine, vincristine, procarbazine,
median ollow-up period o 50 months, the event-ree prednisone)/ABV (doxorubicin, bleomycin, vinblas-
survival (EFS) rate was 69%.40 tine) ollowed by IFRT or subtotal nodal irradiation
(STNI) alone.45 Patients receiving combined-modality
MD Anderson Approach to Therapy or NLPHL: treatment had a signicantly superior 5-year EFS (98%
Summary vs 74%) and better 1-year OS estimates (97% vs 92%).
As a result o these two large randomized controlled
We treat patients with stage IA and IIA NLPHL with IFRT. trials and the recognition o notable long-term side
It is rare or stage I or II patients to present with B symp- eects and high relapse rates, EFRT monotherapy has
toms, but i a patient does, we administer combined- now been abandoned in avor o combined-modality
CHAPTEr 13
modality therapy with an anthracycline-containing therapy, which is now the standard treatment or
chemotherapy regimen ollowed by IFRT, particularly early-stage HL.
or stage IIB. Our preerred regimen is R-CHOP, and Combined-modality therapy has evolved based on
patients with advanced-stage disease receive six cycles the nding that this approach results in high reedom
o this regimen. Patients who experience relapse are rom recurrence in early-stage HL and that ecacy
considered or extended rituximab therapy. For patients can be maintained using less toxic chemotherapy and
with evidence o transormation to DLBCL or TCRBCL, RT regimens. At MDACC, investigators perormed a
i anthracycline-containing chemotherapy was already retrospective analysis o 286 patients with early-stage
given, we use salvage chemotherapy with regimens HL treated with chemotherapy ollowed by IFRT or
such as rituximab plus ICE (iosamide, carboplatin, and EFRT with a median dose o 40 Gy.46 Five-year relapse-
etoposide) ollowed by ASCT. ree survival (RFS) and OS rates were 88% and 93%,
respectively. The type and number o chemotherapy
cycles used did not signicantly aect RFS and OS.
Classical Hodgkin Lymphoma However, the 5-, 10-, and 15-year cumulative risks
The common practice or treatment and participa- o developing solid tumors in patients treated with
tion in clinical trials is to divide patients with cHL into chemotherapy and IFRT were 0%, 6.9% and 11.4%,
three treatment groups: early-stage avorable, early- respectively. These results were strikingly more avor-
stage unavorable, and advanced stage. able than those o chemotherapy plus EFRT (2.7%,
11.1%, and 28.7%, respectively).
Favorable Early-Stage Classical Hodgkin There are many completed and ongoing trials
addressing issues o the best modality, best RT eld,
Lymphoma
optimal dose o RT, optimal combination o drugs,
Treatment o patients with early-stage HL is evolving. number o cycles, and optimal timing o chemother-
Historically, wide-eld RT or EFRT without chemo- apy, with the goals being to maintain ecacy and
therapy was the standard o care.41 Extended-eld RT minimize toxicities (Table 13–8).22,47–51 The key study
produced superior disease-ree survival (DFS) results in combined-modality therapy or the current standard
compared with IFRT.42 More than 90% o patients treatment is the HD-10 trial by the GHSG.22 This study
achieved CR with this approach; however, the relapse had our arms testing two versus our cycles o ABVD
rate was unacceptably high (≥30%). In addition, EFRT ollowed by 20 versus 30 Gy o IFRT in patients with
had considerable long-term side eects. In a large pro- avorable early-stage HL. This trial addressed both the
spective analysis o over 15,000 HL patients, the actu- optimal dose o RT and the optimal number o cycles
arial risk o developing a solid tumor was 21.9% at 25 o chemotherapy. The ABVD two- and our-cycle
years ater HL diagnosis, with the absolute risk being arms both had CR rates o 97%. The 20- and 30-Gy
nearly 50%. Female breast and lung cancers were com- IFRT groups had CR rates o 97% and 98%, respec-
mon secondary malignancies.43 tively. With a median ollow-up period o 7.5 years,
In an attempt to improve these results, the GHSG there were no dierences among the our groups with
and EORTC conducted key studies comparing RT respect to PFS, FFTF, and OS. However, the our-cycle
ABVD and 30-Gy IFRT treatment groups induced higher relapse rates. Five-year FFTF rates were 93%,
more toxicity than the less intensive treatment groups. 81%, 89%, and 77% with ABVD, ABV, AVD, and
Based on these data, the least toxic regimen, two cycles AV, respectively. Based on results rom this trial, both
o ABVD and 20 Gy o IFRT, is the current preerred dacarbazine and bleomycin cannot be omitted rom
approach or patients with avorable early-stage HL. this regimen or avorable early-stage disease without
In an attempt to urther reduce toxicity, the GHSG a substantial loss o ecacy, and the standard treat-
conducted the HD-13 trial, a study that was designed ment remains ABVD ollowed by IFRT.
to determine whether bleomycin or dacarbazine can Several studies have evaluated the utility o interim
be omitted rom the ABVD regimen.48 This our-arm PET imaging or treatment stratication. The EORTC/
trial investigated ABVD, AVD (doxorubicin, vinblas- Lymphoma Study Association (LYSA)/Fondazione Ital-
tine, dacarbazine), ABV, and AV (doxorubicin, vinblas- iana Linomi (FIL) H10 trial was conducted to assess
tine) plus 30 Gy o IFRT. In this trial, the ABV and AV whether involved-node radiotherapy (INRT) could be
plus IFRT arms were closed because o concern or omitted without compromising PFS in patients attain-
ing a negative early PET scan ater two cycles (PET-2) o
TABLE 138 Key Tials o Patients with ABVD as compared with standard combined-modality
Favoable Ealy-Stage Hodgkin Lymphoma treatment.47 Patients were randomized to receive stan-
dard therapy with INRT or an experimental arm that
Trial Trial Design omitted RT i the PET was interpreted as negative
Milan 1990 to 1997 ABVD × 4 → STLI (Deauville score [DS] 1 or 2) ater two cycles o ABVD.
CHAPTEr 13
ABVD × 4 → IFRT Patients with a positive interim PET (DS ≥3) contin-
ued treatment with two cycles o escalated BEACOPP.
Stanord Stanord V × 8 weeks → IFRT
The chemotherapy-only arm was closed because o
EORTC/GELA H9F EBVP × 6 → IFRT 20 Gy an increased number o events, and all patients with
EBVP × 6 → IFRT 30 Gy
a negative PET ndings received additional RT. Five-
EBVP × 6 → alone
year PFS was signicantly lower in the experimental
GHSG HD10 ABVD × 2 → IFRT 2 Gy arm than the standard arm (87% and 99%, respec-
ABVD × 4 → IFRT 20Gy
tively).52 In contrast, the UK RAPID trial showed non-
ABVD × 2 → IFRT 30 Gy
inerior outcomes or patients who omitted RT ater
negative PET scan (DS 1 or 2).53 Patients were random-
GHSG HD13 ABVD × 2 → IFRT 30 Gy
ized to IFRT or no urther treatment i the PET result
ABV × 2 → IFRT 30 Gy
was negative ater three cycles o ABVD. Three-year
AVD × 2 → IFRT 30 Gy
AV × 2 → IFRT 30 Gy PFS rates were 93.8% and 90.7%, and 3-year OS rates
in an intent-to-treat analysis were 97.0% and 99.5%
EORTC/LYSA/FIL H10F ABVD × 3 → INRT 30 Gy (+6 Gy)
in patients who received IFRT and no urther treat-
ABVD × 2 → then PET scan
- I PET negative → ABVD × 2
ment, respectively. Thus, there was a nonsignicant
- I PET positive → BEACOPP trend toward improved PFS or patients who received
escalated × 2 → INRT 30 Gy IFRT. In a post-hoc analysis o this trial, investigators
(+ 6 Gy) reported that only patients with a PET DS score o 5
GHSG HD16 ABVD x 2 → IFRT 20 Gy had inerior PFS compared with patients with a DS
ABVD x 2 → then PET scan score o 4 or less, thereby warranting treatment escala-
- I PET negative → stop tion only or patients with a DS score o 5.28
treatment In a similar study, the GHSG HD-16 trial random-
- I PET positive → IFRT 20 Gy ized patients with avorable early-stage cHL to two
UK RAPID ABVD × 3 → then PET scan cycles o ABVD and 20 Gy IFRT or to an experimental
- I PET negative (DS ≤4) → arm o two cycles o ABVD with PET-guided treatment,
stop treatment omitting IFRT i the PET-2 was negative (DS <3). With
- I PET positive → ABVD × 1 + a median ollow-up period o 45 months, the 5-year
30 Gy IFRT PFS rates were 93.4% in the standard therapy arm
ABV, doxorubicin, bleomycin, vinblastine; ABVD, doxorubicin, bleomycin, and 86.1% in the experimental arm. O the patients
vinblastine, dacarbazine; AV, doxorubicin, vinblastine; AVD, doxorubicin,
vinblastine, dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, who received IFRT, 5-year PFS rates were signicantly
cyclophosphamide, vincristine, procarbazine, prednisone; EBVP, epirubicin, dierent in the PET-2–negative and PET-2–positive
bleomycin, vinblastine, prednisone; EORTC, European Organization or Research
and Treatment o Cancer; FIL, Fondazione Italiana Linormi; GELA, Groupe d’Etude patients (93.2% and 88.4%, respectively; P = .047),
des Lymphomes de l’Adulte; GHSG, German Hodgkin Lymphoma Study Group; which was more pronounced when using the more
IFRT, involvedeld radiotherapy; INRT, involvednode radiotherapy; LYSA,
Lymphoma Study Association; PET, positron emission tomography; Stanord V, common liver cut-o or PET scoring, DS less than 4
mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, (5-year PFS rates 93.1% and 80.9%, respectively; P =
prednisolone; STLI, subtotal lymphoid irradiation.
.0011), suggesting that IFRT cannot be saely omitted
in PET-2–negative patients without signicant loss o TABLE 139 Key Tials o Patients with
local tumor control.54 The question o whether treat- Unavoable Ealy-Stage Hodgkin Lymphoma
ment can be urther reduced based on the results o
the PET scan is the subject o ongoing clinical trials. Trial Trial Design
The GHSG HD-17 trial is investigating the potential ABVD × 6 → IFRT 36 Gy to >5 cm
equivalence o IFRT and INRT. Small phase II studies disease
are investigating the option o using novel agents such Stanord V × 12 weeks → IFRT 36 Gy
as nivolumab or brentuximab vedotin (BV) to replace to >5 cm disease
RT and bleomycin with avorable early results.55,56
EORTC/GELA H9U ABVD × 6 → IFRT (36–40 Gy)
ABVD × 4 → IFRT (36–40 Gy)
The MD Anderson Approach or Favorable Early-
BEACOPP × 4 → IFRT (36–40 Gy)
Stage Classical Hodgkin Lymphoma
GHSG HD11 ABVD × 4 → IFRT 30 Gy
The treatment or avorable early-stage HL is still evolv-
ing. Patients are screened or clinical protocol options
i available. As standard therapy, we use two cycles o BEACOPP baseline × 4 → IFRT 30 Gy
ABVD plus 20 Gy o IFRT or this group o patients. In BEACOPP baseline × 4 → IFRT 20 Gy
patients in whom the radiotherapy eld crosses vital GHSG HD14 ABVD × 4 → IFRT 30 Gy
tissues, including breast tissue and coronary arteries, BEACOPP escalated + ABVD × 2 →
CHAPTEr 13
we use three cycles o ABVD ollowed by interim PET IFRT 30 Gy

imaging. I PET negative (DS ≤4), no urther treatment EORTC/LYSA/FIL ABVD × 4 → INRT 30Gy (+ 6 Gy)
is given; i PET positive (DS = 5), one additional cycle H10U
o ABVD is given with 30 Gy o IFRT.
ABVD × 2 → then PET scan
I PET negative → ABVD × 4
Unavorable Early-Stage Hodgkin Lymphoma I PET positive → BEACOPP escalated
Combined-modality approaches consisting o our × 2 → INRT 30 Gy (+ 6 Gy)
cycles o chemotherapy ollowed by IFRT represent GHSG HD17 BEACOPP escalated + ABVD × 2 →
the standard o care or patients with unavorable IFRT 30 Gy
early-stage HL. Multiple trials have shown that reduc- BEACOPP escalated + ABVD × 2 →
tion o radiation eld does not lead to inerior clini- then PET scan
cal outcomes. In a retrospective analysis conducted at I PET negative → stop treatment
MDACC, 286 patients (1980–1995) with early-stage I PET positive → INRT 30 Gy
HL received chemotherapy ollowed by IFRT or EFRT. ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BEACOPP, bleomycin,
The type and number o chemotherapy regimens used etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,
prednisone; ECOG, Eastern Cooperative Oncology Group; EORTC, European
did not signicantly aect RFS and OS. There was a Organization or Research and Treatment o Cancer; FIL, Fondazione Italiana
trend toward a higher risk o secondary tumors in the Linomi; GELA, Groupe d’Etude des Lymphomes de l’Adulte; GHSG, German
Hodgkin Lymphoma Study Group; IFRT, involvedeld radiotherapy; INRT,
EFRT group.46 Given the relapse rates with ABVD, involvednode radiotherapy; LYSA, Lymphoma Study Association; PET, positron
there is interest in evaluating alternative more inten- emission tomography; Stanord V, mechlorethamine, doxorubicin, vinblastine,
vincristine, bleomycin, etoposide, prednisone; SWOG, Southwest Oncology
sive regimens (Table 13–9).47,57–60 Group.
To address whether ABVD or the Stanord V regi-
men (mechlorethamine, doxorubicin, vinblastine, vin-
cristine, bleomycin, etoposide, prednisone) would be HD-11 trial randomized patients to our arms o ther-
the best approach or patients with bulky unavorable apy: our cycles o ABVD ollowed by 30 versus 20
early-stage HL, the SWOG and Eastern Cooperative Gy o IFRT or our cycles o BEACOPP baseline ol-
Oncology Group (ECOG) conducted the intergroup lowed by 30 versus 20 Gy o IFRT. FFTF results were
2496 trial.57 In this study, patients with bulky una- better with BEACOPP than with ABVD or patients
vorable early-stage disease (patients with advanced- who received 20 Gy o IFRT, whereas there were no
stage disease were also enrolled in this trial) received dierences between the BEACOPP and ABVD arms
six cycles o ABVD ollowed by IFRT, 36 Gy to bulky or patients who received 30 Gy o IFRT. OS did not
disease greater than 5 cm, or 12 weeks o Stanord V dier signicantly between the our treatment arms.
ollowed by the same IFRT plan o care. In this study, BEACOPP also induced more toxicity in comparison
there were no dierences between ABVD and Stan- with ABVD; thereore, our cycles o ABVD remained
ord V with respect to ORR and FFS. the standard or these patients with unavorable early-
In another study o therapy more intensive than stage HL.59 However, in a ollow-up study, in an attempt
ABVD or unavorable early-stage cHL, the GHSG to reduce the toxicity observed with BEACOPP, the
GHSG HD-14 trial evaluated our cycles o ABVD ol- A trial conducted by the National Cancer Institute
lowed by 30 Gy o IFRT versus two cycles o BEA- o Canada and the ECOG indicated that chemother-
COPP escalated ollowed by two cycles o ABVD (2 apy-only approaches appear possible in patients with
+ 2) ollowed by 30-Gy IFRT or this same group o unavorable early-stage cHL, at least in patients with
patients.58 At a median ollow-up period o 43 months, nonbulky disease.61 The trial randomized patients
there was better tumor control (5-year FFTF estimate with unavorable early-stage disease to receive either
o 94.8%) with the 2 + 2 protocol compared with the our to six cycles o ABVD or two cycles o ABVD ol-
ABVD arm (5-year FFTF o 87.7%), although there was lowed by STNI. At a median ollow-up period o 11.3
no signicant dierence in OS between the two arms years, reedom rom disease progression was better in
because o more toxic deaths in the 2 + 2 arm. patients who received combined-modality treatment;
Using a similar rationale, the EORTC designed the however, OS was better or patients treated with
H9U trial, comparing three dierent less versus more chemotherapy alone. This was mainly caused by the
intensive therapies.60 Patients received either our or increased number o deaths rom secondary neoplasia
six cycles o ABVD ollowed by IFRT or our cycles o among patients who had received combined-modality
BEACOPP ollowed by IFRT. Patients in CR/Cru (CR treatment. Because o results o this study and others
unconrmed) ater chemotherapy received 30 Gy o previously mentioned, STNI elds have been aban-
IFRT with those in partial remission (PR) receiving 36 doned in avor o limited elds ater ABVD or vari-
Gy in total. Four cycles o ABVD ollowed by IFRT ants. Chemotherapy alone may still be an option or
was noninerior to six cycles o ABVD or our cycles selected patients with nonbulky unavorable early-
CHAPTEr 13
o BEACOPP with IFRT (5-year EFS, 86%, 89%, and stage HL, given similar excellent OS results with and
90%, respectively) with no dierences in 5-year OS without RT, but the combined-modality therapy
rates and ewer toxic events compared with BEA- approach remains a standard o care.
COPP. Based on these two trials, our cycles o ABVD
chemotherapy remains the standard comparator or The MD Anderson Approach to Unavorable
patients with unavorable early-stage HL. Early-Stage Classical Hodgkin Lymphoma
Similar to avorable early-stage HL, current trials or
patients with unavorable early-stage HL, such as the Treatment with our cycles o ABVD plus 30 Gy o
EORTC/Groupe d’Etude des Lymphomes de l’Adulte IFRT is our standard-o-care option or unavorable
H10U and GHSG HD-17, are evaluating treatment early-stage HL. We screen patients or any available
stratication according to the result o an interim PET clinical protocols. I patients have elevated short- or
scan. The standard arm in the EORTC/LYSA/FIL H10U long-term risks associated with RT, such as young
trial consisted o our cycles o ABVD ollowed by 30 emale patients who might need signicant breast tis-
Gy o INRT irrespective o the result o an interim PET sue irradiation because o bulky masses at diagnosis,
scan perormed ater the second cycle o ABVD. In the six cycles o ABVD without RT is an acceptable alter-
experimental arm, patients with negative PET results native, especially i the PET-2 result is interpreted as
received a total o six cycles o ABVD without consoli- negative or active disease.
dation RT, whereas patients with positive PET results
continued treatment with two cycles o escalated BEA- Advanced-Stage Hodgkin Lymphoma
COPP beore receiving INRT. However, as or patients
with early-stage avorable HL, the chemotherapy-only Treatment o patients with advanced-stage HL usu-
arm (six cycles o ABVD) was closed because o an ally consists o six to eight cycles o chemotherapy.
increased number o events, so that all patients with The ABVD regimen was shown to be eective and
negative PET results received additional RT. There was less toxic than MOPP and MOPP/ABVD in a random-
no dierence in the 1-year PFS between the standard ized clinical trial by the Cancer and Leukemia Group
and experimental arms (97.3% and 94.7%, respec- B (CALGB).62 With ABVD, MOPP, and MOPP/ABVD,
tively). In the GHSG HD-17 trial, all patients received 5-year ailure-ree survival rates were 61%, 50%, and
chemotherapy according to the 2 + 2 regimen beore a 65%, and 5-year OS rates were 73%, 66%, and 75%,
PET scan was perormed. In the standard arm, patients respectively. Based on this trial, the chemotherapy
received an additional 30 Gy o IFRT irrespective o regimen most oten used in the United States became
the results o the PET scan. In the experimental arm, ABVD. However, the GHSG subsequently reported
patients with negative PET scan results stopped treat- that escalated BEACOPP induced better PFS results
ment, whereas patients with positive PET scan results would ABVD or advanced-stage HL. Many trials are
received 30 Gy o INRT. This ongoing trial plans to addressing whether one regimen may be more suitable
evaluate whether it is possible to spare RT in patients or the treatment o advanced HL than another, and
with a negative PET scan ater intensive escalated the issue has been the subject o ongoing debate or
BEACOPP. more than decade (Table 13–10).26,62–66
TABLE 1310 Key Tials o Advanced-Stage Hodgkin Lymphoma
Trials Design
CALGB ABVD × 6 to 8
ABVD/MOPP × 12
MOPP × 6 to 8
GHSG HD9 COPP/ABVD × 8
BEACOPP baseline × 8
BEACOPP escalated × 8
GHSG HD12 BEACOPP escalated × 8 → IFRT to bulk/residual mass
BEACOPP escalated × 8
BEACOPP escalated × 4 + BEACOPP baseline × 4 → IFRT to bulk or residual mass
BEACOPP escalated × 4 + BEACOPP baseline × 4
GHSG HD15 BEACOPP escalated × 8 → IFRT to PETpositive residual masses ≤2.5 cm
BEACOPP escalated × 6 → IFRT to PETpositive residual masses ≤2.5 cm
BEACOPP14 × 8 → IFRT to PETpositive residual masses ≤2.5 cm
CHAPTEr 13
LYSA H34 ABVD × 8

GITIL ABVD × 6 to 8 depends on the response ater our cycles
HDCT is planned by protocol at the time o progression or relapse
GHSG HD18 BEACOPP escalated × 2 → then PET scan
I PET negative
Additional BEACOPP escalated × 4
I PET positive
Additional BEACOPP escalated × 4 + rituximab
CALGB ABVD × 6 to 8
ABVD/MOPP × 12
SWOG S0816 ABVD × 2 → then PET scan
- I PET negative (DS≤3), then ABVD × 4
- I PET positive (DS≥4), then BEACOPP × 6
RATHL ABVD × 2 → then PET scan
- I PET negative (DS≤3), then ABVD × 4 or AVD × 4
- I PET positive (DS ≥4), then BEACOPP × 4 or eBEACOPP × 4
ECHELON1 A+AVD × 2 → then PET scan
- I PET negative (DS ≤4), then A+AVD × 4
- I PET positive (DS = 5), then alternative rontline therapy
A + AVD, brentuximab vedotin, doxorubicin, vinblastine, dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; AVD, doxorubicin, vinblastine,
dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; CALGB, Cancer and Leukemia Group B; COPP,
cyclophosphamide, vincristine, procarbazine, prednisone; GHSG, German Hodgkin Lymphoma Study Group; GITIL, Gruppo Italiano Terapie Innovative nei Linomie;
HDCT, highdose chemotherapy; IFRT, involvedeld radiotherapy; LYSA, Lymphoma Study Association; MOPP, mechlorethamine, vincristine, procarbazine, prednisone;
PET, positron emission tomography; SWOG, South West Oncology Group; RATHL, Response adapted therapy or Hodgkin Lymphoma.
In the original BEACOPP study or advanced cHL, the arms. With BEACOPP escalated, COPP/ABVD, and
GHSG HD-9 trial, a three-arm randomized trial evalu- BEACOPP baseline, 5-year FFTF rates were 87%, 69%,
ated our cycles o COPP/ABVD versus eight cycles o and 76%, respectively. Five-year OS rates were 91%,
BEACOPP baseline versus eight cycles o BEACOPP 83%, and 88%, respectively. Because o concerns o
escalated.66,67 The BEACOPP escalated arm provided toxicity with escalated BEACOPP, the GHSG HD-12
signicantly a better survival rate than the other two trial investigated whether the number o cycles o
BEACOPP escalated could be deescalated by evalu- S0816 trial studied results o therapy or patients with
ating eight cycles o BEACOPP escalated versus our stage III or IV disease.69 All patients underwent staging
cycles o BEACOPP escalated plus our cycles o BEA- by PET ollowed by two cycles o ABVD and a repeat
COPP baseline (4 + 4), along with the eect o consoli- PET scan (PET-2). I the PET-2 result was negative,
dation RT or sites o initial bulk or residual disease.65 the patient received our additional cycles o ABVD.
Severe toxicity and therapy-related death rates were I the PET-2 scan result was positive, treatment was
similar in both arms, and the survival outcome was changed and intensied to BEACOPP escalated or six
slightly inerior in the 4 + 4 regimen. Thus, the trial cycles or patients who were seronegative or human
could not address how to decrease the toxicity while immunodeciency virus (HIV); BEACOPP standard
maintaining the ecacy o eight cycles o BEACOPP or six cycles was given to those who were seroposi-
escalated. Their next trial (HD15) also aimed to reduce tive). This trial was also the rst American study to
treatment toxicity without compromising ecacy.26 use centralized real-time intergroup review (SWOG,
The trial evaluated the role o response evaluation ECOG, CALGB) o the PET scan results or treatment
based on PET scan in assessing the need or IFRT. Che- decisions. The 5-year PFS o PET-2–positive patients
motherapy consisted o eight cycles o BEACOPP esca- with PET-2–positive disease was still lower than that
lated, six cycles o BEACOPP escalated, or eight cycles reported or those who had PET-2–negative disease
o BEACOPP-14, a time-dense variant o the BEA- (66% and 76% respectively) even though they received
COPP baseline protocol. Additional localized RT was six more cycles o BEACOPP escalated ater PET-2.70
only applied to patients who had PET-positive resid- The Gruppo Italiano Terapie Innovative nei Lin-
CHAPTEr 13
ual lymphoma larger than 2.5 cm at the end o che- omi (GITIL) conducted a similar trial.71 In the GITIL
motherapy. With eight cycles o BEACOPP escalated, HD0607, all patients received two cycles o ABVD
six cycles o BEACOPP escalated, and eight cycles o and then underwent PET-2. I the results were nega-
BEACOPP-14, the 5-year FFTF rates were 85%, 89%, tive, they received another our cycles o ABVD with
and 85%, respectively, and the 5-year OS rates were or without RT. I the PET-2 results were positive, the
92%, 95%, and 95%, respectively. The negative pre- patient received our cycles o BEACOPP escalated and
dictive value o the post chemotherapy PET scan was two cycles o BEACOPP baseline. The 3-year PFS rates
very high (94.1% at 12 months), allowing omission o patients with positive and negative PET-2 scans
o PET negative residua. The superiority o six cycles were 60% and 87%, respectively.72 In patients with
o BEACOPP escalated was mainly attributed to the both interim and post-ABVD-negative PET who had a
lower rate o treatment-related adverse events (AEs) large nodal mass 5 cm or larger at diagnosis, the addi-
and ewer deaths caused by secondary neoplasia com- tion o radiotherapy did not improve PFS (3 year PFS
pared with those observed with the more intensive 97% and 93%, respectively, P = .29), adding to ear-
regimens. lier suggestions that PET negativity at PET-2 and the
The GHSG HD-18 trial urther evaluated the utility end o therapy (PET-EOT) may allow deletion o RT
o the interim PET scan ater two cycles o eBEACOPP altogether. However, those with PET-2 positivity ater
to adapt treatment intensity.68 Patients with a positive two cycles o ABVD had inerior results, and urther
PET ater two cycles o eBEACOPP were randomized improvements are needed with this approach.
to six additional cycles o eBEACOPP or eBEACOPP The Response-Adapted Therapy or Advanced
with rituximab (this was amended to our additional Hodgkin Lymphoma (RATHL) trial also used a PET-2
cycles in June 2011 based on the GHSG HD-15 results). adapted strategy to assess the impact o treatment
Patients with negative PET-2 results were randomized deescalation in the PET-2–negative population by
to six additional cycles o eBEACOPP or two addi- omitting bleomycin. All patients received two cycles
tional cycles. RT was recommended or lesions o 2.5 o ABVD ollowed by PET imaging. Patients with
cm or larger in the largest diameter with residual FDG negative PET-2 results were randomized to either our
uptake ater chemotherapy. O the PET-2–positive urther cycles o ABVD or AVD. Patients with positive
patients, there was no survival benet with the addi- PET-2 results proceeded with either BEACOPP-14 or
tion o rituximab. However, survival was similar in the eBEACOPP in a nonrandomized ashion. In the PET-2–
PET-2–negative patients who received six additional negative patients, the regimen without bleomycin just
cycles o eBEACOPP compared with two additional ell short o the specied nonineriority margin (3-year
cycles (5-year PFS 90.8% and 92.2%, respectively) with PFS, 85.7% and 84.4%, respectively) with higher rates
ewer severe inections and organ toxicities in patients o respiratory AEs in the ABVD group than the AVD
only receiving two additional cycles o eBEACOPP. group.73 The 3-year PFS rates or patients with PET-2–
Thereore, or patients with a negative PET-2 results, positive and PET-2–negative scans were 67% and
the standard o care became our cycles o eBEACOPP. 85%, respectively. Although not strictly meeting the
Using a dierent approach that escalated therapy specied nonineriority margin, many clinicians in the
or PET-2–positive disease, investigators o the SWOG United States have adopted the practice o dropping
bleomycin in patients with negative PET-2 results ater survival in these young patients. Most o the institutes
two cycles o ABVD with minimal impact on PFS. The in the United States are still using ABVD as the rst-
relatively poor results with escalation to BEACOPP line chemotherapy backbone o treatment or patients
ater a positive PET-2 result in this trial were similar to with HL, mostly because o its high ecacy, high tol-
those previously reported in other studies. erability, and lower toxicity rates compared with BEA-
Even with the results o the GHSG HD-9 trial, ini- COPP escalated.75
tial chemotherapy or advanced-stage HL is still a mat- Ater the introduction o BV or patients with
ter o debate. The standard arm used in the HD-9 trial relapsed or reractory cHL, investigators conducted a
was COPP/ABVD, not ABVD alone. Three random- phase III randomized study (ECHELON-1) to incorpo-
ized trials have been conducted to address this issue. rate this novel agent into initial therapy o advanced-
An Italian group conducted the HD2000 trial and LYSA stage cHL. 77 Because o signicant pulmonary toxicity
conducted the H34 trial to compare the outcomes o associated with concomitant administration o this
randomized therapy with BEACOPP and ABVD.63,74,75 agent and bleomycin, this anti-CD30 antibody–drug
In the HD2000 trial, patients were randomly assigned conjugate was substituted or bleomycin in the ABVD
to receive six cycles o ABVD, our cycles o BEA- regimen (A + AVD); patients with advanced cHL
COPP escalated plus two cycles o BEACOPP baseline, received six cycles o A+AVD or six cycles o ABVD.
or six courses o CEC (cyclophosphamide, lomustine, All patients underwent PET-2 restaging, and those
vindesine, melphalan, prednisone, epidoxorubicin, with a DS score o 5 had the option o switching to
vincristine, procarbazine, vinblastine, and bleomy- alternative rontline therapy. At a median ollow-up
CHAPTEr 13
cin). Patients who received BEACOPP had higher period o 2 years, modied PFS rates were superior in
PFS and OS rates than patients who received ABVD the A +AVD group compared with the ABVD group
(5-year PFS, 81% and 68%; 5-year OS, 92% and 84%, (82% vs 77%) with lower rates o pulmonary toxic-
respectively). In the H34 trial, patients were randomly ity. However, higher rates o neutropenia and periph-
assigned to receive eight cycles o ABVD or our cycles eral neuropathy (all grades) were reported in the A
o BEACOPP escalated plus our cycles o BEACOPP + AVD group. At a 3-year update, results remained
baseline. Both PFS and OS were higher in the BEA- superior or those receiving A + AVD.78 In the North
COPP arm than the ABVD arm (5-year PFS, 93% and American subgroup, patients with a high-risk IPS (≥4)
75%; 5-year OS, 99% and 92%, respectively), results appeared to have a statistically signicant PFS benet
similar to those reported rom the HD2000 study. with A + AVD compared with ABVD, with a hazard
Thereore, in GHSG trials, BEACOPP has been a stan- ratio (HR) o 0.396.79 Two-year PFS and OS results
dard o care or younger patients with advanced-stage or this NA subgroup overall were 88% and 76.4%,
cHL. Unortunately, or patients older than 65 years o and 97% and 93.2%, respectively (P = .094). Based on
age, standard-dose BEACOPP was toxic in the HD9 these dierences at 2 years between the A + AVD and
study, a randomized study o the regimen versus ABVD groups, a number o US centers now admin-
COPP–ABVD, causing 21% early deaths in this older ister A + AVD as initial therapy or advanced-stage
population.76 cHL, especially or patients with high IPS or preex-
Regardless o these excellent results in younger isting lung disease; granulocyte colony-stimulating
patients by the GHSG, the GITIL has reported that actor support and careul monitoring o peripheral
ABVD has a similar ecacy to BEACOPP i high- neuropathy and hepatic unction are mandatory with
dose chemotherapy (HDCT) is planned at the time this regimen.
o relapse or reractory disease.64 In the GITIL trial, In one phase 2 study, BV was given as initial therapy
patients were randomly assigned to either our cycles to patients with cHL 60 years o age or older who were
o BEACOPP escalated plus our cycles o BEACOPP considered ineligible or standard chemotherapy.80
baseline or to six to eight cycles o ABVD, each ol- Ninety-one percent o the patients responded, with
lowed by local RT when indicated. Patients with a 73% CR rate. Unortunately, the median PFS result
residual or progressive disease ater the initial therapy with BV alone was only 10.5 months. Brentuximab
were to be treated with high-dose salvage therapy has also been studied in combination with other drugs
with ASCT. The 7-year FFTF was signicantly better (nivolumab, dacarbazine, bendamustine) in another
with BEACOPP than ABVD (85% vs 73%); however, small study o older patients with cHL who were
there was no signicant dierence in the 7-year OS not considered eligible to receive chemotherapy.81
between arms ater completion o the overall planned Responses were good or all o the regimens in this
treatment (89% vs 84%). Although two o these three trial; unortunately, results with BV appeared inerior
randomized trials showed some benet in survival compared with results ater the combination o this
with BEACOPP, longer ollow-up periods are essential drug with either nivolumab or DTIC. The combina-
to conrm the conclusion because toxicities, includ- tion o brentuximab with bendamustine was consid-
ing secondary malignancies, are issues or long-term ered more toxic than the other combinations. Another
small phase II trial has shown early promising activity burden (assessed by CT) were predictive o inerior
o the anti-PD1 antibody, nivolumab, as an alternative outcomes.89 With PET imaging, the total metabolic
to bleomycin in combination with AVD, and results o tumor volume (TMTV) measures both tumor size and
the randomized phase III SWOG S1826 trial compar- activity o the tumor and the microenvironment. A pro-
ing N-AVD and A-AVD are awaited.82 spective analysis o 294 patients with early-stage cHL
rom the H10 trial ound high initial TMTV (>147 cm3)
to be highly prognostic or inerior PFS (5-year rates o
Predictors of Outcomes for Advanced- 71% and 92%, respectively; P <.0001) and OS (83%
Stage Classical Hodgkin Lymphoma and 98%, respectively; P = .0001).90 However, TMTV
The Value o Positron Emission Tomography in was not predictive o PFS or OS results or advanced
Hodgkin Lymphoma HL in the PET-adapted HD18 trial cohort, possibly
because o a low number o progression events with
Staging by PET scan is proven as a standard o care, but eBEACOPP.91
PET is also a valuable tool or evaluation o response Investigators have reported that circulating tumor
and prediction o outcomes in patients with HL. In one DNA (ctDNA) can predict outcomes o therapy or
study, an interim PET scan obtained ater two cycles o cHL. A study o 112 patients with newly diagnosed
therapy (PET-2) was a stronger prediction o outcome and reractory cHL identied nonsynonymous somatic
than the IPS, with 2-year PFS results or patients with mutations in ctDNA samples, evaluating previously
positive PET-2 results o 13% compared with 95% or described TNFAIP3, ITPKB, GNA13, and B2M genes.
CHAPTEr 13
those with negative PET-2 results.83 The PET-2 also STAT6 was the most requently mutated gene in
strongly predicts treatment ailure.84 In a meta-anal- 40% o cases.92 Genotyping o the tumor rom HRS
ysis, a positive PET-2 result in low-intermediate–risk cell–enriched samples identied 96 somatic muta-
advanced HL patients was a reliable predictor o poor tions compared with no mutations rom the tumor
response.85 Interim PET scans are now routinely incor- sample rom areas devoid o HRS cells. Genotyping
porated into clinical trial designs, can stratiy high and o plasma ctDNA identied 106 somatic mutations
low risk patients, and guide treatment escalation or with a sensitivity o 87.5%, with the additional muta-
deescalation strategies. However, the role o interim tions in the plasma ctDNA thought to be caused by
PET imaging ater two cycles o either ABVD or esca- subclonal or anatomic heterogeneity o the tumor. A
lated BEACOPP remains controversial in practice or 2-log-old drop o ctDNA was associated with superior
the individual patient despite integration in numerous PFS despite interim PET positivity likely because o the
upront studies in advanced cHL. Historical studies notion that FDG avidity refects the metabolic activity
that demonstrated that positive PET imaging ollow- o the infammatory component o the mass, whereas
ing two cycles o ABVD were associated with poor ctDNA more accurately refects tumor burden. Fur-
outcomes were inherently fawed because treatment ther studies incorporating ctDNA monitoring and PET
ailure was determined by imaging with histologic imaging are needed to establish the role o ctDNA in
conrmation o relapse rarely perormed.86–88 Given a predicting clinical outcomes.
historically high alse-positive rate or FDG-PET imag-
ing in patients with cHL, this may have overestimated The MD Anderson Approach to Management o
the positive predictive value o PET-2 imaging ater
Advanced-Stage Classical Hodgkin Lymphoma
ABVD therapy. In addition, there are no large studies
documenting concordance o PET positivity and his- We screen patients or available protocols or initial
tologic ndings or cHL. Given the disease biology o treatment o advanced-stage disease. As a standard o
cHL, comprising a minority o Reed-Sternberg cells care, we treat these patients a PET-2–adapted approach.
surrounded by an infammatory inltrate, a alse-pos- For patients with high-risk disease (IPS ≥4), we use six
itive PET-2 result may be possible. Thereore, other cycles o A + AVD with interim response assessment
markers are needed as alternative methods to identiy using PET-2 imaging. I the PET-2 is interpreted as DS
poor responders with truly chemoreractory disease.88 4 or less, we recommend completing six cycles in total
o A + AVD. I the disease is PET-2–positive (DS 5),
Other Predictors o Response and Outcomes or we transition to non–BEACOPP-based salvage therapy
such as ICE or clinical trials using anti-PD1 agents ol-
Classical Hodgkin Lymphoma
lowed by ASCT. In patients with non-high-risk disease
Investigators have demonstrated that tumor burden, as (IPS <4) or with contraindications to BV such as preex-
assessed with biochemical markers or by CT imaging, isting neuropathy or liver disease, we use a RATHL-
is prognostic or outcomes. A retrospective analysis style approach with two cycles o ABVD ollowed by
o patients with early-stage cHL rom the HD10 and interim PET-2 imaging. I PET-2 negative in this situa-
HD11 trials showed that elevated ESR and large tumor tion (DS ≤3), we delete bleomycin and complete our
additional cycles o AVD. I PET-2–positive (DS 4 or 5), TABLE 13-11 Salvage Chemotheapy regimens
we transition to non–BEACOPP-based salvage therapy o Hodgkin Lymphoma
ollowed by ASCT i the patient is transplant eligible.
We reserve IFRT or patients who have presented Regimen ORR (%) CR (%)
with an initial bulky mass with residual bulk at the DHAP 88 21
end o therapy. Based on phase II data, we avor the ASHAP 70 34
ollowing regimens in specic patient cohorts. Older
ESHAP 73 41
patients (older than 65 years) receive two lead-in doses
o single-agent BV (1.8 mg/kg once every 3 weeks), MINE 73 34
then six cycles o AVD, then our consolidative doses ICE 85 26
o single-agent BV in responding patients.93 HIV-posi- IGEV 81 54
tive patients receive six cycles o A + AVD with careul GND 70 19
medication review to avoid interactions with strong
GDP 62 10
CYP3A4 inhibitors to minimize toxicity.94
Nivolumab (+/ ICE i 94 91
not in CR)90
rEFrACTOrY Or rELAPSED ASHAP, doxorubicin, methylprednisolone, cytarabine, cisplatin; CR, complete
response; DHAP, dexamethasone, cytarabine, cisplatin; ESHAP, etoposide,
HODGKIN LYMPHOMA methylprednisolone, cytarabine, cisplatin; GDP, gemcitabine, dexamethasone,
cisplatin; GND, gemcitabine, vinorelbine, pegylated liposomal doxorubicin; ICE,
CHAPTEr 13
iosamide, carboplatin, etoposide; IGEV, iosamide, gemcitabine, vinorelbine;

Although many patients with HL are cured with MINE, mitoguazone, iosamide, vinorelbine, etoposide; ORR, overall response
rate.
rontline therapy, 10% to 15% o patients with early-
stage disease with unavorable risk actors and 40%
o patients with advanced-stage disease with high-
risk actors can develop relapse or reractory disease. beore ASCT had an EFS o greater than 80%.96 The
Relapsed HL can be divided into three subgroups: early DHAP regimen provided similar results, with ORR o
relapse within 12 months o CR ater rst-line chemo- 89% and CR rate o 21%.97 Gemcitabine-containing
therapy, late relapse ater CR more than 12 months regimens are also eective in therapy o patients with
ater rst-line chemotherapy, and primary reractory relapsed or reractory cHL. A phase II study o single-
HL (patients who never achieve a CR). Moskowitz and agent gemcitabine, 200 mg/m2 given on days 1, 8, and
colleagues95 identied the ollowing three prognostic 15 o a 28-day schedule, produced an ORR o 43%
actors associated with EFS in patients receiving ICE with a CR rate o 14%.98 The GVD regimen (gem-
ollowed by HDCT and ASCT: CR less than 1 year, citabine, vinorelbine, and pegylated liposomal doxoru-
extranodal disease, and presence o B symptoms. The bicin) was evaluated by the CALGB in 91 patients with
5-year EFS rate was 83% in patients with zero to one relapsed or reractory HL. The ORR was 70%, with
actor compared with 10% i all three actors were a CR rate o 19%.99 The 4-year PFS and OS rates or
present.95 transplant-naïve patients treated with GVD ollowed
by ASCT were 52% and 70%, respectively. In patients
in whom prior transplant had ailed, the 4-year DFS
Standard Therapy for Relapsed or and OS rates were 10% and 34%, respectively. The
Refractory Classical Hodgkin Lymphoma GDP regimen produced similar results, with an ORR o
For patients with relapsed or reractory disease ater 62% and a CR rate o 10%.100 A combination regimen
standard rontline management, additional salvage named IGEV (iosamide, gemcitabine, vinorelbine)
chemotherapy ollowed by HDCT plus ASCT is the was evaluated in 91 patients and produced an ORR o
standard approach. One o the key goals o salvage 81% with a high CR rate o 54%; 60% o patients with
chemotherapy is to achieve CR beore ASCT. The primary reractory disease responded to IGEV.101
response rates o multiple salvage regimens are listed
in Table 13–11. It is dicult to directly compare these High-Dose Chemotherapy with
regimens because they have not been evaluated in ran-
Autologous Stem Cell Transplantation for
domized clinical trials.
Although all patients at relapse should undergo
Relapsed Hodgkin Lymphoma
screening or protocol therapy, the most common For patients with chemotherapy-sensitive disease, the
salvage chemotherapies outside clinical trials are the treatment o choice ater relapse is HDCT ollowed
platinum-containing regimens such as ICE or DHAP by ASCT. This recommendation is based on reports
(cisplatin, cytarabine, dexamethasone). With ICE, the rom two historically important, randomized clinical
ORR was 88%, and the CR rate was 26%.95 Using vari- trials.102,103 In the BNLI study, patients with relapsed or
ations o this this regimen, patients with PET negativity reractory HL received BEAM (carmustine, etoposide,
Table 13-12 Initial Management o the Patient with HL Establishing the Diagnosis
Diagnosis Workup
- FNA alone is insufcient - History and physical examination, including:
- Hematopathology review o all slides with at least one tumor o B symptoms (ever, sweats, weight loss)
parafn block; rebiopsy i consult material is nondiagnostic o ETOH intolerance
- Coreneedle biopsy may be adequate i diagnostic, but an o Pruritus
excisional or nodal biopsy is recommended o Fatigue
- Recommend staining or CD15, CD30, T and B panels, CD20, o Perormance status
PAX5 o Examination o nodes
- Adequate immunophenotype to conrm diagnosis o Spleen, liver
o Parafn panel or HL including NLPHL: - CBC, dierential, platelets
o CD20, PAX5, CD30, CD3, CD15 and CD45 (LCA) - LDH; LFTs, including alkaline phosphatase, AST, ALT,
o EBER and albumin, BUN, creatinine
- EBV proteins (ie, LMP1) recommended or NS grade 2 or - ESR
anaplastic variants - Screening or HIV1, HIV2, hepatitis B and C (HBcAb,
O use in certain circumstances: HBsAg, HCVAb)
- Immunohistochemical studies: - Chest radiography
o LMP1 - CT o the neck, chest, abdomen, and pelvis
o BOB1, OCT2, and CD79a (dierential diagnosis with Bcell - PETCT
CHAPTEr 13
lymphoma, unclassiable with eatures intermediate between - MUGA or ECG
classical HL and DLBCL and primary mediastinal large Bcell - Counseling: ertility, psychosocial i clinically indicated
lymphoma). Useul in selected cases:
o CD21, CD23, or CD35 (ollicular dendritic cell markers), - Pregnancy test: women o childbearing potential
CD57, BCL6, and IgD in cases o NLPHL (may help with Tcell/ - Discuss ertility issues and sperm banking or patients
histiocyterich large Bcell lymphoma) o childbearing potential
o CD2, CD43, ALK, and EMA (dierential diagnosis with - Semen cryopreservation i chemotherapy or pelvic RT
anaplastic largecell lymphoma) is contemplated
Strongly recommend:
- Core biopsy or tissue banking by protocol
ALK, anaplastic lymphoma kinase; ALT, alanine aminotranserase; AST, aspartate aminotranserase; BUN, blood urea nitrogen; CBC, complete blood count; CT, computed
tomography; DLBCL, diuse large Bcell lymphoma; EBER, EpsteinBarr virusencoded small RNA; ECG, echocardiography; EBV, EpsteinBarr virus; EMA, epithelial
membrane antigen; ESR, erythrocyte sedimentation rate; ETOH, alcohol; HBcAb, hepatitis B core antibody; HBsAg, hepatitis B surace antigen; HCVAb, hepatitis C virus
antibody; HIV, human immunodeciency syndrome; HL, Hodgkin lymphoma; LDH, lactated dehydrogenase; LFT, liver unction test; MUGA, multigated acquisition;
NLPHL, nodular lymphocyte–predominant Hodgkin lymphoma; NS, nodular sclerosis; PET, positron emission tomography; RT, radiation therapy.
cytarabine, and melphalan) at high doses ollowed by scan results have signicantly higher EFS and ailure-
an ASCT or at lower doses (mini-BEAM) without an ree survival rates compared to patients with positive
ASCT. The 3-year reedom rom second treatment ail- pre-ASCT PET scan results.105–107 In another trial, a
ure was signicantly better or patients who received European intergroup study evaluated a dose-intensi-
HDCT (53% and 10%, respectively). The GHSG/ ed regimen beore ASCT.108 Patients were randomly
European Group or Blood and Marrow Transplanta- assigned ater two cycles o DHAP to ASCT or sequen-
tion (EBMT) randomized trial compared our cycles o tial cyclophosphamide, methotrexate, and etoposide
Dexa-BEAM (dexamethasone plus BEAM) versus two beore ASCT. There were no signicant dierences
cycles o Dexa-BEAM ollowed by ASCT or patients between the two treatment arms in terms o mortality,
with relapsed cHL. At 3 years, the FFTF in the high- FFTF, and OS. Thus, the less toxic approach consist-
dose therapy group was 55% compared with 34% ing o two cycles o DHAP (or other salvage regimen
ater our cycles o chemotherapy. These studies were such as ICE) ollowed by HDCT and ASCT remained
perormed beore development o the PET and anti- the standard o care or patients with relapsed HL.
CD30 therapy. Achievement o PET negativity is also an established
Multiple investigators have reported that response goal or these patients beore ASCT, but the role o
to salvage chemotherapy is a strong predictor o long- anti-CD30 antibody therapy remained unclear beore
term outcome ater ASCT. In one study, the 5-year OS the development o BV.
or patients who were in CR at the time o ASCT was Patients with disease progression ater ASCT uni-
79% compared with 59% or those in PR and 17% or ormly have a poor outcome. In a study o patients
those with resistant disease at the time o ASCT.104 with HL who ailed ASCT, the median time to pro-
Studies have shown the impact o pre-ASCT PET scan gression ater the next therapy was only 3.8 months,
results on EFS; those with negative pre-ASCT PET and the median survival ater ASCT ailure was 26
months.9 An international multicenter retrospec- remission or stable disease ater salvage therapy. This
tive study showed that the survival o patients who suggests that BV can achieve CR by PET in a consid-
relapsed ater an ASCT did not improve rom 1981 to erable subset o patients with platinum-reractory HL
2007.109,110 However, there has been a major advance beore ASCT.
in the treatment o relapsed or reractory cHL in the Maintenance therapy with BV ater ASCT was
past 10 years: development o novel agents or the evaluated in a placebo-controlled randomized phase
disease. III study (AETHERA).115,116 Patients were enrolled in
this study i they had (1) disease considered reractory
to rontline therapy, (2) relapse less than 12 months
Immunotherapeutic Agents for Relapsed ater rontline therapy, or (3) relapse 12 months or
or Refractory Classical Hodgkin more ater rontline therapy with extranodal disease.
Lymphoma At 5 years o ollow-up, PFS rates were superior in the
Brentuximab Vedotin BV compared with placebo cohorts (59% and 41%,
respectively) with 90% o patients who received BV
CD30 was considered an ideal target or monoclo- reporting signicant improvement or resolution o
nal antibody therapy or HL because its expression is associated peripheral neuropathy.117 Patients with
highly restricted to HRS cells. BV (SGN-35) is an intra- high-risk disease, dened as the presence o two or
venously administered antibody–drug conjugate that more risk actors (relapse <12 months or reractory to
consists o the CD30-specic monoclonal antibody rontline therapy, best response o PR or stable disease
CHAPTEr 13
conjugated with monomethyl auristatin E (MMAE) by to most recent salvage therapy, extranodal disease at
linker peptide. Binding o the antibody–drug conjugate pretransplant relapse, B symptoms at pretransplant
to CD30 on the cell surace causes internalization o relapse, two or more prior salvage therapies) demon-
the drug by endocytosis, and the drug subsequently strated more pronounced benet (5-year PFS HR, 0.42)
travels to the lysosome, where proteases cleave the with BV maintenance therapy. Thereore, BV con-
linker and release MMAE to the cytosol.111 Released solidation should be oered to high-risk patients who
MMAE binds to tubulin and disrupts the microtubule develop relapse ater rst-line chemotherapy.
polymerization, resulting in cell cycle arrest and apop- In an attempt to improve responses beore ASCT,
totic death o CD30-expressing cells. Ater reports o investigators perormed a phase II study o BV in com-
ecacy in a phase I trial in 45 patients with relapsed or bination with ICE chemotherapy as salvage therapy
reractory CD30-positive hematologic malignancies, beore ASCT. Patients received two cycles o BV-ICE
investigators conducted a pivotal phase II trial o 102 beore evaluation, and patients in CMR received an
patients with HL with relapse using this drug alone ol- additional dose o BV only rather than a third cycle
lowing HDCT and ASCT.112,113 Patients received BV 1.8 o BV-ICE. O the 39 patients in the ecacy analysis,
mg/kg every 3 weeks up to a maximum o 16 cycles. 69% achieved a CMR, and 26% achieved a partial (P)
The ORR was 75%, with a CR rate o 34%. These data MR, with a 1-year PFS o 69% post ASCT.118 In another
led to the rst drug approval by the US Food and Drug phase II study o 66 patients who received BV in com-
Administration (FDA) or the treatment o patients bination with ESHAP chemotherapy beore ASCT,
with HL in more than 30 years. Durable remission the pretransplant CMR was 80%, with a PMR o
was reported with a longer ollow-up period, and the 7%, and a projected 1-year PFS o 87% ater ASCT.119
median OS and PFS were 40.5 months and 9.3 months, BV was also studied in a phase II trial that combined
respectively.114 The 3-year PFS rate o patients who this drug with bendamustine beore ASCT; the pre-
achieved CR with BV was 58%. This survival outcome transplant CMR and PMR rates were 79% and 5%,
is notable considering that the patients enrolled in this respectively, with projected 3-year PFS and OS rates
trial had disease progression ater ASCT. o 67% and 88%, respectively.120 No signicant excess
Achieving CR beore ASCT is the key to better in toxicity was reported in the trials evaluating BV in
outcomes in patients with relapsed or reractory HL. combination with chemotherapy beore ASCT; how-
Thereore, BV is oten used as a third-line therapy ever, a longer ollow-up period is required to evaluate
in patients who have not achieved CR ater second- whether improved pretransplant responses translate to
line salvage chemotherapy such as ICE. The Seattle improved survival outcomes.
group retrospectively evaluated the ecacy o BV in Bendamustine is a biunctional alkylating agent
patients who had disease reractory to platinum-based derived rom 2-chloroethylamine that had been a
salvage chemotherapy.6 Fiteen patients who had PET- standard chemotherapy or patients with indolent
positive disease ater platinum-based salvage therapy lymphoma (ollicular lymphoma and mantle cell lym-
received a median o our cycles o BV. PET scan nega- phoma).121,122 The Memorial Sloan-Kettering Cancer
tivity occurred in eight (53%) o 15 patients but was Center conducted a phase II trial o bendamustine in
only observed in patients who had achieved partial patients with HL who had relapse ater ASCT or were
not eligible or ASCT.123 Patients received bendamus- strategies may be eective or chemotherapy-rerac-
tine 120 mg/m2 on days 1 and 2 o a 28-day cycle or tory disease. However, the durability o response ater
six planned cycles. The ORR was 53%, with a 33% CR ASCT is still to be determined, with reported 1-year
rate; the median PFS was 5.2 months. Preliminary data PFS and OS rates o 79% and 97%, respectively.
o a phase I/II study or the combination o bendamus- Nivolumab has also been evaluated in combina-
tine and BV or relapsed or reractory transplant-naïve tion with other novel agents. In a phase I/II study,
patients produced an ORR o 94%, with a CR rate o nivolumab in combination with BV was evaluated as
82%.124 At the time o report, 20 o 34 patients who initial salvage therapy or 62 patients with relapsed or
had a response to this combination had undergone reractory HL, resulting in an ORR o 82% with a CR
ASCT. rate o 61%.128 Grade 3 or higher AEs occurred in 31%
BV also appears eective in therapy o patients with o patients with no patients discontinuing therapy
relapse ater allogeneic stem cell transplantation (allo- because o immune-related AEs. In a separate phase II
SCT). In one retrospective analysis o 184 patients with study, a risk-adapted approach was applied in patients
relapsed cHL ater allo-SCT, 88 had received BV salvage ages 5 to 30 years with relapsed or reractory HL. Four
therapy, and 104 did not. O the patients who received cycles o nivolumab in combination with BV were
BV, 29% achieved a CR and 45% PR with signicantly administered, and patients achieving less than CMR
more patients alive at last ollow-up compared with ater induction received additional cycles o BV plus
patients who did not (34% and 18%, respectively; bendamustine or intensication. O the 44 patients
P = .003).125 However, salvage BV did not aect the who have been treated, only 11 (25%) received BV
CHAPTEr 13
incidence o chronic grat-versus-host disease, and plus bendamustine intensication. The ORR, CR rate,
1-year OS rates post recurrence ater allo-SCT were and 1-year PFS rate were 82%, 59%, and 91%, respec-
similar (76% and 67%, respectively). tively.129 Nivolumab has also been investigated as part
o a triplet combination with ipilimumab and BV in a
Programmed Death-1 Inhibitors phase I study o 64 patients with relapsed or rerac-
tory HL. Across all dose levels, the triplet combina-
PD-1 ligand is overexpressed on malignant Reed-Stern- tion demonstrated impressive outcomes with an ORR
berg cells in HL, acilitating immune evasion rom anti- o 95%, CR rate o 84%, and 1-year PFS o 72%.130
tumor cells. Nivolumab is a PD-1 immune checkpoint This study also compared doublet combinations o
inhibitor antibody that selectively blocks the interac- nivolumab plus BV and BV plus ipilimumab in separate
tion between PD-1 and its ligands PD-L1 and PD-L2. arms; nivolumab-containing cohorts appeared to have
By inhibiting PD-1 interaction, nivolumab can enhance superior outcomes.
T-cell unction, which results in antitumor activity. Another PD-1 inhibitor, pembrolizumab, has also
Nivolumab has been evaluated in a multicenter phase received FDA approval or the treatment o patients
II trial or patients with relapsed or reractory cHL with relapsed or reractory HL based on pivotal
with or without prior exposure to BV or prior ASCT. single-agent phase II data. A total o 210 patients
O 243 treated patients, the ORR was 69% with a with relapsed or reractory HL were enrolled in three
median PFS o 14.7 months.126 Based on promising sin- separate cohorts to receive pembrolizumab 200 mg
gle-agent activity, nivolumab has gained FDA approval once every 3 weeks based on prior exposure to BV or
or relapsed or reractory HL ater ASCT. ASCT. Across all cohorts, the ORR was 72%, the CR
PD-1 inhibition with nivolumab has been explored rate was 28%, and the median duration o response
in a phase II study as salvage therapy at rst relapse 16.5 months.131 Pembrolizumab was well tolerated
in relapsed or reractory cHL.127 Thirty-nine patients with grade 3 or 4 AEs occurring in 12% o patients.
with relapsed or reractory cHL received 3 mg/kg o Avelumab, a human IgG-1 monoclonal antibody that
nivolumab every 2 weeks or six cycles ollowed by selectively binds to PD-L1 has been evaluated in a
interim PET imaging. I patients were in CR, they pro- phase 1 study o 31 patients with relapsed or rerac-
ceeded to ASCT, whereas seven patients with PR or tory HL and has promising activity with an ORR o
stable disease proceeded to receive nivolumab in com- 55% and CR rate o 6% across all dose levels.132
bination with ICE chemotherapy or two cycles. Ater
six cycles o nivolumab, the ORR was 90%, and CR was
Allogeneic Stem-Cell Transplantation
77%; i the patients who were treated with nivolumab
and ICE were included, the ORR was 94%, and CR was The main advantage o an allo-SCT is its grat-ver-
91%. PD-1 inhibition was well tolerated, with mainly sus-HL eect. Retrospective studies have suggested
grade 1 to 2 AEs (atigue, rash, ever, and thrombocy- this eect because o lower relapse rates in allo-SCT
topenia). The impressive response rates to PD-1 inhibi- patients with chronic grat-versus-host disease (GVHD)
tion at rst relapse compared with historical data with and responses ater donor lymphocyte inusion.133 Ini-
salvage chemotherapy indicate that alternative salvage tial studies o allo-SCT in HL patients described high
rates o nonrelapse mortality (NRM), up to 61%. durable remissions are observed ollowing this promis-
More recent studies evaluated therapy with reduced- ing approach.
intensity conditioning (RIC), treatment associated
decreased treatment-related mortality (TRM); in these Bispecifc Antibodies and Antibody–Drug
studies, RIC allo-SCT induced long-term remissions in Conjugates
about 30% o patients.134,135
The EBMT reviewed 168 patients who had under- Bispecic antibodies are immunoglobulin molecules
gone allo-SCT.135 Seventy-nine patients received mye- containing two dierent antigen binding sites, one
loablative conditioning, and 89 patients received RIC. directed against specic tumor antigens and the other
Fity-two percent o patients had undergone a prior toward native immune eector cells. A phase Ib study
ASCT, and 45% had chemotherapy-sensitive disease. o a CD30 bispecic antibody targeting CD16A on nat-
The NRM was signicantly lower, and OS was sig- ural killer cells in combination with pembrolizumab
nicantly better with RIC versus myeloablative condi- demonstrated promising clinical activity in patients
tioning. One-year NRM was 23%, and 5-year PFS and with relapsed or reractory HL. O 30 patients, the
OS were 18% and 28%, respectively, in patients who ORR and CR rates were 88% and 46%, respectively,
received RIC. with an estimated 6-month PFS rate o 77% at the
At MDACC, we reviewed the outcomes o 58 highest dose level.140 The treatment was well tolerated,
patients who received RIC with fudarabine–melpha- with grade 3 or higher toxicity occurring in only 13%
lan in preparation or allo-SCT.136 Overall, 83% o o patients. A separate phase 1 study investigated an
CHAPTEr 13
patients had undergone a prior ASCT and 52% had anti-CD25 antibody conjugated to a pyrrolobenzodi-
chemotherapy-sensitive disease at the time o allo- azepine dimer toxin was investigated in a phase 1 trial
SCT. The TRM at 2 years was 15%, with nearly hal in adult patients with relapsed or reractory HL. O the
o the TRM occurring within the rst 100 days ater 37 patients treated at the highest dose cohort, the ORR
allo-SCT. The incidence o chronic GVHD was 73%. was 86% and CR rate o 43% in a heavily pretreated
The 2-year PFS and OS rates were 32% and 64%, population without excess toxicity.141 However, dura-
respectively. There was a trend toward improvement bility o responses have not been reported because
in PFS or those with chemotherapy-sensitive disease o limited ollow-up. Thereore, despite promising
but not or OS. Allo-SCT is still an important option activity with bispecic antibodies and antibody–drug
or eligible patients who develop relapse ater ASCT. conjugates, longer ollow-up is needed to determine
durability o responses.
Chimeric Antigen Receptor T-Cell Therapy
The MD Anderson Approach to Relapsed or
Anti-CD30 chimeric antigen receptor (CAR) T-cell
therapy attempts to overcome the limited bioavail- Reractory Classical Hodgkin Lymphoma
ability and short hal-lives o anti-CD30 monoclonal Patients with relapsed or reractory HL are planned
antibodies such as BV. A phase I study evaluated an or second-line or salvage chemotherapy ollowed by
anti-CD30 CAR T product with dual CD28 and 4-1BB an ASCT. We screen patients who have relapsed or
co-stimulatory domains in nine patients with relapsed reractory HL or current clinical trial options. Patients
or reractory CD30-positive lymphomas. O the nine who respond to salvage chemotherapy are planned
patients, six (67%) had HL with a CR rate o 78% and to undergo ASCT. We oer BV maintenance therapy
a median PFS o 13 months among all patients.137 In ater ASCT or patients deemed high risk based on
a separate phase 1 study o 14 patients with relapsed (1) relapsed or progressive HL occurring less than 12
or reractory HL who received an anti-CD30 CAR T months rom end o rontline therapy; (2) a history o
product, the ORR was 67%, and the CR rate was 58% reractory HL, dened as progression during or ailure
or the evaluable patients.138 In an update, incorporat- to achieve CR ater rontline therapy; or (3) extrano-
ing two dierent phase I/II studies, these latter inves- dal involvement at the time o pre-ASCT relapse. For
tigators evaluated results or 41 patients with relapsed patients who ail to achieve a CMR beore ASCT, we
or reractory cHL who received anti-CD30 CAR-Ts.139 use either BV in combination with salvage chemother-
The median number o prior therapies was seven apy (ICE or bendamustine) or a PD-1 inhibitor (pem-
(range, 2–23), and 32 o these patients received fuda- brolizumab or nivolumab single agent, or nivolumab in
rabine-based T-cell depletion. O these 31, 72% had a combination with BV) to deepen the response beore
response, and 59% had CR. The 1-year PFS was 36%, ASCT. In patients who have reractory disease or
and the OS was 94%. CAR T–related cytokine release relapse ater ASCT, we consider BV (i not previously
syndrome in this study occurred in 10 patients and was reractory to BV) as single agent or in combination
grade 1; signicant neurotoxicity did not occur. A lon- with bendamustine or nivolumab. In BV-reractory
ger ollow-up period is required to establish whether patients, we consider nivolumab or pembrolizumab
as single-agent therapy. Given the benets versus risks achievements have occurred on both ronts, including
o allo-SCT, a subset o patients can be potentially a decrease o both the number o cycles o chemo-
considered or this approach, particularly otherwise therapy and the doses o RT or patients with early-
healthy patients who achieve complete remission with stage disease and introduction o BV into rontline
addition therapies. regimens paired with chemotherapy. The advent o
PD-1 inhibitors has demonstrated the ability to have
signicant ecacy even in patients with BV-resistant
CONCLUSION disease. Future directions are anticipated to increase
the ocus on evaluating the ecacy o combinations
Although standard rontline chemotherapy with or o targeted agents, with likely uture trials exploring
without RT oers a high cure rate or patients with the potential activity o chemotherapy-ree targeted
cHL, approximately 20% o patients develop rerac- treatment combinations in the rontline setting. Better
tory or relapsed disease. Thus, the challenge that understanding o the molecular biology o both cHL
remains is how to best develop strategies o therapy and NLPHL will also lead to more rationally designed
that increase the cure rates or the reractory and novel agent trials and allow us to best select treatment
relapsed group o patients while decreasing both strategies. The uture o HL treatment has evolved sig-
short- and long-term toxicities, including secondary nicantly over the past decade, and these successes
malignancies, or patients who are cured o their dis- will only be signicantly multiplied over the next
ease with current standard approaches. Huge recent decade to ollow.
CHAPTEr 13
J For avorable earlystage classical HL, omitting radi J The A (BV)AVD regimen is recommended or clas
ation consolidation ater two cycles o ABVD based sical HL patients who are young (younger than
on PET negativity is associated with a risk o treat 60 years), with stage IV disease, and with high IPS
ment ailure based on the GHSG HD16 study. (score 4–7) because patients with these eatures
J For unavorable earlystage classical HL, omit beneted the most in the ECHELON1 trial by the
ting RT based on a PETadapted strategy provides substitution o BV or bleomycin in ABVD.
results that are noninerior to those achieved with J The AAVD regimen is associated with a high risk o
chemotherapy plus RT based on the GHSG HD17 neutropenia, and growth actor support is required
trial. However, therapy must be escalated BEACOPP to minimize the risk o neutropenic ever.
× 2, ollowed by ABVD × 2. J Beore beginning salvage chemotherapy and ASCT
J In advancedstage classical HL, i treating with ABVD, based on PET positivity, one must conrm histo
interim PET scan should be perormed ater two pathologic relapsed or reractory classical HL.
cycles, and bleomycin may be saely omitted with a
negative PET scan result based on the RATHL study.
19. Mauch P, Tarbell N, Weinstein H, et al. Stage IA and IIA

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phoma (CHL). Hematol Oncol. 2017;35(suppl 2):67. 138. Ramos CA, Torrano V, Bilgi M, et al. CD30-chimeric antigen
133. Peggs KS, Hunter A, Chopra R, et al. Clinical evidence o a grat- receptor (CAR) T cells or therapy o Hodgkin lymphoma (HL).
versus-Hodgkin’s lymphoma eect ater reduced-intensity Hematol Oncol. 2019;37(suppl 2):168.
allogeneic transplantation. Lancet. 2005;365(9475):1934-1941. 139. Ramos C, Grover N, Beaver A, et al. Anti-CD30 CAR-T cell
134. Devetten MP, Hari PN, Carreras J, et al. Unrelated donor therapy in relapsed and reractory Hodgkin lymphoma. J Clin
reduced-intensity allogeneic hematopoietic stem cell trans- Oncol. 2020;38(32):3794-3804.
plantation or relapsed and reractory Hodgkin lymphoma. Biol 140. Ansell SM, Bartlett NL, Chen RW, et al. Investigating saety
Blood Marrow Transplant. 2009;15(1):109-117. and preliminary ecacy o AFM13 plus pembrolizumab in
135. Sureda A, Robinson S, Canals C, et al. Reduced-intensity con- patients with relapsed/reractory Hodgkin lymphoma ater
ditioning compared with conventional allogeneic stem-cell brentuximab vedotin ailure. Hematol Oncol. 2019;37(suppl 2):
transplantation in relapsed or reractory Hodgkin’s lymphoma: 177-178.
an analysis rom the Lymphoma Working Party o the Euro- 141. Collins G, Horwitz S, Hamadani M, et al. Analysis o clinical
pean Group or Blood and Marrow Transplantation. J Clin determinants driving saety and ecacy o camidanlumab
Oncol. 2008;26(3):455-462. tesirine (ADCT-301, CAMI) in relapsed/reractory (R/R classical
136. Anderlini P, Saliba R, Acholonu S, et al. Fludarabine-melphalan Hodgkin lymphoma [CHL]). Hematol Oncol. 2019;37(suppl 2):
as a preparative regimen or reduced-intensity conditioning 95-97.
CHAPTEr 13
14 Systemic Immunoglobulin Light
Chain Amyloidosis
Gregory P. Kauman
Muzafar H. Qazilbash
Krina Patel
Sheeba Thomas
Robert Z. Orlowski
Hans C. Lee
KEY CONCEPTS
 Systemic light chain (AL) amyloidosis is a rare protein  Historical cohorts o patients with severe cardiac involve-
deposition disease typically ound accompanied by an ment have a poor prognosis o 4 to 6 months, though
indolent plasma cell dyscrasia, although it can also be recent studies show this can be greatly improved with
ound concomitantly with multiple myeloma. successul treatment.
 In the systemic presentation (some cases are localized),  Plasma cell–directed therapy with or without high-
commonly aected organs may include the heart, kidneys, dose melphalan and autologous stem cell rescue is
liver, gastrointestinal tract, and peripheral nervous system. the treatment o choice or patients with confrmed
 Diagnosis requires histologic evidence o amyloid depo- systemic AL.
sition in tissues either by aspiration o abdominal sub-  Multidisciplinary care is benefcial because these
cutaneous at or biopsy o the organs involved, with the patients have distinct clinical presentations, symptoms,
demonstration o clonal plasma cell disorder and abnor- and risks compared with patients with other plasma cell
mal ree light chain in serum or urine. dyscrasias.
Systemic light chain (AL) amyloidosis is a rare plasma primarily by the extent and severity o cardiac involve-
cell prolierative disorder. It results rom organ deposi- ment with patients having severe cardiac involvement
tion o amyloid brils that consist o the NH2-terminal being at high risk or early death, although this risk
amino acid residues o the variable portion o the light is somewhat abrogated with successul plasma cell–
chain immunoglobulin molecule. The estimated age- directed treatment. However, beyond overall survival
adjusted incidence is nine to 14 cases per million per- (OS), patients with AL oten have chronic symptoms
son-years, and around 4000 new cases are estimated relating to the morbidity o amyloid organ involvement
annually in the United States. About 75% o cases are and decreased quality o lie. The exact pathophysiol-
derived rom lambda light chain. AL amyloidosis typi- ogy o organ or tissue damage in AL amyloidosis is
cally results primarily rom a small plasma cell clone not completely understood, but the reduction o serum
in the bone marrow or may rarely be associated with ree light chain concentration ater chemotherapy
another B-cell malignancy. Coexisting AL amyloid treatment results in improved cardiac unction and
deposits are identied in 10% to 15% o patients with suggests that both circulating amyloidogenic ree light
multiple myeloma (MM). chains in addition to those deposited play an impor-
The commonly aected organs include the heart, tant role in organ dysunction. New therapies targeting
kidneys, liver, gastrointestinal tract, and peripheral the underlying plasma cell clone are improving hema-
nervous system. This leads to clinical symptomatology tologic response rates and potentially patient survival
o nephrotic syndrome, cardiomyopathy, hepatomeg- with the disease, and therapies that directly target
aly, neuropathy, macroglossia, anemia, carpal tunnel the already deposited light chain amyloid continue in
syndrome, and periorbital purpura. Prognosis is driven development at this time.
323
324 Scion II Lymphoma and Myeloma
EPIDEMIOLOGY AND RISK FACTORS light chains are thought to also play a signicant role
in mediating organ dysunction, particularly cardiac
Light chain amyloidosis is typically ound with an dysunction in AL. This is evidenced by studies in
underlying low-grade or indolent plasma cell popula- model organisms demonstrating worsened cardiac
tion in the bone marrow, though is also ound con- dysunction ater inusion o amyloid light chains,
comitantly with MM and less commonly with other though not normal control light chains in the absence
hematolymphoid neoplasms. Estimates o the inci- o amyloid bril deposition, and clinical evidence
dence and prevalence o AL have been drawn rom showing early concordance in improvement in car-
population-based studies in the United States and diac unction with reduction o circulating involved
European countries ranging rom three to 14 cases per amyloid light chains.12–14
million-person years.1–4 There are an estimated 12,000 In comparison with MM, plasma cells o AL amy-
people living in the United States with AL. loidosis are generally o lower clonal burden and have
Less is known about specic risk actors or devel- lower rates o prolieration.15 The amyloid clone is
oping AL amyloidosis. Studies have identied male oten enriched or the t11;14 structural abnormality
gender and age as risk actors, though these are also risk detected by fuorescence in situ hybridization, ound
actors or the development o plasma cell neoplasms in up to 50% o patients with AL,16 and genome-
and monoclonal gammopathy o undetermined signi- wide association studies show cyclin D1 playing a
cance (MGUS) as well.5,6 prominent role in AL.17
Chapter 14
PATHOPHYSIOLOGY AND GENETICS CLINICAL PRESENTATION AND

AND MOLECULAR CLASSIFICATION DIAGNOSTIC WORK-UP
The nature o the undamental events relating to The clinical presentation o AL amyloidosis depends
protein misolding and amyloid bril ormation and on the spectrum and severity o organ involvement.
deposition are not ully understood, though actors The common clinical eatures at diagnosis include
relating to the underlying light chain sequence and cardiomyopathy typically presenting as heart ail-
posttranslational modication, co-deposition o other ure with preserved ejection raction (up to 80%
proteins, and microenvironment actors in the tissue o patients), nephrotic syndrome with or without
are all thought to have impact. The underlying light renal insuciency (up to 60% o patients), sensory
chain variable region gene usage (IGVL) is thought axonal neuropathy, autonomic neuropathy, and
to play a role in amyloidogenesis and pattern o hepatosplenomegaly. 18 Symptoms o systemic AL
organ tropism. In one study o 821 AL patients, spe- are oten vague initially, and this leads requently
cic IGVL patterns assessed by mass spectrometry to delay in diagnosis o this rare condition. 19 Many
was associated with localized versus systemic AL, patients have multisystem involvement at diagnosis
and specic patterns associated with organ involve- (Table 14–1).
ment such as LV6-57 patients being more likely to The diagnosis o AL requires histologic evidence o
have renal involvement and LV1-44 patients being amyloid deposition in tissues either by aspiration o
more likely to have cardiac involvement.7 Posttrans- abdominal subcutaneous at or biopsy o the organs
lational modication including N-glycosylation has involved, with the demonstration o clonal plasma cell
been associated with light chain amyloidosis, and its disorder and abnormal ree light chain in serum or urine
mechanism in amyloid brillogenesis is supported (Table 14–2). The pathognomonic diagnostic eature
by the nding that isoelectric points o AL poly- o amyloid deposition is a positive tissue stain with
peptides spread heterogeneously and may orm by Congo red to demonstrate apple-green bireringence
electrostatic interaction o oppositely charged par- under polarized light. Standard pathological tests, such
ticles.8 N-glycosylation o light chains in systemic AL as the use o antibodies or serum κ or λ light chains
is more prevalent compared with light chains ound in immunohistochemistry, have low sensitivity or the
in non-amyloid plasma cell dyscrasias and contrib- diagnosis.20 Mass spectrometry–based proteomic anal-
utes to mass or charge heterogeneity and potentially ysis o amyloid tissue should be pursued when avail-
amyloidogenesis. 9,10 Co-deposition o other proteins able.21 This helps conrm the type o amyloid protein
with amyloid brils including serum amyloid P com- because more than 10 orms o systemic amyloidosis
ponent and apolipoproteins is thought to play a role are currently known, and correct typing is imperative
in bril development and tissue deposition, though or appropriate treatment, particularly with targeted
the exact mechanism is debated. 11 In addition to the therapies available or distinct amyloid subtypes such
deposition o amyloid brils, circulating amyloid as transthyretin (TTR) amyloidosis.
C 14 Systemic Immunoglobulin Light Chain Amyloidosis 325
tbl 14–1 Clinicl psnions of Immunoglobulin Lig Cin amyloidosis
Organ Involvement Clinical Presentation

Kidney Nephrotic syndrome Renal ailure
Heart Abnormal electrocardiogram: low voltages in the standard leads
Nondilated cardiomyopathy
Arrhythmia
Peripheral and autonomic nervous system Numbness
Muscle weakness
Carpal tunnel syndrome
Postural hypotension
Erectile dysunction
Altered bowel habit
Anhidrosis
Gastrointestinal tract Macroglossia
Early satiety
Diarrhea
Malabsorption
Gastrointestinal bleeding
Chapter 14
Hepatomegaly
Coagulation system Periorbital purpura (raccoon eyes)
Abnormal clotting tests
Lie-threatening bleeding
Assessment o amyloid organ involvement is per- echocardiography, cardiac magnetic resonance imag-
ormed at diagnosis with the use o serum biomarkers ing (MRI) studies, 24-hour urine studies or albu-
such as troponin-T or I, NT-proBNP (N-terminal pro minuria, and other studies as deemed clinically
b-type natriuretic peptide) levels, electrocardiography, appropriate.
tbl 14–2 Lbooy nd pologic evluion of Immunoglobulin Lig Cin amyloidosis
Laboratory Evaluation
CBC with dierential
Serum creatinine
Liver enzyme and bilirubin
Coagulation tests: prothrombin time, partial thromboplastin time, actor X
SPEP and immunofxation
UPEP and immunofxation
Serum ree light chains
24-hour urine protein
Cardiac troponin, BNP, or NT-proBNP
Cardiac testing: ECG, echocardiogram, cardiac MRI, chest radiography
Peripheral nervous system: EMG, nerve conduction test
Pulmonary unction tests
Pathologic Evaluation
Bone marrow aspiration and biopsy with immunohistochemistry staining or κ and λ light chain
Abdominal at pad aspiration or organ biopsy with Congo red staining or amyloid
Mass spectrometry or amyloid protein identifcation
BNP, brain natriuretic peptide; ECG, electrocardiography; EMG, electromyography; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro b-type natriuretic
peptide; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.
PROGNOSIS AND STAGING RESPONSE CRITERIA

Even though patients commonly have a low burden o The overall aims o therapy or patients with AL
clonal plasma cells, long-term survival outcome is poor are to improve and stabilize organ unction and
in those presenting with advanced cardiac involve- improve patient quality o lie and survival. Because
ment. However, depending on the particular pattern therapy has centered on the targeting o the under-
and severity o organ involvement, survival outcomes lying plasma cell clone to reduce circulating light
are very broad. We do note additionally that beyond chain burden, response criteria have included both
liespan, the patient’s quality o lie can be severely hematologic and organ-based response categories
impacted by his or her amyloid burden even without (Table 14–4). Notably, historical response criteria
cardiac involvement. Although patients with severe were validated in patients presenting with dFLC lev-
cardiac involvement at diagnosis have been reported els greater than 50 mg/L, which is denoted as mea-
to have a median survival period o 4 to 6 months ver- surable disease; about 90% o patients at diagnosis
sus 16 months in those without it, data have shown meet this threshold o dierential ree light chains
that successully treated patients who have obtained (dFLC). A minority o patients present at diagnosis
deep hematologic responses have improved survival.5 with low dFLC levels, and a separate hematologic
Cardiac dysunction is best assessed by the elevation response category has been validated or this popu-
o cardiac biomarkers such as brain natriuretic peptide lation dened as achieving a dFLC below 10 mg/L.25
(BNP) and NT-proBNP, as well as cardiac troponin-T More recently, analysis o achieving this less than 10
Chapter 14
(cTnT) and troponin I (cTnI). Many studies have con- mg/L dFLC threshold has been validated in a broader
rmed the prognostic signicance o markers o cardiac cohort o patients with AL presenting with measur-
injury and dysunction in patients with AL amyloido- able disease (dFLC >50 mg/L) and termed stringent
sis, and they been incorporated in the staging system dFLC response, with support or superior outcomes
or AL amyloidosis22,23 (Table 14–3). The rst o the two among this population compared with historical
main staging systems in AL, both originating with the hematologic Very Good Partial Response (VGPR) or
Mayo Clinic group, is the European modication o the Complete Response (CR) outcomes.26 However, or
Mayo 2004 staging system, which assigns points or NT- practical purposes, a hematologic VGPR or deeper
proBNP greater than 332 ng/L and cTnT greater than response is the goal o upront plasma cell–directed
0.035 ng/mL; patients with both markers elevated are therapy. Organ responses strongly correlate with
then stratied by NT-proBNP levels greater than or less improved patient survival and outcomes and remain
than 8500 ng/L to dierentiate stage IIIA and IIIB. Like- a central goal o therapy. Organ response deni-
wise, in the Revised Prognostic Scoring System rom the tions are typically based on biomarker reductions
Mayo Clinic group, patients are assigned a score o 1 or and other markers o cardiac or renal unction. A
each o the dierence between involved and uninvolved cardiac response requires a 30% or greater reduc-
light chain (FLC-di) 18 mg/dL or greater, cTnT 0.025 ng/ tion in NT-proBNP levels with absolute reduction o
mL or greater, and NT-proBNP 1800 pg/mL or greater. greater than 300 ng/L, and a renal response requires
The median OS times o patients with Mayo stage I, II, a 50% reduction o at least 0.5 g/day o proteinuria
III, and IV (score 0, 1, 2, and 3, respectively) are 94, 40, 14, on 24-hour urine collection without increase in cre-
and 5.8 months, respectively.24 atinine clearance o 25% over baseline. 27 Obtaining
taBLe 14–3 Sging of Immunoglobulin Lig Cin amyloidosis
Stage Biomarkers Stage Survival Period (months)

Mayo 2004 with European NT-proBNP >332 ng/L I: 0 points 86
modifcation23 cTnT >0.035 ng/mL II: 1 point 43
IIIA: 2 points and NT-proBNP 17
<8500 ng/L
IIIB: 2 points and NT-proBNP
>8500 3–5
24
Revised Mayo Clinic staging NT-proBNP >1800 ng/L I: 0 points 93
cTnT >0.025 ng/mL II: 1 point 62
dFLC >180 mg/L III: 2 points 13
IV: 3 points 6
cTnT, cardiac troponin-T; dFLC, dierence between the involved and uninvolved light chains; NT-proBNP, N-terminal pro b-type natriuretic peptide.
taBLe 14–4 Immunoglobulin Lig Cin A randomized trial comparing HDT-ASCT with
amyloidosis rsons Cii standard-dose melphalan plus high-dose dexa-
methasone showed no dierences in hematologic
Category Criteria or organ response. Landmark analysis examining
Complete response Normal ree light chain ratio and only patients surviving more than 6 months ater
levels; negative serum and urine transplant also showed no survival benet or HDT-
immunofxation ASCT.32 However, almost 25% o the patients in this
Very good partial dFLC <40 mg/L study received reduced-dose melphalan condition-
response ing, which has been associated with poor transplant
Partial response >50% reduction in dFLC
outcomes. Moreover, the 24% treatment-related
mortality rate in the HDT-ASCT arm was unusually
No response Less than partial response
high, and the lack o careul patient selection and use
dFLC, dierence between the involved and uninvolved light chains. o tertiary transplant centers may have biased results
against HDT-ASCT. A meta-analysis o 12 studies o
HDT-ASCT showed no superiority o HDT-ASCT
a deep hematologic response is intrinsically linked over conventional chemotherapy. 33 However, in the
to later obtaining an organ response and improved MD Anderson Cancer Center experience, improved
survival.28 More recently, deeper biomarker-graded 10-year survival outcomes were reported in patients
organ responses have been shown superior to stan- undergoing HDT-ASCT compared with conventional
Chapter 14
dard denitions o binary organ response; although chemotherapy.31 At centers with extensive experi-
prognostic, the ramications on treatment are ence in treating patients with AL amyloidosis, HDT-
not ully understood, and the aim o plasma cell– ASCT provides promising outcomes with careul
directed therapies continues to be deep hematologic patient selection. Patients with organ involvement o
response.29 Still, there remains a population o need two or ewer organs and AL amyloidosis with renal
who have persistent organ morbidity because o involvement show the best overall outcome with
deposited amyloid despite achieving hematologic HDT-ASCT.
response to upront therapy.
Induction Therapy Before High-Dose
TREATMENT Therapy with Autologous Stem Cell
Transplantation
Treatment or patients with AL amyloidosis shares Induction chemotherapy is requently administered
similar drug classes targeted to malignant plasma or cytoreduction beore HDT-ASCT, particularly
cells as that or MM, consisting mainly o various che- in patients with concurrent asymptomatic or symp-
motherapy combinations or high-dose therapy with tomatic myeloma. Hematologic and organ responses
autologous stem cell transplantation (HDT-ASCT). with the inclusion o novel agents in induction ther-
The choice o treatment should be based on risk apy can also lead to improvement in perormance
stratication. Patients with good perormance status status and result in transplant eligibility or newly
and normal cardiac markers should be considered or diagnosed patients. 34 A randomized trial evaluating
HDT-ASCT or induction chemotherapy ollowed the role o induction therapy containing bortezomib
by HDT-ASCT. and dexamethasone ollowed by HDT-ASCT versus
HDT-ASCT in patients with newly diagnosed AL
High-Dose Therapy with Autologous Stem amyloidosis showed better responses and survival
Cell Transplantation outcomes with induction therapy.35 In our experience,
incorporation o novel agent induction therapy beore
HDT-ASCT has been used since the early 1990s, transplant is associated with improved survival.36
and it is an eective treatment modality associ- Based on retrospective studies and clinical experi-
ated with hematologic and organ responses as well ence, the combination o bortezomib, cyclophospha-
as long-term survival.30,31 It is associated with high mide, and dexamethasone (CyBorD) has evolved to
treatment-related mortality rate ranging rom 13% become a standard-o-care chemotherapy regimen
to 43%, especially in patients with cardiac involve- or newly diagnosed AL amyloidosis.34,37 Whereas
ment. Careul patient selection based on comorbid- conventional lenalidomide-based myeloma induc-
ity index and cardiac staging is the key to successul tion regimens such as bortezomib, lenalidomide, and
outcome o high-dose therapy in AL amyloidosis. dexamethasone (VRD) can lead to deep hematologic
responses, lenalidomide-related toxicity even at sig- Relapsed or Refractory Immunoglobulin

nicant dose reductions has tempered their use in AL Light Chain Amyloidosis
amyloidosis patients.. 38 Deep and rapid hematologic
responses with the incorporation o the anti-CD38 There is no standard o care or relapsed or reractory
monoclonal antibody daratumumab to CyBorD AL amyloidosis, although a number o small studies
have also been reported..39 An ongoing randomized have investigated the use o novel agents approved
study comparing this regimen with CyBorD alone or the treatment o patients with MM in this set-
has shown signicantly improved rates o VGPR or ting. Lenalidomide has been evaluated in two phase 2
deeper responses (79 vs 49%), leading to improved studies in relapsed or reractory AL amyloidosis with
rates o cardiac organ responses at 6 months (42 vs an overall response rate (ORR) o 67% and 39%.44,45
22%) or patients with newly diagnosed AL amyloi- However, treatment was also associated with signi-
dosis (NCT03201965).40 cant toxicities such as atigue and myelosuppression,
requiring requent lenalidomide dose reductions and
treatment discontinuations. Pomalidomide has shown
Maintenance Therapy After High-Dose a similar ORR o 48% to 68%,46–48 and its use gener-
Therapy with Autologous Stem-Cell ally avored over lenalidomide because o better toler-
Transplantation ance in patients with AL amyloidosis. The proteasome
inhibitors (PIs) carlzomib49 and ixazomib50 have dem-
There are minimal data to support maintenance
onstrated ORRs o 63% and 52%, respectively, includ-
treatment in AL amyloidosis ater HDT-ASCT, and
Chapter 14
ing in patients who were previously PI reractory.

it is not routinely administered. However, deci-
Given the known cardiopulmonary adverse events
sions are individualized to a given patient and can
associated with carlzomib, it should be used with
be considered in patients with AL amyloidosis with
caution in careully selected patients and –generally
concurrent myeloma. Moreover, consolidation or
avoided in patients with cardiac amyloid involvement.
maintenance therapy (or both) can also be con-
Finally, the saety, tolerability, and promising ecacy
sidered in patients achieving less than VGPR ater
o daratumumab in relapsed or reractory AL amyloi-
HDT-ASCT given the prognostic signicance o
dosis have been reported in two recent prospective
achieving at least a hematologic VGPR in patients
studies showing deep hematologic responses with ≥
with AL amyloidosis. 41
VGPR or deeper response rates o 86% and 48%.51,52
Induction Therapy for Transplant-

Ineligible Patients CONCLUSIONS
The combination o melphalan and dexamethasone
Systemic AL remains a rare disease in which patients
(MDex) has long been considered a standard o care
benet rom multidisciplinary care beyond that pro-
or rst-line treatment o transplant-ineligible patients
vided solely by the treating hematologist. Medical
and is associated with a good hematologic response
management o patients with cardiac amyloidosis
(67%) and low toxicity (4%). 42 More recently, results
oten diers rom standard heart ailure treatment,
rom the EMN-03 study were reported, which evalu-
and cardiologists and other specialists experienced
ated the combination o MDex versus bortezomib,
in the management o AL such as nephrologists,
melphalan, and dexamethasone (BMDex) in patients
hepatologists, and neurologists, oten at specialized
not undergoing HDT-ASCT. 43 Overall response
tertiary centers, do make a dierence in the care
(81%) and ≥ VGPR or deeper response (64%) signi-
o patients. With the incorporation o additional
cantly higher with BMDex versus MDex (56% and
novel agents, including monoclonal antibodies,
38%, respectively). Cardiac progression rates also
obtaining deeper hematologic responses and organ
avored BMDex, although at a median ollow-up
responses, patient outcomes are expected to con-
time o 25 months, no OS dierence had yet been
tinue to improve, though ultimately these patients
observed between the two regimens. CyBorD also
require long-term ollow-up with their amyloid
remains an excellent option or transplant-ineligible
teams because each patient’s constellation o organ
patients with AL amyloidosis.
involvement and symptoms is unique.

J Confrmation o the diagnosis with tissue mass involvement; starting chemotherapy beore
spectrometry is benefcial when easible. consideration or stem cell transplantation is
J Be cautious o the possibility o patients presenting appropriate.
with concomitant MGUS and other orms o cardiac J Patients with worsening organ unction because
amyloidosis such as TTR (this is not as rare as one o increasing amyloid burden oten require reiniti-
may think). ating or a change in therapy even beore involved
J Organ biopsies are not always required i another serum ree light chains may ormally meet criteria
surrogate site can provide the diagnosis, but con- or hematologic relapse.
sider cardiac imaging ,including cardiac MRI, to J Anti–amyloid fbril–directed antibodies continue
careully rule out or rule in cardiac AL involvement in development and may provide a uture avenue
when in doubt. or expanding how we are able to directly treat the
J Quick initiation o plasma cell–directed ther- disease.
apy is warranted or patients with severe organ
Chapter 14
22. Dispenzieri A, Gertz M, Kyle R, et al. Serum cardiac tropo-

reFereNCeS nins and N-terminal pro-brain natriuretic peptide: a stag-
ing system or primary systemic amyloidosis. J Clin Oncol.
1. Quock TP. Epidemiology o AL amyloidosis: a real-world study 2004;22(18):3751-3757.
using US claims data. Blood Adv. 2018;2(10):1046-1053. 23. Wechalekar AD, Shonland SO, Kastritis E, et al. A European
2. Kyle RA, Linos A, Beard CM, et al. Incidence and natural his- collaborative study o treatment outcomes in 346 patients with
tory o primary systemic amyloidosis in Olmsted County, cardiac stage III AL amyloidosis. Blood. 2013;121(17):3420-3427.
Minnesota, 1950 through 1989. Blood. 1992;79(7):1817-1822. 24. Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic
3. Pinney JH, Smith CJ, Taube, et al. Systemic amyloido- staging system or light chain amyloidosis incorporating car-
sis in England: an epidemiological study. Br J Haematol. diac biomarkers and serum ree light chain measurements. J
2013;161(4):525-532. Clin Oncol. 2012;30(9):989-995.
4. Hemminki K, Li X, Forsti A, et al. Incidence and survival in 25. Milani P, Basset M, Russo F, et al. Patients with light-chain
non-hereditary amyloidosis in Sweden. BMC Public Health. amyloidosis and low ree light-chain burden have distinct clini-
2012;12(1):974. cal eatures and outcome. Blood. 2017;130(5):625-631.
5. Kyle RA, Gertz MA. Primary systemic amyloidosis: clini- 26. Manwani R, Cohen O, Sharpley F, et al. A prospec-
cal and laboratory eatures in 474 cases. Semin Hematol. tive observational study o 915 patients with systemic
1995;32(1):45-59. AL amyloidosis treated with upront bortezomib. Blood.
6. Quarta CC, Kruger JL, Ralk RH. Cardiac amyloidosis. Circula- 2019;134(25):2271-2280.
tion. 2012;126(12):e178-e182. 27. Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines
7. Kourelis TV, Dasari S, Theis JD, et al. Clariying immuno- o the conduct and reporting o clinical trials in systemic light-
globulin gene usage in systemic and localized immunoglobu- chain amyloidosis. Leukemia 2012; 26:2317.
lin light-chain amyloidosis by mass spectrometry. Blood. 28. Kauman GP, Dispenzieri A, Gertz MA, et al. Kinetics o
2017;129(3):299-306.
Chapter 14
organ response and survival ollowing normalization o the

8. Kaplan B, Livneh A, Gallo G. Charge dierences between in serum ree light chain ratio in AL amyloidosis. Am J Hematol.
vivo deposits in immunoglobulin light chain amyloidosis and 2015;90(3):181-186.
non-amyloid light chain deposition disease. Br J Haematol. 29. Eckhert E, Witteles R, Kauman G, et al. Grading cardiac
2007;136(5):723. response in AL amyloidosis: implications or relapse and sur-
9. Milani P, Barnidge D, Murray D, et al. Glycosylation o immu- vival. Br J Haematol. 2019. 186(1):144-146.
noglobulin light chains is associated with amyloidosis. Clin 30. Jaccard A, Moreau P, Leblond V, et al. High-dose melphalan
Lymphoma Myeloma Leuk. 2017;17(1 suppl):E104. versus melphalan plus dexamethasone or AL amyloidosis. N
10. Kumar S, Dispenzieri A, Dasari S, et al. Mass spectrometric Engl J Med. 2007;357(11):1083-1093.
approach to identiy N-glycosylation o light chain in patients 31. Parmar S, Kongtim P, Champlin R, et al. Auto-SCT improves
with immunoglobulin light chain amyloidosis (AL). Cancer Res. survival in systemic light chain amyloidosis: a retrospective
2018;33:254–257. analysis with 14-year ollow-up. Bone Marrow Transplant.
11. Gallo G, Wisniewski T, Choi-Miura NH, et al. Potential role o 2014;49(8):1036-1041.
apolipoprotein-E in brillogenesis. Am J Pathol. 1994;145(3):526. 32. Madan S, Kumar SK, Dispenzieri A, et al. High-dose mel-
12. Palladini G, Lavatelli F, Russo P, et al. Circulating amyloido- phalan and peripheral blood stem cell transplantation or
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type B decrease simultaneously in association with improve- 2012;119(5):1117-1122.
ment o survival in AL. Blood. 2006;107(10):3854-3858. 33. Mhaskar R, Kumar A, Behera M, et al. Role o high-dose che-
13. Liao R, Jain M, Teller P, et al. Inusion o light chains rom motherapy and autologous hematopoietic cell transplantation
patients with cardiac amyloidosis causes diastolic dysunction in primary systemic amyloidosis: a systematic review. Bio Blood
in isolated mouse hearts. Circulation. 2001;104(14):1594-1597. Marrow Transplant. 2009;15(8):893-902.
14. Oberti L, Rognoni P, Barbiroli A, et al. Concurrent structural 34. Mikhael JR, Schuster SR, Jimenez-Zepeda VH, et al. Cyclo-
and biophysical traits link with immunoglobulin light chain phosphamide-bortezomib-dexamethasone (CyBorD) produces
amyloid propensity. Sci Rep. 2017;7(1):16809. rapid and complete hematologic response in patients with AL
15. Gertz MA, Kyle RA, Greipp PR. The plasma cell labeling amyloidosis. Blood. 2012;119(19):4391-4394.
index: a valuable tool in primary systemic amyloidosis. Blood. 35. Huang X, Wang Q, Chen W, et al. Induction therapy with
1989;74(3):1108-1111. bortezomib and dexamethasone ollowed by autologous stem
16. Paiva B, Martinez-Lopez J, Corchete LA, et al. Phenotypic, cell transplantation versus autologous stem cell transplantation
transcriptomic , and genomic eatures o clonal plasma cells in alone in the treatment o renal AL amyloidosis: a randomized
light-chain amyloidosis Blood. 2016;127(24):3035-3039. controlled trial. BMC Med. 2014;12:2..
17. Da Silva Filho MI, Forsti A, Weinhold N, et al. Genome-wide 36. Arough A, Saliba RM, Hamdi A, et al. Impact o induction
association study o immunoglobulin light chain amyloidosis therapy on the outcome o immunoglobulin light chain amy-
in three patient cohorts: comparison with myeloma. Leukemia. loidosis ater autologous hematopoietic stem cell transplanta-
2017;31(8):1735-1742. tion. Biol Blood Marrow Transplant. 2018;24(11):2197-2203.
18. Milani P, Merlini G, Palladini G. Light chain amyloidosis. Medi- 37. Palladini G, Sachchithanantham S, Milani P, et al. A European
terr J Hematol Infect Dis. 2018. 10(1):e2018022. collaborative study o cyclophosphamide, bortezomib, and
19. Lousada I, Comenzo RL, Landau H, et al. Light chain amyloido- dexamethasone in upront treatment o systemic AL amyloi-
sis: patient experience esurvey rom the Amyloidosis Research dosis. Blood. 2015;126(5):612-615.
Consortium. Adv Ther. 2015;32(10):920-928. 38. Kastritis E, Dialoupi I, Gavriatopoulou M, et al. Primary treat-
20. Satoskar A, Burdge K, Cowden D, et al. Typing o amyloido- ment o light-chain amyloidosis with bortezomib, lenalido-
sis in renal biopsies: diagnostic pitalls. Arch Pathol Lab Med. mide, and dexamethasone. Blood Adv. 2019;3(20):3002-3009.
2007;131(6):917-922. 39. Palladini G, Kastritis E, Maurer MS, et al. Daratumumab
21. Vrana J, Gamez J, Madden B, et al. Classication o amy- plus CyBorD or patients with newly diagnosed AL amy-
loidosis by laser microdissection and mass spectrometry- loidosis: saety run-in results o ANDROMEDA. Blood.
based proteomic analysis in clinical biopsy specimens. Blood. 2020;136(1):71-80.
2009;114(24):4957-4959.
40. Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous dara- 46. Sanchorawala V, Shelton AC, Lo S, et al. Pomalidomide and
tumumab + cyclophosphamide, bortezomib, and dexametha- dexamethasone in the treatment o AL amyloidosis: results o
sone (CyBorD) in patients with newly diagnosed light chain a phase 1 and 2 trial. Blood. 2016;128(8):1059-1062.
(AL) amyloidosis: primary results rom the phase 3 Andromeda 47. Dispenzieri A, Buadi F, Laumann K, et al. Activity o pomalido-
study. Abstract Book: 25th Congress o the European Hematol- mide in patients with immunoglobulin light-chain amyloido-
ogy Association Virtual Edition. HemaSphere 2020;4:1-1168. sis. Blood. 2012;119(23):5397-5404.
41. Landau H, Hassoun H, Rosenzweig MA, et al. Bortezomib and 48. Palladini G, Milani P, Foli A, et al. A phase 2 trial o pomalido-
dexamethasone consolidation ollowing risk-adapted melpha- mide and dexamethasone rescue treatment in patients with AL
lan and stem cell transplantation or patients with newly diag- amyloidosis. Blood. 2017;129(15):2120-2123.
nosed light-chain amyloidosis. Leukemia. 2013;27(4):823-828. 49. Cohen AD, Landau H, Scott EC, et al. Saety and ecacy o
42. Palladini G, Russo P, Nuvolone M, et al. Treatment with oral carlzomib (CFZ) in previously-treated systemic light-chain
melphalan plus dexamethasone produces long-term remissions (AL) amyloidosis. Blood. 2016;128(22):645.
in AL amyloidosis. Blood. 2007;110(2):787-788. 50. Sanchorawala V, Palladini G, Kukreti V, et al. A phase 1/2 study
43. Kastritis E, Leleu X, Arnul B, et al. A randomized phase iii trial o the oral proteasome inhibitor ixazomib in relapsed or rerac-
o melphalan and dexamethasone (MDex) Versus bortezomib, tory AL amyloidosis. Blood. 2017;130(5):597-605.
melphalan and dexamethasone (BMDex) or untreated patients 51. Sanchorawala V, Sarosiek S, Schulman A, et al. Saety, tolerabil-
with AL amyloidosis. Blood. 2016;128(22). ity, and response rates o daratumumab in relapsed al amyloi-
44. Sanchorawala V, Wright DG, Rosenzweig M, et al. Lenalido- dosis: results o a phase II study. Blood. 2020135(18):1541-1547.
mide and dexamethasone in the treatment o AL amyloidosis: 52. Roussel M, Merlini G, Chevret S, et al. A prospective phase 2
results o a phase 2 trial. Blood. 2007;109(2):492-496. trial o daratumumab in previously treated systemic light-chain
45. Dispenzieri A, Klein CJ, Mauermann ML. Lenalido- amyloidosis. Blood. 2020;135(18):1531-1540.
mide therapy in a patient with POEMS syndrome. Blood.
2007;110(3):1075-1076.
Chapter 14
15 Waldenström Macroglobulinemia
Melody Becnel
Gregory P. Kaufman
Elisabet E. Manasanch
Krina Patel
Hans C. Lee
Robert Z. Orlowski
Sheeba Thomas
KEY CONCEPTS
 Waldenström macroglobulinemia (WM) is synony- consciousness, and a bleeding diathesis. Therapy or
mous with lymphoplasmacytic lymphoma as well as hyperviscosity consists o prompt initiation o plasma
the presence o a monoclonal immunoglobulin (Ig) M exchange ollowed by systemic therapy.
gammopathy.  As with other low-grade lymphoid malignancies, asymp-
 Most cases are associated with a mutation in MYD88, tomatic patients and those without signifcant cytopenias
which oers a better prognosis than MYD88 wild-type or other end-organ maniestations can be observed with
cases. close ollow-up.
 CXCR4 mutations are associated with increased IgM levels  Therapy should be initiated or symptomatic hypervis-
and a higher risk o hyperviscosity. cosity, hemoglobin less than 10 g/dL, platelet count
 Patients with WM are at risk or symptomatic hypervis- 100,000 K/uL or less, bulky adenopathy, symptomatic
cosity syndrome, which may present with visual distur- organomegaly, symptomatic cryoglobulinemia, or signif-
bances, dizziness, cardiopulmonary symptoms, decreased cant peripheral neuropathy
BACKGROUND are oten associated with higher IgM levels and there-
ore increased risk o hyperviscosity.11,12
Waldenström macroglobulinemia (WM) is an uncom-
mon, low-grade malignancy characterized by the
presence o lymphoplasmacytic cells together with CLINICAL PRESENTATION AND
the presence o a monoclonal immunoglobulin (Ig) DIAGNOSTIC WORK-UP
M paraproteinemia.1 The median age at diagnosis
is between 63 and 68 years o age, men are more Many patients with WM are asymptomatic at the time
commonly aected than women, and the disease is o diagnosis. When symptoms develop, they are caused
more common among whites than those o other by tumor infltration (cytopenias, hepatomegaly, sple-
populations.2 Approximately, 90% o WM cases are nomegaly), circulating IgM (hyperviscosity, cryoglobu-
associated with a mutation o the myeloid dieren- linemia, cold agglutinin anemia), or tissue deposition
tiation primary response 88 (MYD88) gene located o IgM (neuropathy, glomerular disease, amyloidosis).
on chromosome 3p22. WM cases having wild-type Patients with symptomatic hyperviscosity syndrome
MYD88 are associated with worse outcomes and a may present with visual disturbances, dizziness, car-
higher propensity to transorm into an aggressive diopulmonary symptoms, decreased consciousness,
lymphoma compared with cases having the MYD88 and a bleeding diathesis. Polyneuropathies are com-
mutation.3–11 O WM cases having the MYD88 muta- mon. Some are associated with antigenic targets o the
tion, approximately one third also have a mutation monoclonal serum IgM, including myelin-associated
o chemokine receptor 4 (CXCR4); CXCR4 mutations glycoprotein (MAG) and sulatide. Others are caused
333
334 Sction II Lymphoma and Myeloma
by direct tumor inltration, tissue deposition o IgM, abdomen, and pelvis) or positron emission tomogra-
the amount and properties o the circulating monoclo- phy (PET)–CT scans to evaluate or extramedullary
nal IgM, binding o unidentied antigens, or associated disease. An ophthalmologic examination should be
amyloidosis.2 Patients may also present with cold or perormed to look or retinal changes (hemorrhages
warm autoimmune hemolytic anemia, iron-deciency or “sausage vessels”) in patients with suspected
anemia, or dilutional anemia.2 hyperviscosity syndrome. 15,16 In patients with neu-
Initial evaluation (Table 15–1) o patients with sus- ropathy, standard evaluation or endocrinopathies
pected WM should include a complete blood count and vitamin deciencies should be accompanied by
with dierential, serum chemistries, liver unction evaluation with nerve conduction studies, electromy-
tests, viral hepatitis serologies, serum protein elec- ography, and serum studies or antimyelin associated
trophoresis (SPEP) and immunoxation, quantita- glycoprotein (MAG) and antiganglioside 1 (GM1)
tive immunoglobulin levels, and a β2-microglobulin. antibodies. 11,16 Abdominal at pad biopsy with Congo
In patients suspected o having cryoglobulinemia, red staining should also be perormed to evaluate or
a cryocrit should be drawn and together with SPEP associated amyloidosis.
and quantitative immunoglobulin specimens should
immediately be placed in a 37°C water bath to acili-
tate accurate assessment.13 A serum viscosity level PROGNOSTIC STRATIFICATION
and a cold agglutinin titer or Coombs test should be
drawn i hyperviscosity or hemolytic anemia is sus- Patients with symptomatic WM may be risk strati-
ChapTer 15
pected. Iron-deciency studies should be considered ed according to the International Prognostic Scor-
or patients with a microcytic anemia.13 Bone marrow ing System or WM (ISSWM). This system considers
biopsy should be perormed to demonstrate inltra- ve covariates, namely, advanced age (older than 65
tion by lymphoplasmacytic cells; determine the cause years), hemoglobin 11.5 g/dL or less, platelet count
o anemia; and when indicated, evaluate or systemic 100 × 109/L or less, β2-microglobulingreater than 3
light chain (AL) amyloidosis. Flow cytometry typi- mg/L, and serum monoclonal protein concentration
cally demonstrates a pattern o sIgM+, CD19+, CD20+, greater than 7.0 g/dL. Low risk is dened as having
CD22 +, CD79+.14 Testing or the MYD88 L265P gene one or no adverse characteristics except or advanced
mutation in the marrow or peripheral blood can help age, intermediate-risk as two adverse characteristics
distinguish WM rom marginal zone lymphoma or only advanced age, and high risk as more than two
and multiple myeloma, in which the incidence o adverse characteristics. In a series, o 587 patients,
this mutation is low.3–10 Patients should have base- 5-year survival rates were 87%, 68%, and 36%, or
line computed tomography (CT) scans (neck, chest, these respective subgroups (P <.001).17 Among those
Tbl 15–1 Initil Wok-u fo Wldnstöm Mcoglobulinmi
Essential Testing Useful Under Certain Circumstances

History and physical examination Fundoscopic examinationc
CBC with dierential, BUN, creatinine, electrolytes, liver Coombs test
unction tests, uric acid, LDH, β2-microglobulin Anti-MAG) antibody and anti-GM1 antibody
Peripheral blood smear EMG and NCS
Quantitative immunoglobulins (IgG, IgM, IgA) Congo red staining o abdominal at pad biopsy and/or bone
Serum light chain assay (kappa and lambda) marrow biopsy
SPEP and immunoxation Coagulation testing and vWD testing i there is bleeding or
24-hour UPEP and immunoxation bruising
Serum viscositya
Hepatitis B and C serology
Cryocritb
Cold agglutinin titer
Unilateral bone marrow aspirate and biopsy with
immunohistochemistry and/or fow cytometry and CXCR4
and MYD88 L265P AS-PCR testing
PET-CT or CT o the neck, chest, abdomen, and pelvis
a
Most patients with serum viscosity o <4 cP will not have symptoms o hyperviscosity.
b
I cryocrit result is positive, then initial and ollow-up cryocrit and serum protein electrophoresis (SPEP) samples should be measured under warm conditions.
c
When hyperviscosity is suspected or immunoglobulin (Ig)M >/-3g/dL.
AS-PCR, Allele-specic polymerase chain reaction; BUN, blood urea nitrogen; CBC, complete blood count; CT, computed tomography; EMG, electromyography; LDH,
lactate dehydrogenase; NCS, nerve conduction study; PET, positron emission tomography; UPEP, urine protein electrophoresis; vWD, von Willebrand disease.
Ct 15 Waldenström Macroglobulinemia 335
deemed to be high risk, elevated lactate dehydro- o bortezomib-rituximab with or without dexa-
genase increases the likelihood o death rom WM methasone result in an overall response rate (ORR)
(90% vs 60%).18 o 57% to 83%. Carlzomib–rituximab–dexametha-
sone showed an ORR o 68%.25,26 Comparable ORRs
(77%–96%) have been seen with alkylating agent-
MANAGEMENT based regimens (R-CHOP [rituximab, cyclophospha-
mide, doxorubicin hydrochloride, = Oncovin, and
Asymptomatic patients and those without signi- prednisone], Rituximab, cyclophosphamide, vincris-
cant cytopenias or other end-organ maniestations tine, prednisone, R-cyclophosphamide–dexametha-
can be ollowed every 3 months during the rst year sone, and rituximab-bendamustine); however, o
(with longer ollow-up intervals thereater in the set- these, R-bendamustine is the preerred regimen given
ting o disease stability).19 In such patients, lielong improved progression-ree survival (PFS) and ewer
ollow-up is necessary because the risk o developing adverse eects.11,27–30 The use o single-agent ritux-
symptomatic disease is approximately 6% in the rst imab should be reserved or patients unable to tol-
year, 39% at 3 years, and 55% at 5 years.19 Higher M erate combination chemotherapy because ORRs and
protein and marrow inltration have been associated PFS are low (20%–50% and 12–24 months, respec-
with increased risk o progression to symptomatic tively). 11,31,32 Rituximab must be used with caution
disease. 19 in patients with highly elevated IgM levels because
Therapy should be initiated or symptomatic hyper- o the potential or an associated IgM fare. In these
ChapTer 15
viscosity, hemoglobin less than 10 g/dL, platelet count cases, it is prudent to delay administration o ritux-
100,000 K/uL or less, bulky adenopathy, symptomatic imab until ater the patient has received cytoreduc-
organomegaly, symptomatic cryoglobulinemia, or sig- tive therapy.33 In 2015, the Bruton tyrosine kinase
nicant peripheral neuropathy (Table 15–2).20 Therapy (BTK) inhibitor ibrutinib was approved by the Food
or hyperviscosity consists o prompt initiation o and Drug Administration or patients with symptom-
plasma exchange ollowed by systemic therapy.21 atic WM. In a phase II trial o 63 patients, ibrutinib
Given the risk o precipitating symptomatic hyper- was associated with a single-agent partial response
viscosity in patients with high levels o circulating rate o 57% and an ORR o 90% in previously treated
IgM, packed red cell transusions should be used con- patients.11,34 In subset analysis, patients with MYD88
servatively and preerably administered ater plasma L265P mutations responded better (major response
exchange in high-risk patients. rate, 80%) to ibrutinib than did those without the
mutation. However, patients with CXCR4 mutations
in addition to MYD88 mutations had a less avorable
Frontline Therapy response (major response rate, 60%).11 O note, ibru-
When autologous stem cell transplant (ASCT) may tinib is not cytotoxic and thereore must be continued
be considered at relapse, nucleoside analogs should until evidence o progression or unacceptable toxicity.
be avoided beore stem cell harvest, and primary A phase 3 trial comparing ibrutinib–rituximab versus
therapy with a proteasome inhibitor or alkylator, rituximab in both newly diagnosed and relapsed or
together with rituximab with or without dexa- reractory patients with WM noted an ORR o 95%
methasone should be considered. 21–26 Combinations in the combination group compared with 48% in the
rituximab arm.35,36
When uture ASCT is not a consideration, nucleoside
analog–based combinations with either fudarabine or
Tbl 15–2 Ttmnt Indictions fo cladribine could be considered as alternatives to previ-
Wldnstöm Mcoglobulinmi ously detailed regimens.37–40 In a trial by the Walden-
ström’s Macroglobulinemia Clinical Trials Group,
• Symptomatic hyperviscosity (eye grounds, neurologic
fudarabine–rituximab demonstrated an ORR o 96%
changes)
and median PFS o 51.2 months.40 Cladribine has also
• Hemoglobin <10 g/dL (caused by marrow involvement,
hypersplenism, or cold agglutinin hemolytic anemia) been studied alone and in combination with cyclophos-
• Platelet count ≤100,000/µL phamide and/or rituximab. In 18 previously untreated
• Bulky adenopathy patients with WM who received two cycles o cladrib-
• Symptomatic organomegaly ine, cyclophosphamide, and rituximab, the ORR was
• Symptomatic cryoglobulinemia 94%, and the median time to response was 2.4 months;
• Amyloidosis at 5 years, 83% o patients remained alive.39 However,
• Neuropathy the use o nucleoside analogs must be weighed against
• Cryoglobulinemia the risk (~6%–12%) o second malignancies and trans-
• Pseudo von Willebrand disease ormation to large-cell lymphoma.41
Regimen Selection multicenter MAINTAIN trial did not note any improve-
ment in PFS or OS or the group that received
Choice o therapy should take into consideration both 2 years o maintenance rituximab.12,43 In light o this, the
disease- and patient-related actors, including genomic use o maintenance rituximab remains controversial and
inormation, comorbidities, and presenting signs and cannot be routinely recommended at this time.
symptoms. In patients with both MYD88 and CXCR4
mutations who need rapid therapeutic benet, the pre-
erred regimen is rituximab with either and bendamus- TREATMENT AT DISEASE RELAPSE
tine or bortezomib and dexamethasone. However, i a
rapid response is not needed, treatment with ibrutinib At relapse, patients may be retreated with a previ-
with or without rituximab could also be considered. ously successul regimen i their initial remission lasted
In patients with MYD88 mutations but wild-type at least 1 year. When the initial disease-ree-interval
CXCR4, all o these regimens are likely to be eec- is shorter, use o one o the other regimens (detailed
tive, so the choice o regimen is primarily based on the earlier) should be considered.
side eect prole. In patients with neither mutation, For patients intolerant to rituximab, the ully human
a chemotherapy-based regimen as described earlier is monoclonal anti-CD20 antibody oatumumab may be
the preerred rst-line agent.12 useul. In patients who have previously received ritux-
With respect to patient-related actors, providers imab, two cycles o oatumumab were associated with
should consider the patient’s age, unctional status, an ORR o 52%.44
ChapTer 15
and comorbidities when selecting a regimen. Bort- The role o stem cell transplantation in patients with
ezomib can be associated with a signicant risk o WM is still being dened. In a retrospective review o
neuropathy; thereore, in patients with baseline 158 patients (32% had at least three prior lines o ther-
neuropathy, this agent ideally should be avoided as apy) the 5-year PFS and OS with ASCT were 39.7%
rontline therapy. Carlzomib can be used in lieu o and 68.5%, respectively.45 Several groups have also
bortezomib in patients with neuropathy, but cau- studied allogeneic stem cell transplantation in patients
tion should be used in older adult patients and in with WM. The 5-year PFS was between 49% and 56%
those with cardiopulmonary disease, given the risk but with notable treatment-related mortality.46
or toxicity. In patients with cardiac disease, ibruti-
nib should also be used cautiously, given the risk o
atrial brillation. For patients with a history o atrial FUTURE DIRECTIONS
brillation or who develop treatment-emergent atrial
brillation, careul co-management with a cardiolo- Many new therapies are under study or patients with
gist is essential. Additionally, because antithrombotic WM. These include next-generation proteasome inhib-
therapy with aspirin or anticoagulation is needed itors (eg, ixazomib), phosphoinositide 3-kinaseinhibi-
in most patients with atrial brillation, urther cau- tors, the histone deacetylase inhibitor panobinostat,
tion is needed with the use o ibrutinib given the immune checkpoint inhibitors, monoclonal antibod-
increased risk or bleeding with this agent. Newer ies such as the anti-CD38 antibody daratumumab,
BTK inhibitors with less o-target eects o bleeding and chimeric antigen receptor T-cell therapies. Some
and arrhythmias are being evaluated as single agents o the most promising agents are the BCL2 inhibitor
and in combination therapy in various ongoing trials. venetoclax and the CXCR4 inhibitor ulocuplumab.47
In addition, second-generation Bruton tyrosine kinase
inhibitors, such as zanubrutinib, and ERK pathway
Maintenance inhibitors are also being evaluated. The development
Although retrospective studies have shown improved o these and other agents together with emerging
PFS and overall survival (OS) in patients who received knowledge about the molecular drivers o this disease
maintenance rituximab (the recommendation is or eight continues to propel the eld orward and allow or
inusions over 2 years),42 the prospective, randomized, more rational targeted therapies.11,12,47

J Many patients present asymptomatically. The work- J In patients with both MYD88 and CXCR4 mutations
up should include laboratory studies (reer to the who need rapid therapeutic benet, the preerred
text or specics), staging CT or PET-CT scans, bone regimen is rituximab with either and bendamustine
marrow biopsy, and CXCR4 testing o the marrow or bortezomib and dexamethasone. I a rapid
or blood. Ophthalmology evaluation should be response is not needed, ibrutinib with or without
perormed. Other testing should be guided by the rituximab could also be considered. In patients with
patient’s symptoms. neither mutation, a chemotherapy-based regimen
J In patients with WM and neuropathy, nerve conduc- such as rituximab–bendamustine is the preerred
tion studies, electromyography, and serum studies rontline regimen given improved PFS and ewer
or anti-MAG and anti-GM1 antibodies should be adverse eects.
evaluated. J Rituximab should be used with caution in patients
J Higher M protein and marrow inltration have with signicantly high IgM levels because IgM fare
been associated with increased risk o progression can occur.
to symptomatic disease. However, M protein levels J At relapse, patients may be retreated with a previ-
alone should not be used to determine the timing ously successul regimen i their initial remission
o treatment. lasted at least 1 year.
ChapTer 15
20. Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and
reFereNCeS criteria to initiate therapy in Waldenstrom’s macroglobulin-
emia: consensus panel recommendations rom the Second
1. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological International Workshop on Waldenstrom’s Macroglobulin-
denition o Waldenstrom’s macroglobulinemia: consensus emia. Semin Oncol. 2003;30:116-120.
panel recommendations rom the Second International Work- 21. Dimopoulos MA, Kastritis E, Owen RG, et al. Treatment rec-
shop on Waldenstrom’s Macroglobulinemia. Semin Oncol. ommendations or patients with Waldenstrom macroglobulin-
2003;30:110-115. emia (WM) and related disorders: IWWM-7 consensus. Blood.
2. Dimopoulos MA, Panayiotidis P, Moulopoulos LA, et al. 2014;124:1404-1411.
Waldenström’s macroglobulinemia: clinical eatures, complica- 22. Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M, et al. Pri-
tions, and management. J Clin Oncol. 2000;18:214. mary therapy o Waldenstrom macroglobulinemia (WM) with
3. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic muta- weekly bortezomib, low-dose dexamethasone, and rituximab
tion in Waldenstrom’s macroglobulinemia. N Engl J Med. (BDR): long-term results o a phase 2 study o the European
2012;367:826-833. Myeloma Network (EMN). Blood. 2013;122:3276-3282.
4. Gachard N, Parrens M, Soubeyran I, et al. IGHV gene eatures 23. Ghobrial IM, Xie W, Padmanabhan S, et al. Phase II trial
and MYD88 L265P mutation separate the three marginal zone o weekly bortezomib in combination with rituximab in
lymphoma entities and Waldenstrom macroglobulinemia/lym- untreated patients with Waldenstrom macroglobulinemia. Am
phoplasmacytic lymphomas. Leukemia. 2013;27:183-189. J Hematol. 2010;85:670-674.
5. Jimenez C, Sebastian E, Chillon MC, et al. MYD88 L265P is a 24. Thomas SK, Haygood TM, Qazilbash MH, et al. et al. A phase
marker highly characteristic o, but not restricted to, Walden- II trial o bortezomib-rituximab ollowed by autologous stem
strom’s macroglobulinemia. Leukemia. 2013;27:1722-1728. cell harvest (SCH) and cladribine-cyclophosphamide-rituximab
6. Landgren O, Tageja N. MYD88 and beyond: novel opportuni- (2CdA-Cy-Rit) consolidation as primary therapy o Walden-
ties or diagnosis, prognosis and treatment in Waldenstrom’s
ChapTer 15
ström’s macroglobulinemia (WM). Blood, 122(21):4396.

macroglobulinemia. Leukemia. 2014;28:1799-1803. 25. Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy
7. Mori N, Ohwashi M, Yoshinaga K, et al. L265P mutation o the o Waldenstrom macroglobulinemia with bortezomib, dexa-
MYD88 gene is requent in Waldenstrom’s macroglobulinemia methasone, and rituximab: WMCTG clinical trial 05-180. J Clin
and its absence in myeloma. PloS One. 2013;8:e80088. Oncol. 2009;27:3830-3835.
8. Poulain S, Roumier C, Decambron A, et al. MYD88 L265P 26. Treon SP, Tripsas CK, Meid K, et al. Carlzomib, rituximab,
mutation in Waldenstrom macroglobulinemia. Blood. and dexamethasone (CaRD) treatment oers a neuropathy-
2013;121:4504-4511. sparing approach or treating Waldenstrom’s macroglobulin-
9. Varettoni M, Arcaini L, Zibellini S, et al. Prevalence and clini- emia. Blood. 2014;124:503-510.
cal signicance o the MYD88 (L265P) somatic mutation in 27. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine
Waldenstrom’s macroglobulinemia and related lymphoid neo- plus rituximab versus CHOP plus rituximab as rst-line treat-
plasms. Blood. 2013;121:2522-2528. ment or patients with indolent and mantle-cell lymphomas:
10. Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenstrom an open-label, multicentre, randomised, phase 3 non-inerior-
macroglobulinemia, immunoglobulin M monoclonal gam- ity trial. Lancet. 2013;381:1203-1210.
mopathy, and other B-cell lymphoprolierative disorders using 28. Rummel M, Lerchenmller C, Greil R. Bendamustine-ritux-
conventional and quantitative allele-specic polymerase chain imab induction ollowed by observation or rituximab main-
reaction. Blood. 2013;121:2051-2058. tenance or newly diagnosed patients with Waldenstrom’s
11. Castillo JJ, Treon SP. What is new in the treatment o Walden- macroglobulinemia: results rom a prospective randomized,
strom macroglobulinemia? Leukemia. 2019;33:2555-2562. multicenter study (StiL NHL 7-2008 -MAINTAIN-; ClinicalTri-
12. Vaxman I, Gertz M. Waldenstrom’s macroglobulinemia in the als.gov Identier: NCT00877214). Blood. 2012;120(21):2739.
era o immunotherapy. Leuk Lymphoma. 2020:1-13. 29. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, et al.
13. Treon SP. How I treat Waldenstrom macroglobulinemia. Blood. Primary treatment o Waldenstrom macroglobulinemia with
2009;114:2375-2385. dexamethasone, rituximab, and cyclophosphamide. J Clin
14. Konoplev S, Medeiros LJ, Bueso-Ramos CE, et al. Immuno- Oncol. 2007;25:3344-3349.
phenotypic prole o lymphoplasmacytic lymphoma/Walden- 30. Ioakimidis L, Patterson CJ, Hunter ZR, et al. Comparative out-
strom macroglobulinemia. Am J Pathol. 2005;124:414-420. comes ollowing CP-R, CVP-R, and CHOP-R in Waldenstrom’s
15. Menke MN, Feke GT, McMeel JW, Treon SP. Ophthalmo- macroglobulinemia. Clin Lymphoma Myeloma. 2009;9:62-66.
logic techniques to assess the severity o hyperviscosity 31. Gertz MA, Rue M, Blood E, et al. Multicenter phase 2 trial
syndrome and the eect o plasmapheresis in patients with o rituximab or Waldenstrom macroglobulinemia (WM): an
Waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma. Eastern Cooperative Oncology Group Study (E3A98). Leuk
2009;9:100-103. Lymphoma. 2004;45:2047-2055.
16. Dimopoulos MA, Kastritis E. How I treat Waldenstrom macro- 32. Dimopoulos MA, Zervas C, Zomas A, et al. Treatment o
globulinemia. Blood. 2019;134:2022-2035. Waldenstrom’s macroglobulinemia with rituximab. J Clin
17. Morel P, Duhamel A, Gobbi P, et al. International prognostic Oncol. 2002;20:2327-2333.
scoring system or Waldenstrom macroglobulinemia. Blood. 33. Ghobrial IM, Fonseca R, Greipp PR, et al. Initial immunoglobu-
2009;113:4163-4170. lin M “fare” ater rituximab therapy in patients diagnosed with
18. Kastritis E, Kyrtsonis MC, Hadjiharissi E, et al. Validation Waldenstrom macroglobulinemia: an Eastern Cooperative
o the International Prognostic Scoring System (IPSS) or Oncology Group Study. Cancer. 2004;101:2593-2598.
Waldenstrom’s macroglobulinemia (WM) and the impor- 34. Treon SP, Tripsas CK, Yang G, et al. A prospective multicenter
tance o serum lactate dehydrogenase (LDH). Leuk Res. study o the Bruton’s tyrosine kinase inhibitor ibrutinib in
2010;34:1340-1343. patients with relapsed or reractory Waldenstrom’s macroglob-
19. Kyle RA, Therneau TM, Dispenzieri A, et al. Immunoglobulin ulinemia Blood. 2013;122:251.
m monoclonal gammopathy o undetermined signicance and 35. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial o
smoldering Waldenstrom macroglobulinemia. Clin Lymphoma ibrutinib plus rituximab in Waldenström’s macroglobulinemia.
Myeloma Leuk. 2013;13:184-186. N Engl Med. 2018;378:2399-2410.
36. Buske C, Tedeschi A, Trotman J, et al. Ibrutinib treatment in naive patients with Waldenstrom macroglobulinaemia who
Waldenström’s macroglobulinemia: ollow-up ecacy and respond to a rituximab-containing regimen. Br J Haematol.
saety rom the iNNOVATETM study. Blood. 2018;132:149. 2011;154:357-362.
37. Laszlo D, Andreola G, Rigacci L, et al. Rituximab and subcuta- 43. Rummel MJ, Lerchenmller C, Hensel M, et al. Two years
neous 2-chloro-2’-deoxyadenosine combination treatment or rituximab maintenance vs. observation ater rst line treat-
patients with Waldenstrom macroglobulinemia: clinical and ment with bendamustine plus rituximab (B-R) in patients
biologic results o a phase II multicenter study. J Clin Oncol. with Waldenström’s macroglobulinemia (MW): results
2010;28:2233-2238. o a prospective, randomized, multicenter phase 3 study
38. Leblond V, Johnson S, Chevret S, et al. Results o a random- (the StiL NHL7-2008 MAINTAIN trial). Blood. 2019;134
ized trial o chlorambucil versus fudarabine or patients with (suppl 1):343.
untreated Waldenstrom macroglobulinemia, marginal zone 44. Furman RR EH, DiRienzo CG, Hayman SR, et al. A phase II
lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. trial o oatumumab in subjects with Waldenstrom’s macro-
2013;31:301-307. globulinemia. Blood. 2011;118:3701.
39. Weber DM, Dimopoulos MA, Delasalle K, et al. 2-Chloro- 45. Kyriakou C, Canals C, Sibon D, et al. High-dose therapy and
deoxyadenosine alone and in combination or previously autologous stem-cell transplantation in Waldenstrom macro-
untreated Waldenstrom’s macroglobulinemia. Semin Oncol. globulinemia: the Lymphoma Working Party o the European
2003;30:243-247. Group or Blood and Marrow Transplantation. J Clin Oncol.
40. Treon SP, Branagan AR, Ioakimidis L, et al. Long term out- 2010;28:2227-2232.
comes to fudarabine and rituximab in Waldenstrom’s macro- 46. Kyriakou C, Canals C, Cornelissen JJ, et al. Allogeneic stem-
globulinemia. Blood. 2009;113:3673-3678. cell transplantation in patients with Waldenström macroglobu-
41. Leleu X, Tamburini J, Roccaro A, et al. Balancing risk versus linemia: report rom the Lymphoma Working Party o the
benet in the treatment o Waldenström’s Macroglobulinemia European Group or Blood and Marrow Transplantation. J Clin
patients with nucleoside analogue-based therapy. Clin Lym- Oncol. 2010;28:4926-4934.
ChapTer 15
phoma Myeloma. 2009;9:71-73. 47. Zanwar S, Abeykoon JP, Kapoor P. Novel treatment strategies
42. Treon SP, Hanzis C, Manning RJ, et al. Maintenance rituximab in the management o Waldenstrom macroglobulinemia. Curr
is associated with improved clinical outcome in rituximab Hematol Malig Rep. 2020;15:31-43.
16 Multiple Myeloma
Paul Lin
Gregory P. Kaufman
Hans C. Lee
Elisabet E. Manasanch
Melody Becnel
Sheeba Thomas
Donna Weber
Robert Z. Orlowski
Krina Patel
KEY CONCEPTS
 The updated International Myeloma Working Group trials are investigating quadruplet therapy, with promising
(IMWG) criteria or multiple myeloma includes patients initial results, and they could become standard o care
with bone marrow plasmacytosis o at least 60%, an in the uture.
involved-to-uninvolved serum-ree light-chain ratio o  As o 2020, autologous transplant ater induction che-
at least 100, or more than one ocal lesion on magnetic motherapy remains the standard o care and has shown
resonance imaging (MRI) studies o at least 5 mm in size signifcant improvement in progression-ree survival. This
in addition to the criteria o hypercalcemia, renal disease, might change in the uture depending on disease risk
anemia, and bone disease (CRAB). status, and minimal residual disease testing.
 The IMWG now recommends advanced imaging, such as  Maintenance therapy ater autologous transplant is
whole-body low-dose computed tomography (CT), positron recommended because it has been shown to signifcantly
emission tomography–computed tomography (PET-CT), or improve progression-ree survival.
MRI to evaluate or bone disease because it can detect up
 As o 2020, there is no indication to treat patients with
to 80% more lesions compared with plain flm radiographs.
smoldering myeloma. However, this could change in the
 Triplet therapies, such as with a proteasome inhibitor, uture, because recent trials have shown that treatment
immunomodulatory drugs, and steroids have shown o high-risk smoldering myeloma can potentially delay its
signifcant improvement over doublet therapy. Ongoing progression to myeloma.
Plasma cell dyscrasias are heterogeneous disorders gammopathy, perinephric fuid collection, and intra-
arising rom the prolieration o a monoclonal popu- pulmonary shunting) syndrome. The spectrum o
lation o plasma cells. Some o these disorders can MGUS, SMM, and MM represents a natural progres-
present serendipitously as benign processes that can sion o the same disease. This chapter ocuses on the
be observed; others are highly aggressive and require etiology, genetics, biology, diagnosis, clinical eatures,
immediate intervention. The most common plasma and current therapy o MM.
cell dyscrasia is monoclonal gammopathy o undeter- Major recent discoveries have changed the way we
mined signicance (MGUS), a benign condition that understand, diagnose, and treat plasma cell dyscrasias.
can be observed. Related disorders include smoldering The initial sequencing o the myeloma genome and
multiple myeloma (SMM), multiple myeloma (MM), single-cell genetic analysis paved the way or the con-
solitary plasmacytoma o the bone, extramedullary cept o intraclonal heterogeneity and Darwinian selec-
plasmacytoma, Waldenström macroglobulinemia, pri- tion o clones. Increasingly sensitive diagnostic and
mary amyloid light-chain amyloidosis, heavy-chain monitoring techniques allow or more accurate diag-
disease, POEMS (polyneuropathy, organomegaly, nosis, minimal residual disease (MRD) monitoring,
endocrinopathy, monoclonal gammopathy, and skin and detection o early relapse. New diagnostic criteria
changes) syndrome, and TEMPI (telangiectasias, ele- or MM have been implemented, and the introduction
vated erythropoietin and erythrocytosis, monoclonal o novel classes o agents such as immunomodulatory
341
342 Scion II Lymphoma and Myeloma
drugs and proteasome inhibitors has led to improved Although MM is not an inherited disease, more than
overall survival. In addition, immunotherapy using 100 amilial cases have been reported in the literature.
monoclonal antibodies against dierent myeloma tar- The largest series described 39 unique amilies with 79
gets including CD38 and SLAMF7 (CS1) has signi- cases o MM. Both dominant and recessive inherited
cantly improved outcomes or patients with relapsed traits may play a role in amilial MM. Large genomic
and/or reractory disease. studies have identied low penetrant genetic variants
that coner a modest increase in the risk o developing
MM.1,2 Based on epidemiologic and amilial aggrega-
MULTIPLE MYELOMA tion studies, most o the inherited risk o developing
MM may result rom dierent genetic polymorphisms,
MM is a malignant prolieration o plasma cells. In each o which has only a small eect on the predispo-
virtually all cases, myeloma cells (as well as their pre- sition to develop disease.3
cursors MGUS and SMM) secrete immunoglobulins
(Igs). Usually, myeloma cells secrete IgG (60%); other Pathophysiology and Genetics/Molecular
types are less common (IgA 20%, IgD 2%, IgE <0.1%,
biclonal <1%). Light-chain-only secretion is noted in
Classifcation
18%; less than 5% o patients do not secrete a heavy- MM arises rom terminally dierentiated B cells or
or light-chain immunoglobulin (nonsecretory MM). even early committed B cells (germinal-center B cells)
that maniest clinically as more dierentiated plasma
Chapter 16
cells. The major role o normal dierentiated plasma

Epidemiology and Risk Factors cells is to produce Igs (antibodies) to ght inections.
In 2019, approximately 32,000 people were diagnosed To become an eective part o the adaptive immune
with MM in the United States with, 12,960 deaths system, B cells must undergo Ig gene rearrangement
rom the disease. The median age at diagnosis is 69 and anity maturation in response to antigens pre-
years. The incidence is highest in the age range o 65 sented by antigen-presenting cells within the lymph
to 74 years (27.7%), ollowed by the 75- to 84-year-old node germinal center. For this to occur, hypervariable
range (24.7%). The annual age-adjusted incidence o regions in the Ig heavy-chain locus (IGH in chro-
the disease per 100,000 population is 7.2 among white mosome 14q32) undergo programmed mutations
men and 4.3 among white women. Among Blacks, the (somatic hypermutation) through which, among oth-
requency doubles to 14.8 in men and 10.5 in women. ers, double DNA strand breaks and chromosomal
There is also a dierence in mortality by racial group. translocations are generated. The primary etiology
The annual age-adjusted mortality rate per 100,000 is o MM has been linked to IGH translocations and
4.0 and 2.5 in White men and women, respectively, increased copies o odd-numbered chromosomes
and 7.7 and 5.3 in Black men and women, respectively. (hyperdiploidy), which result in cyclin D dysregula-
The incidence and mortality rates are lowest among tion. These events can be observed early in the course
Asians and Pacic Islanders. o monoclonal gammopathies (such as in MGUS or
Risk actors that predispose to MGUS and MM SMM) as well as in MM, suggesting that they are
point toward common shared etiologic environmen- primary genetic events. Initial whole-genome and
tal and genetic actors. Age is a risk actor or MGUS, exome sequencing in 38 patients with MM conrmed
because its prevalence is our times higher among indi- the complexity o genetic alterations seen in MM and
viduals at least 80 years old than among those 50 to uncovered secondary mechanisms o transormation
59 years old. Increased risk o MGUS has also been to MM.4 Secondary events included mutations in the
reported in rst-degree amily members o patients oncogene MYC (most commonly observed in plasma
with MGUS and MM (risk ratio between 2 and 3). In cell leukemia or aggressive orms o MM), mutations
a study o Black and White women o similar socio- in the nuclear actor-κβ (NF-κβ) pathway, includ-
economic status, obesity, black race, and increasing ing BRAF and RAS, and chromosome copy number
age conerred an increased risk o MGUS. Personal abnormalities such as deletions, amplications, or
and amily history o autoimmune or infammatory additions. Changes in DNA methylation patterns are
disorders as well as inections have been linked to an also important secondary events leading to increased
increased risk o MGUS and MM. Exposure to inec- tumor diversity and more aggressive orms o plasma
tions has been hypothesized to be involved in the cell dyscrasias.
malignant transormation o MM, or it could represent Dierent tests or gene expression proling (GEP)
impaired immunity associated with MGUS and SMM, are available or molecular classication o MM. As o
which oten precedes a diagnosis o MM. Radiation this writing, molecular proling o MM is mostly used
exposure, pesticides, and cleaners are also associated or research purposes (eg, identication o high-risk
with an increased risk o MGUS and MM. MM or inclusion in clinical trials). These tests may
C 16 Multiple Myeloma 343
become increasingly important as we develop more by plasma cells, which lead to decreased erythropoi-
personalized treatment or MM. esis, or decreased erythropoietin levels as a result o
Serial genomic analysis during the disease course renal disease.8
o patients with myeloma has identied dierent Bone pain is common, occurring in 60% o patients,
MM subclones within the same tumor. This has been and related to increased resorption o bone, leading to
termed intraclonal heterogeneity. In this model, dier- lytic bone lesions. Painul vertebral compression rac-
ent myeloma subclones compete or selection as they tures can occur and may represent a medical emergency
are exposed to the microenvironment and therapeu- when associated with symptoms o cord compression.
tic pressures.5 Single-cell genetic analysis at diagnosis Increased bone resorption has been attributed to ac-
conrmed that MM is highly heterogeneous and char- tors such as RANK ligand (RANKL), osteoprotegerin
acterized by the accumulation o a diverse range o (OPG), macrophage infammatory protein (MIP)-1α,
mutations at the subclonal level.6 In this scenario, the IL-6, and IL-3, which stimulate osteoclast activity in
acquisition o new mutations leads to new subclones areas inltrated by plasma cells as a result o interac-
with dierent clinical phenotypes and sensitivities to tions between plasma cells and the microenvironment
therapy. Intraclonal heterogeneity in myeloma has (Fig. 16–1).
many potential implications or therapy, suggesting An elevated creatinine is a presenting sign in 50%
that subclonal targeting in combination therapies may o patients. Renal disease is oten attributed to light-
be needed to eradicate the multiple subclones. Increas- chain cast nephropathy resulting rom precipitation o
ing genetic complexity is seen with progression rom light chains that bind to Tamm-Horsall mucoproteins
Chapter 16
MGUS to MM and plasma cell leukemia, which may secreted by cells in the ascending loop o Henle. These
suggest that earlier treatment may result in improved precipitated complexes obstruct the distal convoluted
clinical outcomes. tubules and collecting ducts, leading to tubular atrophy
The bone marrow microenvironment also plays a and interstitial brosis. Other causes o renal ailure
role in the etiology o MM and its related disorders. include hypercalcemia, leading to nephrocalcinosis, as
Upregulation o cytokines that increase vascular per- well as amyloidosis, heavy-chain disease, and light-
meability, prolieration, or cell homing (interleukin chain disease.
[IL]-6, vascular endothelial growth actor, and insulin- Hypercalcemia o higher than 11 mg/dL is present
like growth actor) have been involved in the progres- in 10% o patients and represents a medical emergency
sion to MM. Gene expression proling has revealed requiring hydration with isotonic saline and bisphos-
that modulation o certain genes can lead to a per- phonate therapy with zoledronic acid or pamidronate
missive microenvironment that promotes growth o in moderate or severe cases. Calcitonin can also be
myeloma subclones, leading to active disease.7 Thus, used to rapidly reduce serum calcium levels.
targeting the microenvironment is an area o extensive Other common presenting symptoms include
research that, combined with therapeutic targeting o atigue (32%) and weight loss (20%). As a result o
myeloma subclones, may lead to improved outcomes. immune dysunction, patients are at risk or inec-
New and eective antimyeloma combination thera- tions. About 7% to 18% o patients may present with
pies and well-designed clinical trials are needed to test extramedullary plasmacytomas. Less common symp-
these hypotheses. toms include ever, splenomegaly, hepatomegaly, and
lymphadenopathy.
The clinical presentation o MM and its precur-
sors is variable. Patients with MGUS or SMM are
oten incidentally diagnosed based on workup or a
low albumin-to-globulin ratio, high serum protein,
or other conditions such as autoimmune diseases,
peripheral neuropathy, skin rashes, or hemolytic
anemias.
In contrast, patients initially presenting with MM
usually have at least one o the CRAB criteria (hyper-
Calcemia, Renal disease, Anemia, and Bone disease),
classically used to dene symptomatic MM. Anemia
is the most common nding, occurring in 73% o
patients, and is typically a normocytic, normochromic FIGUre 16–1 Radiographic image o the skull showing
anemia. Anemia can be caused by a variety o actors, “punched out” osteolytic lesions characteristic o multiple
including marrow replacement or cytokine production myeloma.
Diagnostic Workup – A CT scan can be helpul in the characterization

o sot tissue masses in the case o extramedul-
Once a plasma cell dyscrasia is suspected, a compre- lary plasmacytomas and can direct to an area to
hensive diagnostic workup should be initiated to dem- be biopsied.
onstrate the presence or absence o a clonal plasma cell – An MRI scan is useul or evaluating the axial skel-
disorder, to determine whether end-organ damage is eton in the presence o symptoms and assessing
present, and to evaluate laboratory markers related or spinal cord compression. It can also identiy
to prognosis. These should include the ollowing abnormal marrow uptake because T1-weighted
components. images will show a diuse decrease in marrow
signal intensity but will enhance with the admin-
Laboratory Studies istration o contrast.
• Complete blood count – PET-CT can be prone to alse-positive indings
• Serum chemistries including creatinine, calcium, albu- but has more speciicity because o its increased
min, lactate dehydrogenase (LDH), β2-microglobulin, metabolic uptake at the site o lytic lesions, and
and immunoglobulin levels (IgG, IgA, IgM) is the preerred initial baseline advanced imaging
• Serum protein electrophoresis with immunoxa- modality at the MDACC, in combination with
tion to quantiy monoclonal protein (M-protein) skeletal surveys.
and determine immunoglobulin isotype – There is no role or nuclear bone imaging because
bone scan isotopes are not taken up by lytic
Chapter 16
• Serum-ree light-chain assay to evaluate the ratio o

serum κ to λ light chains lesions.
• Urinalysis with 24-hour urine collection with pro-
tein electrophoresis and immunoxation (Fig. 16–2) Bone Marrow Aspiration and Biopsy
• Morphologic review and immunohistochemistry
Imaging Studies (Fig. 11–3)
• The International Myeloma Working Group • Flow cytometry or immunophenotyping o plasma
(IMWG) now recommends that advanced imag- cells:
ing with either whole-body low-dose computed – Plasma cells are positive or CD38 and CD138.
tomography (CT), positron emission tomogra- – Normal plasma cells have higher expression o
phy–computed tomography (PET-CT), or magnetic CD19 and CD45; malignant plasma cells typically
resonance imaging (MRI) be used because they can lack these surace antigens.
detect up to 80% more lesions compared with plain – Malignant plasma cells have increased expression
lm radiographs.9 o CD56 and CD117; normal plasma cells have
– An advanced imaging modality is particularly weak expression o these markers.
recommended in the diagnosis o SMM to detect • Conventional cytogenetic karyotyping.
subtle bone lesions that would warrant the ini-
tiation o treatment. It is also helpul in assessing
baseline disease burden as an adjunct to serum
and urine markers beore initiation o treatment
in MM.
Serum 2
Serum Protein Electrophoresis ELP G A M K L
FIGUre 16–2 Serum protein electrophoresis demonstrates FIGUre 16–3 Multiple myeloma bone marrow aspirate.
an M-protein peak (let). Immunofxation confrms it to be Some plasma cells have cytoplasmic immunoglobulin
monoclonal IgG lambda type. inclusions (Wright-Giemsa, 500×).
• Fluorescent in situ hybridization (FISH) or recur- therapeutic plasma exchange should not be delayed
rent chromosomal deletions, amplications, and while waiting or the results o serum viscosity
translocations that have prognostic signicance. level.
These include:
– Deletion 13q14, deletion 17p13 (TP53), and dele-
tion o 1p32.
Myeloma Diagnostic Criteria
– Ampliication o 1q21. Based on the above workup, a diagnosis o a plasma
– Translocations involving the immunoglobulin cell dyscrasia may be made, as summarized in
heavy-chain locus on chromosome 14q32 and Table 16–1.10 Historically, SMM and MM have been
its common partners, including 11q13 (CCND1), distinguished by the presence o end-organ damage as
4p16 (FGFR3 and MMSET), 16q23 (c-MAF), 6p21 dened by CRAB criteria. The 2014 updated IMWG
(CCND3), and 20q12 (MAFB). criteria were revised to reclassiy some SMM patients
• GEP o the CD138+ bone marrow aspirate plasma as having MM (even in the absence o symptoms) i
cells to identiy high-risk MM and to acilitate inclu- the patient has clonal bone marrow plasmacytosis o
sion in clinical trials. at least 60%, an involved-to-uninvolved serum-ree
light-chain ratio o at least 100, or more than one ocal
Other Tests lesion on MRI studies o at least 5 mm in size. Patients
with SMM and at least one o these biomarkers have
• Abdominal wall at pad biopsy (warranted i there a 70% to 80% chance o progression to MM at 2 years
Chapter 16
are signs and symptoms suggestive o amyloidosis; compared with 20% (10% per year) in the absence o
see separate chapter), which should be stained with these high-risk eatures.
Congo red. Amyloid brils show green birerin-
gence under polarized light.
• Serum viscosity (i there are concerns or hyperviscos- Staging and Risk Stratifcation
ity usually caused by elevated IgM levels in Walden- The course o MM is heterogeneous. Risk stratica-
ström macroglobulinemia; see separate chapter). tion using staging and prognostic tools can help stratiy
Hyperviscosity should be a clinical diagnosis, and patients in clinical trials and may help guide therapy.
tbl 161 Dfniions o MGUS, SMM, nd MM by 2014 IMWG Cii
Defnition Progression Rate

Premalignant Monoclonal • Monoclonal protein <3 g/dL • 1% per year or MGUS
gammopathy o • Clonal bone marrow plasma cells <10% • 0.3% per year or light-
undetermined • Absence o CRABa criteria related to plasma cell clonal chain MGUS
signicance disorder
(MGUS) • In light-chain MGUSb, urinary monoclonal protein
must be <500 mg/24 h
Smoldering • Serum monoclonal protein ≥3 g/dL or urinary 10% per year (see
multiple monoclonal protein ≥500 mg/24 h and/or bone Table 16-4 or risk
myeloma marrow plasmacytosis 10%–60% stratication in SMM)
(SMM) • Absence o CRAB criteriaa or amyloidosis
Multiple myeloma • Clonal bone marrow plasma cells ≥10% or biopsy- Not applicable
(MM) proven bony or extramedullary plasmacytoma AND
• Evidence o end-organ damage attributed to a
plasma cell disorder as dened by CRABa criteria OR
≥1 biomarker o malignancy, which includes bone
marrow clonal plasmacytosis ≥60%, involved-to-
uninvolved serum-ree light chains ≥100, or >1 ocal
lesion on MRI studies that is at least 5 mm in size
a
CRAB criteria:
1. HyperCalcemia: Serum calcium >1 mg/dL above the upper limit o normal or >11 mg/dL.
2. Renal insuciency: creatinine clearance <40 mL/min or serum creatinine >2 mg/dL.
3. Anemia: hemoglobin <2 g/dL below the lower limit o normal or <10 g/dL.
4. Bone lesions: one or more osteolytic lesions on skeletal survey, CT scan, or PET-CT.
b
Dened as abnormal ree light-chain ratio (<0.26 or >1.65) in the absence o immunoglobulin heavy-chain expression on immunoxation.
Adapted with permission rom Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria or the diagnosis o multiple
myeloma, Lancet Oncol 2014 Nov;15(12):e538-e548.
tbl 162 risk Sifcion o Nwly Dignosd Mulil Mylom
Revised International Staging System

Stage I Parameters: Albumin ≥3.5 g/dL, β2-microglobulin <3.5 mg/L, normal LDH, no high-risk
chromosomal abnormalities
Median Overall Survival: Not reached
Stage II Parameters: Neither stage I nor stage III
Median Overall Survival: 83 months
Stage III Parameters: β2-microglobulin ≥5.5 mg/L and either high LDH or high-risk chromosomal
abnormalities
Median Overall Survival: 43 months
High-risk chromosomal abnormalities as determined by interphase FISH:
del(17p), t(4;14), t(14;16)
Risk Stratication
Standard risk t(11;14)
t(6;14)
Hyperdiploid karyotype
Intermediate risk t(4;14)
Chapter 16
Del 13q
Hypodiploid karyotype
High risk Del 17p13
Amplication o 1q21
t(14;20)
t(14;16)
Lactate dehydrogenase ≥2× institutional upper limit o normal
Plasma cell leukemia
High-risk gene expression proling signature
International Staging System and FISH. The presence o del(17p), t(4;14), t(14;16),
t(14;20) gain 1q, or p53 mutation is considered high-
The International Staging System (ISS) was established
risk MM. Recently, high-risk myeloma was urther
in 2005 by the IMWG ater a retrospective analysis o
dened as double-hit myeloma when two high-risk
the outcomes o more than 10,000 patients across 17
actors are present, and triple-hit myeloma when three
dierent centers. In this study, β2-microglobulin and
or more high-risk actors are present. More risk actors
albumin were powerul correlates o median survival,
portend worse outcomes. Risk stratication based on
and patients could be categorized into three stages
these criteria is summarized in Table 16–2.
based on serum levels at diagnosis. The staging system
was subsequently revised to include LDH and high-
risk chromosomal abnormalities (Table 16–2). Because Response Criteria
β2-microglobulin is excreted renally, high levels may International Myeloma Working Group Uniorm
be ound in the presence o renal ailure, which makes Response Criteria
the interpretation o the ISS in this setting challenging.
The ISS is the preerred staging method and has sup- The IMWG proposed new guidelines in 2006 to stan-
planted the previously used Durie-Salmon staging sys- dardize response criteria in MM and to dene disease
tem, which was conounded by observer-dependent progression to acilitate comparisons o outcomes
variables. It is important to note that the ISS has only between treatment centers and or reporting results in
been validated at the time o diagnosis in patients with clinical trials. These International Uniorm Response
MM and should not be extrapolated to patients with Criteria guidelines are summarized in Table 16–3.
MGUS or SMM. Assessment o response with M-protein measure-
ments using serum protein electrophoresis, urine pro-
tein electrophoresis, and serum-ree light-chain assay
Risk Stratication
is recommended prior to each cycle o therapy. Bone
In addition to the ISS, patients can be stratied into stan- marrow biopsy is necessary to monitor disease in the
dard-, intermediate-, and high-risk categories based on absence o a measurable M-protein in the serum or
cytogenetic ndings by both conventional karyotyping urine or to document a complete or stringent complete
tbl 163 IMWG Innionl Uniom rsons Cii
Response Category Criteria

sCR Meets criteria or CR PLUS
Normal ree light chain ratio AND
No clonal cells in bone marrow by immunohistochemistry or immunouorescence
CR Negative serum and urine immunoxation AND
Disappearance o any sot tissue plasmacytomas AND
≤5% plasma cells in bone marrow
VGPR Serum and urine M-protein detectable by immunoxation but negative M-protein OR
≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h
PR ≥50% reduction o serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg
per 24 h
I unmeasurable serum and urine M-protein, ≥50% decrease in the diference between involved and
uninvolved FLC levels
I unmeasurable serum and urine M-protein serum FLC assay, ≥50% reduction in plasma cells is
required in place o M-protein, as long as baseline bone marrow plasma cell percentage was ≥30%
In addition to above criteria, a ≥50% reduction in the size o any baseline sot tissue plasmacytoma is
required
Chapter 16
SD Not meeting criteria or CR, VGPR, PR, or progressive disease
PD Increase o ≥25% rom baseline in at least one o the ollowing:
• Serum M-component (the absolute increase must be ≥0.5 g/dL)
• Urine M-component (the absolute increase must be ≥200 mg/24 h
• Dierence between involved and uninvolved FLC levels if serum and urine M-protein are
unmeasurable (the absolute increase must be >10 mg/dL)
• Bone marrow plasma cell percentage (the absolute % must be ≥10%)
Development o new bone lesions or sot tissue plasmacytomas or denite increase in size o existing
bone lesions or sot tissue plasmacytomas
Development o hypercalcemia >11.5 mg/dL related to plasma cell dyscrasia
CR, complete response; FLC, ree light chain; IMWG, International Myeloma Working Group; M-protein, monoclonal protein; PD, progressive disease; PR, partial
response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
Adapted with permission rom Durie BG, Harousseau JL, Miguel JS, et al. International uniorm response criteria or multiple myeloma, Leukemia 2006
Sep;20(9):1467-1473.
response. Serial imaging assessments may be required or harmonized MRD detection assay and analysis by
i sot tissue plasmacytomas are present at baseline. multiparameter fow cytometry in clinical practice and
in clinical trials is ongoing.
Minimal Residual Disease
In recent years, the raction o patients achieving deep Treatment o Newly Diagnosed Multiple
responses, including complete remission, ater initial Myeloma
MM therapy has increased signicantly. This corre- Ater the diagnostic workup and risk stratication are
lates with improved progression-ree survival (PFS) complete, patients who meet the criteria or MM as
and overall survival (OS) in several studies11 With a dened by IMWG criteria should initiate therapy. The
deepened level o remission, more sensitive methods most important initial assessment is whether a patient
to assess and monitor MRD have been investigated. is a candidate or high-dose chemotherapy and autolo-
These include fow cytometry, allele-specic poly- gous stem cell transplantation (SCT), largely based on
merase chain reaction, and next-generation sequenc- existing comorbidities and age. In the transplant-eligi-
ing–based assays.12 MRD may soon be used as a valid ble population, current MM standard o care involves
surrogate end point to compare treatment strategies rontline chemotherapy, ollowed by consolidative
and advise on consolidation and maintenance thera- high-dose melphalan and autologous SCT, ollowed by
pies. As o this writing, MRD assessment by multi- maintenance therapy. Some chemotherapy agents (eg,
parameter fow cytometry is the most reproducible melphalan) may adversely aect stem cell collection
method in MM. It has a sensitivity o 10–5 i at least and should be avoided in the initial therapy o trans-
2 × 106 cells rom bone marrow aspirates are ana- plant-eligible patients. Melphalan may be included in
lyzed. An international eort to adopt standardized the rontline therapy o transplant-ineligible patients.
Frontline Therapy or Transplant-Eligible Patients and dexamethasone versus vincristine, doxorubicin,
and dexamethasone (VAD) therapy beore autolo-
A number o dierent regimens can be used in the ront-
gous SCT.15 Postinduction ORR (78.5% vs 62.8%),
line setting or transplant-eligible patients. These usu-
higher VGPR rates (37.7% vs 15.1%), and complete
ally consist o two- or three-drug combinations, and the
response (CR) or near complete response rates (14.8%
choice o therapy is individualized based on actors such
vs 6.4%) all avored the bortezomib and dexametha-
as patient comorbidities (neuropathy, diabetes), preerred
sone arm over the VAD arm. There was also a trend
route o administration (oral, intravenous, or subcutane-
toward improved median PFS in the bortezomib and
ous), and underlying disease biology (eg, bortezomib in
dexamethasone arm (36.0 vs 29.7 months) but no
t(4;14) and del 13q). Patients are usually given two to our
dierence in OS. In a separate analysis, initial treat-
cycles o therapy beore stem cell collection to reduce dis-
ment with bortezomib and dexamethasone beore
ease burden beore proceeding to high-dose chemother-
autologous SCT was shown to overcome the adverse
apy and autologous stem cell rescue. Given the evidence
prognostic eatures o t(4;14) in relation to event-ree
that the depth and duration o response may translate
survival (EFS) and OS compared with VAD, although
into improved long-term outcomes, we generally preer
del 17p remained a poor prognostic actor regardless
the three-drug regimens over the two-drug regimens as
o the treatment regimen. Herpes simplex prophy-
initial therapy in newly diagnosed patients.
laxis with acyclovir or valacyclovir should be given
with bortezomib-containing regimens. Subcutaneous
Lenalidomide and Dexamethasone administration o bortezomib is preerred because
Chapter 16
The ecacy o the second-generation immunomodu- it has similar ecacy as the intravenous route with
latory drug (IMiD) lenalidomide was shown in a ran- decreased peripheral neuropathy.16
domized phase 3 study comparing lenalidomide plus
high-dose dexamethasone (Len/Dex) versus placebo Cyclophosphamide, Bortezomib, and
plus high-dose dexamethasone.13 Overall response rates Dexamethasone
(ORR), dened as a partial response or greater, and very
good partial response (VGPR) rates were signicantly The addition o oral cyclophosphamide to bortezomib
higher in the Len/Dex arm (78% and 63%, respectively) and dexamethasone (CyBorD) was studied in phase 2
versus the placebo/Dex arm (48% and 16%, respec- trials. In the EVOLUTION phase 2 trial, patients were
tively). The one-year PFS rate was also higher in the Len/ randomly assigned to receive bortezomib, lenalidomide,
Dex arm (78% vs 52%), although there was no signi- and dexamethasone (VRD); bortezomib, lenalidomide,
cant dierence in OS between the two groups (94% vs cyclophosphamide, and dexamethasone); or CyBorD, all
88%). Grade 3 or 4 neutropenia was higher with Len/ ollowed by maintenance bortezomib or our 6-week
Dex (21% vs 5%), as was the rate o venous thrombo- cycles.17 The study was later amended to add an addi-
embolism (23.5% vs 5%) despite aspirin prophylaxis. tional day 15 dose o cyclophosphamide, in addition
To possibly decrease the dexamethasone dose, a to days 1 and 8, in patients receiving CyBorD. Patients
randomized study was conducted with lenalidomide receiving the modied CyBorD regimen achieved an
in combination with high-dose dexamethasone (40 ORR o 82%, with a VGPR or better rate o 53% and a
mg on days 1–4,8–11, and 17–20 every 4 weeks) ver- CR rate o 47%. The one-year PFS rate was 100%.
sus low-dose dexamethasone (40 mg on days 1,8, 15, In another phase 2 study, standard twice-weekly
and 22 every 4 weeks).14 Patients receiving high-dose (days 1,4, 8, and 11) bortezomib was compared with
dexamethasone achieved a higher ORR (79% vs 68%) weekly bortezomib (days 1,8, 15, and 22) in combination
ater our cycles o therapy. However, a second interim with weekly cyclophosphamide and dexamethasone.18
analysis at one year demonstrated a statistically sig- ORR (88% vs 93%) and VGPR rates (60% vs 61%) were
nicant superior OS in the low-dose dexamethasone similar in both the twice-weekly and weekly bortezo-
arm compared with the high-dose arm (96% vs 87%). mib groups. In addition to demonstrating the ecacy o
This was attributed to increased toxicities o high-dose the three-drug combination o CyBorD, this study also
dexamethasone therapy including venous thrombo- suggested that weekly (instead o twice-weekly) bort-
embolism and inections. Based on this study, lenalido- ezomib could be used to reduce treatment-related tox-
mide is recommended to be given in combination with icity because it resulted in ewer grade 3 and 4 adverse
low-dose dexamethasone. events compared with the twice-weekly schedule (37%
and 3% vs 48% and 12%, respectively).
Bortezomib and Dexamethasone
The proteasome inhibitor bortezomib in combina- Bortezomib, Lenalidomide, and Dexamethasone
tion with dexamethasone was studied as rontline The ecacy o VRD has also been demonstrated in
therapy in a large phase 3 trial comparing bortezomib several phase 2 and 3 trials. As mentioned, VRD was
also included as one o the arms in the phase II EVO- regimen or a xed duration o 72 weeks versus melpha-
LUTION trial, which resulted in an 85% ORR, with a lan, prednisone, and thalidomide (MPT) in 6-week cycles
VGPR or better rate o 51% and a CR rate o 24%.17 or 72 weeks were compared in a randomized phase 3
The phase 3 Southwest Oncology Group (SWOG) study in more than 1500 transplant-ineligible patients.28
S0777 trial showed a median progression ree survival Although the ORRs were similar between the three
(mPFS) o 41 months or VRd vs 29 months or Rd and arms, median PFS avored continuous Rd (25.5 months)
a medium OS (mOS) or VRd that was not reached versus 18 cycles o Rd (20.7 months) and MPT (21.2
vs 69 months.19 In addition, the role and timing o months). There was a trend toward improved 3-year
autologous SCT are being reexamined in the era o OS with continuous Rd (59%) versus xed-duration Rd
novel agents in a large international phase 3 trial o (56%) and MPT (51%). There was also a trend toward
rontline VRD ollowed by lenalidomide maintenance ewer grade 3 and 4 adverse events in the continuous
therapy (with the option o SCT at the time o relapse) Rd arm (70%) compared with the MPT arm (78%), in
versus VRD ollowed by autologous SCT per the cur- particular grade 3 and 4 neutropenia and neuropathy.
rent standard o care (NCT01208662). The phase 3 However, there was a higher incidence o grade 3 and
ENDURANCE trial evaluating the second-generation 4 inections with continuous Rd (29%), likely related to
proteasome inhibitor carlzomib in combination with the longer duration o glucocorticoid use.
lenalidomide and dexamethasone (KRd) in the ront- A community-based phase 3B trial compared bort-
line setting showed similar results to RVD.20 These ezomib and dexamethasone (BD) versus bortezomib,
studies will clariy the role o triplet combinations in thalidomide, and dexamethasone (BTD) versus mel-
Chapter 16
the rontline setting and provide insight as to whether phalan, prednisone, and bortezomib (MPB) ollowed
deeper responses, including molecular responses, with by maintenance bortezomib.29 The ORR, PFS, and OS
the multiple novel agents in combination, ultimately were similar across all three arms. Discontinuation
translate into improved long-term outcomes. because o adverse events was highest in the BTD arm
Monoclonal antibodies have been gaining interest (35%) compared with BD (24%) and MPB (30%). This
in the rontline setting as quadruplet therapies, such demonstrates the saety and ecacy o the use o BD in
as in the GRIFFIN trial with daratumumab (CD38 the elderly population. RVD can also be used because
antibody) combined with bortezomib, lenalidomide, patients in the SWOG S0777 trial mentioned above were
dexamethasone, which have shown promising results not required to receive transplant. Furthermore, a regi-
with superior stringent CR rates.21 However, not all men with decreased dose o lenalidomide (15 mg instead
quadruplet therapies are benecial, because the addi- o the usual 25 mg) and dexamethasone (20 mg vs 40
tion o elotuzumab (SLAMF7 antibody) to bortezo- mg) termed “RVD lite” can also be considered in more
mib, lenalidomide, dexamethasone did not improve rail patients because it was shown to have an ORR o
PFS in the phase 2 SWOG-1211 trial.22 86% with a mPFS o 35.1 months.30 In general, the incor-
poration o novel agents to combination therapy has
Frontline Therapy or Transplant-Ineligible improved ORR and long-term outcomes in older adult,
Patients transplant-ineligible patients. However, treatment must
be individualized based on comorbidities and disease
Initial treatment regimens or transplant-eligible patients characteristics as well as the patient’s own goals o care.
can also be used in transplant-ineligible patients. With-
out the need to collect autologous stem cells, the alkyl-
ating agent melphalan can be incorporated into rontline Stem Cell Transplantation
therapy in nontransplant candidates. For 40 years, mel-
Autologous Stem Cell Transplantation
phalan and prednisone (MP) represented the standard
o care or transplant-ineligible patients. Trials adding High-dose melphalan without autologous SCT was
other novel therapies to the MP backbone such as tha- rst reported in 1983 by McElwain and colleagues rom
lidomide,23 lenalidomide,24,25 and bortezomib26 dem- the Royal Marsden Hospital. Compared with chemo-
onstrated improved ORR and PFS. More recently the therapy alone, intensied chemotherapy ollowed by
phase 3 ALCYCONE trial showed that the addition o autologous SCT appears to prolong OS in previously
daratumumab to bortezomib plus MP (VMP) resulted untreated patients with MM. One comparative study
in a 36-month rate o OS o 78% in the D-VMP group and two randomized trials showed that autologous SCT
compared with 67.9% in the VMP group ater a median provided survival benets o approximately 12 months.
ollow-up o 40.1 months.27 However, in the US, non– In the French IFM 90 trial, high-dose chemother-
melphalan-containing combinations now orm the new apy supported by autologous SCT was compared
standard o preerred regimens. with conventional chemotherapy in 200 previously
Lenalidomide and low-dose dexamethasone (Rd) in untreated patients younger than 65 years old with
4-week cycles until disease progression versus the same MM.31 The results showed a higher CR rate (22% vs
5%) and higher rates o 5-year EFS (28% vs 10%) and Fermand et al compared early and late autologous
OS (52% vs 12%) in the autologous SCT group. The SCT and reported a similar OS.35 However, the aver-
median OS in patients assigned to the SCT arm was 13 age time without symptoms, treatment, and treat-
months longer (57 vs 44 months). ment toxicity were signicantly better with early
The Medical Research Council Myeloma VII trial autologous SCT. A retrospective study o 167 patients
compared conventional-dose chemotherapy with who received induction therapy containing at least
high-dose therapy and autologous SCT in 401 previ- one o three novel agents (lenalidomide, thalido-
ously untreated patients younger than 65 years old mide, or bortezomib) ollowed by autologous SCT,
with MM.32 The rates o CR were signicantly higher either within 12 months o diagnosis or later, ound
in the autologous SCT group (44% vs 8%). Intent-to- a higher CR rate in the early autologous SCT arm but
treat analysis showed a signicantly higher rate o OS no dierence in PFS or OS. The potential benet o
and PFS with SCT. Compared with standard therapy, early versus late autologous SCT was assessed in a
autologous SCT increased median OS by almost 12 trial that randomly assigned patients between 55 and
months (54.1 vs 42.3 months). There was a trend 65 years o age to either conventional chemotherapy
toward a greater survival benet in patients with poor alone or chemotherapy ollowed by autologous SCT.
prognosis (dened by β2-microglobulin level >8 mg/L). With a median ollow-up o 120 months, a trend
In three other randomized studies, however, there toward better event ree survival (EFS), but no OS
has been no survival benet with autologous SCT.33–35 benet, was observed in patients undergoing early
Comparison among these trials is dicult because o the transplantation.35 Finally, the US Intergroup Trial
Chapter 16
variability in patient eligibility, including age, induction S9321 ound no PFS or OS benet with early SCT. 33
chemotherapy, conditioning regimen or SCT, and de- A recent cost analysis study by Pandya et al suggests
nitions o response. The timing o transplantation given that early autologous SCT is cost eective compared
the existence o the new triplet regimens was evaluated with delayed autologous SCT.39
in the large 700-patient French IFM 2009 trial.36 Patients At MDACC, we oer autologous SCT to all eligible
received either VRD or eight cycles or VRD or three patients ater induction therapy regardless o age. We
cycles ollowed by autologous SCT and two additional use a preparative regimen o melphalan 200 mg/m2 or
cycles o VRD, with both arms receiving lenalidomide busulan and melphalan (unless the patient is treated
maintenance or one year. The transplant group had a in a clinical trial with a novel preparative regimen). In
signicantly longer mPFS o 50 months vs 36 months selected patients (>70 years old or dialysis dependent),
with a higher CR o 59% versus 48% and MRD nega- we lower the melphalan dose to 140 mg/m.2 We oer
tivity o 79% versus 65%. The nontransplant group tandem autologous SCT only in the setting o a clini-
underwent transplantation ater salvage therapy or cal trial or i there is signicant residual disease ater
relapsed disease. Overall survival at our years was not rst autologous SCT. A second salvage transplant is an
signicantly dierent (82% vs 81%). Thus, autologous option or patients with relapsed disease; we oer this
SCT has become the standard o care or eligible patients mainly to patients whose benet rom transplant was
based on perormance status and organ unction. more than 18 months and whose disease burden can
Many dierent preparative regimens have been be signicantly reduced by salvage chemotherapy. We
assessed over the last 20 years, but ew have compared oer maintenance therapy ater transplantation (dis-
the dierent regimens. One prospective randomized cussed later).
trial by the IFM directly compared two dierent prepara- At MDACC, we only perorm reduced-intensity
tive regimens37 in 282 newly diagnosed patients younger allogeneic SCT. We use the tandem autologous plus
than 65 years old and ound that high-dose melphalan allogeneic SCT approach only in the setting o a clini-
at 200 mg/m2 to be superior to a combination o mel- cal trial. Allogeneic SCTs are oered to patients with
phalan 140 mg/m2 plus 8 Gy o total-body irradiation, relapsed, chemotherapy-sensitive disease who are less
mainly because o reduced toxicity including mucositis than 70 years old, have an HLA-identical sibling or
and transplant-related mortality. A recent phase 3 ran- unrelated donor, and are in good general physical con-
domized clinical trial rom MDACC compared busulan dition because toxicity is signicant. Our preparative
and melphalan with melphalan alone and ound that the regimen is a combination o fudarabine and melpha-
combination resulted in a median PFS o 64.7 months vs lan (100 or 140 mg/m2), with antithymocyte globulin
43.5 months, but at a cost o increased grade 2–3 muco- added or unrelated donor SCT.
sitis (74% vs 14%).38 Melphalan remains the standard o To improve outcomes o autologous transplantation
care, but the addition o novel agents to conditioning is by adding a grat-versus-myeloma component, current
being investigated, especially in high-risk patients. laboratory research and clinical trials at MDACC are
Transplantation can be perormed either early ocused on eradicating MRD ater autologous SCT
ater induction therapy or later at disease progression. using cellular therapy and vaccines.
Maintenance Therapy Alternative maintenance strategies have been

investigated. Bortezomib maintenance was investi-
To delay the time to disease recurrence, maintenance gated in the phase 3 Hemato-Oncologie voor Volwas-
therapy ater autologous SCT has been explored to senen Nederland (HOVON)-65/German Multicenter
limit growth o residual malignant plasma cells. Initial Myeloma Group (GMMG)-HD4 trial, where patients
maintenance strategies included intereron-α, although were randomly assigned to receive either vincristine,
treatment-related toxicities made it challenging to doxorubicin, dexamethasone (VAD), or bortezomib,
administer. The approval o thalidomide in the late doxorubicin, and dexamethasone (PAD) induction, ol-
1990s renewed interest in maintenance therapy. Multi- lowed by high-dose melphalan and autologous SCT.46
ple trials showed improvements in PFS and sometimes Patients were then randomized again to receive either
OS with thalidomide maintenance ater autologous thalidomide or bortezomib maintenance therapy or
SCT. Toxicities related to long-term therapy, notably two years. The CR, PFS, and OS rates all avored bort-
peripheral neuropathy, made it dicult to tolerate. ezomib-containing induction and maintenance regi-
Given its more avorable side eect prole, mens, and benet was also noted in high-risk patients
lenalidomide maintenance therapy ater autologous with del 17p. The phase 3 TOURMALINE-MM3 study
SCT was next explored. The Cancer and Leukemia investigated the oral proteasome inhibitor, ixazomib,
Group B (CALGB) study randomized patients to as maintenance ater transplantation and ound an
lenalidomide or placebo maintenance starting 100 increase in mPFS to 26.5 months compared with 21.3
days ater autologous SCT. 40,41 With a median ollow- months with placebo.47 There is an ongoing nonine-
Chapter 16
up o 91 months, mPFS was signicantly greater in riority trial comparing ixazomib with lenalidomide
the lenalidomide arm (57.3 vs 28.9 months) as was maintenance (NCT02253316). In addition, other dou-
the mOS (113.8 months vs 84.1 months). The IFM blet combination maintenance trials are ongoing; the
reported a similar trial in which patients received two phase 3 AURIGA (MMY3021) trial is currently evaluat-
4-week cycles o consolidation with lenalidomide ing the rate o conversion to MRD negativity ater one
25 mg ater autologous SCT beore being randomly year o treatment (NCT03901963).
assigned to lenalidomide maintenance versus pla- In general, at MDACC we oer patients lenalido-
cebo.42 PFS also avored lenalidomide maintenance mide maintenance therapy ater autologous SCT. In
(median PFS, 41 vs 23 months), but there was no di- the setting o high-risk cytogenetic eatures, a combi-
erence in OS at our years. Finally, in the Myeloma nation proteasome inhibitor with IMiD maintenance
XI trial, rom the UK, PFS was also improved (39 vs should be considered based on available data or bort-
20 months), though with no dierence in OS ater a ezomib and carlzomib.48,49
median ollow-up o 31 months. However, prespeci-
ed subset analysis showed that the 3-year OS in
transplantation-eligible patients was 87.5% versus Treatment o Relapsed/Reractory Multiple
80.2% in the control group. The transplant-ineligible Myeloma
group showed no signicant OS benet. The lon-
We recommend enrollment in clinical trials when
ger lenalidomide maintenance appears to increase
possible or all patients with relapsed/reractory
the time o response. In one study, they ound that
MM. Alternatively, there are a number o therapeu-
lenalidomide continued or more than 24 months led
tic options that have gained regulatory approval that
to an improved mPFS ater transplant o 77 months
may be considered in this setting. Treatment usually
compared with patients who had 12 to 24, and less
involves combinations o triplets.
than 12 months o maintenance, with a mPFS o 6.5
and 26 months, respectively. 43
Studies have reported an increase in second primary Immunomodulatory Drugs
malignancies with lenalidomide maintenance (8% in Many patients may already be on maintenance lenalid-
the CALGB and IFM studies) versus placebo (3% in omide at the time o disease recurrence.
CALGB and 4% in IFM). However, when all compet- Pomalidomide is a third-generation IMiD with
ing actors or death are considered (including death greater in vivo potency than thalidomide and lenalido-
rom relapsed MM), patients have a much higher risk mide. In a phase 3 study in relapsed/reractory MM,
o mortality rom other causes rather than secondary patients were randomly assigned to receive either
malignancies.44,45 Potential risks and benets o lenalid- pomalidomide plus low-dose dexamethasone (Pd)
omide maintenance should be discussed with patients versus only high-dose dexamethasone.50 Around 75%
to make inormed decisions. Lenalidomide mainte- patients were double reractory to both lenalidomide
nance can also be considered in nontransplant patients and bortezomib. The ORR was 35% with Pd versus
ater initial therapy based on the phase 3 MPL-L versus 10% with high-dose dexamethasone. The median
MPL versus MP study.24 PFS was 4.0 months with Pd versus 1.9 months with
high-dose dexamethasone. Based on these results, results,56 with one study showing an ORR o 87% with
pomalidomide gained FDA approval or reractory MM 31% CR when given at rst relapse.57 OS results are
with prior bortezomib and lenalidomide exposure. still immature. Although earlier studies established the
maximum tolerated dose o carlzomib at 20 mg/m2
Proteasome Inhibitors or cycle 1 and 27 mg/m2 twice weekly or subsequent
cycles, phase 1 and 2 data have emerged demonstrating
Bortezomib has shown ecacy in relapsed MM in two the saety and ecacy o higher doses o carlzomib
large randomized phase 3 trials. The APEX phase 3 trial up to 56 mg/m2 administered over 30 minutes com-
compared intravenous bortezomib to high-dose dexa- pared with a 2- to 10-minute intravenous bolus given
methasone; ORR, PFS, and OS were all superior in the in earlier studies.58 However, the SWOG randomized
bortezomib arm. As mentioned, subcutaneous bort- phase 2 study comparing high-dose versus low-dose
ezomib is avored over the intravenous route because carlzomib (with dexamethasone in both arms) dem-
o similar ecacy and less peripheral neuropathy.16 onstrated no dierence in response rate, PFS, or OS,
Bortezomib has also been studied in combination but with higher rates o atigue, thrombocytopenia,
with other agents. The addition o pegylated liposo- and peripheral neuropathy with the higher dose.59
mal doxorubicin in combination with bortezomib Finally, based on the ENDEAVOR, A.R.R.O.W., and
gained regulatory approval ater demonstrating supe- CHAMPION-1 trials, weekly dosing o carlzomib
rior PFS compared with bortezomib monotherapy in at 70 mg/m2 has an ecacy prole comparable with
relapsed/reractory bortezomib-naïve patients with carlzomib at twice-weekly dosing o 56 mg/m2 and
Chapter 16
MM, although the ORRs were not statistically dier- oers a convenient and well-tolerated option. Regres-
ent between the two groups.51 Phase 2 data o VRD in sion analyses o all patients in the trials who received
relapsed/reractory MM resulted in an ORR o 64%. carlzomib 70 mg/m2 weekly versus 56 mg/m2 twice
Median PFS was 8.5 months, and median OS was 30 weekly, estimated a PFS hazard ratio o 0.91 and an
months.52 The CyBorD regimen may also be consid- ORR odds ratio o 1.12.60
ered in relapsed MM based on phase 2 data.
The second-generation proteasome inhibitor carl-
zomib has gained regulatory approval or patients
exposed to bortezomib and an IMiD and whose disease The FDA has approved the anti-CD38 antibodies,
was reractory to the last therapy. Like bortezomib, daratumumab and isatuximab, and the anti-SLAMF7
carlzomib inhibits the chymotrypsin-like activity o antibody, elotuzumab. Antibody therapy has modest
the 20S proteasome, but its unique structural proper- to no ecacy as monotherapy and is thus used in com-
ties allow or greater specicity and irreversible bind- bination with other drugs.
ing to its target. The ecacy o carlzomib in relapsed/ A number o dierent proteasomes, IMiD com-
reractory MM was established in a single-arm phase 2 binations with daratumumab, have been tested. For
trial o 266 patients, with an ORR o 24%, all o whom example, the phase 3 POLLUX trial comparing lenalid-
received prior IMiD therapy, and all but one patient omide, dexamethasone with or without daratumumab
received prior bortezomib.53 Only 12% o patients in patients with one or more prior treatments, ound
reported any grade o treatment-emergent periph- that ater a ollow-up o more than 3.5 years, the ORR
eral neuropathy. In the phase 3 ENDEAVOR study, was 92.9% with daratumumab versus 76.4% without,
carlzomib was compared with bortezomib,54 with leading to a mPFS o 44.5 months versus 17.5 months.61
approximately 50% o the patients receiving prior Patients who only had one prior therapy had a mPFS
bortezomib, and approximately 70% receiving a prior that was not reached compared with 19.6 months
immunomodulatory agent. The mPFS was 18.7 versus with lenalidomide, dexamethasone alone. In patients
9.4 months, which led to an increase in the mOS to with two prior lines o therapy, daratumumab has
47.6 compared with 40 months. been combined with pomalidomide and dexametha-
The role o carlzomib in relapsed and/or rerac- sone, which led to an ORR o 60%, with a mPFS o 8.8
tory MM continues to evolve while it is being tested months, and mOS o 17.5 months.62 Daratumumab and
in combination with other novel agents. Results o the PI combinations have also shown improved outcomes
phase 3 ASPIRE study comparing KRd with lenalido- or relapsed or reractory myeloma. Per the CAS-
mide and dexamethasone (Rd) have been reported.55 TOR trial, daratumumab with bortezomib and dexa-
In this study, 66% o patients received prior bortezo- methasone demonstrated a 1-year PFS rate o 60.7%
mib and 20% received prior lenalidomide. The mPFS versus 26.9% in the control group o bortezomib and
was signicantly longer with KRd compared with Rd dexamethasone.63 More recently, the CANDOR trial
(26.1 vs 16.6 months), and the mOS was 48.3 vs 40.4 showed a signicant improvement in PFS or the triplet
months. The combination o carlzomib, pomalido- combination o daratumumab, carlzomib, and dexa-
mide, and dexamethasone has also shown promising methasone versus carlzomib and dexamethasone
(median PFS not reached vs 15.8 months, respectively, Antibody Drug Conjugate
with a median ollow-up o 17 months).64
An antibody drug conjugate couples an antibody with
Intravenous daratumumab has been associated with
a chemotherapeutic agent to deliver a higher dose o
a high rate o inusion reactions, and thus requires pro-
the chemotherapy to a cancer cell than is normally
longed inusion times. To overcome this, subcutane-
possible because o toxicity. The phase 2 DREAMM-2
ous daratumumab was developed and was recently
study tested belantamab maodotin, an anti–B-cell
approved by the FDA based on the PAVO trial, which
maturation antigen (BCMA) antibody coupled to a
showed similar responses to IV daratumumab.65
microtubule-disrupting agent, mono-methyl auristatin
Isatuximab has also been FDA approved based on the
F (MMAF), as single-agent treatment in triple-rerac-
phase 3 ICARIA-MM trial. In patients who progressed
tory patients who have progressed on at least three
on two prior treatments including lenalidomide and a
prior lines o treatment including a proteasome inhibi-
proteasome inhibitor, patients who received isatux-
tor, IMiD, and anti-CD38 antibody.73 The study com-
imab with pomalidomide and dexamethasone had
pared two doses and achieved a response rate o 31%
a mPFS o 11.5 months compared with 6.47 months
to 34%. The mPFS ranged rom 2.9 to 4.9 months. The
with pomalidomide, dexamethasone alone.66
most serious adverse event was keratopathy, which
Elotuzumab has not been eective as a single
aected 70% to 74% o patients and was the most
agent.67 However, in the phase 3 ELOQUENT-2 trial
common reason treatment was discontinued. Recently,
o patients who have received one to three prior lines
the FDA approved single-agent use in relapsed rerac-
o therapy, elotuzumab in combination with lenalido-
tory patients with a rigorous REMS program. The
Chapter 16
mide and dexamethasone had a mPFS o 19.4 months
ongoing DREAMM-6 trial combines belantamab with
compared with 14.9 months with lenalidomide and
bortezomib and dexamethasone in patients with one
dexamethasone alone,68 which led to a mOS o 48.3
or more prior lines o therapy (NCT03544281).
months versus 39.6 months ater patients had been ol-
lowed or at least 5.9 years.69 Later in the randomized
phase 2 ELOQUENT-3 trial, elotuzumab in combina- Histone Deacetylase Inhibitor
tion with pomalidomide and dexamethasone demon- Although histone deacetylase (HDAC) inhibitors only
strated a mPFS o 10.3 months versus 4.7 months or have modest activity as single agents, the potential o
pomalidomide and dexamethasone.70 HDAC inhibitors has been most pronounced in com-
bination with other anti-MM drugs, namely bortezo-
Nuclear Export Inhibitor mib. Disruption o aggresome ormation by HDAC
inhibition may provide potent synergy with protea-
It has been ound that myeloma cells overexpress the
some inhibition by interering with protein turnover
nuclear exporter protein, exportin 1 (XPO1).71 XPO1
and inducing the unolded protein response. Based on
is involved in the movement o many proteins across
this rationale, the pan-deacetylase inhibitor panobi-
the nucleus, including important tumor suppressor
nostat was studied in combination with bortezomib
proteins such as p53, retinoblastoma, and proteins
and dexamethasone and compared with placebo, bort-
that regulate the cell cycle, immune response, and
ezomib, and dexamethasone in a large phase 3 trial.74
more. Recently, an XPO1 inhibitor, selinexor, was
Patients receiving panobinostat with bortezomib and
tested in triple-reractory patients who had pro-
dexamethasone had a signicantly longer mPFS o 12
gressed on a proteasome inhibitor, IMiD, and dara-
versus 8.1 months, although OS was not signicantly
tumumab. 72 There was an ORR o 26% with a mPFS
dierent between the groups. Concerns have been
o 3.7 months and a mOS o 8.6 months. Thrombo-
raised about drug ecacy (measured only by PFS) in
cytopenia and anemia were major adverse events,
the setting o signicant toxicities, particularly grade 3
with 58% and 44%, respectively, having grade 3 or
and 4 thrombocytopenia, diarrhea, and atigue.
4 toxicity. Fatigue, nausea, decreased appetite, and
Unortunately, other HDAC inhibitor trials have
weight loss were also signicant adverse events
shown mixed benets. For example, the phase 3 VAN-
with 73%, 72%, 56%, and 50%, respectively, hav-
TAGE 088 trial comparing bortezomib in combination
ing any grade toxicity. Based on these results, the
with or without vorinostat showed only a modest
FDA has approved the medication or patients who
improvement in mPFS o 7.6 months versus 6.8 with
have received at least our prior therapies and have
placebo, and the trial with belinostat was stopped due
progressed on at least two proteasome inhibitors,
to instances o toxicity.75
two IMiDs, and an anti-CD38 antibody. The ongo-
In the uture, more selective HDAC inhibitors with
ing phase 3 BOSTON trial will introduce selinexor
ewer o-target eects may need to be developed and
in combination with bortezomib and dexametha-
tested or the ull potential o this therapeutic approach
sone to patients ater one to three prior treatments
to be realized.
(NCT03110562).
Investigational Agents with a response rate o 70% at the maximum toler-

ated dose.82 Unortunately, the antibody requires our
Although IMiDs and proteasome inhibitors now orm
weeks o continuous inusion. The longer-acting and
the backbone o most MM regimens, both in the
thus shorter-inusion version, AMG 701, is also being
upront and relapsed settings, several promising new
investigated in a phase 1/2 trial (NCT03287908).
classes o investigational agents have shown both saety
and promising ecacy in phase 1 and 2 clinical trials.
CELMoDs
Chimeric Antigen Receptor T Cells Unique rom immunomodulatory drugs such as
lenalidomide and pomalidomide, CELMoDs are larger
Cellular therapy with chimeric antigen receptor (CAR)
molecules that are potent modulators o the Cereblon
T cells are T cells modied with an activating recep-
E3 ligase complex and work by quickly degrading the
tor that binds to specic antigens present on the
proteins Ikaros and Aiolos. Data rom the phase 1 trial
myeloma cell surace. The most popular target is the
or Iberdomide (CC-220) revealed that the dose ranged
BCMA, which is an ideal target because it is primar-
rom 0.3 to 1.2 mg; however, the maximum tolerated
ily ound only on mature B cells. CAR T cells against
dose (MTD) was not reached. Grade 3–4 adverse events
BCMA alone is being investigated in more than 60
were reported in 72% patients and included neutro-
trials around the world. The largest and most mature
penia, thrombocytopenia, neuropathy, and atigue (in
trial to date is the phase 2 KarMMA trial, which tested
26%, 11%, 2%, and 0% patients, respectively). This
the BCMA CAR T cell, idecabtagene vicleucel, at three
Chapter 16
study is ongoing, including combinations with daratu-

dierent doses in patients with three or more prior
mumab and bortezomib.83 Recently, the phase 1 data
treatments.76 They ound an ORR o 73% in the 128
rom a trial evaluating CC-92480 conrmed the maxi-
patients treated in all doses combined with a mPFS o
mum tolerated dose o 1 mg or 21 or 28 days, and a 55%
8.6 months or 11.3 months at the highest dose. Like
ORR in a group o patients where 90% were reractory
other CAR therapies, cytokine release syndrome was
to lenalidomide and pomalidomide and had a median
common, aecting 84% o patients, though most were
o six lines o therapy. Grade 3–4 adverse events were
grade 1 or 2. Neurotoxicity was also present in 18%
reported in 88% o patients and included neutropenia
o patients across all doses. Other BCMA CAR T cell
(53%), inections (30%), anemia (29%), and thrombo-
trials include the EVOLVE trial, which tests dierent
cytopenia (17%), with 9% having grade 3 atigue.84
ratios o CD4 to CD8 T cells and modied antigen–
binding domain,77 or the CARTITUDE-1 trial, which
tests two BCMA-binding domains in a single CAR.78 BCL-2 Inhibitor
Early results also showed high response rates o 91% The BCL-2 inhibitor, venetoclax, has also been inves-
to 100%, though with smaller numbers and shorter tigated in MM. The phase 3 BELLINI trial investigated
ollow-up compared with the KarMMA trial. venetoclax in combination with bortezomib and dexa-
A number o other targets on the myeloma cell sur- methasone in patients who had received one to three
ace are also being investigated, such as CD38, CS1, and prior lines o therapy.85 The addition o venetoclax
others.79 CAR T cells have also been combined with showed a signicantly longer mPFS o 23.2 months
other medications such as with a gamma-secretase compared with 11.4 months with placebo. However,
inhibitor that prevents the cleavage o BCMA rom the this resulted in a decrease in OS, with the veneto-
myeloma cell surace, which leads to increased BCMA clax arm having a mOS o 33.5 versus not reached
surace expression and decreased circulating BCMA with the placebo. Subset analysis ound that most
that could act to neutralize BCMA therapy.80 To over- o the response came rom the t(11:14) patients, and
come the possibility o complete antigen loss, CAR T those patients had improved OS compared with the
cells that target multiple antigens simultaneously are non-t(11:14) patients treated with venetoclax. There
also being investigated.81 is now an ongoing phase 3 trial looking at just the
t(11:14) subset o patients comparing venetoclax with
Bispecic T-Cell Engager pomalidomide in combination with dexamethasone
(NCT03539744).
A bispecic T-cell engager (BITE) is an antibody that
couples a tumor-binding domain with an anti-CD3
domain, thus bringing the tumor cells in close proximity Melfuen
to T cells. In a dose-nding study, a BITE coupling anti- Melfuen is a peptide drug conjugate between an alkyl-
BCMA to CD3, AMG 420, has been tested in patients ating agent and a lipophilic peptide. When the drug
who progressed ater two or more lines o treatment, enters myeloma cells, the peptide is cleaved, which
and was ound to have an overall response rate o 31% traps the hydrophilic alkylating agent within the cell.86
The HORIZON study looked at patients who were Monoclonal Gammopathy o Undetermined
reractory to pomalidomide or anti-CD38 and had Signifcance
received two or more lines o therapy and ound that
patients who received melfuen and dexamethasone The 2014 IMWG guidelines dene MGUS as a serum
had an ORR o 29%, with a mPFS o 4.2 months and M-protein less than 3 g/dL, less than 10% clonal mar-
mOS o 11.6 months.87 The phase 3 OCEAN trial is row plasma cells, and absence o end-organ damage
ongoing (NCT03151811). (CRAB criteria and myeloma-dening events; see
Table 16–1) attributed to an underlying plasma cell
prolierative disorder. The 2014 standard o care or
Kinesin-Spindle Protein
MGUS is surveillance every 6 to 12 months with a
Kinesin-spindle protein (KSP) is a protein involved in physical examination and typical MM serum and urine
the separation o the centrosome during cell division. studies. Patients with MGUS can also be risk stratied
A KSP inhibitor, lanesib is being evaluated as a single or progression to MM according to established mod-
agent or in combination with other medications such els, with some arguing or only history and physical
as bortezomib. In a phase 1 trial investigating lane- examination in low-risk MGUS (IgG subtype, M-pro-
sib, carlzomib, and dexamethasone in patients with tein <1.5g/dL, normal serum-ree light-chain ratio)
a median o ve prior lines o therapy, the ORR was because risk o progression at 20 years is only 5% in
37%.88 this group (Table 16–4).89
Chapter 16
tbl 164 risk Sifcion Modls o MGUS nd SMM
MGUS
Mayo Clinic100 No. o Risk Factors No. o Patients 20-Year Progression (%)
Risk actors: 0 449 5%
1) M-protein >1.5 g/dL 1 420 21%
2) Non-IgG MGUS 2 226 37%
3) FLC ratio <0.26 or >1.65 3 53 58%
Total 1148 20%
PETHEMA101 5-year progression (%)
Risk actors 0 127 2%
1. ≥95% abnormal PCs by bone marrow 1 133 10%
ow cytometry 2 16 46%
2. DNA aneuploidy Total 276 8.5%
SMM
Mayo Clinic102 No. o Risk Factors No. o Patients 5-Year Progression (%)
1. Bone marrow plasma cells ≥10% 2 115 51%
2. M-protein ≥3g/dL 3 82 76%
3. FLC ratio <0.125 or >8 Total 273 51%
PETHEMA101
1. ≥95% abnormal PC 1 22 46%
2. Immunoparesis 2 39 72%
Total 89 46%
SWOG103 2-Year Progression (%)
1. GEP70 score >–0.26104 1 29 29.1%
2. M-protein >3 g/dL ≥2 17 70.6%
3. Involved serum FLC >25 mg/dL Total 79 34.2%
FLC, ree light chain; GEP70, gene expression proling 70; IgG, immunoglobulin G; immunoparesis, decreased in uninvolved immunoglobulins below the lower limit
o normal; MGUS, monoclonal gammopathy o undetermined signicance; PC, plasma cells; PETHEMA, Program para el Tratamiento de Hemopatias Malignas; SMM,
smoldering multiple myeloma; SWOG, Southwest Oncology Group.
Smoldering Multiple Myeloma techniques and ound that the 3-year PFS was 91%
or the lenalidomide group compared with 66% in the
Smoldering MM is dened as having a serum M-pro- observation group.94 The benet was ound in all risk
tein o at least 3.0 g/dL and/or at least 10% more groups, though it was more pronounced in the Mayo
marrow plasma cells without evidence o end-organ 2018 high-risk group with a HR o 0.09. No OS ben-
damage as dened by CRAB criteria and MM-dening et has been shown yet and 51% o the patients on the
events (see Table 16–1). Compared with MGUS, this lenalidomide arm came o trial with a median o 11
premalignant clonal plasma cell prolieration carries a cycles o treatment; 15.6% o these patients came o as
higher risk o progression to overt MM. In a large ret- a result o disease progression.
rospective study o 276 patients with SMM ollowed At MDACC, we recommend that patients with
over 26 years, the risk o progression to MM was 10% high-risk SMM be enrolled in a clinical trial. In the
per year or the rst 5 years, 3% per year or the next 5 absence o clear data, we would otherwise recommend
years, and 1% per year or the last 10 years. observation and close surveillance in these patients,
There is great heterogeneity in the SMM disease although this practice may change soon as we gather
course. Some patients may remain asymptomatic data rom relevant trials ocused on high-risk SMM.
or the rest o their lives, whereas others may rapidly
develop disease that meets MM criteria. Eorts have
been made to risk stratiy SMM to help predict the clini- Solitary Plasmacytoma o Bone
cal course, guide surveillance strategies, and design trials A solitary plasmacytoma o bone is dened by the
Chapter 16
or early intervention. The Mayo 2008 risk stratication presence o a plasmacytoma without bone marrow evi-
model ound that patients with both clonal bone mar- dence o monoclonal plasma cells, lytic bony lesions,
row plasmacytosis o at least 10% and serum M-protein or other clinically signicant sequelae o MM. About
at least 3 g/dL had an 87% chance o MM progression 24% to 72% o patients with a solitary plasmacytoma
at 15 years compared with 70% with only 10% or more have a monoclonal protein in the serum or urine. Ini-
marrow plasma cells (but monoclonal protein o <3 g/ tial workup should include all o the aorementioned
dL) and 39% with only monoclonal protein o at least serum and urine laboratory studies used in evaluation
3 g/dL (but <10% bone marrow plasma cells).90 The o MM, as well as advanced imaging with PET-CT or
model was later revised in the Mayo 2018 risk stratica- MRI to rule out multiocal disease that would upstage
tion, where they ound that bone marrow plasma cells the disease to MM. Biopsy o the solitary plasmacy-
higher than 20%, M-protein more than 2 g/dL, and ree toma to demonstrate clonal plasma cells and a unilat-
light-chain ratio more than 20 where independent pre- eral bone marrow biopsy to rule out systemic disease
dictors o progression.91 Patients with no risk actor had are necessary. Treatment should include radiation
a time to progression o 110 months compared with 68 therapy o at least 40 Gy, although one may consider
months i patients had one risk actor, and 29 months a dose o up to 50 Gy or lesions greater than 5 cm.
with two or more risk actors. A number o other ac- Ater radiation therapy, surveillance should be per-
tors have been shown to increase the risk o progression ormed with serial measurements o serum and urine
such as high-risk cytogenetics (del 17p, t(4;14), ampli- M-protein levels and imaging studies, initially done
cation o 1q21), ≥95% aberrant marrow plasma cells every three months and then less requently. Patients
by fow cytometry, IgA M-protein, immunoparesis o who progress to overt MM during surveillance should
uninvolved immunoglobulins, circulating plasma cells ollow the treatment guidelines or MM.
by slide-based immunofuorescence, and proteinuria.92 Patients with solitary plasmacytoma o bone oten
The benets o preemptive treatment o high-risk progress to MM within 2 to 4 years, with a median
SMM are still unclear. Until this is urther claried, treat- OS o 7.5 to 12 years. In one study, persistence o a
ment o high-risk SMM should be undertaken preer- serum M-protein one year ater radiation therapy
entially through clinical trials. A phase 3 trial rom the was an adverse prognostic actor predicting a 10-year
Spanish myeloma group comparing lenalidomide and myeloma-ree survival o 29% compared with 91%
dexamethasone versus observation in high-risk patients with undetectable M-protein. Another study ound
ound an improvement in median PFS in the treatment that an abnormal ree light-chain ratio and a serum
arm (median PFS, not reached vs 26 months) and a sig- M-protein greater than 0.5 g/dL were signicant
nicant 3-year OS benet (94% vs 80%, P = .03).93 How- adverse actors or disease progression at 5 years.
ever, the excessive mortality rate in the observation arm
or patients with SMM has raised concerns that some
o these patients should have been classied as having POEMS Syndrome
symptomatic myeloma given that advanced imaging POEMS syndrome, also known as osteosclerotic
was not used to detect bone metastasis. A recent phase myeloma, is a paraneoplastic syndrome related to
3 trial addressed this issue by using modern imaging an underlying clonal plasma cell disorder. The major
diagnostic criteria are polyneuropathy, monoclonal radiation therapy may be appropriate. Patients with
gammopathy, sclerotic bone lesions, elevated vascu- diuse sclerotic lesions, disseminated marrow involve-
lar endothelial growth actor (VEGF), and Castleman ment, or relapsed disease within 6 months o complet-
disease. Minor eatures include organomegaly, endo- ing radiation therapy should receive systemic therapy
crinopathy, characteristic skin changes, papilledema, adapted largely rom therapy or MM. Alkylators such
extravascular volume overload, and thrombocytosis. as melphalan are the mainstay o treatment; lenalido-
The diagnosis o POEMS syndrome is made with three mide has shown promise with manageable toxicity.96,97
o the major criteria, two o which must include poly- Therapies based on CHOP also show responses. Tha-
neuropathy and a clonal plasma cell neoplasm, and at lidomide and bortezomib have activity but could exac-
least one o the minor criteria (Table 16–5).95 Patients erbate disease-related peripheral neuropathy. Benet
may have delays in diagnosis because it is rare and rom anti-VEGF antibodies is unproven.96
resembles other neurologic diseases, most commonly High-dose melphalan and autologous SCT can lead
chronic infammatory demyelinating polyradiculoneu- to prolonged remission and signicant improvement in
ropathy. The natural history o POEMS syndrome is clinical symptoms. Sixteen patients with POEMS syn-
dened by progressive polyneuropathy and sclerotic drome underwent autologous SCT at MDACC99,100;
bone disease, which leads to signicant morbidity, all had signicant or complete resolution o clinical
along with mortality i respiratory compromise occurs. symptoms, and 4-year PFS and OS rates or the entire
POEMS syndrome should be distinguished rom the cohort were 80.2% and 100%, respectively. Ten-year
Castleman disease variant o POEMS syndrome, PFS and OS rates were 59.4% and 80%, respectively.
Chapter 16
which has no clonal plasma cell association and usu- Prompt recognition and institution o supportive care
ally no peripheral neuropathy. measures and therapy directed against the plasma cell
The pathogenesis o this syndrome is not known. clone result in the best outcomes.
Risk stratication is based solely on the clinical pheno-
type. The extent o plasma cell clonal disease correlates
with prognosis in POEMS, but the number o clinical FUTURE DIRECTIONS
criteria does not. Treatment is aimed at eradicating the
underlying plasma cell clone and control o symptoms. The last decade has seen unprecedented advances in
With one to three sclerotic plasmacytomas (usually the treatment o plasma cell dyscrasias. The advent o
<1 cm in diameter each) without marrow inltration, novel agents, notably proteasome inhibitors, IMiDs,
localized radiation therapy may suce. For patients and monoclonal antibodies have resulted in a doubling
with a dominant sclerotic bone lesion, rontline o the lie expectancy in patients with MM. Many
challenges remain. For example, MM is still consid-
ered mostly an incurable disease, and a subgroup o
tbl 165 Dignosic Cii o pOeMS patients with high-risk MM have not beneted as sub-
Syndom stantially rom recent therapeutic advances. Promising
investigational agents including immunotherapeutic
Major criteria Polyneuropathy approaches and rational combinations to overcome
Monoclonal plasma cell disorder resistance are being tested.
Sclerotic bone lesion Future work involves identiying predictive bio-
Castleman disease markers to help individualize therapy in MM and
VEGF elevation related plasma cell dyscrasias to help maximize e-
Minor criteria Organomegaly cacy while balancing treatment toxicity. In high-risk
Extravascular volume overload SMM, the role o early preemptive therapy needs to be
Endocrinopathy claried. Improving our understanding o the molecu-
Skin changes lar pathogenesis o MM and its genetic drivers through
Papilledema molecular proling and rening current risk stratica-
Thrombocytosis/polycythemia tion models remain our key priorities. Another impor-
Other Pulmonary hypertension tant question is the role and timing o autologous SCT
Clubbing in the era o novel agents. Finally, as new drug combi-
Weight loss nations induce deeper responses in the rontline set-
Hyperhidrosis
ting, signicance o achieving molecular remissions is
Thrombosis
an area o intense research ocus. Bridging these knowl-
Low vitamin B12 level
edge gaps will improve on the advances achieved over
Diagnosis o POEMS syndrome is made with three o the major criteria, two o the last decade and oer greater individualized treat-
which must include polyneuropathy and a clonal plasma cell neoplasm, and at
least one o the minor criteria. ment approaches, leading to possible cure o MM and
VEGF, vascular endothelial growth actor. its related disorders.

J Patients suspected to have MM, and all smolder- J Patients should be placed on maintenance ater
ing myeloma patients should receive advanced autologous SCT with either single-agent lenalido-
imaging, such as whole-body low-dose CT, PET- mide or bortezomib. High-risk patients should be
CT, or MRI to evaluate or asymptomatic bone placed on doublet maintenance.
disease. J Proteasome inhibitors, immunomodulatory drugs,
J Transplant-eligible patients should receive a and CD38 monoclonal antibodies represent drugs
three-drug combination up ront, comprised o a used in up-ront and early relapse therapies.
proteasome inhibitor, immunomodulatory drug, J Supportive therapies such as shingles prophylaxis
and steroids. (monoclonal antibodies and PIs), appropriate
J Patients should receive autologous SCT ater induc- anticoagulation or DVT prevention (IMiDs and
tion chemotherapy. The treatment regimen is steroids), bisphosphonate therapy or bone
melphalan, but high-risk patients receive busulan/ strengthening, and bacterial prophylaxis or rail
melphalan. patients are imperative.
Chapter 16
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myeloma. N Engl J Med. 2017;376(14):1311-1320. gression. J Clin Oncol. 2007;25(25):3892-3901.
37. Moreau P, Facon T, Attal M, et al. Comparison o 200 mg/m(2) 52. Richardson PG, Xie W, Jagannath S, et al. A phase 2 trial o
melphalan and 8 Gy total body irradiation plus 140 mg/m(2) lenalidomide, bortezomib, and dexamethasone in patients
melphalan as conditioning regimens or peripheral blood stem with relapsed and relapsed/reractory myeloma. Blood.
cell transplantation in patients with newly diagnosed multiple 2014;123(10):1461-1469.
myeloma: nal analysis o the Intergroupe Francophone du 53. Siegel DS, Martin T, Wang M, et al. A phase 2 study o single-
Myélome 9502 randomized trial. Blood. 2002;99(3):731-735. agent carlzomib (PX-171-003-A1) in patients with relapsed and
Chapter 16
38. Bashir Q, Thall PF, Milton DR, et al. Conditioning with busul- reractory multiple myeloma. Blood. 2012;120(14):2817-2825.
an plus melphalan versus melphalan alone beore autolo- 54. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carl-
gous haemopoietic cell transplantation or multiple myeloma: zomib or bortezomib in relapsed or reractory multiple
an open-label, randomised, phase 3 trial. Lancet Haematol. myeloma (ENDEAVOR): an interim overall survival analy-
2019;6(5):e266-e275. sis o an open-label, randomised, phase 3 trial. Lancet Oncol.
39. Pandya C, Hashmi S, Khera N, et al. Cost-eectiveness analysis 2017;18(10):1327-1337.
o early vs. late autologous stem cell transplantation in multiple 55. Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement
myeloma. Clin Transplant. 2014;28(10):1084-1091. in overall survival with carlzomib, lenalidomide, and dexa-
40. McCarthy PL, Owzar K, Homeister CC, et al. Lenalidomide methasone in patients with relapsed or reractory multiple
ater stem-cell transplantation or multiple myeloma. N Engl J myeloma. J Clin Oncol. 2018;36(8):728-734.
Med. 2012;366(19):1770-1781. 56. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase
41. Holstein SA, Jung S-H, Richardson PG, et al. Updated analy- I/II trial o carlzomib and pomalidomide with dexametha-
sis o CALGB (Alliance) 100104 assessing lenalidomide versus sone (Car-Pom-d) in patients with relapsed/reractory multiple
placebo maintenance ater single autologous stem-cell trans- myeloma. Blood. 2012;120(21):74-74.
plantation or multiple myeloma: a randomised, double-blind, 57. Sonneveld P, Zweegman S, Cavo M, et al. Carlzomib,
phase 3 trial. Lancet Haematol. 2017;4(9):e431-e442. pomalidomide and dexamethasone (KPd) in patients with mul-
42. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide main- tiple myeloma reractory to bortezomib and lenalidomide. The
tenance ater stem-cell transplantation or multiple myeloma. EMN011 Trial. Blood. 2018;132(suppl 1):801.
N Engl J Med. 2012;366(19):1782-1791. 58. Lendvai N, Hilden P, Devlin S, et al. A phase 2 single-cen-
43. Amsler IG, Jeker B, Mansouri Taleghani B, et al. Prolonged sur- ter study o carlzomib 56 mg/m2 with or without low-
vival with increasing duration o lenalidomide maintenance dose dexamethasone in relapsed multiple myeloma. Blood.
ater autologous transplant or multiple myeloma. Leuk Lym- 2014;124(6):899-906.
phoma. 2019;60(2):511-514. 59. Ailawadhi S, Sexton R, Lentzsch S, et al. Low-dose versus
44. Thomas A, Mailankody S, Korde N, et al. Second malignan- high-dose carlzomib with dexamethasone (S1304) in patients
cies ater multiple myeloma: rom 1960s to 2010s. Blood. with relapsed-reractory multiple myeloma. Clin Cancer Res.
2012;119(12):2731-2737. 2020;26(15):3969-3978.
45. Palumbo A, Bringhen S, Kumar SK, et al. Second primary 60. Moreau P, Stewart KA, Dimopoulos M, et al. Once-weekly (70
malignancies with lenalidomide therapy or newly diagnosed mg/m2 ) vs twice-weekly (56 mg/m2 ) dosing o carlzomib in
myeloma: a meta-analysis o individual patient data. Lancet patients with relapsed or reractory multiple myeloma: A post
Oncol. 2014;15(3):333-342. hoc analysis o the ENDEAVOR, A.R.R.O.W., and CHAM-
46. Sonneveld P, Schmidt-Wol IGH, van der Holt B, et al. Bort- PION-1 trials. Cancer Med. 2020;9(9):2989-2996.
ezomib induction and maintenance treatment in patients with 61. Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus
newly diagnosed multiple myeloma: results o the random- lenalidomide and dexamethasone in relapsed/reractory mul-
ized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. tiple myeloma: extended ollow-up o POLLUX, a randomized,
2012;30(24):2946-2955. open-label, phase 3 study. Leukemia. 2020;28(suppl_4):iv52–10.
47. Dimopoulos MA, Gay F, Schjesvold F, et al. Oral ixazomib 62. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus
maintenance ollowing autologous stem cell transplantation pomalidomide and dexamethasone in relapsed and/or rerac-
(TOURMALINE-MM3): a double-blind, randomised, placebo- tory multiple myeloma. Blood. 2017;130(8):974-981.
controlled phase 3 trial. Lancet. 2019;393(10168):253-264. 63. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab,
48. Joseph NS, Kauman JL, Dhodapkar MV, et al. Long-term bortezomib, and dexamethasone or multiple myeloma. N Engl
ollow-up results o lenalidomide, bortezomib, and dexa- J Med. 2016;375(8):754-766.
methasone induction therapy and risk-adapted maintenance 64. Dimopoulos M, Quach H, Mateos M-V, et al. Carlzomib,
approach in newly diagnosed multiple myeloma. J Clin Oncol. dexamethasone, and daratumumab versus carlzomib and
2020;38(17):1928-1937. dexamethasone or patients with relapsed or reractory multiple
myeloma (CANDOR): results rom a randomised, multicentre, 80. Pont MJ, Hill T, Cole GO, et al. γ-Secretase inhibition increases
open-label, phase 3 study. Lancet. 2020;396(10245):186-197. ecacy o BCMA-specic chimeric antigen receptor T cells in
65. Usmani SZ, Nahi H, Mateos M-V, et al. Subcutaneous delivery multiple myeloma. Blood. 2019;134(19):1585-1597.
o daratumumab in relapsed or reractory multiple myeloma. 81. Fernández de Larrea C, Staehr M, Lopez AV, et al. Dening
Blood. 2019;134(8):668-677. an optimal dual-targeted CAR T-cell therapy approach simul-
66. Attal M, Richardson PG, Rajkumar SV, et al. Isatuximab taneously targeting BCMA and GPRC5D to prevent BCMA
plus pomalidomide and low-dose dexamethasone versus escape–driven relapse in multiple myeloma. Blood Cancer Dis-
pomalidomide and low-dose dexamethasone in patients with cov. 2020;1(2):146-154.
relapsed and reractory multiple myeloma (ICARIA-MM): a 82. Topp MS, Duell J, Zugmaier G, et al. Anti–B-cell maturation
randomised, multicentre, open-label, phase 3 study. Lancet. antigen BiTE molecule AMG 420 induces responses in multiple
2019;394(10214):2096-2107. myeloma. J Clin Oncol. 2020;38(8):775-783.
67. Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, 83. Lonial S, van de Donk NWCJ, Popat R, et al. First clinical (phase
multicenter, open-label, dose escalation study o elotu- 1b/2a) study o iberdomide (CC-220; IBER), a CELMoD, in
zumab in patients with advanced multiple myeloma. Blood. combination with dexamethasone (DEX) in patients (pts) with
2012;120(3):552-559. relapsed/reractory multiple myeloma (RRMM). J Clin Oncol.
68. Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus 2019;37(suppl 15):8006.
lenalidomide and dexamethasone in relapsed/reractory mul- 84. Richardson PG, Vangsted AJ, Ramasamy K, et al. First-in-
tiple myeloma: extended 4-year ollow-up and analysis o human phase I study o the novel CELMoD agent CC-92480
relative progression-ree survival rom the randomized ELO- combined with dexamethasone (DEX) in patients (pts) with
QUENT-2 trial. Cancer. 2018;124(20):4032-4043. relapsed/reractory multiple myeloma (RRMM). J Clin Oncol.
69. Dimopoulos MA, Weisel K, Lonial S, et al. Elotuzumab 2020;38(suppl 15):8500.
plus lenalidomide/dexamethasone or relapsed/reractory 85. Kumar S, Harrison SJ, Cavo M, et al. Updated results rom
multiple myeloma: nal overall survival results rom the BELLINI, a phase III study o venetoclax or placebo in combi-
Chapter 16
phase 3 ELOQUENT-2 trial. Clin Lymphoma Myeloma Leuk. nation with bortezomib and dexamethasone in relapsed/rerac-
2019;19(10):e15-e16. tory multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8509.
70. Dimopoulos MA, Dyteld D, Grosicki S, et al. Elotuzumab plus 86. Wickström M, Nygren P, Larsson R, et al. Melfuen - a pepti-
pomalidomide and dexamethasone or multiple myeloma. N dase-potentiated alkylating agent in clinical trials. Oncotarget.
Engl J Med. 2018;379(19):1811-1822. 2017;8(39):66641-66655.
71. Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implica- 87. Mateos M-V, Oriol A, Larocca A, et al. Clinical activity o
tions o targeting XPO1-mediated nuclear export in multiple melfuen in patients with triple-class reractory multiple
myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(5):335-345. myeloma and poor-risk eatures in an updated analysis o
72. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor- HORIZON (OP-106), a phase 2 study in patients with relapsed/
dexamethasone or triple-class reractory multiple myeloma. N reractory multiple myeloma reractory to pomalidomide and/
Engl J Med. 2019;381(8):727-738. or daratumumab. Blood. 2019;134(suppl 1):1883.
73. Lonial S, Lee HC, Badros A, et al. Belantamab maodotin or 88. Lee HC, Shah JJ, Feng L, et al. A phase 1 study o lanesib,
relapsed or reractory multiple myeloma (DREAMM-2): a carlzomib, and dexamethasone in patients with relapsed and/
two-arm, randomised, open-label, phase 2 study. Lancet Oncol. or reractory multiple myeloma. Blood Cancer J. 2019;9(10):1-5.
2020;21(2):207-221. 89. Go RS, Rajkumar SV. How I manage monoclonal gammopathy
74. San-Miguel JF, Yoon S-S, Beksac M, et al. Overall survival o o undetermined signicance. Blood. 2018;131(2):163-173.
patients with relapsed multiple myeloma treated with pano- 90. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and
binostat or placebo plus bortezomib and dexamethasone (the prognosis o smoldering (asymptomatic) multiple myeloma. N
PANORAMA 1 trial): a randomised, placebo-controlled, phase Engl J Med. 2007;356(25):2582-2590.
3 trial. Lancet Haematol. 2016;3(11):e506-e515. 91. Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratication
75. Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo o smoldering multiple myeloma incorporating revised IMWG
in combination with bortezomib in patients with multiple diagnostic criteria. Blood Cancer J. 2018;8(6):59-10.
myeloma (VANTAGE 088): a multicentre, randomised, double- 92. Dispenzieri A, Stewart AK, Chanan-Khan A, et al. Smoldering
blind study. Lancet Oncol. 2013;14(11):1129-1140. multiple myeloma requiring treatment: time or a new
76. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene denition¿ Blood. 2013;122(26):4172-4181.
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apy, in patients with relapsed and reractory multiple myeloma dexamethasone or high-risk smoldering multiple myeloma. N
(RRMM): initial KarMMa results. J Clin Oncol. 2020;38(suppl Engl J Med. 2013;369(5):438-447.
15):8503-8503. 94. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial o
77. Mailankody S, Jakubowiak AJ, Htut M, et al. Orvacabtagene lenalidomide versus observation in smoldering multiple
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antigen receptors or multiple myeloma. Biochem Soc Trans. o anti-VEGF monoclonal antibody (bevacizumab) or POEMS
2016;44(2):397-405. syndrome. J Neurol Neurosurg Psychiatry. 2013;84(12):1346-1348.
99. Patel K, Nusrat M, Shah N, et al. Durable responses with autol- on multiparameter fow cytometry analysis o bone marrow
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Bone Marrow Transplant. 2014;49(3):465-466. 103. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin
100. Saini NY, Patel RD, Varma A, et al. Long-term durable ecacy ree light chain ratio is an independent risk actor or progres-
o autologous stem cell transplantation in POEMS syndrome. sion o smoldering (asymptomatic) multiple myeloma. Blood.
Am J Hematol. 2019;94(3):E72-E74. 2008;111(2):785-789.
101. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum ree light 104. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic,
chain ratio is an independent risk actor or progression in and imaging predictors o myeloma progression rom asymp-
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2005;106(3):812-817. 2014;123(1):78-85.
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to identiy risk o progression in monoclonal gammopathy o multiple myeloma. Blood. 2006;108(6):2020-2028.
uncertain signicance and smoldering multiple myeloma based
Chapter 16
17 Cllular Thrapy for Lymphoma
Sairah Ahmed
Simrit Parmar
Sattva Neelapu
KEY CONCEPTS
 Adoptive cellular immunotherapy with chimeric antigen  Relapse ater CAR T-cell therapy remains a signicant chal-
receptor (CAR) T-cell therapy has changed the treatment lenge and, although the exact mechanisms causing tumor
landscape o B-cell non-Hodgkin lymphoma (NHL), espe- escape remain unknown, relapse ater CAR T-cell therapy
cially or aggressive B-cell lymphomas. that targets the CD19 antigen can be categorized broadly
 CAR T-cell therapy is FDA approved or poor-risk diuse as (1) antigen loss, (2) lack o CAR T-cell persistence, or (3)
large B-cell lymphoma (DLBCL) and mantle cell lymphoma host-specic actors.
(MCL) when no other eective treatment options are avail-  Real-world analyses highlight that patient response rates
able, and it has shown long-term remissions in up to 40% and toxicity proles were similar to the pivotal trials, while
o patients without other treatment options. being inclusive o patients who would not t within the
 CAR T-cell–related toxicities remain important potential highly restrictive parameters o clinical trials.
complications o this therapy, which includes acute tox-  Trials are ongoing in multiple lymphoma histologies
icity with cytokine-release syndrome and neurotoxicity, including T-cell lymphoma and Hodgkin lymphoma, in
as well as long-term complications such as inection and addition to novel autologous CAR constructs and alloge-
cytopenias. neic CAR T and natural killer (NK) cells.
For decades, the standard treatment or hematologic cell therapy is FDA approved or the treatment o
malignancies has been systemic chemotherapy, radia- certain non-Hodgkin lymphoma (NHL) types, as well
tion, and stem cell transplantation (SCT). Exploit- as B-cell acute lymphoblastic leukemia (ALL) and is
ing the immune system to attack cancer cells is not a currently being evaluated in clinical trials or ollicu-
novel concept. In act, the development o allogeneic lar lymphoma (FL), marginal zone lymphoma (MZL),
stem cell transplantation (allo-HCT) rst highlighted T-cell lymphoma (TCL), and Hodgkin lymphoma (HL).
the potential o T-cells to eliminate cancer cells. As o There are more than 750 cellular therapies in develop-
this writing, immune eector cells, including T-cells ment, and approximately hal o these are in clinical
and natural killer (NK) cells, which have been geneti- trials.1 This chapter will review current paradigms in
cally engineered to express a chimeric antigen receptor cellular therapy or lymphoma.
(CAR), constitute a powerul new class o therapeutic
agents to treat patients with hematologic malignan-
cies, and have resulted in a paradigm shit in the treat- CAR T-CeLL DeSIGN
ment o relapsed lymphoma in particular. However,
this emerging therapy also brings with it a dierent The concept o using CAR T-cells to target tumor sur-
toxicity prole compared with chemotherapy and ace antigens was described in the late 1980s, but rst-
challenges in management related to cytokine-release generation CARs, which included only the receptor
syndrome (CRS) and immune eector cell–associ- component CD3ζ as an intracellular domain, showed
ated neurotoxicity syndrome (Fig. 17–1). Adoptive limited ecacy.2 These rst-generation designs did
363
364 Secion II Lymphoma and Myeloma
Conditioning CART First Tumor

Chemotherapy Infusion Assessment
Screening Days -5, -4, -3 (PET scan)
Leukapheresis
Manufacturing Day 0 Day 7 Day 28
Days 2-10 Follow-Up Period

Assessment for (Post-Treatment Assessment
Toxicity and Long-Term Follow-Up)
FIGURE 17–1 Graphic representation of CAR T-cell therapy from screening to post-treatment assessment.
not include costimulatory domains and, as such, did the specicity o the receptor to recognize antigens
ChaptER 17
not provide a second signal or ull T-cell activation; on the cell surace independently o major histocom-
were more prone to apoptosis; and had limited in vivo patibility complex molecules. CD19 has requently
expansion potential, resulting in poor cytotoxicity.3 been the target antigen in B-cell lymphoid malignancy
Signicant responses were observed only ater because o its requent and high-level expression in
researchers went back to the gene construct and added these malignancies, the act that it has higher expres-
a single costimulatory domain derived rom either sion relative to other potential targets like CD20 or
CD28 or 4-1BB—the so-called “second-generation” CD22, and its inherent restriction to B-cell lineages
CAR T-cells.4 The addition o costimulatory signal- in healthy tissue. The transmembrane domain o the
ing domains and intracellular signal transduction CAR construct primarily plays a role in stabilizing the
molecule (CD3ζ, derived rom the T-cell receptor) in CAR, whereas the intracellular endodomain provides
second-generation CARs led to improvement in T-cell the necessary signals to activate the T-cells ater anti-
activation, enhanced survival capabilities, and a more gen recognition. The intracellular part is based on the
selective expansion o modied T-cells in vivo. A viral structure o the T-cell receptor (TCR) coupled with one
vector is usually used to deliver the genetic material, or more costimulatory domains, allowing to transduce
which includes the targeting antibody-based single- the antigen recognition into T-cell activation.8
chain ragment variable region, a hinge and transmem- The antitumor activity o ourth-generation CAR
brane domain, a costimulatory domain, and the CD3ζ T-cells are even urther enhanced by additional genetic
signaling domain, into the patient’s T-cells. These modications—or example, by the addition o trans-
second-generation receptors orm the basis o the cur- genes or cytokine secretion (eg, interleukin [IL]-12).9–11
rently approved CAR T-cell therapies. It is now becom-
ing increasingly clear that each type o costimulatory
domain has specic roles in CAR T-cell signaling; or CAR T-CeLL MANUFACTURING AND
example, CD28-based CAR T-cells exhibit more ADMINISTRATION
potent eector cell unctions but limited persistence,
whereas 4-1BB tends to drive the CAR T-cells toward Most CARs are manuactured rom autologous T-cells,
a central memory phenotype, resulting in improved collected rom the patients via leukapheresis. The pro-
persistence.5,6 Third-generation CAR T-cells combine cess typically involves washing o the apheresis prod-
the signaling potential o two costimulatory domains uct, T-cell selection, T-cell activation, gene transer,
(eg, both CD28 and 4-1BB), with the aim to urther T-cell expansion, ormulation, and cryopreservation.
improve prolieration, cytokine secretion, and in vivo The T-cells are stimulated ex vivo, a viral vector or alter-
persistence; and in comparison with the outcomes native transer technology (ie, electroporation) is used
o second-generation CAR T-cells, they have shown to transmit genes containing the CAR to the T-cell, the
improved eector unctions and in vivo persistence in CAR T-cells are expanded, and a pharmaceutical intra-
preclinical studies.7 venous cell inusion product is usually administered
The CAR molecule is composed o three key as a single inusion. The median time rom leukapher-
domains: an ectodomain, a transmembrane domain, esis to CAR T-cell administration diers depending
and an endodomain. The extracellular part redirects on the product and manuacturing process but usually
Cer 17 Cellular Therapy for Lymphoma 365
requires two to ve weeks, and the entire process rom dened as reractory to second-line or subsequent
reerral to inusion can take up to two months.12 Many therapy, or relapsed disease within one year ater
o the initial clinical trials did not allow bridging ther- autologous SCT (auto-SCT). Median age was 58 years
apy; however, in practice many patients require ther- and the oldest patient treated was 76 years. Eligibility
apy or disease control beore inusion o CAR T-cells. criteria included Eastern Cooperative Oncology Group
The optimal therapeutic regimen or bridging depends (ECOG) perormance status o 0 or 1, an absolute lym-
on the patient’s treatment history and prior toxicities; phocyte count greater than 100 cells/μL, and adequate
however, it is important that enough time be allowed bone marrow and organ unction. Patients with pri-
between bridging and CAR T-cell inusion—a washout mary or secondary central nervous system (CNS) lym-
period—to allow recovery rom any adverse events. phoma were not eligible, and patients could not have
In general, recommended washout times are at least received prior allogeneic SCT. The patient population
two weeks or systemic chemotherapy, our weeks or was heavily pretreated with a median o three prior
pegylated l-asparaginase, and 72 hours or steroids.13 therapies.19
Bridging therapy can include steroids or symptom O 111 patients enrolled, axi-cel was successully
control, radiation, chemotherapy, or a combination. manuactured or 110, and 101 were treated. Median
Lymphodepleting (LD) chemotherapy is admin- time rom leukapheresis to the delivery o the T-cell
istered beore the inusion o CAR T-cells and most product to the treating center was 17 days. Per pro-
commonly consists o fudarabine and cyclophospha- tocol, bridging chemotherapy ater apheresis was not
mide. The choice o drug used or LD chemotherapy allowed. LD chemotherapy consisted o 500 mg/m2
ChaptER 17
may impact adoptively transerred T-cell expansion per day o cyclophosphamide and 30 mg/m2 per day
and persistence because LD decreases the number o o fudarabine on days –5 to –3, and the axi-cel dose
T-cells in vivo, including regulatory T-cells, and conse- was 2 × 106 CAR T-cells per kilogram o body weight.
quently upregulates cytokines such as IL-7 and IL-15, The best overall response rate (ORR) as determined
which promote T-cell expansion and enhance the anti- was 83%, including 58% o patients who achieved
lymphoma activity o the CAR T-cells.14,15 Patients complete response (CR). At two years o ollow-up,
with B-ALL and B-cell lymphoma who received cyclo- 39% o patients were in ongoing remission. Median
phosphamide and fudarabine lymphodepletion beore progression-ree survival (PFS) or the entire popula-
CAR T-cell inusion had better in vivo CAR T-cell tion was 5.9 months, median duration o response was
expansion and persistence, compared with those who 11.1 months, and the two-year rate o overall survival
received cyclophosphamide alone who had shorter in (OS) or the entire population was 50.5%.
vivo persistence o CAR T-cells.16–18 Patients generally The incidence o any grade CRS was 93% occur-
receive LD chemotherapy or three days (days –5 to ring at a median o 2 days rom CAR T-cell inusion,
–3), ollowed two days later by a single inusion o though only 13% o patients had severe CRS (grade
cells on day 0; this can take place outpatient or inpa- 3–5). Sixty-our percent o patients experienced neu-
tient based on institutional preerence. rotoxicity with a median time to onset o 5 days,
whereas 28% experienced severe neurotoxicity (grade
≥3). This study used the grading criteria by Lee and
CAR T-CeLL THeRAPY IN colleagues or CRS and Common Terminology Criteria
AGGReSSIVe B-CeLL LYMPHOMA or Adverse Events criteria or neurologic toxicity.19,20
Among all patients, 43% and 27% received tocili-
As o this writing, two CAR T-cell products, tisagen- zumab and corticosteroids, respectively. Additional
lecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel), toxicities included cytopenias and hypogammaglobu-
have approval by the FDA or the treatment o certain linemia. Four adverse event–related deaths occurred
B-cell NHL types in adults; and a third, lisocabtagene on study, two o which were attributed to axi-cel.
maraleucel (liso-cel), is also submitted to the FDA or Tisa-cel targets the same CD19 antigen as axi-cel
approval. Both tisa-cel and axi-cel are commercially but uses a lentiviral vector and a 4-1BB costimulatory
available or relapsed or reractory (rel/re) large B-cell domain.21 Eligibility or this trial included patients
lymphoma in patients who have received at least two having received at least two prior lines o therapy or
prior regimens. DLBCL, transormed ollicular lymphoma, or high-
Axi-cel is an anti-CD19 CAR T-cell product gener- grade B-cell lymphoma with rearrangements o MYC
ated using a retroviral vector and uses a CD28 costimu- and BCL2 or BCL6 (double-/triple-hit lymphoma).
latory domain. The pivotal phase 1/2 registration trial, As with axi-cel, adequate organ and bone marrow
ZUMA-1, enrolled 111 patients with the diagnoses o unction were required, and patients could not have
DLBCL (n = 77), transormed ollicular lymphoma (n = received prior allo-SCT or have history o CNS dis-
16), and primary mediastinal B-cell lymphoma (n = 8).19 ease. LD chemotherapy preceding tisa-cel inusion
All patients had chemotherapy-reractory disease, was most commonly cyclophosphamide (250 mg/
m2/day) and fudarabine (25 mg/m2/day) or 3 days, allowed on trial. Eligibility included a minimum o
although bendamustine (90 mg/m2/day) or 2 days two prior lines o therapy, and this protocol did allow
was permissible. The dose o tisa-cel was 0.6–6.0 bridging chemotherapy ater apheresis beore inusion
× 108 CAR T-cells. One hundred sixty-ve patients o cells. LD chemotherapy consisted o 300 mg/m2 o
were enrolled, o whom 111 received tisa-cel inusion. cyclophosphamide and 30 mg/m2 o fudarabine or 3
Patients had a median age o 56 years, and the oldest days, ollowed 2 to 7 days later by liso-cel inusion.
patient was 76 years. O 70 patients assessed or gene Three hundred orty-our patients received leu-
arrangement, 27% had double-/triple-hit lymphoma, kapheresis; 269 patients received liso-cel (DL1, n =
and the median number o prior treatments or all 51; DL2, n = 177; DL3, n = 41). Twenty-ve patients
patients was three. Approximately one-hal o patient received nonconorming product; product could not
had experienced relapse ater an auto-SCT. In contrast be manuactured or two patients. Thirteen percent o
to ZUMA-1, the majority (92%) o patients received patients had double-/triple-hit lymphoma, and median
bridging therapy ater apheresis, while median time prior lines o therapy was 3, with 67% o patients hav-
rom enrollment to inusion was 54 days. The best ing chemo-reractory disease. The median age was 63
ORR was 52%, with 40% o patients achieving CR years and the oldest patient treated was age 86 years.
and at 1 year, approximately one-third o all treated Among patients evaluable or ecacy (n = 256), the
patients were in an ongoing remission including 65% best ORR was 73% with a best CR rate o 53%; and at
o those who responded to treatment, and 1-year over- 1 year, 58% o patients remained alive. At 12 months
all survival was 49%. o ollow-up, the median duration o response had
ChaptER 17
In contrast to axi-cel, CRS was graded using the not been reached, and 44% o patients were in ongo-
University o Pennsylvania scale and observed in 58% ing remission.12 The median PFS was 6.8 months, and
o patients, occurring at a median o 3 days ater treat- median OS was 21.1 months. As with prior studies,
ment. Twenty-three percent o patients had severe durable responses were observed across all high-risk
CRS and 21% had neurologic toxicity, o which 12% subsets, including double-/triple-hit lymphoma and
was categorized as severe. Tocilizumab was adminis- chemo-reractory disease.
tered to 14% o patients, with 10% o patients receiv- Toxicity and CRS was graded using the same crite-
ing corticosteroids. No deaths were attributable to ria by Lee et al20 that was used or axi-cel in Zuma 1;
CAR T-cell therapy with tisa-cel. As with other anti- and in this study was 37% and occurred at a median o
CD19 CAR T-cell products, cytopenias were common 5 days, with severe CRS observed only in one patient
and could be prolonged. On-target B-cell depletion and (1%). The rate o any neurologic toxicity was 23%,
hypogammaglobulinemia were observed, with 30% with 13% o patients experiencing severe neurologic
o patients receiving intravenous immunoglobulin at toxicities. There were no deaths related to CRS or
the discretion o the treating physician.21 neurologic toxicities in the study. Tocilizumab and
Liso-cel is also a CD19-directed CAR T-cell prod- corticosteroids were administered to 17% and 21%
uct using a lentiviral vector and 4-1BB costimulation o patients, respectively. Prolonged grade 3 or higher
domain and is currently under review with the FDA cytopenia (based on laboratory assessment at day 29)
or approval or commercial use. Compared with axi- was reported in 37% o patients. The pivotal cohort o
cel and tisa-cel, which are both produced using bulk this study has completed accrual but has not yet been
autologous T-cells, liso-cel manuacturing separately reported, and this product remains investigational
transduces and expands CD4+ and CD8+ CAR T-cells pending FDA approval.
and administers them at a xed 1:1 ratio that allows Given the outcomes o the pivotal trials, these three
or precise dosing to every patient.22 The TRAN- products—axi-cel, tisa-cel, and liso-cel—can all be con-
SCEND study was designed as a dose-escalation and sidered eective treatments or patients with chemo-
dose-expansion study ollowed by a pivotal cohort in reractory DLBCL or transormed ollicular lymphoma
relapsed/reractory (R/R) DLBCL. Patients were treated beyond second-line therapy. However, there are dis-
at doses o 5 × 107 dose level (DL; DL1) or 1 × 108 (DL2) tinct dierences among the products, which require
or 1.50 × 108 (DL3) CAR T-cells. Eligible patients had appropriate treatment selection or a given patient.
DLBCL, double-/triple-hit lymphoma, primary medi- Axi-cel has proven to have the most rapid vein to vein
astinal B-cell lymphoma (PMBCL), FL grade 3b, and time rom apheresis to inusion, which is important
DLBCL transormed rom indolent histologies. There or patients with rapid disease kinetics. Conversely,
was no minimal absolute lymphocyte count required incidence o CRS and neurotoxicity seems to be higher
or enrollment, though patients did have to exhibit with axi-cel than with either o the two 4-1BB costim-
adequate organ and bone marrow unction similar to ulated products, tisa-cel and liso-cel, likely refecting
the other pivotal trials. Patients with both prior allo- dierences in the kinetics o T-cell expansion and
HSCT o immune suppression and/or secondary CNS prolieration conerred by the costimulation domains.
involvement with measurable systemic disease were Tisa-cel and liso-cel have lower overall rates o CRS
and neurologic toxicity and, overall, a later onset o TOXICITY AND SIDe eFFeCTS
these toxicities; thereore, centers oten choose to
administer this treatment in the outpatient setting.23 O Distinct rom chemotherapy-associated side eects,
note, toxicity grading scale selection was not standard- CAR T-cell–mediated toxicities are unique and poten-
ized with the pivotal trials. Tocilizumab and steroids tially lie threatening such as CRS and immune eec-
were received by 43% and 27% o patients treated tor cell–associated neurotoxicity syndrome (ICANS,
with axi-cel and 14% and 10% o patients treated with previously termed CAR-T-cell–related encephalopathy
tisa-cel, respectively, suggesting less toxicity with tisa- syndrome). Many o these eects are on target and
cel. Because o anticipated toxicity dierences, axi- reverse when the CAR T-cell expansion subsides. 28
cel–treated patients received CAR T-cell therapy as an CRS is caused by cytokine elevations as a result o
inpatient, whereas 61% o patients received tisa-cel as immune activation o large numbers o lympho-
an outpatient.24,25 cytes, which can maniest as ever, hypotension,
Two multicenter retrospective analyses evaluated and/or hypoxia.20,29 CRS typically occurs within the
the use o commercial axi-cel ater FDA approval.26,27 rst week ater CAR T-cell inusion and peak CAR
In these studies, patients oten did not strictly meet the T-cell levels and serum IL-6 levels have strongly cor-
eligibility criteria o the pivotal trial but were treated related with the severity o CRS. Those at highest
in accordance with the FDA label. Most commonly, risk or adverse outcomes rom severe CRS include
the dierence was with the administration o bridg- patients with large tumor burdens, comorbidities, or
ing therapy ater apheresis; however, patients were development o early-onset CRS within three days
ChaptER 17
also older than those in the pivotal trial, with patients o inusion.30 Comparisons o CRS severity across
treated up to age 83 years. The study reported by Nas- CAR T studies is complicated by the use o dier-
toupil et al included 295 patients, with 274 patients ent grading systems, which beore the consensus
treated. The nal CAR T-cell product did not meet guidelines, were product specic—ie, the Penn scale
FDA specications in seven patients. (tisa-cel)31 and the Lee scale (axi-cel).20 A consensus
The median time rom apheresis to start o LD statement to standardize CRS grading was endorsed
chemotherapy was 21.5 days; however, the delivery by American Society o Transplantation and Cellular
o the product was approximately 15 to 16 days ater Therapy (ASTCT) in 2019, which employs a grading
apheresis. The time to initiation o LD was delayed scale using ever, and/or hypoxia, and hypotension
awaiting count recovery because o bridging therapy, (Table 17–2).32
which a majority o patients received; this is in con- Although many cases o CRS may be sel-limited
trast to the ZUMA-1 trial, in which approximately and treated with supportive care alone, the mainstay
55% patients received any orm o bridging therapy. or treatment o severe CRS are tocilizumab and corti-
General characteristics included a median age o 60 costeroids. Tocilizumab is an anti–IL-6 receptor antag-
years (range, 21–83), stage III/IV in 83%, ECOG per- onist approved by the FDA in August 2017 to treat
ormance status (PS) 0–1 in 81%, three or more lines CRS when the rst CAR T-cell product was approved.
o therapy in 75% o cases, and relapsed post auto- It can induce a rapid reversal o CRS and has become
HCT in 33%. Interestingly, 43% o patients (124/286) the standard o care or this complication. 19,33 Corti-
would not have been eligible or the ZUMA-1 trial costeroids are also eective in the management o
per the trial eligibility criteria, yet overall ecacy was toxicities ater CAR T-cell therapies because they
similar to the ZUMA-1 trial, with 3-month ORR and suppress infammatory responses. Corticosteroids
CR rates o 81% and 57%, respectively.26 Jacobson et are oten administered i the patient does not have a
al reported on 108 patients who received axi-cel; o rapid response to IL-6 receptor blockade, and it can be
those, 104 were evaluable or ecacy. The median given in a number o ways including with initial tocili-
age was 63.8 years, ECOG PS 0–1 in 90% o cases, zumab, concurrently with subsequent doses o tocili-
prior auto-HCT in 27%, and prior allo-HCT in 3%. zumab i there is inadequate response, or as a single
About 52% o the evaluable patients received bridging agent ater tocilizumab. The general principle guiding
chemotherapy ater apheresis; 60% o patients would steroids or treatment o CART toxicity is that they
have not met criteria or the ZUMA-1 clinical trial. In should be prescribed at the lowest eective dose or
the 95 patients evaluable or response, the best ORR the shortest possible duration to limit the risk o abro-
and CR rates were 71% and 44%, respectively. Simi- gating CAR T-cell ecacy and persistence. However,
larly, about 50% o patients who initially had a PR, as o this writing, the dose and duration o steroids
achieved CR at a later time.27 These studies highlight required to irreversibly impair CAR T-cell ecacy is
that response rates and toxicity proles were similar to unknown. There are reports that early and prolonged
the pivotal trial while being inclusive o patients who use o high-dose corticosteroids are associated with
would not t within the highly restrictive parameters early progression and death in patients treated with
o clinical trials (Table 17–1). axi-cel.34
tble 171 pivol trils for ani-CD19 CaR t-Cell ery Mulicener trils in aggressive B-Cell NhLs
Cll Product Axicl Tisacl Lisocl

Trial ZUMA1 19
JULIeT 21
TRANSCeND22
Costimulatory and T-cell CD28 and CD3ζ 4-1BB and CD3ζ 4-1BB and CD3ζ
activation domains
Vector Retrovirus Lentivirus Lentivirus
6 8
Number o cells inused 2 × 10 CAR T-cells per kg 0.6–6.0 × 10 CAR T-cells 5 × 107 or 1 × 108 or 1.5 × 108
CD4:CD8 ratio = 1:1
Median prior LOT 3 3 3
2 2
LD regimen Cy 500 mg/m /day or 3 days Cy 250 mg/m /day or 3 days Cy 300 mg/m2/day or 3 days
Flu 30 mg/m2/day or 3 days Flu 25 mg/m2/day or 3 days Flu 30 mg/m2/day or 3 days
OR
Bendamustine 90 mg/m2 IV
daily or 2 days
Number enrolled (inused) 111 (101) 165 (111) 342 (268)
Number response-evaluable 101 93 256
ChaptER 17
Lymphoma subtypes DLBCL, TFL, PMBCL DLBCL, TFL DLBCL, HGBCL, DLBCL
transormed rom FL, CLL
and MZL, PMBCL and FL3B
Best ORR (CR) 83% (58%) 52% (40%) 73% (53%)
Median DoR 11.1 months ater median Not reached ater median Not reached ater median
ollow-up o 27.1 mo ollow-up o 14 mo ollow-up o 12 mo
12-month PFS 44% 31% 44%
12-month OS 59% 49% 58%
FDA Approval Status Approved Approved Under review
Toxicity
CRS All grades 93% 58% 42%
CRS grade ≥3 13% 22% 2%
NT all grades 64% 21% 30%
NT grade ≥3 28% 12% 10%
LOT, lines o therapy; NR, not reached; NT, neurotoxicity.
Neurologic toxicity is the second clinically signi- is being explored in clinical trials to assess its role in
cant adverse event associated with CAR T-cell therapy. mitigation o CRS and ICANS.
Early descriptions oten combined CRS and ICANS Common clinical maniestations o ICANS are
under the overarching term CRS, but growing under- expressive aphasia or language disturbance, impair-
standing o these toxicities suggest they are distinct ments o attention, cognitive processing, and changes
entities with dierent pathophysiology and manage- in handwriting. However, symptoms can be diverse
ment recommendations. ICANS typically occurs ater and include encephalopathy (conusion or delir-
the peak o CRS (oten >3 days later) and rarely occurs ium), motor weakness, tremor, headache, seizures,
without antecedent CRS, and peak symptoms occur depressed level o consciousness, and, rarely, diuse
on days 5 to 9. ICANS may be aected by patient- cerebral edema.36,37 In both ICANS and CRS, there is
specic actors including disease type, disease burden, likely overlap in the pathophysiology o toxicity in
treatment history, and patient age, as well as product- which it is suggested that endothelial activation is
specic actors such as CAR design, cell manuac- the driving mechanism. ICANS is characterized by
turing conditions, CAR T-cell dose, preconditioning increased blood-brain barrier (BBB) permeability, cap-
regimen, and product potency.33 Anecdotal data indi- illary leak, and disseminated intravascular coagulation,
cate that the IL-1 antagonist, anakinra, may be eec- with increased infammatory cytokines, CAR T-cells,
tive in patients with severe CRS and ICANS, 35 and it and myeloid cells in cerebrospinal fuid.38 The ASTCT
tble 172 aStCt CRS Consensus Grding32
CRS Paramtr Grad 1 Grad 2 Grad 3 Grad 4

a
Fever Temperature ≥38 °C Temperature ≥38 °C Temperature ≥38 °C Temperature ≥38 °C
WITH
Requiring multiple
Requiring a
Not requiring vasopressors
Hypotension None vasopressor with or
vasopressors (excluding
without vasopressin
vasopressin)
AND/ORb
Requiring high-fow
Requiring positive
nasal cannula,c
Requiring low-fow pressure (eg, CPAP,
acemask,
Hypoxia None nasal cannulac or BiPAP, intubation
nonrebreather
blow-by and mechanical
mask, or Venturi
ventilation)
mask
a
Fever is dened as temperature ≥38 °C not attributable to any other cause.
b
CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause.
c
Low-fow nasal cannula is dened as oxygen delivered at ≤6 L/minute. High-fow nasal cannula is dened as oxygen delivered at >6 L/minute.
ChaptER 17
BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure.
consensus guidelines or grading ICANS uses an updated available and the absolute benet is unknown. Di-
encephalopathy screening tool, the Immune Eector erent corticosteroids are used depending on institu-
Cell Encephalopathy (ICE) score, in addition to assess- tional standards, although dexamethasone use is most
ment o level o consciousness, seizure, motor nd- common because it has excellent CNS penetration,
ings, and elevated intracranial pressure/cerebral edema whereas high-dose methylprednisolone is used in the
(Tables 17–3 and 17–4). more severe cases o ICANS based on experience with
In contrast to CRS, tocilizumab is not eective or ulminant neuroinfammatory disorders.38 Prophylactic
ICANS as a single agent, which is likely both a unc- anticonvulsants are largely standard, although the data
tion o the multiactorial pathogenesis o ICANS, in supporting their use are lacking.
addition to the inability o tocilizumab to cross the In addition to CRS and ICANS, there are CAR T-cell–
BBB.37 Most centers are using corticosteroids as rst- associated side eects as well as organ-specic toxicity
line therapy or isolated ICANS with the addition o associated with CAR T-cell therapy. Cytopenias have
tocilizumab to corticosteroids given or ICANS that been commonly documented ater CAR T-cell inusion
develops concurrently with CRS. with grade 3–4 anemias, thrombocytopenia, or leuko-
Steroid recommendations are based on clinical penia reported beyond 28 days in more than 30% o
trial experience because no randomized trial data are patients.21,39 Although not lie threatening, hypogam-
maglobulinemia as a result o prolonged B-cell aplasia
can lead to inectious complications. Some centers
tble 173 aStCt ICE assessmen tool for routinely administer intravenous immunoglobulin,
Enceloy in aduls whereas others restrict usage to patients who have
repeated inections. In severe CRS, a cytokine signa-
Orintation Orientation to year, month, city, ture mirroring that o hemophagocytic lymphohistio-
hospital: 4 points cytosis/macrophage activation syndrome (HLH/MAS)
Naming Ability to name 3 objects: 3 points can occur, with optimal treatment still to be dened
Following Ability to ollow simple commands: 1 although high-dose steroids, tocilizumab, and some-
Commands point times anakinra have been used with success.6,40
Writing Ability to write a standard sentence: 1 Most patients who receive CAR T-cell immunother-
point apy have poor immune unction caused by the eects o
their malignancy, prior cytotoxic treatment, and manage-
Attntion Ability to count backwards rom 100 by
10: 1 point ment or CRS and ICANS, including steroids, which can
cause urther immune suppression. Data on inectious
Grading by score:
Grade 1: 7–9 points complications are still preliminary, but there is a sugges-
Grade 2: 3–6 points tion that prolonged neutropenia and higher-grade CRS,
Grade 3: 0–2 points
Grade 4: unarousable, unable to complete assessment which may be a surrogate or prolonged corticosteroid
tble 174 aStCt ICaNS Consensus Grding for aduls32
Nurotoxicity Domain Grad 1 Grad 2 Grad 3 Grad 4

ICE score 7–9 points 3–6 points 0–2 points 0 Unarousable
Depressed level o Awakens Awakens to voice Awakens only to tactile Unarousable or requires
consciousness spontaneously stimulus vigorous or repetitive
tactile stimuli
to arouse; stupor or coma
Seizure NA NA Any clinical seizure, ocal Lie-threatening
or prolonged seizure
Generalized, that resolves (>5 min); or repetitive
rapidly or nonconvulsive clinical or
seizures on EEG that electrical seizures without
resolve return to
with intervention baseline in between
Motor ndings NA NA NA Deep ocal motor
weakness such as
hemiparesis or
paraparesis
ChaptER 17
Raised ICP/cerebral NA NA Focal/local edema with or Diuse cerebral edema on

edema without neuroimaging;
hemorrhage on decerebrate or
neuroimaging decorticate posturing; or
cranial
nerve VI palsy; or
papilledema; or
Cushing triad
EEG, electroencephalogram; ICP, intracranial pressure.
use, increase the risk o all inections (viral, bacterial, and antigen can be categorized broadly as (1) antigen loss,
ungal.) The increased risk or invasive ungal inections (2) lack o CAR T-cell persistence, or (3) host-specic
in patients who have a history o prior auto- or allo-HCT actors.
or development o lie-threatening CRS and/or neuro- A well-characterized mechanism o resistance in
toxicity has led most centers to broaden ungal prophy- patients with ALL is the loss o tumor expression o
laxis in these high-risk patients.41 At our center, patients the extracellular CD19 epitope, to which the CAR
receive prophylaxis or Pneumocystis jiroveci pneumonia, binds. This can occur because o alterations in CD19
herpes zoster, and herpes simplex inection rom time o secondary to acquired mutations and loss o hetero-
CAR inusion to at least 12 months post inusion. Fun- zygosity.42,43 Patients treated on ZUMA-1 with DLBCL
gal prophylaxis is divided into low risk and high risk, who received axi-cel demonstrated a loss o tumor
with mold coverage or high-risk patients continuing CD19 as evaluated by immunohistochemistry or fow
at least 30 days ater completion o steroids or the time cytometry by local pathologic evaluation and was
point when high-risk eatures were identied. High risk described in 3 o 11 (27%) patients with biopsies at
is dened as history o leukemia, recipient o auto- or relapse ater CAR T-cell therapy.19 Approaches to over-
allo-HCT, history o mold inection, neutropenia lasting come antigen loss include multispecic CAR T-cells to
more than 14 days, grade 3 or 4 CRS/ICANS, receipt o target more than one antigen, coadministration o two
more than 3 days o steroids, or history o HLH/MAS. separate CAR T-cell products, or even a mixed product
with heterogeneous CAR T-cells.44
Lack o persistence has been attributed to T-cell
ReLAPSe AND FAILURe OF CAR exhaustion. CAR T-cell exhaustion may arise rom
T-CeLL THeRAPY actors beore chemotherapy, alterations in the tumor
microenvironment, contributions rom circulating
Despite the success with CAR T-cell therapy, treatment cells, or it could be associated with variations in the
ailure remains a major challenge. Although the exact manuacturing process. “Exhausted” CAR T-cells are
mechanisms causing tumor escape remain unknown, less prolierative, have a higher number o inhibitory
relapse ater CAR T-cell therapy that targets the CD19 receptors (ie, programmed death 1 [PD-1]), and are
less potent/cytotoxic than nonexhausted T-cells. T-cell actors at leukapheresis, including worse PS, interna-
exhaustion is a complex phenomenon and is accompa- tional prognostic index (IPI) score o at least 3, bulky
nied by an upregulation o inhibitory receptors, such disease, and elevated lactate dehydrogenase. O note,
as PD-1, TIM-3, and LAG-3.45 Multiple environmental while in this group o 124 patients, BT was adminis-
and T-cell–intrinsic mechanisms contribute toward the tered to 50%, the patients who received radiation as
acquisition o an exhausted phenotype and, as a result, BT had an apparent increased CR rate (82%) compared
these cells have poor eector cell unction and reduced with those treated with chemotherapy alone (38%),
ecacy.25 O-label use o the PD-1–blocking antibod- without any increase in CAR T-cell–related toxicity.49
ies, pembrolizumab and nivolumab, has resulted in
clinical responses with evidence or enhanced CAR
T-cell unction and antitumor activity through the re- INDOLeNT LYMPHOMAS
expansion and restored antitumor activity o exhausted
CAR T-cells.25 The phase 1 results o ZUMA-6, which Early trials with CAR T-cells initially commenced
adds PD-L1 blockade with atezolizumab ater axi-cel with enrollment o indolent NHLs (iNHL); however,
inusion, has shown a manageable saety prole with the rst-generation anti-CD19 CAR T-cells (with-
CRS and neurotoxicity rates that are not signicantly out costimulation) reported no clinical ecacy in FL
increased, despite a suggestion or greater CAR T-cell cases.50 Turtle et al reported on 8 FL patients treated
expansion compared with ZUMA-1. The expansion with the 4-1BB CAR T-cell construct (1:1 CD4/CD8
cohort is currently under investigation.46 In addition ratio),7 o 8 patients achieved CR rates with all ongo-
ChaptER 17
to T-cell exhaustion, regulatory T-cells and myeloid- ing at a median ollow-up o 24 months.51 The larg-
derived suppressor cells may suppress CAR T-cell est single-institution data in CAR T-cell therapy or
prolieration and cytokine production, leading to a the treatment o FL to date come rom the analysis
dampening o the antitumor response. It is impor- o tisa-cel rom the University o Pennsylvania that
tant to note that persistence has not been correlated included 14 FLs. These FL patients had relapsed within
directly with the presence or lack o durable long-term 24 months o initial diagnosis and remained reractory
response. Long-term ollow-up rom ZUMA-1 demon- to at least two lines o therapy.52,53 Patients received
strates that 75% o patients with ongoing responses a variety o conditioning regimens and included FL
had B-cell recovery, and data rom JULIET showed patients with poor prognosis eatures, including prior
no link between expansion, T-cell concentration, and multiple therapies (median o 5), relapsed post auto-
clinical outcomes. HCT (21%) and allo-HCT (1 patient). The updated
Host actors driving CART ecacy continue to be analysis showed a 3-month ORR and CR o 79%
dened. The depth o lymphodepletion beore CAR (11/14) and 71% (10/14), respectively. The median PFS
T-cell inusion has been shown to impact treatment was not reached, and 70% o patients with FL were
outcomes. Data comparing fudarabine/cyclophos- disease ree at a median ollow-up o 28.6 months.53
phamide as LD conditioning versus cyclophospha- Interim results rom ZUMA-5, a phase 2, multi-
mide alone LD conditioning showed the ormer was center study o axi-cel in patients with R/R iNHL, was
associated with increased CAR T-cell expansion, per- reported in abstract orm earlier this year. The trial eli-
sistence, and improved response rates, indicating that gibility included R/R FL (grades 1–3a) or MZL (nodal
lymphodepletion is an important driver o response.18 or extranodal) ater at least two lines o therapy, and
Tumor burden may also correlate to outcomes; patients ECOG PS o 0–1. Patients received LD chemotherapy
with ALL with less than 5% blasts demonstrated a ollowed by axi-cel inusion at 2 × 106 CAR T-cells/kg.
superior OS compared with those with a higher disease To date, 96 pts (80 FL; 16 MZL) received axi-cel with
burden in multiple reports.47 Locke et al reported data a median ollow-up o 12.8 months (range, 1.9–28.8).
rom ZUMA-1 suggesting that high tumor volumes are These patients had a median age o 63 years (range,
associated with inerior durable responses in DLBCL.48 34–79), 49% o patients were male, 52% had stage IV
Although bridging therapy was not allowed on the ini- disease, 51% had ollicular lymphoma IPI o at least
tial ZUMA-1 trial, when CAR T-cell therapy is used in 3, and 49% had high tumor bulk. This was a heav-
the real-world setting, oten bridging chemotherapy is ily pretreated population with a median 3 prior lines
used to control disease until the time o cell inusion. o therapy, and 54% o patients had progressed less
Pinnix et al reported patients who received subsequent than 2 years ater initial anti-CD20 monoclonal anti-
axi-cel inusion with or without bridging therapy (BT) body (mAb)-containing therapy (POD24), whereas
and reported that those who received BT had a worse 73% were reractory to the last prior treatment. O 96
PFS and OS when compared with those who did not patients evaluable or ecacy, ORR was 93% (80%
receive BT. In this study, BT consisted o chemother- CR rate). Patients with FL (n = 80) had an ORR o 95%
apy, radiation, or a combination o both. Patients who (81% CR rate). Patients with MZL (n = 16) had an ORR
received bridging were more likely to have adverse o 81% (75% CR rate). Overall, 68% o FL patients
had ongoing responses as o the data cuto. The rate lymphomas. Because o shared antigen expression
o grade 3 or higher CRS was 8%, whereas grade 3 between normal, malignant, and therapeutic T-cells,
or higher ICANS was 17%.54 These data support anti- CAR T-cell therapy targeting T-cell malignancies can
CD19 CAR T-cell therapy as a promising therapy in potentially lead to CAR T-cell ratricide (sel-killing)
iNHL, and there are a number o trials that are ongoing and prolonged T-cell aplasia. 60,61 CD5 and CD7 have
in this patient population. been identied as potential targets, with signicant
antitumor activity seen in preclinical models.62 The
phase 1 results were reported in abstract orm o a
CeNTRAL NeRVOUS SYSTeM CD5 CAR T-cell trial or treatment o CD5-positive
LYMPHOMA T-cell malignancies in ve patients at two dose levels
(1 × 107 and 5 × 107 CAR T-cells/m 2) with a median
The early CAR T-cell trials excluded patients with o our prior lines o therapy (range, 2–8). CRS
primary (PCNSL) or secondary CNS (SCNSL) lym- occurred in three o ve patients (all at DL2); how-
phoma because o the concern o increased risk o ever, the highest-grade CRS or ICANS observed was
neurotoxicity. In general, CNS lymphoma is chal- grade 2. On disease reevaluation 4 to 8 weeks post-
lenging to treat because o the limited penetration CD5 CAR T-cell inusion, three o ve evaluable
o chemotherapy and immunotherapy through the patients obtained an objective response (one on DL1
BBB. Although there are reports o documented CNS and two on DL2). Two patients achieved CR and a
penetration o CAR T-cells in leukemia, small studies third had a mixed response and then responded to an
ChaptER 17
have only recently shown active CAR T-cells in lym- additional inusion. All o the patients who achieved
phoma. 55–57 There have now been a number o reports a response then proceeded to allo-HCT. 63 Although
that have shown ecacy o commercial CAR T-cell this is a small series, it shows ecacy targeting CD5
therapy without a signicant increase in ICANS in as an antigen or CAR T-cell therapy. Larger studies
patients with SCNSL. Fiteen patients with a recent with longer ollow-up are needed to assess whether
history or active SCNSL treated with axi-cel reported this is a pathway that could be easible, devoid o the
an ORR o 75% (including two achieving CR with allogeneic transplant as consolidation.
active SCNSL) without a signicant dierence in tox- CD30 is almost universally expressed in anaplas-
icity compared with patients without CNS involve- tic large-cell lymphomas (ALCL), and in a proportion
ment. 58 In another series, eight patients with CNS o other T-cell lymphoma types, including cutaneous
involvement were treated with tisagenlecleucel. Two T-cell lymphomas. CD30 is an excellent candidate
o eight patients had systemic disease in addition to or immune-based therapies because o its restricted
CNS involvement at the time o inusion. All patients expression on tumor cells, with limited expression on
received CNS-directed therapy or reractory dis- a small subset o activated normal (nonmalignant) lym-
ease up until lymphodepletion. No patients required phocytes, leading to low risk or o-tumor, on-target
tocilizumab or high-dose steroids or the manage- toxicity.64 Two trials o CD30-directed CAR T-cells
ment o CRS and/or ICANS, with durable responses published have included T-cell lymphomas in addition
noted in a small minority o patients. 55 This experi- to other CD30-expressing disease. The largest series
ence is echoed by Siddiqi et al, who report on an reported on 18 patients with R/R CD30+ lymphoma (17
ongoing phase 1 trial investigating an autologous with HL and one with cutaneous ALCL) with an anti-
CD19-specic, hinge-optimized, CD28 costimula- CD30 CAR,65 which utilized the 4-1BB costimulatory
tory CAR with a truncated estimated glomerular l- endodomain and a lentiviral vector or T-cell engineer-
tration rate, which does not exclude patients with ing. The patient population was heavily pretreated and
PCNSL or SCNSL. Three patients with PCNSL and there was no CRS observed; however, the responses
our with SCNSL were treated without any grade 3 were modest, with seven patients attaining a PR and six
or higher CRS or ICANS and an ORR o 57%. 59 Fur- patients with stable disease. There were no CRs and the
ther data are needed to qualiy the long-term durable ORR was 39%. The median PFS was 6 months.
response o autologous CD19–directed CAR T-cell Using a dierent construct, Ramos et al reported
therapy in CNS lymphoma, but there are ample data the results o nine patients with R/R CD30+ lym-
that conrm no increase above baseline in terms o phoma (six with HL, two with ALCL, and one with
toxicity, specically neurotoxicity. DLBCL evolved to HL). For this trial, the CD30 CAR
included a CD28 costimulatory endodomain and was
delivered into T-cells via a gamma retroviral vector.
T-CeLL LYMPHOMA These patients exhibited mild CRS and three patients
attained CR, whereas another three had stable dis-
TCLs are associated with an overall poor prognosis ease; notably, those who attained CR had prolonged
and do not have as many treatment options as B-cell disease-ree time periods.66
There are a number o clinical trials investigating 61% and 83%, respectively. In terms o toxicity, 26%
CD30 as a target or CAR T-cell therapy, both with o patients had grade 3 or higher cytopenias lasting
autologous and allogeneic constructs.67 beyond 90 days ater the administration o brexu-
cel. Overall, any grade CRS occurred in 91% o the
patients and most cases were grade 1 or 2 (in 76%
MANTLe CeLL LYMPHOMA o patients), whereas 15% were grade 3 or higher. A
total o 63% o patients had neurologic events with-
Mantle cell lymphoma (MCL) comprises about 5% o out any deaths attributed to ICANS. ICANS grade 1
newly diagnosed NHL, and the median age at diag- or 2 occurred in 32% o the patients and events o
nosis is about 68 years, with a subset o patients who grade 3 or higher occurred in 31%. The median dura-
do exceptionally poorly based on histology, TP53 tion o a neurologic event was 12 days, with events
gene mutation, and actors that dene the mantle cell ully resolving in 37 o 43 patients (86%). There were
international prognostic index.68,69 MCL is uniormly two deaths associated with inection. Given these
CD19 positive and amenable to CD19-directed immu- results, we will likely see a shit in paradigm as with
notherapies or cellular immunotherapies. Preliminary DLBCL in timing o transplantation or MCL.
data rom the TRANSCEND study, using liso-cel, in
nine heavily pretreated MCL patients (all with prior
Bruton tyrosine kinase inhibitor exposure, three with HODGKIN LYMPHOMA
prior auto-HCT) showed an encouraging ORR o
ChaptER 17
78%. In the pivotal ZUMA-2 trial, KTE-X19 product HL is characterized by Reed-Sternberg cells that are
(brexucabtagene autoleucel) was tested in patients CD19 negative and CD30 positive within an immu-
with R/R MCL. 70 KTE-X19 is an anti-CD19 CAR nosuppressive tumor microenvironment containing
T-cell therapy produced in a manuacturing process CD19+ B cells. Studies using autologous anti-CD30
that removes circulating CD19-expressing malignant CAR65 with the 4-1BB costimulatory endodomain
cells or use in patients with leukemia or MCL. The and a lentiviral vector have recently reported the
removal o these cells reduces the possible activation outcomes o 41 patients with R/R HL treated at two
and exhaustion o anti-CD19 CAR T-cells during the independent centers. Documented CD30 expression
ex vivo manuacturing process. Brexucabtagene auto- by immunohistochemistry was required, but there
leucel has just recently received commercial approval was no specic cuto. Bridging chemotherapy was
based on the results o the ZUMA-2 pivotal trial. allowed beore lymphodepletion, and LDC consisted
Conditioning chemotherapy consisted o fudarabine o either cyclophosphamide 500 mg/m 2 per day and
at a dose o 30 mg/m2 per day, and cyclophosphamide fudarabine 30 mg/m2 per day or 3 days (fu/cy);
at a dose o 500 mg/m2 per day was administered on bendamustine alone at 90 mg/m2 per day or 2 days
days −5, −4, and −3 beore a single intravenous inu- or bendamustine 70 mg/m2 per day and fudarabine
sion o brexucabtagene autoleucel (brexu-cel) was 30 mg/m2 per day or 3 days (fu/benda). The cell
administered at a dose o 2 × 10 6 CAR T cells/kg on dose at the expansion level was 2 × 10 8 cells/m 2. The
day 0. There was no phase 1 study because the dose bendamustine-alone arm did not have any patients
was determined on the basis o studies o axi-cel in who responded, whereas the fu/cy arm had an ORR
patients with large B-cell lymphoma and o KTE-X19 o 65% with a CR rate o 47%, and the fu/benda arm
in patients with ALL.19,71 In contrast to the ZUMA-1 had an ORR o 80% and CR rate o 73%. The 1-year
trial, beore conditioning and ater apheresis, patients PFS or patients with measurable disease was 41%
who had a high disease burden could receive BT. The or all patients who received fudarabine-based lym-
choice was at the investigator’s discretion—glucocor- phodepletion and 61% or those who achieved CR
ticoid, ibrutinib, or acalabrutinib (or a combination as initial response. 72 Given these results, a planned
o glucocorticoid plus ibrutinib or acalabrutinib)— phase 2 trial is pending using the fu/benda regimen
with the intent o BT to keep the disease stable dur- or lymphodepletion.
ing the manuacturing period. Seventy-our patients
were enrolled and product was manuactured or
71 patients and administered to 68; 96% o the ALLOGeNeIC CAR T-CeLLS
patients had a dose successully manuactured, with
KTE-X19 delivered to the site in a median o 16 To overcome the cumbersome and expensive process
days ater apheresis. The ecacy analysis showed o manuacturing patient-specic autologous CAR
85% had an objective response and 59% had a CR. T-cells, there are also eorts ongoing to develop allo-
At a median ollow-up o 12.3 months, 57% o the geneic o-the-shel CAR T-cell therapy approaches,
60 patients in the primary ecacy analysis were in which allows generation o about 100 doses rom
remission, whereas the 12-month PFS and OS were each apheresis product and thereore could lower
the cost o this therapy. Allogeneic CAR T-cells have An alternative strategy or allogeneic CAR T-cell
many potential advantages, such as a decreased cost therapy is to use a dierent cell type such as NK cells,
as a result o the implementation o industrialized NK T-cells, or gδ T-cells, which are not known to
and scaled-up production pathways. “O-the-shel” cause GVHD and thereore do not require the addi-
allogeneic CAR T-cells are premanuactured rom tional gene editing such as knocking out the TCR.
third-party healthy donors and expanded in high Indeed, in a small phase 1 study o 11 patients with
numbers beore treatment to be made available to B-cell malignancies, administration o allogeneic anti-
patients on demand and thereore may provide poten- CD19 CAR NK cells with NK cells–derived cord blood
tial solutions to the delays aced by the autologous induced CR in eight patients with no CRS, ICANS,
CAR T-cell therapy including: (1) Time to manuactur- or GVHD. 76 These early data are highly encouraging
ing, (2) need or interim bridging therapies, (3) risk o regarding the saety, easibility, and short-term e-
malignant contamination, (4) T-cell variability, (5) risk cacy o allogeneic CAR T-cell therapy. However, lon-
o insucient T-cell expansion, (6) T-cell dysunction, ger ollow-up is needed to determine the durability o
and (7) limited opportunity or redosing. However, the responses.
certain unique challenges arise as a unction o the
allogenic cell source, including grat-versus-host dis-
ease (GVHD) and the durability o the injected cells. NOVeL CAR DeSIGNS
Most o the allogeneic CAR T-cell candidates utilize
cellular gene-editing approaches to ensure complete Empowering CAR T-cells to be able to recognize
ChaptER 17
removal o the TCR. Transcription activator–like eec- a combination o antigens on the cell surace o the
tor nucleases (TALEN) were the rst technology to be tumor may help avoid antigen escape and/or reduce
used in patients or αβTCR removal,73 including or toxicity. These next-generation CARs, including mul-
ALLO-501 (described below). There are a number o titargeted CAR congurations, include the ollowing.
gene-editing technologies currently being used preclin- “OR”-gate CARs, where the binding o either
ically in addition to those in clinical trials or allogeneic CAR to its cognate antigen is enough to drive ull T-cell
CARs. These include clustered, regularly interspaced, activation. This strategy is to overcome tumor resis-
short palindromic repeat (CRISPR), as well as antigen tance. These include:
receptor complex (ARC) – editing mega-nucleases or • Dual CARs77: coexpress two dierent CARs in one
genome engineering which is the incorporation o the cell
DNA-binding domain rom transcription activator– • Tandem CARs78: contain two dierent single-chain
like eectors into hybrid nucleases (mega-transcrip- variable ragments in a single CAR molecule that can
tion activator–like eectors) and zinc ngers.74 either be stacked in a series or as a looped structure
O note, ALLO-501 is an investigational anti-CD19 The major advantage resides in the act that the
CAR T-cell product that has been genetically modi- presence o both targets allows or an enhanced T-cell
ed to eliminate TCRα expression, with the goal o unction, which makes them more ecient than a
reducing the risk o GVHD. ALLO-647 is an inves- pooled combination o CAR T-cells at inducing anti-
tigational mAb that selectively targets and binds tumor responses.79,80 However, such a strategy o tar-
CD52 on T-cells, triggering a host immune response geting two antigens may result in increased risk or
that depletes CD52-positive T-cells. The ALLO-501 toxicity, especially when treating solid tumors.
CAR T-cell product is also genetically engineered to “AND” -gate CARs, where CAR T-cells are ully
remove the CD52 cell surace protein. When the anti- activated only when antigen A and antigen B are recog-
CD52 mAb is administered during lymphodepletion, nized.81 This strategy is to minimize toxicities.
the patient’s CD52-positive T-cells are targeted. This These include:
strategy supports the persistence and expansion o the • Combinatorial CARs82: combine two constructs
donor CAR T-cells. The multicenter, open-label, phase where one bears the CD3z signaling moti and the
1 ALPHA study examined the saety and ecacy o other bears the costimulatory signaling domain. In
sequential treatment with ALLO-647 and ALLO-501 in this split-signal approach, recognition o a single
22 patients with R/R DLBCL or FL who were treated antigen, which may happen in normal cells, leads
with at least two prior lines o therapy, including an to suboptimal T-cell activation and limited killing o
anti-CD20 mAb.75 Among 19 patients evaluable or normal cells. In tumors where both antigens may
ecacy, the ORR was 63% and the CR rate was 37%. be expressed, ull T-cell activation is achieved ater
Although numbers are small, higher ALLO-647 doses engagement o both single-chain variable ragments
during lymphodepletion were thought to be associated (scFvs) to their cognate antigens.
with deeper responses, with 27% and 50% o patients • Synthetic notch (synNotch) receptor CARs that
in the ALLO-647 39 mg and ALLO-647 90 mg groups, induce the transcription o a CAR ater antigen rec-
respectively, achieving a CR. ognition o their cognate antigen.81 Activation o
one receptor (synNotch) induces the expression o CAR T-cells ater tumor recognition by the anti-
a second receptor (CAR) that induces T-cell activa- body switch.86,87
tion ater antigen recognition. Full T-cell activation In a more recent approach, universal CAR T-cells
and tumor elimination occur only when both anti- are designed where the split-CAR system named
gens are expressed. However, tumor escape o CAR “SUPRA CAR” combines zipCAR T-cells containing an
T-cells through loss o the rst antigen targeted by extracellular leucine zipper with an scFv domain used
the synNotch receptor is a major limitation o this to a second leucine zipper (zipFv).88
strategy. These versatile systems allow or the combination
On-switch CARs83, which remain inactive until o universal CAR T-cells with zipFvs targeting dier-
specic activating agents are added, assembling a ully ent antigens to avoid tumor escape. At the same time,
unctional receptor. These are designed as ragmented modulating the dose or anity o the antibody-based
CAR receptors, where the extracellular antigen-binding switches may control toxicities. In the case o SUPRA
module is dissociated rom the intracellular signaling CAR T-cells, T-cell activation can be prevented when
components. Assembly o these two receptors in the necessary by the addition o a competitive zipFv that
presence o a heterodimerizing small molecule, such can bind with high anity to the zipFv with tumor
as tacrolimus-based analogs, leads to CAR T-cell acti- specicity.88
vation. The magnitude o responses depends on the
dosage o the drug, which allows or titratable control.
Inhibitory CARs (iCARs),84 which inhibit T-cell FUTURe DIReCTIONS
ChaptER 17
activation ater antigen recognition in normal cells.
This is a strategy to limit toxicity. This includes the Although CAR T-cell therapy is among the most
coexpression o a classic CAR with an antigen-specic dynamic therapies developed or lymphoma over the
iCAR bearing the signaling domain o an immunoin- past ew decades, urther work is needed to improve
hibitory receptor (ie, CTLA-4 or PD-1). Engagement o its saety, ecacy, and aordability. Several reports
iCARs to antigens in normal cells can constrain T-cell indicate that altering the design o the CAR molecule
unctions, which can be resumed in the absence o the could improve the saety prole without aecting
iCAR-targeted antigen and ater antigen recognition the ecacy. Ghorashian and colleagues showed that
by the activating CAR. One o the challenges o this lowering the binding anity o the scFv by having a
approach is the identication o cell surace antigens similar on-rate but aster o-rate to the CD19 target
that are expressed in normal cells but absent in tumor lowers the incidence o severe CRS without aect-
cells, a problem that is complementary to the obstacle ing ecacy in patients with B-cell ALL.89 Ying et al
o identiying tumor-specic antigens absent in normal demonstrated that altering the length o the hinge and
tissues. transmembrane domain o the CAR molecule coners
Universal or switchable CAR T-cells, which dierent properties, such as dierent cytokine proles
remain inactive until antibody-based molecules target- with preserved cytolytic activity.90 In a phase 1 trial in
ing a tumor antigen are supplied to reconstitute a ully 25 patients with B-cell lymphoma, an optimized hinge
active CAR construct. A dierent strategy that could and transmembrane domain resulted in a 55% CR rate
simultaneously address antigen escape while mitigat- with only grade 1 CRS and no ICANS.90 As discussed
ing toxicities is the utilization o so-called “universal previously, the 4-1BB costimulatory domain appears
CARs.” Instead o engineering T-cells with xed-anti- to induce lower toxicity rates compared with the
gen specicities, these CAR therapies are composed o CD28 costimulatory domain.19,81,92 Preclinical studies
two parts: also indicate that the CD3ζ signaling domain could be
1. An antibody-based molecule that recognizes modied to avor better persistence o the CAR T-cells
a tumor antigen and is modied to express a while reducing infammation.93
“switch”; and Preclinical and correlative studies rom clinical tri-
2. A universal CAR T-cell without tumor specic- als suggest that the unctional phenotype o the T-cells
ity by itsel, which contains a construct with an in the apheresis and CAR T-cell products could aect
extracellular portion that binds to the switch and saety and ecacy. In patients with lymphoma, the
is linked to the intracellular signaling domains. polyunctionality o the CAR T-cells was associated
In a rst approach, universal CAR T-cells were with both response and toxicity.94 In patients with
designed to bind to: CLL, apheresis products with higher requency o early
a. biotinylated antigen-specic molecules85; memory CD8+ T-cells dened by CD27+CD45RO–
b. small-molecule fuorescein isothiocyanate 86; resulted in better-quality CAR T-cell products and
and better clinical ecacy.95 Deng and colleagues demon-
c. short peptide in the antibody-based switch, allow- strated that a higher requency o memory phenotype
ing activation o the corresponding switchable in the CAR T-cell product was associated with better
durability o response, whereas a higher requency In summary, three anti-CD19 CAR T-cell therapy
o exhausted phenotype was associated with inerior products have been approved or the treatment o R/R
outcome.96 Together, these results indicate that the LBCL and/or MCL. These products are now being
saety and ecacy o CAR T-cell therapy could be evaluated in other subtypes o NHL, and randomized
improved by transducing the CAR gene into specic trials are ongoing to directly compare CAR T-cell ther-
subsets o T-cells. Other strategies to improve e- apy with SCT at rst relapse in patients with DLBCL.
cacy o CAR T-cell therapy include targeting multiple In additional, use o CAR T-cell therapies against novel
antigens simultaneously to overcome antigen escape, targets in B-cell lymphoma and HL and T-cell lympho-
which has been reported in around 30% o patients mas are in development. The high ecacy o CAR
ater anti-CD19 CAR T-cell therapy in DLBCL.19,26 T-cell therapy together with the appeal o a single
CAR T-cells targeting other pan–B-cell antigens such inusion to induce durable remission and possible cure
as CD20, CD22, CD79b, and BAFF-R are in various suggests that this may be the beginning o a paradigm
stages o preclinical and clinical development, either as shit on how the management o lymphomas is likely
CARs against single targets or CARs against multiple to evolve in the uture.
antigens targeted simultaneously.97–100
MD ANDeRSON PRACTICe TIPS

ChaptER 17
J Current data suggest that CAR T-cell therapy is pre- cells. CRS generally develops within the rst week
erred over allo-SCT as the rst choice in patients ater inusion, whereas ICANS occurs ater the peak
whose disease has relapsed ater auto-SCT in most o CRS (oten >3 days later), with peak symptoms
clinical situations. Allogeneic transplant should be occurring during days 5 to 9. Upon standard treat-
reserved or patients who either have no CAR ther- ment with high-dose steroids, ICANS is mostly tran-
apy options or have had disease relapse ater CAR sient, with a median duration o 5 to 11 days, but
T-cell therapy. can ollow a prolonged course in individual patients.
J Delivering CAR T-cell therapy requires a compre- Correctly identiying CRS and ICANS is imperative
hensive multidisciplinary approach with highly or appropriate treatment with IL-6 antagonists and
specialized medical teams, including subspecialty corticosteroids.
medicine and emergency and critical care groups J More than 20% o CD19 CAR T-cell–treated patients
that quickly evaluate and treat patients or compli- have protracted or recurrent neutropenia and/or
cations. At MDACC, we have a core group o hema- thrombocytopenia beyond 4 weeks ater inusion.
tologic malignancy, stem cell transplant, critical Our standard procedure is or patients to remain on
care, neurology, emergency medicine, cardiology, viral and Pneumocystis pneumonia prophylaxis or
inectious disease, pulmonary, renal, psychiatry, one year post inusion o CAR T-cells.
physiatry, and palliative medicine specialists who J In the relapsed/reractory setting, patients with
take part in the care o patients. lymphoma continue to have a poor prognosis, and
J It is vital to appreciate that patients may exhibit these patients should be reerred to high-volume
toxicity at variable time points ater inusion o centers where clinical trials are available
22. Abramson JS, Gordon LI, Palomba ML, et al. Updated saety
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T-cell antigen receptor. Cancer Res. 2012;72:1844-1852. tics o anti-CD19 CAR T-cell inusion products associated with
86. Rodgers DT, Mazagova M, Hampton EN, et al. Switch-medi- ecacy and toxicity in patients with large B-cell lymphomas.
ated activation and retargeting o CAR-T cells or B-cell malig- Nat Med. 2020;26(12)1878-1887.
nancies. Proc Natl Acad Sci U S A. 2016;113:E459-468. 97. Lee SY, Olsen P, Lee DH, et al. Preclinical optimization o a
ChaptER 17
87. Ma JS, Kim JY, Kazane SA, et al. Versatile strategy or control- CD20-specic chimeric antigen receptor vector and culture
ling the specicity and activity o engineered T cells. Proc Natl conditions. J Immunother. 2018;41:19-31.
Acad Sci U S A. 2016;113:E450-458. 98. Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells
88. Cho JH, Collins JJ, Wong WW. Universal chimeric antigen induce remission in B-ALL that is naive or resistant to CD19-
receptors or multiplexed and logical control o T cell responses. targeted CAR immunotherapy. Nat Med. 2018;24:20-28.
Cell. 2018;173:1426-1438, e1411. 99. Ormhoj M, Scaro I, Cabral ML, et al. Chimeric antigen
89. Ghorashian S, Kramer AM, Onuoha S, et al. Enhanced CAR T receptor T cells targeting CD79b show ecacy in lym-
cell expansion and prolonged persistence in pediatric patients phoma with or without cotargeting CD19. Clin Cancer Res.
with ALL treated with a low-anity CD19 CAR. Nat Med. 2019;25:7046-7057.
2019;25:1408-1414. 100. Qin H, Dong Z, Wang X, et al. CAR T cells targeting BAFF-
90. Ying Z, Huang XF, Xiang X, et al. A sae and potent anti-CD19 R can overcome CD19 antigen loss in B cell malignancies. Sci
CAR T cell therapy. Nat Med. 2019;25:947-953. Transl Med. 2019;11(511):eaaw9414.
Section III Stem Cell
Transplantation
Section Editor: Elizabeth J. Shpall
18 Autologous Hematopoietic Progenitor-Cell Transplantation
19 Allogeneic Transplantation
20 Alternative Donor Transplants: Cord Blood Transplant
21 Alternative Donor Transplants: Haploidentical Hematopoietic

22 Cellular Therapy in Allogeneic Hematopoietic Cell

Transplantation
18 Autologous Hematopoietic
ProgenitorCell Transplantation
Neeraj Saini
Yago Nieto
Key Concepts
 The use o autologous hematopoietic progenitor-cell  Management o relapsed or primary reractory Hodgkin
transplant (AHPCT) overcomes myelotoxicity o high- lymphoma in patients should be a salvage strategy using
dose chemotherapy (HDC). Thereore, drugs with a one or more lines o therapy, including regimens such
markedly myelosuppressive side eect profle and as bendamustine/brentuximab vedotin or iosamide/
a steep dose-response eect are preerred. The most carboplatin/etoposide aiming at a positron emission
common nonhematologic regimen-related toxicity (RRT) tomography–negative remission beore AHPCT. Patients
is oropharyngeal mucositis, which is rarely lie threaten- with a high-risk or disease relapse should be consid-
ing. The most common among the potentially severe ered or post-AHPCT maintenance with brentuximab
extramedullary RRT are interstitial pneumonitis and vedotin.
veno-occlusive disease o the liver.  Modern treatment o newly diagnosed myeloma should
 HDC with AHPCT has been the standard o care or chemo- include induction with a proteasome inhibitor and an
sensitive, relapsed diuse large B-cell lymphoma (DLBCL) immunomodulatory drug (eg, bortezomib/lenalidomide/
or the last three decades. However, the results remain dexamethasone [VRD]) ollowed by melphalan-based
suboptimal in patients whose disease relapses less than HDC and AHCPT, and consolidation and/or maintenance
one year ater completion o rontline chemoimmuno- with drugs like lenalidomide, with the goal o achieving a
therapy (eg, R-CHOP). minimal residual disease-negative remission.
 In ollicular lymphoma, HDC with AHPCT should be con-  Tandem cycles o carboplatin-containing HDC with AHPCT
sidered or high-risk relapses occurring within two years o should be considered or any patient with a germ-cell
completing rontline therapy (POD24) or second or more tumor in the second or later relapse. Their role in the frst
advanced relapses. relapse is still undetermined.
BASIC CONCEPTS ollowed by autologous or allogeneic transplantation

o HPCs to restore hematopoiesis. Pluripotent HPC
High-dose chemotherapy (HDC) with autologous progenitors present in the grat prolierate and di-
hematopoietic progenitor-cell transplant (AHPCT) is erentiate into the mature blood and immune cells.
an eective treatment modality or a variety o hema- AHPCT involves the collection, cryopreservation, and
tologic malignancies and selected solid tumors. This inusion o the patient’s own HPCs.
chapter reviews its current role in the treatment o
cancer, outlining uture directions o progress.
Doses o radiation and chemotherapy are limited GENERAL PROCEDURES FOR
by toxicity to normal tissues and, particularly, the AUTOLOGOUS TRANSPLANTATION
bone marrow. However, the doses o certain chemo-
therapeutic agents and radiation can be substantially Figure 18–1 shows the dierent procedures related to
escalated, exploiting their dose-response eect, when autologous transplantation.
383
384 Scion III Stem Cell Transplantation
Preceding Standard-Dose Chemotherapy o insufcient antitumor eect o HDC. Venues to

improve the activity o HDC include the incorpora-
Standard-dose chemotherapy is usually given to cyto- tion o novel chemotherapy agents (such as gem-
reduce the tumor beore proceeding to AHPCT. In citabine or cloarabine), monoclonal antibodies (such
general, the best outcomes are seen in patients with as rituximab or CD20+ lymphomas), or epigenetic
chemosensitive disease in complete remission, or with modulators (such as vorinostat or azacitidine).6,7 The
minimal tumor burden at the time o transplantation. use o sequential cycles o HDC has been thoroughly
evaluated in myeloma and is usual practice in treating
germ-cell tumors. A major pitall o eorts to improve
Peripheral Blood Progenitor Cell Collection
the efcacy o established HDC is that merely increas-
Peripheral blood progenitor cells (PBPCs) should be ing the total dose o antineoplastic drugs may improve
collected while the patient’s marrow is normocel- the tumor response but will certainly increase the
lular and uninvolved by the malignancy. PBPCs are severity o side eects. Thus, novel HDC regimens
normally present in very low numbers in the blood must have a solid pharmacologic rationale, with care-
but are mobilized into the blood at postchemother- ul consideration o scheduling, and be developed in
apy recovery with granulocyte colony-stimulating well-designed clinical trials aiming or the optimal
actor (G-CSF). PBPCs are collected using apheresis therapeutic index.
with continuous-ow cell separation. The minimal
and optimal CD34+ cell doses or an autologous HPC
transplant are 2 × 106/kg and 5 × 106/kg, respectively.
Reinfusion of Collected Stem Cells
The collected PBPCs are cryopreserved until inusion Stem cells are inused intravenously ater HDC is
to the patient. cleared rom the patient’s bloodstream, usually 1 to 3
Multiple actors have been shown to predict poor days ater completion o this treatment. The cells cir-
success in mobilization and collection, including culate transiently and then home to the bone marrow.
advanced age, amount o preceding chemotherapy, Hematopoiesis is restored within a ew weeks.8 Neu-
presence o marrow-infltrating disease, history o trophils recover typically in 7 to 10 days and platelets
pelvic radiation, prior exposure to certain drugs such recover in 10 to 21 days ater inusion.
as melphalan, carmustine or bendamustine, low pre-
mobilization platelet counts, short interval rom last
chemotherapy cycle to mobilization, inadequate
Supportive Care
chemotherapy mobilizing regimens and/or low-dose Patients usually receive G-CSF or other hematopoi-
G-CSF,1 and previous treatment with multiple cycles etic growth actors to accelerate neutrophil recovery.
o lenalidomide.2 A count o CD34+ cells greater than Patients are routinely prescribed a prophylactic antibi-
Chapter 18
10/mL in peripheral blood is highly predictive o an otic, antiviral, and antiungal therapy or the preven-
adequate collection. Plerixaor is a useul second PBPC- tion o inection during the initial phase o marrow
mobilizing agent, which acts synergistically with engratment and hematologic recovery.
G-CSF and is eective in patients predicted or shown
to be “poor mobilizers.”3
AUTOLOGOUS VERSUS ALLOGENEIC
High-Dose Therapy HPC TRANSPLANTS
Autologous transplants are most eective in diseases The relative role o autologous versus allogeneic trans-
where a several-old dose escalation o myelosup- plants varies or each hematologic malignancy. AHPCT
pressive drugs leads to a markedly increased cyto- is a process that carries less overall morbidity and mor-
toxic eect on the malignancy. Given their steep tality because the reinused cells are neither subject to
dose-response eect, alkylating agents constitute the immunologic rejection nor will produce grat-versus-
backbone o HDC regimens. The activity o alkylat- host disease. On the other hand, there is a potential risk
ing agents depends on the extent o DNA damage o tumor contamination o the autologous grat, par-
and repair. Thus, drugs that inhibit DNA damage ticularly in patients with bone marrow tumor involve-
repair, such as the nucleoside analogs udarabine or ment. In vivo bone marrow purging with monoclonal
cloarabine or leukemia, or gemcitabine or lympho- antibodies preceding PBPC mobilization and apheresis
mas, have been combined with alkylating agents, with in particular, rituximab or CD20+ B-cell lymphomas,
resulting synergy and improved clinical results.4,5 has be shown to be eective. Finally, there is no evi-
The optimal HDC regimen is specifc to each dis- dence that the immune-mediated grat-versus-tumor
ease. The most common cause o ailure ater AHPCT eect associated with allogeneic HPC transplantation
is relapse o the underlying malignancy as a result occurs with AHPCT.
C 18 Autologous Hematopoietic Progenitor-Cell Transplantation 385
The Autologous Transplant Process

1. Collection 5. Reinfusion
Stem cells are collected Thawed stem cells
from the patient’s bone are reinfused into
marrow or blood. the patient.
2. Processing
Blood or bone
marrow is 4. Chemotherapy
processed in the High-dose
laboratory to purify chemotherapy
and concentrate and/or radiation
the stem cells. 3. Cryopreservation
therapy is given
Blood or bone marrow is
to the patient
frozen to preserve it.
FIGURE 18–1 Autologous hematopoietic progenitor-cell transplantation process.
COMPLICATIONS OF HIGH-DOSE The lungs, heart, liver, brain, and kidneys are less
CHEMOTHERAPY commonly aected, generally in heavily pretreated
patients or in those with comorbid conditions. Over-
all, 1% to 4% o patients die rom RRT or inections,
HDC produces proound pancytopenia that usually which makes AHPCT substantially saer than alloge-
lasts rom 7 to 10 days. Inectious complications can neic transplantation.
occur during the neutropenic period (ranging rom Toxic interstitial pneumonitis can occur in up to
uncomplicated neutropenic ever to lie-threatening 40% o patients receiving HDC. It has been described
Chapter 18
sepsis) and up to 6 months or more post-transplant with several dierent chemotherapy agents, such as
in the case o Pneumocystis jiroveci, ungal inections carmustine, busulan, and total-body irradiation.10 It
or zoster reactivation. Antibacterial prophylaxis with is particularly common in patients previously treated
a uoroquinolone, antiviral prophylaxis with acy- with mediastinal radiotherapy. Prompt diagnosis
clovir/valacyclovir, and antiungal prophylaxis with is essential, and steroids are usually eective in its
uconazole are generally started at the time o stem treatment.
cell inusion and continued throughout neutropenia. Cardiac toxicity is uncommon. It can be seen ater
Pneumocystis jiroveci pneumonia prophylaxis (eg, trim- high doses o cyclophosphamide or melphalan. Prior
ethoprim/sulamethoxazole) is usually started at 3 to 4 radiation therapy to the mediastinum or let chest
weeks post-transplant or at least 6 months. Antiviral wall, as well as advanced age are also predictors o an
prophylaxes (acyclovir, valacyclovir) are given or 6 to increased risk o cardiac complications.11 Central ner-
12 months.9 vous system complications are rare, but dementia and
Regimen-related toxicity (RRT) are the side eects o leukoencephalopathy have been described, particu-
HDC in nonhematopoietic tissues, which depend on the larly rom drugs that penetrate the cerebrospinal uid,
specifc regimen. The oral mucosa and the gastrointes- such as carmustine or thiotepa.12 Hypothyroidism and
tinal tract are the most sensitive tissues to these eects. hypoandrogenism are requent and occur 6 months to
Several agents have shown some efcacy in random- 2 years ater transplant.13 Hemorrhagic cystitis, ater
ized clinical trials in the prevention o mucositis (such high-dose cyclophosphamide or iosamide, is uncom-
as amiostine, paliermin, topical glutamine, or laser mon and can be eectively prevented with mesna.14
therapy), whereas many others in common use have Sinusoidal obstruction syndrome (SOS) (or-
not been shown to be eective (such as steroids, sucral- merly known as venoocclusive disease) o the liver
ate, “magical mouthwash,” or topical anesthetics). is clinically characterized by uid retention (despite
optimal use o diuretics), rising direct hyperbiliru- or t-MDS/t-AML include older age at transplant, pre-
binemia, and hepatomegaly that can be painul.15 Its HDC exposure to alkylating agents, topoisomerase II
severity depends on the presence o multiorgan ail- inhibitors and radiotherapy, use o etoposide to mobi-
ure and the velocity o bilirubin rise. Although mild lize the PBPC, use o total-body irradiation as part
cases are oten sel-limited, severe cases can be atal o the AHPCT conditioning, inusion o lower num-
in more than 80% o patients. Several actors predis- bers o CD34+ cells, and multiple transplantations (as
posing to SOS include prior liver impairment, older in myeloma or germ-cell tumors). The prognosis or
age, and iron overload. The use o oral busulan and t-MDS/t-AML is poor, and the only potentially cura-
total-body irradiation has been most commonly asso- tive treatment is an allogeneic stem cell transplant
ciated with SOS, particularly i it is used with cyclo- (SCT).
phosphamide.16 Recently, the introduction o new
calicheamicin immunotoxin conjugated drugs, inotu-
zumab ozogamicin,17 and gemtuzumab ozogamicin, in RESULTS OF AUTOLOGOUS
treatment o leukemia beore transplant has contrib- TRANSPLANTATION
uted to increased incidence o SOS. Andersson et al at
MDACC have pioneered the use o intravenous busul- Non-Hodgkin Lymphoma
an, which eectively addressed the issue o intra-
patient dose-to-dose variability o oral busulan and Autologous transplantation has been extensively stud-
substantially decreased the risk o SOS compared with ied in patients with non-Hodgkin lymphoma (NHL),
its oral ormulation.18 This group also developed the either as rontline consolidation or in patients who are
pharmacokinetic-guided dosing o intravenous busul- reractory to frstline therapy or in relapse.
an, which corrects interpatient variability and urther
decreases the incidence o SOS. Systemic anticoagu- Difuse large Bcell lymphoma
lant and thrombolytic therapies have been shown to
HDC and AHPCT has been or several decades the stan-
be ineective and are associated with major bleeding
dard o care or patients with chemosensitive relapsed
complications. The only FDA-approved drug or the
diuse large B-cell lymphoma (DLBCL) (Fig. 18-2).21
treatment o SOS is defbrotide. In a phase 3 trial, the
Factors such as resistance to salvage chemotherapy,
day +100 complete response (CR) rate was 25.5% or
increased lactic dehydrogenase at the time o relapse
the defbrotide group compared with 12.5 % or the
or progression, prior CR o less than 12 months, and
historical control group.19 Defbrotide was associated
secondary international prognostic index (IPI) (ie, at
with signifcant improvement in day +100 CR and
the time o relapse or progression) score higher than 1
overall survival (OS) rate. Supportive care also plays
are adverse predictors o survival in patients receiving
a crucial role, using diuretics and sodium restriction,
HDC. In the modern era o exposure to rituximab as
Chapter 18
avoidance o hepatotoxins, oxygen support, and renal

part o frstline therapy (R-CHOP), the CORAL study
replacement therapy i needed.
has shown 3-year event-ree survival (EFS) rates o
Finally, therapy-related MDS (t-MDS) and therapy-
around 25% in patients with chemosensitive relapsed
related acute myeloid leukemia (t-AML) are poten-
disease who are undergoing autologous SCT.22
tially devastating complications o AHPCT, with
In contrast to relapsed disease, the efcacy o HDC
a cumulative probability that ranges rom 1.1% at
as rontline consolidation or DLBCL patients in frst CR
20 months to 23% at 4 years.20 With improvement
has not been demonstrated ater many randomized tri-
in the management o post-AHCPT inections and
als, especially when patients previously receive R-CHOP
RRT, t-MDS/t-AML have emerged as the main cause
instead o CHOP.23 Thus, AHPCT is not indicated as con-
o nonrelapse mortality ater AHPCT. There are two
solidation o the frst remission or DLBCL patients.
main types o t-MDS/t-AML: those related to alkyl-
ating agents or radiation, and those related to topoi-
somerase II inhibitors. The ormer group appears 4
to 7 years post-AHPCT, with two-thirds o patients
Follicular Lymphoma
presenting with MDS and one-third with AML with The role o AHPCT in the treatment o patients with
myelodysplastic eatures. There is a high incidence o chemosensitive relapsed ollicular lymphoma (FL)
abnormalities o chromosomes 5 (-5/del(5q)) and 7 (-7/ remains unclear. The classical regimen o high-dose
del(7q)). In contrast, topoisomerase II inhibitor–related cyclophosphamide/total-body irradiation has been
AML oten appears as overt acute leukemia without largely abandoned because o its high risk o t-MDS/t-
preceding MDS, with a shorter latency period o 6 AML. Historically, a major challenge has been contam-
months to 3 years. Most oten, it is associated with ination o the autologous grat by malignant cells.24
translocations involving 11q23 or 21q22. Risk actors More recently, systemic treatment with rituximab has
DLBCL
1st LINE
R/R CR
SALVAGE #1
CAR T *R/R †PR CR
‡R/R SALVAGE #2 CAR T ASCT
CR
RELAPSE < 12 MO. RELAPSE > 12 MO. CR
CAR T CAR T STANDARD RX
FIGURE 18–2 Algorithm for treatment of DLBCL: stepwise description of DLBCL treatment approach and the role of autologous
and allogeneic progenitor-cell transplantation after relapse. ASCT, allogeneic stem cell transplant.
Chapter 18
reduced the numbers o circulating lymphoma cells, HODGKIN LYMPHOMA
thus yielding eective in vivo purging with high likeli-
hood polymerase chain reaction–negative tumor-ree Most patients with Hodgkin lymphoma (HL) are cured
PBPC grats.25 A European randomized trial showed with frstline therapy. However, 20% o patients will
improved PFS and OS ater HDC or chemosensitive not respond to frstline chemotherapy and approxi-
relapsed FL.26 However, that study was conducted in mately 30% will have relapse ater an initial response.
the prerituximab era and is not entirely applicable to HDC has been proven to be benefcial in those two
modern patients. settings with expected long-term EFS o 30% to 40%
Approximately 20% o patients with FL develop or patients with primary reractory tumors that sub-
progression o disease within 2 years (POD24) ater sequently respond to salvage therapy, and o 30% to
completing rontline chemoimmunotherapy. This 65% or patients with chemosensitive relapsed HL
subset o patients has a poor prognosis (5-year OS (Fig. 18-3).30,31
~50%). In a retrospective combined registry analysis Unavorable prognostic eatures or AHPCT include
o CIBMTR and National Lymphocare database, early a frst CR shorter than 1 year, extranodal relapse, B
AHPCT within a year o relapse was associated with symptoms at the time o relapse or progression, bulky
a decreased risk o mortality (HR = 0.63, P = .02) in (>5 cm) lesions at relapse, and relapse within a prior
POD24 FL patients.27,28 Also, subset analyses rom two radiation feld. Patients with no unavorable prognos-
German prospective randomized trials in FL confrmed tic eatures have a long-term EFS o around 70% at
the OS beneft o early AHPCT in POD24 FL patients, 4 years, compared with 20% or less in patients with
with a 5-year OS rate o 77% with transplant versus adverse eatures. PET scan uptake at the time o HD
59% with no transplant (HR = 0.54, P = .03).29 has emerged as the main prognostic actor.32 Thereore,
DLBCL diagnosis and staging
Standard chemotherapy
(RCHOP, R-EPOCH)
Complete remission Partial remission or refractory
Salvage chemotherapy (RICE, RDHAP,

Monitoring
RESHAP)
Cure Relapse Chemoresistant Chemosensitive
2nd line salvage ASCT
Chemoresistant Response
Monitoring
Clinical trial of
Palliative care
new drug
Relapse Cure
Salvage chemotherapy and consider allogeneic

transplant in selected cases
Chapter 18
FIGURE 18–3 Algorithm for treatment of HL: stepwise description of HL treatment approach and the role of autologous and
allogeneic progenitor-cell transplantation after relapse.
PET-adapted salvage therapy aiming at a PET-negative extranodal disease at the start o pretransplant salvage
CR beore transplant using non–cross-resistant lines o chemotherapy) resulted in a signifcant PFS advantage
therapy has been shown to result in improved post- (59% vs 41% at 5 years), but without OS dierences,
AHPCT outcomes.33,34 Approaches to improve survival compared with placebo.37,38 In a small phase 2 trial,
outcomes and prevent relapses ater autologous SCT maintenance pembrolizumab led to 18-month PFS and
have included the development o more eective HDC OS rates o 82% and 100%, respectively.39
regimens and/or post-AHPCT maintenance treatment.
The combination o gemcitabine/busulan/melphalan,
developed at MDACC, resulted in improved 2-year MULTIPLE MYELOMA
PFS (65% vs 51%, P < .01) and OS (89% vs 73%; P <
.001) when compared with matched-pair historical HDC with AHPCT is an established treatment or mul-
patients treated with BEAM, the standard HDC regi- tiple myeloma (MM) (Fig. 18–4). In the era preceding
men in HL.35,36 the introduction o novel antimyeloma agents, AHPCT
In a phase 3 randomized trial, the use o post-AHPCT showed signifcantly superior PFS and OS rates compared
maintenance brentuximab vedotin or 16 cycles in with standard-dose chemotherapy (SDC) in several ran-
patients with primary reractory disease or high-risk domized trials.40–42 Subsequently, the introduction o
relapse (defned as prior CR1 shorter than 1 year or proteasome inhibitors (PI), immunomodulatory drugs
(IMiDs), and monoclonal antibodies in the up-ront with autologous SCT or patients with relapsed dis-
induction treatment led to signifcant improvement ease.49 In general, the outcomes appear more avor-
in the depth o response. In this modern setting, ran- able or patients who had relapse later than 12 months
domized trials have still shown beneft o AHPCT con- ater a frst AHPCT and who respond to subsequent
solidation over nontransplant management including salvage treatment.50 A randomized controlled trial
novel agents. In the randomized IFM 2009 trial, which conducted in the UK comparing salvage AHPCT with
included both PIs and IMiDs in rontline induction treat- salvage SDC showed superior PFS (median 19 months
ment, a higher CR rate (59% vs 48%; P = .03) and mini- vs 11 months, HR 0.36; P < .0001) and OS (median 67
mal residual disease negativity (79% vs 65%; P < .001) months vs 52 months, HR 0.56; P = .01) or the trans-
was observed among patients assigned to the rontline plant arm.51,52
AHPCT arm, which translated into a signifcant PFS
advantage (median 50 vs 36 months; P < .001) and no
OS dierences at short ollow-up.43
Newer HDC Regimens
Maintenance therapy post-transplant with lenalido- For the past 40 years, the standard HDC regimen or
mide has been shown to prolong EFS and perhaps OS, AHPCT in MM has been high-dose melphalan (200
as shown in several randomized studies.44,45 There is mg/m2). The only regimen that has shown superior-
uncertainty about the optimal duration o lenalido- ity over melphalan as rontline consolidation has
mide treatment, because its use ater ASCT has been been intravenous busulan/melphalan (Bu/Mel) in a
associated with a small risk o secondary malignancies randomized trial conducted at MDACC, where Bu/
in the French, but not in the US, study. In the recent Mel resulted in signifcantly better PFS (64 months vs
updates o the US trial, lenalidomide discontinuation 43 months, HR 0.53; P = .02), particularly in the sub-
at 3 years was associated with inerior PFS (80% vs set o patients with high-risk cytogenetics.53 Gem-
61%) and thereore, depending on patient preerence citabine/busulan/melphalan, a regimen built rom Bu/
and tolerability, our preerence has been to continue Mel exploiting the inhibition by gemcitabine o DNA
maintenance therapy indefnitely. Some centers have damage repair, showed in a phase 2 trial conducted
adopted a risk-adapted maintenance approach in at MDACC in patients with relapsed or reractory
newly diagnosed myeloma with double-agent mainte- myeloma, signifcantly superior PFS and OS compared
nance (PI + IMiD) in high-risk patients that has led to with matched-pair historical controls who received
signifcant improvement in survival rates. high-dose melphalan.54 The combinations o PI with
The use o a second course o high-dose melphalan high-dose alkylators, which shows synergy when
(“tandem” transplants) has been compared with a sin- given in the correct sequence, has shown promising
gle transplant in randomized trials in Europe and the clinical results.55–57
US, which have shown conicting results. In the Euro- Other promising new therapies under current inves-
pean trial, patients who received a tandem AHPCT had tigation in myeloma that could be easily implemented
Chapter 18
greater 3-year PFS than patients who received a single in the post-AHCT setting include tumor vaccines58 and
AHPCT (73% vs 60%, respectively) and improved cellular immunotherapy with chimeric antigen recep-
3-year OS compared with single AHCT (89% vs 85%, tor T-cells.59
respectively).46 In contrast, in the US Intergroup study,
the 3-year PFS rate was 58% or tandem AHPCT with
maintenance lenalidomide, 58% or single AHPCT/ SOLID TUMORS
consolidation with our cycles o bortezomib/
lenalidomide/dexamethasone (VRD)/maintenance
lenalidomide, and 54% or AHPCT/maintenance
Germ-Cell Tumors
with lenalidomide.47 Important dierences in study Testicular germ-cell tumors (GCTs) are the most com-
design between both trials probably account or mon malignancy in young men between the ages o 20
their diering results. Importantly, one group which and 35 years. GCTs are highly curable, even in patients
appears to beneft rom tandem transplant is that with advanced disease. Frontline cisplatin-based SDC
o patients with high-risk cytogenetics. Both in the cures 90% o advanced good-risk patients, 80% o those
European and the US trials, the subgroups with high- with intermediate risk and 50% o those with poor risk.
risk cytogenetics have shown superior PFS with To study whether AHPCT could improve results in
tandem AHPCT compared with a single AHPCT.46,48 intermediate- and poor-risk patients, tandem cycles o
HDC were compared with SDC in a US Intergroup trial,
with no signifcant dierences in EFS or OS.60
Role of Salvage or Second Transplant In patients with relapsed disease, the best approach
Several retrospective analyses have demonstrated or salvage therapy remains unsettled. Salvage cisplatin–
durable responses o a second salvage course o HDC based SDC regimens, such as paclitaxel/iosamide/
HL diagnosis and staging
Standard chemotherapy
(ABVD +/– XRT)
Complete remission Partial remission or refractory
Salvage chemotherapy (ICE, DHAP,

Cure relapse
ESHAP)
Resistant to
Chemosensitive
chemotherapy
Second line
Response ASCT +/– XRT
chemotherapy
Relapse Cure
Resistant Brentuximab
Resistant to
Chemosensitive
chemotherapy
Chapter 18
consider allogeneic Consider clinical trial

Continue Brentuximab transplant in selected versus other palliative
cases options versus hospice
FIGURE 18–4 Algorithm for the treatment of MM: stepwise description of MM treatment approach and the role of autologous
and allogeneic progenitor-cell transplantation after relapse.
cisplatin (TIP), result in CR rates o 50% to 60% and Feldman et al tested the use o three cycles o HDC in
long-term EFS o 20% to 30%.61 The use o tandem 107 patients with relapsed disease and unavorable prog-
cycles o HDC with carboplatin and etoposide (CE) nostic eatures. O them, 76% were transplanted at frst
with AHPCT, developed at Indiana University, has relapse, 20% at second relapse, and 4% at third or later
shown efcacy. A retrospective analysis o a cohort relapse; 76% were cisplatin reractory. These patients
o 364 patients transplanted with tandem CE in 2004 received two cycles o paclitaxel/iosamide ollowed
to 2014 showed that patients transplanted in the frst by three cycles o high-dose CE, with 47% EFS at 5
relapse had better outcomes than those transplanted in years.67 The EFS rates in patients in frst relapse and sec-
the second or later relapse (2-year EFS o 63% and 49%, ond or later relapses were 55% and 23%, respectively.
respectively).62 The addition o a third drug, such as Our group at MDACC ocused on patients with
cyclophosphamide, iosamide, paclitaxel, or thiotepa, a very poor prognosis or the development o more
to CE, results in cure o 40% to 50% o patients with potent HDC seeking new synergistic interactions.
cisplatin-sensitive tumors, but only o 4% to 20% o Testing the potential synergy between bevacizumab
those with reractory disease.63–66 and chemotherapy, we conducted a phase 2 trial o
tandem cycles o bevacizumab-HDC in patients with 4 or more positive nodes and, in some trials, 10 or
advanced reractory relapses.68 In our initial report, more positive nodes. Although most trials showed
42 patients with heavily pretreated tumors (median EFS beneft, only two showed OS beneft. A meta-
3 prior relapses), 87% o them cisplatin reractory, analysis o those trials (N = 6210) demonstrated at a
received a frst HDC cycle with bevacizumab and gem- median ollow-up o 6 years a signifcant beneft in
citabine/docetaxel/melphalan/carboplatin ollowed by EFS (HR 0.87, P < .001) but no signifcant dierence
a second AHPCT with bevacizumab + iosamide/ in OS (HR 0.94, P = .13).76 More recently, a long-term
carboplatin/etoposide. At a median ollow-up o 46 report at 20-year ollow-up o the largest o those
months, the EFS and OS rates were 56% and 58%, randomized trials, conducted in the Netherlands,
respectively, clearly exceeding the expected outcomes showed an improved OS or the subset o patients
in this population with very poor prognosis. Bevaci- with very high risk (≥10 more involved nodes) in the
zumab was subsequently omitted in a second cohort HDC arm. 77
seeking to increase treatment tolerability.69 At median Similar to HRPBC, the initial prospective HDC trials
ollow-up o this second cohort o 26 months, the EFS in metastatic breast cancer (MBC) showed very high
and OS rates were 71% and 74%, respectively. These response and CR rates and apparently improved long-
encouraging results, with or without bevacizumab, term disease control. Those results led to randomized
likely result rom a synergistic interaction between trials comparing HDC with SDC in chemosensitive
gemcitabine and the other agents based on DNA dam- MBC. Six o those eight trials demonstrated an EFS
age repair inhibition through suppression o nucleotide advantage or HDC, but only one showed OS bene-
excision repair, a major mechanism o cisplatin resis- ft. A meta-analysis showed a statistically signifcant
tance in GCT cells.70 improvement in PFS (median 11 vs 8 months, HR 0.76;
There is no consensus yet about whether HDC P < .001), however with no statistically signifcant OS
should be considered or all patients in frst relapse. beneft.78
Two cycles o HDC seem more eective than a single In conclusion, randomized trials in the MBC and
cycle.71 Results o tandem cycles o HDC as salvage HRPBC settings have shown improvement in PFS but
treatment appear superior to those expected with have largely ailed to show OS beneft. The meta-anal-
SDC.72 The randomized phase 3 TIGER trial is under- yses did detect a statistically signifcant 13% decrease
way and addresses this important question, comparing in the risk o relapse in HRPBC and a 24% decrease
TI-CE, with three cycles o HDC, with SDC (TIP × 4).73 in the risk o progression in MBC. Although there are
In summary, the current data available rom ran- still populations that might beneft rom HDC, such as
domized trials do not support a standard role or patients with 10 or more involved nodes,77 inamma-
HDC in rontline treatment o GCT. Further clarity tory breast cancer,79 or oligometastatic disease,80 HDC
in its role as part o salvage treatment in frst relapse has been largely abandoned as a treatment or breast
awaits completion o the ongoing randomized TIGER cancer.
Chapter 18
trial. Finally, HDC is widely accepted as an established HDC has been evaluated in other chemosensitive
treatment or patients in second or later relapse. solid tumors in adults, including ovarian cancer, small-
cell lung cancer, melanoma, malignant gliomas, and
sarcomas. Most o those studies were small and ailed
OTHER SOLID TUMORS to show a survival beneft.81
Initial phase 2 studies o HDC in patients with high-

risk primary breast cancer (HRPBC) sparked enthusi- CONCLUSIONS
asm by showing encouraging long-term PFS rates o
57% to 72% in patients with involvement o 10 or In summary, HDC with AHPCT is a sae treatment
more axillary lymph nodes.74,75 These results led to that achieves major tumor cytoreduction and is cura-
a signifcant increase in the number o transplanta- tive or NHL, HL, MM, and GCT in a variety o set-
tions perormed in the 1990s and prompted random- tings. Current studies ocus on improvement o current
ized phase 3 trials. Fiteen randomized trials o HDC HDC regimens and post-transplant strategies to pre-
with AHPCT were conducted or HRPBC, defned as vent regrowth o minimal residual disease.

J As o this writing, there is no role o up-ront autol- improvement in PFS and is routinely considered or
ogous transplant in frst remission in B-cell non- patients with high-risk relapse at MDACC.
Hodgkin (except or selected patients with high-risk J The novel HDC regimen o vorinostat/gemcitabine/
IPI aggressive lymphoma) and Hodgkin lympho- busulan/melphalan or autologous transplant in
mas. In contrast, most patients with T-cell lym- Hodgkin and non-Hodgkin lymphomas has pro-
phoma (except those with ALK-positive anaplastic duced impressive outcomes in high-risk disease-
large-cell lymphoma) seem to beneft rom an up- relapsed patients. Patients with reractory diseases
ront consolidation autologous transplant. and high-risk eatures are oered this novel HDC
J A subset o patients with ollicular lymphoma regimen, preerably as part o a clinical trial, at
who have disease progression within 2 years ater MDACC.
rontline chemoimmunotherapy have a poor prog- J Relapsed GCTs are considered or tandem ASCT at
nosis, and early autologous transplantation is rec- MDACC. High-risk relapses or advanced (second or
ommended in these patients. later) relapses are oered our tandem approach o
J High-risk patients with MM beneft rom dose intensi- gemcitabine/docetaxel/melphalan/carboplatin or
fcation o conditioning chemotherapy. Patients with the frst ASCT and ICE or the second ASCT, which
high-risk characteristics are oered a combination o have shown results that appear to be superior to
intravenous busulan and melphalan at our center. those with the more traditional tandem approach
J Maintenance with brentuximab vedotin ater o carboplatin/etoposide × 2.
autologous transplant in HL has led to signifcant
Chapter 18
18. Andersson BS, Madden T, Tran HT, et al. Acute saety and phar-
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newly diagnosed multiple myeloma (EMN02/HO95): a multi- static germ cell tumors. J Clin Oncol. 2007;25:247-256.
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2020;7:e456-e468. paclitaxel, iosamide, and cisplatin is an eective second-line
47. Stadtmauer EA, Pasquini MC, Blackwell B. Autologous trans- therapy or patients with relapsed testicular germ cell tumors. J
plantation, consolidation, and maintenance therapy in multiple Clin Oncol. 2005;23:6549-6555.
myeloma: results o the BMT CTN 0702 Trial. J Clin Oncol. 62. Adra N, Abonour R, Althouse SK, et al. High-dose chemother-
2019;37:589-597. apy and autologous peripheral-blood stem-cell transplantation
48. Parameswaran Hari, Pasquini MC, Stadtmauer EA, et al. or relapsed metastatic germ cell tumors: the Indiana Univer-
Long-term ollow-up o BMT CTN 0702 (STaMINA) o post- sity experience. J Clin Oncol. 2017;35:1096-1102.
autologous hematopoietic cell transplantation (autoHCT) 63. Siegert W, Beyer J, Strohscheer I, et al. High-dose treatment
strategies in the upront treatment o multiple myeloma with carboplatin, etoposide and iosamide ollowed by autol-
(MM). Presented at the 2020 ASCO Virtual Scientifc Meet- ogous stem-cell transplantation in relapsed or reractory germ
ing. Accessed April 6, 2021. https://meetinglibrary.asco.org/ cell cancer: a phase I/II study. J Clin Oncol. 1994;12:1223-1231.
record/186147/abstract 64. Motzer RJ, Mazumdar M, Bosl GJ, et al. High-dose carboplatin,
49. Shah N, Ahmed F, Bashir Q, et al. Durable remission with etoposide, and cyclophosphamide or patients with reractory
salvage second autotransplants in patients with multiple germ cell tumors: treatment results and prognostic actors or
myeloma. Cancer. 2012;118(14):3549-3555. survival and toxicity. J Clin Oncol. 1996;14:1098-1105.
65. Margolin K, Doroshow JH, Ahn C, et al. Treatment o germ cell or relapsed germ cell tumors¿ The TIGER Trial. J Cancer.
cancer with two cycles o high-dose iosamide, carboplatin, 2011;2:374-377.
and etoposide with autologous stem-cell support. J Clin Oncol. 74. Peters WP, Ross M, Vredenburgh JJ, et al. High-dose chemo-
1996;14:2631-2637. therapy and autologous bone marrow support as consolida-
66. Margolin KA, Doroshow JH, Frankel P, et al. Paclitaxel-based tion ater standard-dose adjuvant therapy or high-risk primary
high-dose chemotherapy with autologous stem-cell rescue breast cancer. J Clin Oncol. 1993;11:1132-1143.
or relapsed germ cell cancer. Biol Blood Marrow Transplant. 75. Gianni AM, Siena S, Bregni M, et al. Efcacy, toxicity, and appli-
2005;11:903-911. cability o high-dose sequential chemotherapy as adjuvant treat-
67. Feldman DR, Sheineld J, Bajorin DF, et al. TI-CE high-dose ment in operable breast cancer with 10 or more involved axillary
chemotherapy or patients with previously treated germ cell nodes: fve-year results. J Clin Oncol. 1997;15:2312-2321.
tumors; results and prognostic actor analysis. J Clin Oncol. 76. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemother-
2010;28:1706-1713. apy with autologous hematopoietic stem-cell transplantation
68. Nieto Y, Tu SM, Bassett R, et al. Bevacizumab/high-dose in metastatic breast cancer: overview o six randomized trials.
chemotherapy with autologous stem-cell transplant or J Clin Oncol. 2011;29:3224-3231.
poor-risk relapsed or reractory germ-cell tumors. Ann Oncol. 77. Steenbruggen TG, Steggink LC, Seynaeve CM, et al. High-
2015;26:2125-2132. dose chemotherapy with hematopoietic stem cell transplant in
69. Nieto Y, Tu S-M, Campbell MT, et al. Inusional gemcitabine + patients with high-risk breast cancer and 4 or more involved
docetaxel/melphalan/carboplatin (GemDMC) ± bevacizumab axillary lymph nodes: 20-year ollow-up o a phase 3 random-
(BEV) as an eective high-dose chemotherapy (HDC) regimen ized clinical trial. JAMA Oncol. 2020;6:528-534.
or reractory o poor-risk relapsed germ-cell tumors (GCT). 78. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemother-
J Clin Oncol. 2017;35(suppl):abstract 4519. apy with autologous hematopoietic stem-cell transplantation
70. Usanova S, Piée-Staa A, Sied U, et al. Cisplatin sensitivity o in metastatic breast cancer: overview o six randomized trials.
testis tumour cells is due to defciency in interstrand-crosslink J Clin Oncol. 2011;29:3224-3231.
repair and low ERCC1-XPF expression. Mol Cancer. 2010:9:248. 79. Cagnoni PJ, Nieto Y, Shpall EJ, et al. High-dose chemotherapy
71. Kilari D, D’Souza A, Fraser R, et al. Autologous hematopoietic with autologous hematopoietic progenitor-cell support as part
stem cell transplantation or male germ cell tumors: improved o combined modality therapy in patients with inamma-
outcomes over 3 decades. Biol Blood Marrow Transplant. tory breast cancer. J Clin Oncol. 1998;16:1661-1668.
2019;25:1099-1106. 80. Nieto Y, Nawaz S, Jones RB, et al. Prognostic model or relapse
72. Lorch A, Bascoul-Mollevi C, Kramar A, et al. Conventional-dose ater high-dose chemotherapy with autologous stem-cell trans-
versus high-dose chemotherapy as frst salvage treatment in plantation or stage IV oligometastatic breast cancer. J Clin
male patients with metastatic germ cell tumors: evidence rom Oncol. 2002;20:707-718.
a large international database. J Clin Oncol. 2011;29:2178-2184. 81. Nieto Y, Jones RB, Shpall EJ. Stem-cell transplantation or
73. Feldman DR, Huddart R, Hall E, et al. Is high dose therapy the treatment o advanced solid tumors. Semin Immunopathol.
superior to conventional dose therapy as initial treatment 2004;26:31-56.
Chapter 18
19 Allogeneic Transplantation
Rohtesh S. Mehta
Chitra Hosing
KEY CONCEPTS
 The numbers o allogeneic hematopoietic stem cell trans-  Relapse o the underlying disease is the leading cause
plantation (HCT) are increasing over time, with an increas- o deaths ater allogeneic HCT, while grat-versus-host
ing use o alternative donors, and with increasing use o disease (GVHD) and inections are the leading causes o
reduced-intensity conditioning (RIC). NRM ater allogeneic HCT.
 Myeloablative conditioning (MAC) or HCT is associated  Risk o relapse may be reduced with the use o maintenance
with a lower risk o relapse compared with RIC, but it is also therapy ater allogeneic HCT, which is an area o active
associated with a higher risk o nonrelapse mortality (NRM). investigation.
 Age, perormance status, and HCT-specic comorbidity  Novel GVHD prophylaxis strategies are being explored to
index are some o the predictors o NRM and are taken into reduce the risk o GVHD and its associated morbidity and
consideration along with the risk o relapse o the underly- mortality.
ing disease, when deciding about conditioning intensity.
Allogeneic hematopoietic stem cell transplantation the rst HCT in humans perormed in the late 1950s.
(HCT) is a potentially curative approach or a variety The initial attempts at transplantation o bone marrow
o malignant and nonmalignant disorders. With the (BM) rom etal or adult cadavers in six patients with
development o novel techniques o transplantation terminal conditions was unsuccessul without engrat-
including the renement o conditioning regimens ment. However, it did provide important saety data
and improved management o transplantation-asso- about the inusion o BM with no case o pulmonary
ciated toxicities, increasing numbers o patients with emboli.4 A ew years later, syngeneic BM transplanta-
advanced age and/or comorbidities are now being tion (BMT) in two children with acute lymphoblastic
transplanted. More than 9000 allogeneic HCTs were leukemia (ALL) ater lethal dose o total-body irra-
perormed in the United States in 20181; about 30% diation (TBI) led to successul engratment, but the
o patients were age 60 years or older and 6% were 70 conditioning intensity was insucient to prevent dis-
years or older.2 This chapter reviews the current state ease relapse.5 Thereater, modications were made to
o the allogeneic HCT in general, with particular atten- intensiy the conditioning regimen beore transplanta-
tion paid to strategies used at MDACC. The in-depth tion. There was a vigorous interest in BMT in the early
discussion o specic diseases and their indications or 1960s, with occasional success stories, but interest
HCT can be ound in their respective chapters. waned owing to extremely poor outcomes, engrat-
ment in less than 40% o cases, and mortality in about
75% o patients.6 This was partly related to the lack o
HISTORICAL BACKGROUND knowledge about grat-versus-host disease (GVHD),
which was not recognized until the mid-1960s,7 and
Research in the eld o HCT intensied ater the unor- inadequate understanding o the human leukocyte
tunate events o nuclear bombing in 1945,3 with one o antigen (HLA) system—the concept o which was
397
398 Scion III Stem Cell Transplantation
incorporated into the HCT setting in the late 1960s. transplantation rom those who will benet the most
The initial cases o successul “HLA-matched” sibling rom it while minimizing the risk o non-elapse mor-
donor (MSD) HCTs were reported in 1968 in two chil- tality (NRM). Among several other elements, two
dren with nonmalignant hematologic disorders.8,9 O patient-related actors that independently aect out-
note, the HLA matching at that time was perormed comes are (1) comorbidities, which determine the risk
using historic serologic methods that detected antibod- o NRM; and (2) disease risk, which impacts the risk o
ies in human serum that were capable o agglutinating relapse and related mortality post-HCT.
human peripheral blood (PB) T-cells or B cells. With One o the most commonly used tools to assess the
these successul cases, and with the mounting under- risk o NRM is the HCT-specic comorbidity index
standing o GVHD and the HLA system, the interest in (HCT-CI),12 which is a combined score o several indi-
BMT reemerged. Soon, the donor pool was expanded vidual comorbidities, including cardiovascular, pulmo-
to involve unrelated donors, and the rst successul nary, hepatic, or renal dysunction, prior solid tumor,
HCT with an HLA-matched unrelated donor (MUD) and diabetes, to name a ew, each o which is assigned
was perormed in 1973 on a 2-year-old boy with a distinct weighted score. Based on the total score,
X-linked chronic granulomatous disorder.10,11 Therea- patients are divided into three risk categories—low (0),
ter, successul cases o partially matched/mismatched intermediate (1–2), and high (≥3), with corresponding
haploidentical donor and umbilical cord blood (UCB) NRM at 2 years o 14%, 21%, and 41%, respectively.12
HCT were reported. Subsequently, a composite scoring system incorporat-
ing age and HCT-CI was developed where one addi-
tional point was assigned or patients with 40 years
COMPONENTS OF ALLOGENEIC or older. Patients with a score o 2 or lower had no
STEM CELL TRANSPLANTATION increased increase o NRM compared with those with
score 0, whereas those with a score o 3 or higher had
The key components o allogeneic HCT include a signicantly higher risk. The risk o NRM varied by
recipient, donor (related or unrelated), stem cell grat the conditioning intensity; it was signicantly lower
source (BM, PB, or UCB), HLA matching between the with NMA—but not ater RIC—than with MAC. For
recipient and the donor (matched or mismatched), patients with a score o 3 or 4, the incidence o NRM at
conditioning regimen intensity (myeloablative 2 years was 17% (NMA), 36% (RIC), and 37% (MAC);
[MAC], nonmyeloablative [NMA], or reduced- and or patients with scores o 5 or above, it was 35%
intensity conditioning [RIC]), GVHD prophylaxis, (NMA), 41% (RIC), and 49% (MAC).13
and post-HCT supportive care. Each o these are dis- To determine disease risk, several systems can be
cussed next individually. used or prognostication that are either disease specic
(eg, European LeukemiaNet [ELN] classication or
Chapter 19
AML,14 Revised International Prognostic Scoring Sys-

Recipient tem [R-IPSS], or MDS15) or generic, such as the revised
Allogeneic HCT is indicated or a variety o malignant disease risk index (DRI).16 The revised DRI (rDRI) clas-
(mostly hematologic and some solid tumors) and non- sies patients into one o the our risk groups based on
malignant disorders (such as aplastic anemia, Fanconi the underlying disease and remission status at the time
anemia and other BM ailure syndromes, hemophago- o HCT, with a 2-year overall survival (OS) o 66%
cytic lymphohistiocytosis, severe combined immu- (low risk), 51% (intermediate risk), 33% (high risk), or
nodeciency, Wiskott-Aldrich syndrome, sickle cell 23% (very high risk).16 In general, patients with inter-
disease, thalassemia major, advanced autoimmune mediate or high/very-high rDRI have an indication
diseases, etc). However, or the purpose o brevity, this or transplantation, whereas low-risk patients benet
chapter will ocus primarily on hematologic malignan- rom nontransplantation approaches.
cies in adults, because acute myelogenous leukemia At MDACC, all patients undergo an extensive
(AML), ALL, myelodysplastic syndrome (MDS), and evaluation beore transplantation to determine disease
myeloprolierative neoplasms (MPNs) are the most risk and to assess comorbidities. There is no specic
common indications that accounted or about 75% age cuto or transplantation, rather a patient’s per-
o all allogeneic HCTs perormed in the United States ormance status, HCT-CI score, DRI, amily and social
in 2018.1 Other hematologic malignancies, such as support, and personal wishes are all taken into consid-
lymphoma, multiple myeloma, chronic lymphocytic eration. In addition, patients older than 60 years and
leukemia, chronic myelogenous leukemia (CML), and those with poor perormance status are also evalu-
nonmalignant diseases accounted or the rest.1 ated by a personalized, multidisciplinary team o the
Given the risk o morbidity and mortality associ- “Enhanced Recovery program,” which includes HCT
ated with allogeneic HCT, it is important to distin- physicians, advanced care providers, nutritionists,
guish patients who are likely to do well without physical and occupational therapists, pharmacists,
C 19 Allogeneic Transplantation 399
rehabilitation physicians, and geriatricians to assess antigenic peptides or presentation to CD4+ T-helper
and address patient railty issues beore HCT. cells. The HLA class III region includes genes involved
in the infammatory response and encode or proteins o
Donor the complement system, heat shock proteins, and tumor
necrosis amily genes.18,19 Further, there are several minor
A majority o allogeneic HCTs in the United States are
histocompatibility antigens (miHAs), which may dier
perormed using an unrelated donor. The numbers o
haploidentical HCT are increasing (21% o all HCT in even when the donor and recipient are identical with
2018) and appear to be converging with that o MSD regard to MHC genes.20 These miHAs are urther classi-
(25% o all HCT in 2018), whereas UCB transplanta- ed as either hematopoietic-restricted minor H antigens
tions have decreased over the past ew years (Fig. 19–1). (crucial or GVT eects), or broadly-expressed minor H
The degree o HLA matching is one o the single most antigens (crucial or both GVT and GVHD).20,21
important determinants o GVHD and grat-versus- For HCT outside the context o clinical trials, only
tumor (GVT) eect. Thereore, it is essential to have a the classical HLA class I genes (A, B, C) and class II genes
thorough grasp o the topic. The major histocompatibil- (DP, DQ, DR) are tested, whereas HLA class III genes
ity complex (MHC), called HLA in humans, is the most and miHAs are not. The denition o “HLA match-
polymorphic gene cluster o the entire human genome, ing” depends on which loci are tested. For example, a
and encodes or a set o proteins on the cell surace that donor may be labeled as a 6/6-HLA match (matched
are responsible or antigen presentation to T-cells. The at HLA-A, -B, and -DRB1), 8/8-HLA match (HLA-A,
HLA complex is located on the short arm o chromo- -B, -C, and -DRB1), 10/10-HLA match (HLA-A, -B,
some 6 within the 6p21.3 region and contains more than -C, -DRB1, and -DQB1) and 12/12-HLA match (HLA-
220 genes categorized into various classes. The class I A, -B, -C, -DRB1, -DQB1-, and -DPB1). In general, a
includes three “classical” genes (HLA-A, B, C), three HLA-identical sibling is considered the gold standard
“nonclassical” genes (-E, -F, -G), and several pseudogenes and is the preerred donor when available versus MUD
(-H, -J, -K, -L, -N, -P, -S, -T, -U, -V, -W, -Y) with more than because o a signicantly lower risk o development o
19,000 alleles.17 The HLA class I antigens are expressed GVHD22,23 and survival advantage noted in some stud-
on all nucleated cells (except those o the central nervous ies in a subset o patients.22,24 In the absence o a suit-
system) and on platelets, and its gene products present able MSD, MUD can lead to comparable outcomes,25–28
endogenous peptides to CD8+ T-cells. The class II genes especially because the techniques o HLA typing are
include HLA-DR (-A, -B1 though -B9), -DQ (-A1, -A2, becoming more sophisticated, and allele-level matching
-B1), -DP (-A1, -A2, -B1, -B2), -DM (-A, -B), -DO (-A across several loci is now being routinely perormed.
and -B) in humans, with more than 7000 alleles identi- Among patients who are 10/10-HLA matched with an
ed.17 The HLA class II antigens are expressed on clas- unrelated donor, -DPB1 mismatch, which is urther cat-
sical antigen-presenting cells (monocytes, macrophages, egorized as permissive or nonpermissive based on the
Chapter 19
dendritic cells, Langerhans cells, and B lymphocytes) and T-cell epitope grouping,29 is o added signicance. For
others, including endothelial cells and thymic epithelial instance, nonpermissive -DPB1 mismatches are associ-
cells; and they encode proteins that display processed ated with an increased risk o NRM and severe acute
Estimated Allogeneic HCT Recipients in the US by Donor Type
5000
4500 URD-BM/PB Matched related donor
4000 Other relative URD-UCB
Number of Transplants
3500
3000
2500
2000
1500
1000
500
0
18
10
14
12
19
16
0
2
86
90
92
96
4
88
94
98
02
06
00
04
08
8
8
8
20
20
20
20
20
20
19
19
19
19
19
19
19
19
19
19
20
20
20
20
20
FIGURE 19–1 Allogeneic HCT recipients in the United States by donor type. (Reproduced with permission from Phelan R, Arora
M, Chen M: Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2020.
https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx)
GVHD, leading to poor OS compared with permissive myeloablative and included high doses o chemother-
-DPB1 mismatches. Compared with -DPB1–matched apy (generally alkylating agents) and/or TBI. However,
patient-donor pairs, permissive -DPB1 mismatches older patients and those with high comorbidities were
have a lower risk o relapse counterbalanced by a high considered ineligible or allogeneic HCT because o sig-
risk o NRM, which leads to similar OS.29 The current nicant regimen-related toxicities. Thereore, doses o
standard at MDACC is to test HLA-A, -B, -C, -DRB1, radiation and/or chemotherapy in preparative regimens
-DQB1, and -DPB1 using high-resolution molecu- were inconsistently reduced to minimize these toxici-
lar methods, such as the polymerase chain reaction, ties, and such regimens were arbitrarily labeled as either
sequence-based typing, or Sanger- or next-generation RIC, where, generally, the dose o alkylating agent(s) or
sequencing, in an attempt to nd a donor matched at all TBI was generally reduced by at least 30%.33,34 A ew
loci (“12/12-HLA match”). The HLA matching require- criteria were then proposed to establish uniormity in
ments or UCB transplantation are somewhat dierent. dening regimen intensity.35 One o them, the “Cham-
Although the terms HLA-matched and HLA-identical plin criteria,” dened RIC as a regimen that “(1) results
are oten used interchangeably, especially with sibling in reversible myelosuppression (usually within 28 days)
donors, in its strictest sense, HLA identity means that the when given without stem cell support; (2) results in
donor and recipient are matched or the entire amino acid mixed chimerism in a proportion o patients at the time
sequence encoded by all HLA loci. Identity is assumed o rst assessment (usually 28–35 days post stem cell
in the setting o related donor transplantation when transplantation); and (3) it is associated with low rates
segregation analysis demonstrates that the donor and o non-hematologic toxicity.” A more concrete denition
recipient have inherited the same maternal and paternal was ormulated by an expert panel rom the National
haplotypes (genotypic HLA identity).30 Otherwise, HLA Marrow Donor Program (NMDP)36 and by the Center
identity can only be veried by sequencing all HLA loci or International Blood and Marrow Transplantation
(phenotypic HLA identity), which is impractical and Registry (CIBMTR).1,37 This dened RIC as a regimen
rarely done. Because there is a strong linkage disequi- that consisted o: (a) <5 Gy TBI when given as a single
librium between HLA-B and -C genes and HLA-DRB1 raction or ≤8 Gy i ractionated; (b) ≤9 mg/kg busulan
and -DQB1 genes,31 HLA matching in a sibling donor can orally (or intravenous [IV] equivalent, 1.0 mg/kg oral
generally be dened by HLA-A, -B, and -DRB1 typing Bu = 0.8 mg/kg IV Bu); (c) <10 mg/kg thiotepa; and (d)
(“6/6 HLA match”), because this would imply match- <140 mg/m2 melphalan (or most recently ≤150 mg/m2
ing at HLA-C and -DQB1 as well (“10/10 HLA match”). melphalan),37 generally with purine analogues such as
However, there is a chance that the HLA-matched sibling fudarabine or cladribine (Fig. 19–2).
may not be HLA-identical, even when they have inherited
the same maternal and paternal haplotypes, although
this is rare. One study using single-nucleotide polymor- Common Conditioning Regimens in Acute Myelogenous
Chapter 19
phism genotyping and ull MHC genomic sequencing to Leukemia (AML) or Myelodysplastic Syndrome (MDS) Allogeneic
HCT in the US, 2009-2019
estimate the level o the MHC identity in HLA-matched
sibling HCT identied that only 4/255 (1.5%) “6/6-HLA- MAC RIC
matched” pairs were mismatched at HLA-DPB1, and 8% 5%
about 4% o the 6/6-HLA-matched sibling-patient pairs
had large genomic dierences in the MHC segment.32 29% 28%
22%
33%
Preparative/Conditioning Regimen
The goal o a conditioning regimen beore stem cell inu-
sion is (a) to eradicate or reduce tumor cell burden (“mye-
loablation,” in the case o malignant disorders), and (b) 42% 34%
to eradicate the recipient’s cytotoxic lymphocytes (“lym-

MAC Bu+Cy+/-others RIC Bu+Flu+/-others
phoablation”), thereby providing immunosuppression to
MAC Bu+Flu+/-others RIC Flu+Mel+/-others
prevent grat rejection. Conditioning regimens are cat-
egorized as either MAC, NMA, or RIC.33 By denition, MAC TBI+/-others RIC TBI+/-others
MAC regimens lead to prolonged and potentially irre- MAC Others RIC Others
versible pancytopenia without hematopoietic stem cell
FIGURE 19–2 Common conditioning regimens in AML or
support, whereas NMA regimens cause minimal or no MDS in allogeneic HCT in the United States from 2007-2017
cytopenia and can thus be administered without stem (Reproduced with permission from Phelan R, Arora M, Chen
cell inusion. The regimens that cannot be classied as M: Current use and outcome of hematopoietic stem cell
either MAC or NMA are labeled as RIC regimens; these transplantation: CIBMTR US summary slides, 2020.
do cause cytopenia and require hematopoietic stem cell https://www.cibmtr.org/ReferenceCenter/SlidesReports/
support.33,34 Historically, all preparative regimens were SummarySlides/pages/index.aspx)
Myeloablative Conditioning (MAC) with pharmacokinetic dose monitoring (“targeted-

busulan”)58 and allows or once-daily administration
Myeloablative regimens can be broadly categorized
o both busulan and fudarabine as a result o a long
as either chemotherapy based or TBI based, the lat-
plasma hal-lie, which is much more practical and
ter used generally in conjunction with chemotherapy.
convenient.
The most commonly used chemotherapy drugs with
With encouraging outcomes noted in multiple stud-
high-dose TBI are cyclophosphamide (Cy/TBI)38–42 and
ies with the Bu/Flu regimen, this has become a stan-
etoposide (TBI/Etoposide),39,40 whereas others such
dard MAC regimen both at MDACC59,60 and at other
as fudarabine (Flu/TBI),43–45 cytarabine,42,46 and mel-
major transplantation centers in North America.61,62 In
phalan,43 are used less commonly. Increasing the total
these Bu/Flu regimens, fudarabine is typically admin-
dose o TBI is associated with signicantly lower risk
istered at a dose o 40–50 mg/m2 on days –6 to –3, and
o relapse, but it is oset by a higher NRM, leading to
each dose is ollowed immediately by IV busulan on
similar OS.47,48–50 Hence, the concept o delivering TBI
days –6 to –3, with the dose adjusted to achieve sys-
over multiple ractions each day was evaluated with
temic exposure represented by an area under the curve
a hypothesis that ractionated regimen would allow
(AUC) o an average 4000–6000 μmol/min per day, or
some recovery o normal tissues between the doses,
total course AUC o 16,000–24,000 μmol/min. More
thus theoretically lowering the toxicity while achiev-
recently, we developed a novel approach o delivering
ing satisactory killing o malignant cells.51–53
myeloablative doses o busulan using a ractionated
Although ecacious, high-dose TBI is associated
(“timed-sequential”) regimen. Patients receive two
with a number o short- and long-term complica-
doses o IV busulan (80 mg/m2 each) one to 2 weeks
tions, including gastrointestinal (GI) and pulmonary
beore HCT (either day –20 and –13, or days –13 and
toxicities, secondary malignancies, retarded growth,
–12), ollowed by IV fudarabine and IV busulan once
and/or intellectual development, cataracts, and endo-
daily on days −6 to –3. The dose o busulan is guided
crine dysunction, to name a ew. These concerns led
by pharmacokinetic analysis, to achieve a total dose
to the development o radiation-ree conditioning
AUC o 16,000–20,000 ± 12% μmol/min.63,64 With
regimens. O these, the combination o busulan with
this approach, we have been able to saely administer
either cyclophosphamide (Bu/Cy) or fudarabine (Bu/
MAC to patients up to 75 years o age and in those
Flu) became the two most commonly used regimens.
with signicant comorbidities63,64—a population that
Busulan was traditionally administered orally at a total
would otherwise be deemed ineligible or MAC HCT.
dose o 16 mg/kg divided our times per day given over
4 consecutive days (1 mg/kg × 16 doses) ollowed by
high-dose cyclophosphamide over 2 to 4 days (total ReducedIntensity Conditioning/
dose about 120–200 mg/kg).54,55 This was oten compli- Nonmyeloablative
cated by excessive toxicities, including potentially atal The recognition o donor T-cell-mediated potent GVT
Chapter 19
veno-occlusive disease (VOD)/sinusoidal obstruction eects emerged rom studies in the late 1970s that
syndrome (SOS) as a result o unpredictable intestinal noted inverse correlation between GVHD and leuke-
absorption and erratic bioavailability o oral busulan, mia relapse.65–69 The hypothesis that GVT existed was
especially when combined with an adverse interaction urther substantiated by the observations o a higher
with cyclophosphamide,56 because its metabolism var- risk o relapse with syngeneic70 than with allogeneic
ies considerably among individuals.57 Further, the use HCT, and higher risk o relapse with T-deplete than
o high-dose dual-alkylating agents, such as in the Bu/ with T-replete grats.71 These ndings collectively led
Cy regimen (both o which can deplete the liver o glu- to the origin o NMA/RIC regimens, where reduction
tathione) can lead to overlapping toxicities.58 There- in conditioning intensity was compensated by depen-
ore, at MDACC, we substituted cyclophosphamide dence on GVT eects, or patients who otherwise
with fudarabine, which is as immunosuppressive as could not tolerate MAC.
cyclophosphamide, has synergistic cytotoxicity with Similar to MAC, NMA and RIC regimens can be
busulan because it potentiates alkylator-induced cell chemotherapy and/or TBI-based. Preclinical work sug-
killing through inhibition o DNA damage repair, and gested that a TBI dose as low as 2 Gy was sucient to
it does not cause SOS because it does not utilize the allow engratment o donor stem cells when used in
glutathione (GSH)/glutathione S-transerases (GST) conjunction with postgrating immunosuppression.72
and the hepatic CYP450-pathaways or metabolism. Early studies rom Fred Hutchinson Cancer Research
Moreover, replacement o oral busulan with IV busul- Center used 2 Gy TBI as the sole conditioning regimen
an (0.8 mg/kg × 16 doses) led to dramatic reduction, in patients with relative contraindications to MAC
but not elimination, o the risk o SOS and improved who underwent MSD HCT.69 Donor lymphocyte inu-
survival.56 Intravenous busulan has more predictable sions (DLI) were given post-HCT in patients with per-
systemic drug exposure, especially when coupled sistent malignancy and/or mixed chimerism. Although
20% ailed to engrat, and relapse mortality was about both donor and recipient. Historically, hematopoietic
27%, the overall outcomes were encouraging, with stem cells were obtained through the harvest o BM
about 67% survival as a result o low NRM (~7%).69 rom posterior superior iliac crests o normal donors.
Later, the addition o fudarabine to the regimen (Flu/ However, over the past decade, PB has become the
TBI) improved donor chimerism and decreased grat most common grat source in adults undergoing MSD
rejection, but the rate o disease relapse/progression or or MUD HCT, and more recently in the haploidentical
related mortality remained signicant.73,74 Other stud- HCT setting as well (Fig. 19–3).1
ies added cyclophosphamide to fudarabine and low- Bone marrow harvest is associated with a generally
dose TBI (Flu/Cy/TBI), a regimen popularly used in the low incidence o complications or the donor and is
setting o CBT75,76 and haploidentical77 HCT. usually perormed on an outpatient basis.89 Immedi-
Among RIC, two that are commonly used at ate complications o BM harvest (related to general
MDACC include fudarabine with an alkylating agent— anesthesia and intubation) are vomiting (about 10%),
either melphalan (Flu/Mel) or low-dose busulan (Bu/ sore throat and hypotension (<10%). The most com-
Flu). Multiple studies rom MDACC reported successul mon complication is pain at the collection site, which
use o purine nucleoside analog-based regimens (mostly requires analgesics (mostly non-narcotics), and occurs
with fudarabine) and melphalan doses ranging rom in about hal o donors and can persist or up to 2 weeks
100–180 mg/m2, with or without other chemotherapy (median 1 day).90,91 The NMDP mandates that the
agents.78–81 In the Bu/Flu-based RIC regimens, total dose duration o anesthesia be less than 150 minutes, dura-
o busulan is 8 mg/kg orally (or 6.4 mg/kg IV) or lower. tion o collection be less than 120 minutes, and allows
The so-called historical “FB2” regimen administered or a maximum o 20 mL/kg (donor weight) o marrow
fudarabine with busulan 3.2 mg/kg IV daily or 2 days to be aspirated, with a predicted median total nucle-
(total dose 6.4 mg/kg IV) versus the traditional mye- ated cell (TNC) cell count/mL o 0.183 × 108/mL.92,93
loablative “FB4” regimen, where busulan 3.2 mg/kg IV Unortunately, the quality o BM harvest is declining
daily was delivered or 4 days (total dose 12.8 mg/kg IV over the years despite increased use o more opti-
daily).82,83 These denitions o FB2 versus FB4 are obso- mal donors (eg, younger males).93 This is concerning
lete because a much lower dose o busulan can also be because the BM TNC dose is a signicant prognostic
delivered over 4 days (0.8 mg/kg IV daily × 4 days, with actor or HCT outcomes. One study stratied patients
a total dose o 3.2 mg/kg IV).84 Further, the concept o into three groups based on the grat TNC dose: <2.5 ×
a xed standard dose o busulan is becoming outdated 108 cells/kg (low dose), 2.5–5 × 108 cells/kg (intermedi-
because the dosing is now routinely determined by the ate dose), and >5 × 108 cells/kg (high dose). Compared
pharmacokinetic analysis, and the RIC regimens include with low- and intermediate-dose groups, patients in
doses that target total course AUC o 16,000 μmol/min the high-dose arm had signicantly lower NRM (41%,
or lower.63,64,85 36%, and 28%, respectively; P = .01) and improved OS
Chapter 19
Whenever possible, the standard at MDACC is to use (45%, 51%, and 56%, respectively; P = .0008) in addi-
MAC, at least or patients with myeloid malignancies, tion to aster and improved engratment.94
given the high risk o relapse and inerior survival with Since the early 1990s, the use o PB-derived stem cells
RIC regimens.37 A phase 3 randomized trial conducted has become increasingly common; they are collected by
by the Blood and Marrow Transplantation Clinical Tri- using recombinant granulocyte colony-stimulating ac-
als Network (BMT-CTN) compared RIC with MAC in tor (G-CSF), given or 4 to 6 days at doses o 6–16 μg/kg
patients up to 65 years o age with AML or MDS. The per day. With this, the hematopoietic stem cells mobilize
trial was stopped prematurely because o a signicantly into the PB, where they may be collected by one or more
higher risk o relapse with RIC (48% vs 13%; P < .001), leukapheresis procedures. A higher dose o CD34+ cells
which translated to inerior disease-ree survival (DFS) is required when using PB as the stem cell source than
with RIC (47% vs 68%, P < .01) despite much lower what can be achieved with BM grat. The typical dose
NRM (4% vs 16%, P = .002) with RIC than with MAC, o inused CD34+ cells ranges rom about 2 × 106/kg to
respectively.37 Similar randomized trials are lacking 10 × 106/kg, with about 4 × 106/kg being the standard at
patients with ALL, although many large retrospective MDACC. Numerous studies including randomized con-
studies suggested higher relapse and lower NRM with trol trials comparing PB with BM have now conrmed
RIC, but similar survival between RIC and MAC.86–88 the ecacy and saety o this approach.95–98 Studies sug-
gest that an almost similar proportion o donors experi-
Sources o Hematopoietic Stem Cells ence adverse events (AEs) with either PB (65%) or BM
(57%) collection, most o which are transient and mild
A separate chapter is dedicated to UCB transplantation, to moderate in severity, although the respective AE pro-
but this chapter will ocus on BM- or PB-derived stem les are dierent. With PB stem cell collection, donors
cells as the source o hematopoietic stem cells. The mostly have AEs related to either high-dose G-CSF (most
choice o stem cell/grat source has implications or commonly bone pain/myalgias, headaches or atigue in
Matched Related Donor Allogeneic HCT in the US in Patients ≥18 Years

2500
BM PB
2250
2000
1750
1500
1250
1000
750
500
250
0
19
14
00
02
03
04
05
06
07
08
09
10
11
12
13
15
16
17
18
01
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
Unrelated Donor Allogeneic HCT in the US in Patients ≥18 Years
4500
URD CB URD BM URD PB
4000
3500
3000
2500
2000
1500
1000
500
0
19
00
02
07
01
03
04
05
06
08
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10
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12
15
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20
20
20
20
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20
20
20
20
20
20
20
20
20
20
20
20
20
20
Haploidentical HCT in the US by Graft Type

1400
BM PB
1200
1000
800
Chapter 19
600
400
200
0
11
12
15
17
09
10
13
14
16
18
19
20
20
20
20
20
20
20
20
20
20
20
FIGURE 19–3 Donors and recipients in allogeneic HCT (Reproduced with permission from Phelan R, Arora M, Chen M: Current
use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2020.
~70% o cases), or related to leukapheresis (tingling, (aGVHD) ater PB versus BM grats (53% vs 41%, P =
numbness, carpal-pedal spasm, etc, caused by citrate .01), with no dierence in relapse, NRM, DFS, or OS.
administration, nausea [20%], problems with access [IV- However, the incidence o grat ailure was higher in
line inltration, hematomas, poor fow, etc, in ~20%]). the BM (9%) than in the PB group (3%), P = .002.100
Other rare leukapheresis-related AEs include chest pain, In the setting o MSD HCT, a randomized trial o PB
headaches, hypotension, syncope, and hypocalcemia- versus BM showed signicantly higher risk o cGVHD
related tetany.99 with PB than with BM (73% vs 56%, respectively; P
Multiple studies evaluated patient outcomes ater = .021), without any dierences in OS (49% vs 57%,
BM or PB grat in both MSD and MUD setting. In recip- respectively) or DFS (13% vs 28%, respectively, or
ients o MUD HCT, a large phase 3 multicenter ran- ALL; 62% vs 47%, respectively, or AML; and 40%
domized controlled trial showed signicantly higher vs 48%, respectively, or CML).101 Another study con-
risk o chronic GVHD (cGVHD), but not acute GVHD rmed high risk o cGVHD (61% vs 45% at 6 years)
with no dierence in risk o relapse with PB versus inhibitors (CNI, such as tacrolimus or cyclosporine),
BM grat. However, NRM and DFS diered between mycophenolate moetil (MMF), sirolimus, or post-
PB and BM by disease and stage. For example, NRM transplantation cyclophosphamide (PTCy).
was similar with PB or BM grat in patients with early Although the use o ex vivo TCD raises concerns
leukemia and advanced CML, but higher with PB in about increased risk o grat ailure105 and relapse,
early CML, and higher with BM in advanced leuke- at least in patients with CML,106,107 it can reduce the
mia. Compared with PB, BM was associated with risk o GVHD dramatically. In a study o 44 patients
higher DFS in early CML (41% vs 61%, respectively) with AML who received TBI-based MAC ollowed by
but it led to lower DFS in those with advanced CML CD34-enriched, T-cell-depleted allograts rom MSD,
(33% vs 25%, respectively).102 Individual patient data the incidence o aGVHD grade II–IV was about 23%
meta-analysis o nine randomized trials103 showed without any post-transplantation GVHD prophy-
signicantly higher risk o grade III–IV aGVHD (odds laxis.108 The addition o in vivo TCD reduced the risk
ratio [OR] 1.39; 95% CI, 1.03–1.88), overall cGVHD o aGVHD urther, as shown in a study o 102 patients
(68% vs 52% at 3 years; OR 1.92; 95% CI, 1.47–2.49; with MDS who received CD34-selected PB HCT ater
P < .000001) and extensive cGVHD (47% vs 31% at 3 MAC with ATG. The cumulative incidence o grades
years; OR 1.89; 95% CI, 1.47–2.42; P < .000001), but II–IV aGVHD was about 10% at day 100 and about
also with signicantly lower risk o relapse (21% vs 16% at day 180. However, the use o T-cell-depleted
27% at 3 years; OR 0.71; 95% CI, 0.54–0.93; P = .01) grats is plagued by slow and poor immune reconsti-
with PB than with BM, respectively, and no dierences tution that leads to signicant risk o inections and
in NRM. In patients with late-stage disease, OS (46% consequent NRM.109 To circumvent these issues, novel
vs 31% at 3 years; OR 0.64; 95% CI, 0.46–0.90; P = techniques o selective lymphocyte depletion such
.01) and DFS (41% vs 27% at 3 years; OR 0.63; 95% as CD3+/CD19+ and αβ T-cells/CD19 depletion are
CI, 0.45–0.87; P = .01) were signicantly superior with being evaluated.110–112
PB grats.103 In vivo TCD is achieved with the use o serotherapy
At MDACC, the grat source o choice or adult with either ATG113,114 or alemtuzumab.115,116 A variety
patients with MSD is PB (except certain diseases such o schedules and ormulations o these have been tested
as aplastic anemia and other bone marrow ailure or GVHD prophylaxis. Alemtuzumab is a humanized
syndromes), and BM or patients with MUD except monoclonal antibody against CD52 that is expressed
in those with highly advanced/reractory disease, on a multitude o immune cells, including T-cells, B
prolonged cytopenias, myelobrosis with spleno- cells, natural killer cells, monocytes, macrophages,
megaly, or other situations where rapid engratment and some granulocytes and eosinophils. Antithymo-
is necessary. cyte globulin contains polyclonal antibodies generated
in animals by inoculation with human thymocytes
Chapter 19
(developing T-cell progenitors that migrate rom the

Grat-Versus-Host Disease Prophylaxis BM to thymus or maturation). These antibodies bind
In a very broad sense, GVHD is an attack on recipient to a variety o human T-cell receptors including CD2,
tissues by the donor’s immune cells and most com- CD3, CD4, CD8, CD25, CD45, and many HLA class I
monly involves the skin, GI tract, and liver in an acute and II molecules, thus depleting lymphocytes rom cir-
setting. The pathophysiology o GVHD starts with culation. Two ormulations approved by the FDA are
the damage to host tissues rom the preparative regi- equine ATG (ATGAM, Pzer) and rabbit ATG (Thymo-
men, or even beore, as a result o underlying disease globulin, Genzyme). Another rabbit ATG ormulation
itsel or inections, resulting in substantial proinfam- is the ATG-Fresenius, which is used in many European
matory changes in endothelial and epithelial cells. The studies and is not approved by the FDA. The immuno-
infammatory cytokines then activate host antigen- suppressive eects and doses o ATG vary signicantly
presenting cells and upregulate adhesion molecules rom one preparation to another.117 In patients with
and several major and minor histocompatibility anti- severe aplastic anemia, immunosuppressive therapy
gens, which leads to enhanced recognition by mature with horse ATG (40 mg/kg/day or 4 days) plus cyclo-
(inused) donor T-cells that secrete cytokines that sporine as an alternative to HCT leads to superior sur-
mediate GVHD.104 Approaches to reduce the risk o vival than with rabbit ATG (3.5 mg/kg/day or 5 days)
GVHD are targeted predominantly toward elimination plus cyclosporine.118 However, no such direct data
or inhibition o donor T-cells, and include T-cell deple- about the superiority o one or the other ormulation
tion (TCD) that can be done ex vivo (CD34+ selected exist in the context o HCT. In contrast to horse ATG,
or T-cell-depleted grats) or in vivo (serotherapy with rabbit ATG is more immunosuppressive and cytotoxic,
either antithymocyte globulin [ATG] or alemtuzumab), depletes lymphocytes more eciently, and induces
or by using post-transplantation immunosuppression the development o regulatory T-regulatory cells,
with agents, such as methotrexate (MTX), calcineurin which have added benets or GVHD prevention.118
Thereore, rabbit ATG continues to be the preerred compared tacrolimus/methotrexate (Tac/MTX) with
agent at many centers, including MDACC or GVHD cyclosporine/MTX in patients who underwent MSD
prophylaxis, especially or patients with an unrelated BMT. Patients in the cyclosporine arm had signicantly
donor. Serotherapy (ATG or alemtuzumab) is gener- higher incidences o grade II–IV aGVHD (44% vs 32%,
ally given beore transplantation in conjunction with respectively; P = .01) and extensive cGVHD (P = .03)
the conditioning regimens. However, because o long than those in the tacrolimus arm, but with similar rates
hal-lives, their lymphodepleting eects last several o grade III–IV aGVHD (17% vs 13%, respectively),
days beyond the day o transplantation. This reduces overall cGVHD (50% and 56%, respectively), and
the risk o GVHD by inhibiting donor T-cells, but also relapse. Yet, patients in the cyclosporine arm also had
intereres with the recovery o donor-derived antiviral a superior 2-year DFS (50% vs 40%; P = .01) and OS
lymphocytes, leading to increased risk o cytomega- (57% vs 47%; P = .02) than the tacrolimus arm, respec-
lovirus and Epstein-Barr virus, adenovirus, and other tively. This was likely related to a signicantly higher
viral reactivation, and may potentially interere with proportion o patients with advanced disease in the
the GVT eects. Because o the almost ubiquitous tacrolimus arm (41% vs 29%; P = .02).123 A subsequent
presence o CD52 on immune cells and signicantly phase 3 trial in patients undergoing MSD or MUD
longer hal-lie, alemtuzumab leads to more intense BMT also showed signicantly higher risk o grade II–
immunosuppression, delayed immune reconstitution IV aGVHD in the cyclosporine versus the tacrolimus
(with CD4 leukopenia lasting almost up to 3 years119), arm (48% vs 18%, respectively; P < .0001), but with
and higher risk o inections than with ATG.120 no dierences in cGVHD, relapse, or OS. However,
The history o using methotrexate (MTX) or one unexplained nding was that among recipients o
GVHD prophylaxis dates back to the late 1950s when MSD, relapse was noted to be signicantly higher in
preclinical studies suggested that “mice which would the tacrolimus than in the cyclosporine group (31% vs
normally succumb to a homograt reaction ollowing 4%, respectively; P = .01).128
lethal, total-body X irradiation and homologous mar- In contrast to CNI, sirolimus inhibits T-cell activa-
row inoculation, may be spared i they are treated tion and prolieration downstream o IL-2. Although
with olic acid antagonist, A-methopterin.”121 Thus, sirolimus also binds with an immunophilin (FKBP-
A-methopterin (methotrexate) became one o the ear- 12), the sirolimus/FKBP-12 complex does not aect
liest drugs used or GVHD prophylaxis.122 It was used calcineurin activity; rather it binds to and inhibits
as a single agent dosed at 15 mg/m2 on day +1, and mammalian target o rapamycin (mTOR), which
10 mg/m2 on days +3, +6, and +11 and then weekly halts cell-cycle progression at the G1→S phase transi-
through day +102.122 Subsequent adaptations included tion.125 Studies also suggest that it promotes tolerance
the addition o a CNI with a shorter course o metho- by expansion o CD4+CD25+FOXP3+ T-regulatory
trexate dosed at 15 mg/m2 on day +1 and 10 mg/m2 on cells (Tregs) as well as dendritic cells.129,130 Com-
days +3, +6, and +11,123 or an even lower-dose regimen pared with Tac/MTX, the tacrolimus/sirolimus (Tac/
Chapter 19
o 5 mg/m2 on days +1, +3, +6, and +11 (“mini-metho- Siro) combination has proound immunosuppres-
trexate” regimen) used at MDACC.124 sive eects, as suggested by higher Treg:Tcon ratio,
As o this writing, CNI is the most commonly and signicantly lower absolute lymphocyte count,
used class o drugs or GVHD prophylaxis, gener- CD3+ cell, CD4+ cell, and conventional T-cell (Tcon)
ally in combination with either MTX or MMF. Both counts in the rst 3 months ater HCT, and delayed
cyclosporine and tacrolimus bind to a cytoplasmic- B-lymphocyte immune reconstitution. 131 Neverthe-
receptor protein called immunophilin (cyclophilin and less, in the BMT-CTN randomized phase 3 clinical
FKBP-12, respectively) and orm a complex that binds trial132 comparing Tac/MTX with Tac/Siro in patients
to calcineurin and inhibits Ca2+-stimulated dephos- with MSD PB HCT, who received myeloablative
phorylation o the cytosolic component o the nuclear TBI-based conditioning (Cy/TBI or TBI/etoposide),
actor o activated T-cells (NFAT). Upon T-cell recep- no dierences were noted in the probability o day
tor activation, calcineurin-induced dephosphorylation 114 grade II–IV aGVHD-ree survival (67% vs 62%;
o NFAT is required to induce a number o cytokine P = .38), grades II–IV aGVHD (26% vs 34%; P = .48),
genes, including interleukin-2 (IL-2). With the inhibi- cGVHD, DFS, or OS. Both tacrolimus and sirolimus
tion o dephosphorylation o NFAT by the calcineu- were started at day −3 to maintain trough serum con-
rin inhibitor/immunophilin complex, the activation o centration o 5–10 ng/mL or tacrolimus and 3–12 ng/
T-cells is thus inhibited.125 mL or sirolimus. Patients in the Tac/Siro arm expe-
The combination o CNI and MTX is superior in rienced signicantly higher incidence o elevation o
reducing the risk o GVHD compared with either creatinine, had a trend toward a higher risk o SOS/
alone.126,127 Which o the two CNIs (tacrolimus or VOD (11% vs 5%; P = .06), and a higher incidence
cyclosporine) is superior was addressed in two large o thrombotic microangiopathy (TMA; 5% vs 1%; P
phase 3 randomized clinical trials.123,128 One trial = .09) than in the Tac/MTX arm. Also, o note, the
myeloablative Bu/Cy arm was stopped prematurely relapse, and NRM were similar among patients who
because o excessive risk o SOS, 132 which was seen received one or two doses o PTCy, the incidence o
in other studies as well.133 extensive cGVHD at one year was signicantly lower
Another immunosuppressant commonly used with in those who received two doses o PTCy than those
CNI is a purine metabolism inhibitor, MMF. It under- who received a single dose (5% vs 25%, respectively;
goes rapid metabolism to its active drug mycophenolic P = .05).77
acid, which is a selective, reversible inhibitor o inosine The ecacy o PTCy was also tested in the setting
monophosphate (IMP) dehydrogenase, an enzyme in o MSD or MUD HCT ater RIC, in the BMT-CTN
the pathway o guanine nucleotide synthesis, critical 1203 multicenter 1:1:1 randomized phase 2 clinical
or B and T lymphocyte prolieration. The combina- trial that evaluated three novel GVHD prophylaxis
tion o CNI/MMF is generally used in the setting o regimens—(1) PTCy/Tac/MMF (n = 92), (2) Tac/MTX
RIC or NMA HCT, and in those with MSD HCT,134 with bortezomib (n = 89), and (3) Tac/MTX with
but it may be a suboptimal approach in the setting o maraviroc (n = 92).144 Each study group was also com-
MAC and unrelated donor HCT.135 It has also been pared separately with a contemporary control group
used eectively with CNI or sirolimus in the setting o o Tac/MTX (n = 224). O these, the PTCy arm was
CBT136,137 or haploidentical HCT with PTCy.77 ound to be the most promising and led to statisti-
Another novel approach to GVHD prophylaxis cally signicant improvement in the primary end point
includes the use o the post-transplantation cytotoxic (GVHD-ree, relapse-ree survival; GRFS: hazard ratio
drug cyclophosphamide. The ecacy o cytotoxic (HR) 0.72, 90% CI 0.54–0.94; P = .044) compared with
drugs, including methotrexate, 6-mercaptopurine controls. The incidence o grade II–IV aGVHD was not
(6-MP), mechlorethamine, and cyclophosphamide to dierent among the arms, but that o grade III–IV was
prevent GVHD was assessed as early as the 1960s.138– signicantly lower only in the PTCy arm than in the
140
In elegantly conducted experiments, Santos and controls (2% vs 13%; P = .008). Similarly, the risk o
Owen noted that cyclophosphamide, when given on cGVHD (28% vs 38%; P = .069), and especially the
days +2, +3, and +5 post-HCT, but not beyond day cGVHD requiring immunosuppression (22% vs 37%;
+7, signicantly reduced the risk o GVHD.139 How- P = .037), were lower only in the PTCy arm. The risk o
ever, because o concerns about its myelotoxicity relapse, NRM, and DFS were similar among all groups,
when used ater transplantation, its use as a GVHD but viral inections appeared to be more common and
prophylaxis strategy ell out o avor until late the occurred in about one-third o patients in the PTCy
1990s/early 2000s, when this concept was revisited arm than other arms (20%–22%).144
by investigators rom the Johns Hopkins University
in the setting o haploidentical HCT. Because o its
unique pharmacology, cyclophosphamide can induce MD ANDERSON CANCER CENTER
APPROACH FOR GVHD PROPHYLAXIS
Chapter 19
maximal immunosuppression without myeloablation,

because it targets cells that express low levels o alde-
hyde dehydrogenase (such as B and T lymphocytes A combination o Tac/MTX is still considered the
and natural killer cells), while sparing cells with a high standard o care among recipients o sibling (without
level o this enzyme, such as the hematopoietic stem ATG) or unrelated (with ATG) donor HCT. However,
cells.141 The saety and ecacy o using cyclophospha- PTCy/Tac/MMF, which is the standard or all haploi-
mide or prevention o both grat rejection and GVHD dentical HCTs, is being used more commonly across
was demonstrated in a pivotal trial by O’Donnell all types o donor transplantations excluding CBT,
et al,142 where patients received T-cell-replete haploi- where the standard is Tac/MMF with ATG. In the
dentical BMT with NMA conditioning (Flu/TBI with Tac/MTX regimen, tacrolimus is initiated on day –2,
or without Cy 14.5 mg/kg/day × 2 days pre-HCT), ol- whereas it is started on day +5 in patients receiving
lowed by single dose o Cy 50 mg/kg IV on day +3 PTCy. Tacrolimus is started at 0.015–0.03 mg/kg per
post-HCT. Because CNI inhibits Cy-induced immu- day via continuous IV inusion with a target level o
nologic tolerance,143 tacrolimus and MMF were added 7–12 ng/mL. In rare certain situations where tacroli-
starting at day +4. Because the risk o grat ailure and mus cannot be used, cyclosporine is used to a target
severe GVHD was still high (~60% at 6 months), the level o 300–400 ng/mL at least or the rst 60 days
regimen was modied and patients received PTCy post-HCT. Sirolimus is typically reserved or patients
either on day +3 (50 mg/kg, n = 28) or on days +3 and who are unable to tolerate tacrolimus, such as those
+4 (50 mg/kg on each day, n = 40), ollowed by tacro- with severe renal dysunction or those with tacroli-
limus and MMF starting one day ater PTCy.77 Grat mus-related neurotoxicity. Methotrexate 5 mg/m2 IV
rejection occurred in 13%, and grades II–IV and III–IV per dose is given on days +1, +3, +6, and +11. MMF is
aGVHD by day 200 were noted in 34% and 6% o dosed at 15 mg/kg IV/by mouth every 8 hours (with a
patients, respectively. Although the risks o aGVHD, max o 1 g/dose).
POST-TRANSPLANTATION o inections such as BK virus and adenovirus); renal

COMPLICATIONS (acute or chronic kidney injury, thrombotic micro-
angiopathy159,160); and CNS toxicity161–163 (posterior
At least mild (grade I) toxicity related to the condi- reversible encephalopathy syndrome [PRES], seizures,
tioning regimen will develop in almost all patients, hemorrhage, inections, encephalopathy), to name a
whereas potentially lie-threatening or atal (grades ew. The most common causes o death within the
III–IV) complications are relatively rare.64,145 A detailed rst 100 days o HCT are relapse o the underlying dis-
description o these complications is beyond the ease (20%–35%), inections (20%–30%), organ ailure
scope o this chapter. Some o the most commonly (20%–25%), and GVHD (~15%). The leading cause o
encountered nonhematologic toxicities include oral death beyond 100 days o HCT is the relapse o the
stomatitis (management reviewed by Keee et al146), underlying disease (50%–60%), whereas inections
GI (nausea, vomiting, and diarrhea), and ebrile neu- (10%–15%), organ ailure (~10%), GVHD (~15%),
tropenia that occurs in more than 80% o patients, and others contribute to the rest (Fig. 19–4).
with documented inections noted in only about 25%
to 50%147,148 (management reviewed by the Inectious Inectious Disease Prophylaxis
Diseases Society o America [IDSA]149 and the Ameri- We use fuoroquinolone (levofoxacin or ciprofoxacin)
can Society or Blood and Marrow Transplantation or antibacterial prophylaxis during the phase o neu-
[ASBMT]150). Other regimen-related complications tropenia as recommended by the IDSA guidelines,149
(besides GVHD) can be dicult to diagnose because or cepodoxime or azithromycin in case o quino-
similar presentation can be caused by several other lone allergies/contraindications. Patients also receive
actors. These include hepatic toxicities (drug-induced prophylaxis against Candida (per IDSA: fuconazole,
or inectious hepatitis or cholestatic disorders, iron itraconazole, voriconazole, posaconazole, or echino-
overload, VOD/SOS; reviewed by Arai et al151); cardio- candins are all acceptable options) and select patients
vascular (hypertension, arrhythmias, cardiomyopathy, (especially those with prior history o invasive mold
fuid volume overload; reviewed by Tichelli et al152 and inection, mismatched HCT, and those receiving in vivo
Blaes et al153); pulmonary (pulmonary edema, diuse TCD) also receive prophylaxis against invasive Asper-
alveolar hemorrhage (DAH), idiopathic pneumonia gillus inections with either posaconazole149 or voricon-
syndrome; reviewed by Yen at al154); bladder (hemor- azole. Antiungal prophylaxis is generally continued
rhagic cystitis,155–158 which could be related to PTCy until at least 2 months rom when immunosuppression
Causes of Death after Adult (age ≥18) Matched Related HCT in the US, 2018-2019
Died within 100 days post-transplant Died at or beyond 100 days post-transplant*
Chapter 19
3% 1%
3% 1%
4%
1%
4%
11%
37%
24% 12%
56%
13%
16% 13%
1%
1%
Primary Disease Graft Rejection Primary Disease Graft Rejection
GVHD Infection GVHD Infection
Organ Failure Hemorrhage Organ Failure Malignancy
Subsequent
Other Unknown Hemorrhage
to HCT
Unknown Other
*Data reflects 3-year mortality
Causes of Death after Adult (age ≥18) Haploidentical Donor HCT in the US,
FIGURE 19–4 Causes of death in matched sibling and unrelated donor HCT in 2016-2017 (Reproduced with permission from
2018-2019
Phelan R, Arora M, ChenDied
M: Current use and outcome of hematopoietic
within 100 days post-transplant
stem cell transplantation: CIBMTR US summary slides, 2020.
Died at or beyond 100 days post-transplant*
2%
5% 3%
2% 3%
2%
Subsequent
to HCT
408 Scion III Stem Cell Transplantation Unknown Other
Causes of Death after Adult (age ≥18) Haploidentical Donor HCT in the US,
2018-2019
2%
5% 3%
2% 3%
2%
20%
12%
5%
32% 60%
12%
8%
8%
27%
1%
Subsequent
to HCT
Unknown Other
Causes of Death after Adult (age ≥18) Unrelated Donor HCT in the US, 2018-2019
2%
2%
4% 1% 2% 3%
1% 1%
27% 13%
26%
14% 53%
Chapter 19
16%
2% 11%
22%
1%
Organ Failure Malignancy Organ Failure Malignancy
Subsequent Subsequent
Hemorrhage Hemorrhage
to HCT to HCT
Unknown Other Unknown Other
FIGURE 19–4 (Cont.)
is discontinued. Antiviral prophylaxis against vari- HCT patients), it is still associated with high mortal-
cella zoster virus/herpes simplex virus is provided ity.165 Hal o PJP inections occur between 2 and 9
with valacyclovir. All cytomegalovirus-seropositive months post-HCT, with the rest being distributed
patients receive prophylaxis with letermovir 480 mg equally beore and ater this period.165 For prophylaxis
by mouth/IV daily starting on day +5, which is con- against PJP, we preer trimethoprim/sulamethoxazole
tinued through day +100.164 Another inection against over atovaquone, pentamidine, or dapsone because it
which prophylaxis is routinely used is Pneumocystis jir- provides additional coverage against Toxoplasma gon-
oveci pneumonia (PJP). Although its incidence appears dii, Nocardia, Stenotrophomonas, and other susceptible
to be decreasing in the modern era (<1% o allogeneic bacteria. Trimethoprim/sulamethoxazole is used as a
double-strength tablet (800/160 mg) once daily three using norethisterone, advanced disease, genetic ac-
times per week, or a single-strength tablet (400/80 mg) tors (GSTM1 polymorphism, C282Y allele, MTHFR
once daily. For patients with contraindications, alter- 677CC/1298CC haplotype), prior history o liver dis-
native regimens include pentamidine 4 mg/kg IV every ease/hepatitis, iron overload, abdominal or hepatic irra-
21 days (or 300 mg inhaled every 28 days), dapsone 100 diation, and previous use o gemtuzumab ozogamicin
mg orally daily, or atovaquone 1500 mg orally daily. O or inotuzumab ozogamicin, to name a ew.172–175 The
these, only atovaquone has activity against toxoplas- pathophysiology involves damage to endothelial cells
mosis. Prophylaxis against PJP is usually started about and hepatocytes by high-dose conditioning, which
3 to 4 weeks post-HCT and is continued or a mini- leads to necrosis o hepatocytes in zone 3 o the liver
mum o 12 months, or at until 2 months ater discon- acinus, engorgement o sinusoids with hepatocytes
tinuation o immunosuppression, whichever is later and red blood cells, and perivenular brosis, leading to
In addition, to shorten the duration o severe neu- obstruction o blood fow through hepatic capillaries
tropenia, all patients receive recombinant granulocyte and venules.172–176
colony-stimulating actor (G-CSF),which is continued The diagnosis o VOD is based purely on clinical pre-
through neutrophil engratment—dened as the rst o 3 sentation. Although radiographic ndings and histology
consecutive days on which the absolute neutrophil count may help, they are never relied on primarily to make
is greater than or equal to 0.5 × 109/L. Multiple phase or exclude the diagnosis. Early initiation o treatment
2/3 clinical trials demonstrated the saety and ecacy o is crucial, because progressive disease, especially when
G-CSF in reducing the period o severe neutropenia by associated with multiorgan ailure, is almost univer-
about one week, which reduces the risks o inections sally atal. Two most commonly used diagnostic cri-
and aids in earlier discharge rom the hospital.166 teria include the Seattle criteria, which was originally
reported by McDonald et al in 1984175 and subse-
quently revised in 1993 (the modied Seattle criteria),173
Hepatic Veno-Occlusive Disease/Sinusoidal and the Baltimore Criteria reported by Jones et al in
Obstruction Syndrome 1987.174 Most recently, the European Group or Blood
The term VOD was used originally to describe a clini- and Marrow Transplantation (EBMT) criteria were
cal syndrome o hepatomegaly, ascites, and jaundice, reported in 2016172 and include the classic VOD criteria
which was thought to be related to ingestion o cer- based on the Baltimore Criteria that occurs within 21
tain toxic chemicals that led to brosis and occlusion days o HCT, and a distinct entity o late-onset VOD
o small hepatic venules. Description o its histologic that can occur beyond 3 weeks, in which case hyper-
ndings can actually be traced back to reports rom bilirubinemia is not mandatory or the diagnosis (Table
the 1920s describing it as “Senecio disease,” related 19–1). To grade the severity o VOD, the EBMT criteria
to ingestion o plants known as Senecio ilicifolius and categorize it as mild, moderate, severe, or very severe
Senecio burchellii that grew as weeds in wheat elds.167 based on time to onset o VOD, degree and kinetics o
Chapter 19
It has also been associated with pyrrolizidine alka- hyperbilirubinemia, transaminases, weight gain, and
loids–induced liver toxicity.168,169 At least in the con- renal unction (Table 19–2).172
text o HCT, when it was subsequently recognized Treatment o VOD involves aggressive support-
that sinusoidal endothelial cells were the primary site ive care, with management o luid and sodium
o the toxic injury, the name was changed to SOS to balance with cautious use o diuretics, minimizing
adequately refect its underlying pathophysiology.170 exposure to hepatotoxic agents, and pain/volume
Yet, both VOD and SOS continue to be used inter- control with narcotics and paracentesis, or hemo-
changeably, and will be reerred to as VOD/SOS in dialysis in patients with severe renal dysunction or
this chapter. reractory luid overload, and the use o deibrotide.
Hepatic VOD/SOS is one o the most serious com- Deibrotide is a “complex mixture o oligonucle-
plications that can occur within the rst ew weeks o otides derived rom the controlled depolymerisa-
HCT, with an expected mortality exceeding 75% to tion o porcine intestinal mucosal DNA.”177 The
80%.171 The reported incidence o VOD ranges rom exact mechanism o its action is unclear but broadly
0 to more than 60%, with a mean incidence o about involves two processes: (1) protection o endo-
14% as reported by an analysis o 135 published stud- thelial cells and (2) restoration o the thrombotic-
ies.171 The wide range in incidence across studies is ibrinolytic balance as a result o its antithrombotic,
likely related to the heterogeneity o the study popula- proibrinolytic, and antiinlammatory properties. 177
tion, type o transplantation, and conditioning regimen In a multicenter phase 3 trial that included patients
used. Risk actors include the use o MAC (especially with VOD/SOS and advanced multiorgan ailure
high-dose TBI and oral or high-dose busulan-based (n = 102), deibrotide was given IV at 25 mg/kg per
regimens), unrelated donor, HLA-mismatched donor, day in our divided doses (6.25 mg/kg IV every 6
older age at HCT, poor perormance status, emales hours), or a minimum o 21 days, and continued until
Table 191 VenoOcclusive Disease (VOD)/Sinusoidal Obstruction Syndrome (SOS)
Modied Seattle
Seattle Criteria Criteria Baltimore Criteria EBMT Criteria
Within 30 days o HCT Within 20 days o HCT Within 21 days o HCT Classical SOS/VOD Late-onset SOS/VOD
in the rst 21 days >21 days ater HCT
ater HCT
Any two o the Any two o the Classical VOD/SOS
ollowing: ollowing: beyond day 21, OR
Hyperbilirubinemia hyperbilirubinemia hyperbilirubinemia ≥2 Bilirubin ≥2 mg/dL Histologically proven
(total serum (total serum mg/dL PLUS at least 2 o 3 SOS/VOD, OR
bilirubin >2 mg/dL) bilirubin >2 mg/dL) PLUS at least 2 o 3 other ndings
other ndings
Hepatomegaly or right Hepatomegaly or right Hepatomegaly Painul hepatomegaly at least 2 o 3 other
upper quadrant upper quadrant ndings
pain pain Bilirubin ≥2 mg/dL (or
34 μmol/L)
Painul hepatomegaly
Weight gain >5%
Ascites
Ascites Ascites
Sudden weight gain Sudden weight gain ≥5% weight gain >5% weight gain AND Hemodynamic
(>2% o baseline (>2% o baseline and/or ultrasound
body weight) body weight) evidence o SOS/
VOD
Table 192 EBMT Criteria or Severity Grading o Suspected SOS/VOD in Adults
Very Severe
Multiorgan
Milda Moderatea Severe Dysunctionb
Time since rst clinical >7 days 5–7 days ≤4 days Any time
symptoms o SOS/VODc
Chapter 19
Bilirubin (mg/dL) ≥2 and <3 ≥3 and <5 ≥5 and <8 ≥8

Bilirubin (μmol/L) ≥34 and <51 ≥51 and <85 ≥85 and <136 ≥136
Bilirubin kinetics Doubling within
48 hours
Transaminases ≤2 × normal >2 and ≤5× normal >5 and ≤8× normal >8× normal
Weight increase <5% ≥5% and <10% ≥5 % and <10% ≥10%
Renal unction <1.2 × baseline at ≥1.2 and ≥1.5 and <2× baseline ≥2× baseline at
transplant <1.5× baseline at at transplant transplant or other
transplant signs o MOD/MOF
Patients belong to the category that ullls two or more criteria. I patients ulll two or more criteria in two dierent categories, they must be classied in the most
severe category. Patient’s weight increase ≥5% and <10% is considered by deault as a criterion or severe SOS/VOD; however, i patients do not ulll other criteria or
severe SOS/VOD, weight increase ≥5 % and <10% is thereore considered a criterion or moderate SOS/VOD.
a
In the case o the presence o two or more risk actors or SOS/VOD, patients should be in the upper grade.
b
Patients with multiorgan dysunction must be classied as very severe.
c
Time rom the date when the rst signs/symptoms o SOS/VOD began to appear (retrospectively determined) and the date when the symptoms ullled SOS/VOD
diagnostic criteria.
resolution o VOD/SOS or until patient discharge.178 DAH (12% and 16%) and GI bleeding (8% and 9%)
Treatment with debrotide resulted in a signicantly were similar. 178 Despite similar rates o hemorrhagic
higher complete remission (CR) rate at day 100 (25% complications, the EBMT guidelines suggest that
vs 12.5%; P = .016) and improved OS at day 100 (38% patients treated with debrotide should receive plate-
vs 25%; P = .01) than in historical controls, respec- let transusions to keep platelets above 30 × 109/L.
tively. The incidence o adverse eects including Debrotide has a short hal-lie (<2 hours), so it can
be held or about 2 hours beore and ater any inva- rash, adverse drug-reaction, viral exanthema, cuta-
sive procedure that may be required. neous eruption o lymphocyte recovery, or GVHD.
Among several agents attempted or prophylaxis Thereore, skin biopsy is oten perormed to help with
against VOD/SOS, including unractionated heparin the diagnosis. Similar to clinical staging and grading,
or low-molecular-weight heparin,179 anti-thrombin histopathologic ndings are also graded based on the
III,180 prostaglandin E1,181,182 and pentoxiylline,183,184 degree o injury noted by the pathologist. One histo-
ursodeoxycholic acid (UDCA)185 appears to be the logic grading system reported by Lerner et al in 1974
most promising, with a very avorable toxicity (“Lerner grading system”) includes changes o basal
prole. In a systematic review o our randomized cell layer vacuolization oten surrounded by lympho-
clinical trials and two historically controlled studies, cytes, commonly called as satellitosis (grade I); grade
compared with no prophylaxis, UDCA was associ- II includes grade I changes plus ocal spongiosis,
ated with signicant reduction o VOD/SOS (relative single necrotic keratinocyte/dyskeratotic epidermal
risk [RR], 0.34; 95% CI, 0.17–0.66) and signicant cell; grade III includes additional changes o orma-
reduction in the risk o transplant-related mortal- tion o dermal-epidermal junction clet; and grade
ity (RR, 0.58; 95% CI, 0.35–0.95), with no eect on IV is the complete loss o epidermis. 192 The utility
aGVHD, relapse, or OS.185 In a randomized trial com- o histologic conrmation or GVHD in conrming
paring UDCA (n = 123) versus controls (n = 119),186 the diagnosis is controversial because many ndings
UDCA was started at 12 mg/kg per day rom a day can also be seen in entities other than GVHD. 193–196
beore conditioning and continued until day +90 One study noted that 25% o GVHD and non-GVHD
post-HCT. Use o UDCA was associated with signi- samples showed no basal vacuolization at all. Simi-
cantly reduced risk o grade III–IV aGVHD; liver, GI, larly, necrotic keratinocytes were noted in both
and severe skin GVHD, lower NRM (19% vs 34%), GVHD and non-GVHD cases, although the GVHD
and improved survival (71% vs 55%) at 1 year.186,187 cases trended to exhibit more necrotic keratinocytes.
Similar to VOD/SOS, it has been hypothesized Further, more than hal (55%) o the GVHD cases
that many other complications in the early post- and about three-quarters (72%) o non-GVHD biop-
HCT period may have an endothelial origin as well. sies showed no or ewer than three necrotic kerati-
These complications include capillary leak syndrome, nocytes per 4-mm biopsy.195 Nevertheless, biopsies
engratment syndrome, transplant-associated micro- can be helpul in excluding other possibilities, espe-
angiopathy (TMA), DAH, and idiopathic pneumonia cially inections, and conrming the diagnosis in the
syndrome.188 Pathophysiology and management o context o strong clinical suspicion.
these are reviewed elsewhere.189 In the GI tract, epithelial cell apoptosis (>1 per
piece) in the crypts is the most important and the
minimal pathologic criteria or histologic diagnosis
ACUTE GRAFT-VERSUS-HOST o GVHD, as recommended by the GVHD consensus
Chapter 19
DISEASE National Institutes o Health (NIH) Pathology Work-
ing Group—categorizing the ndings as negative,
possible, or likely GVHD.197 Apart rom this, there is
Diagnosis and Classifcation no universally accepted grading system or histologic
Although GVHD was traditionally classied as acute classication, and many are modied rom what was
(aGVHD) or chronic (cGVHD) based on the timing originally described by Lerner et al in 1974.192,198 One
o onset (beore or ater 100 days), the distinction o these modied criteria and the one used at MDACC
is predominantly based on clinical presentation. The describes grade 1 histologic changes as the presence o
organs involved by aGVHD, in requency o involve- increased apoptotic epithelial cells without crypt loss;
ment, are skin (maculopapular rash), upper GI tract grade 2: isolated crypt loss or micro-abscess; grade 3: 2
(anorexia, nausea, vomiting), lower GI tract (diar- or more contiguous crypt loss; and grade 4: extensive
rhea, abdominal pain, bleeding), and liver (eleva- crypt loss with mucosal denudation.199 It is important
tions o total serum bilirubin). Two most commonly to realize that histologic grade does not correlate well
used systems or staging and grading o aGVHD are with clinical grade or prognosis, and even “mild” grade
(1) the modied Glucksberg GVHD staging system 1 histologic changes (which are the most common
based on the 1994 Consensus Conerence on Acute ndings in a majority o biopsy specimens) are associ-
GVHD Grading held in Keystone,190 and (2) the ated with signicantly higher risk o NRM (HR = 2.7,
Mount Sinai Acute GVHD International Consortium P = .02) than those with negative ndings.199
(MAGIC) staging system reported by Harris et al in The histologic hallmark o acute liver GVHD is bile
2016 (Table 19–3).191 duct injury with evidence o nuclear enlargement and
The dierential diagnosis o skin rash post-HCT pleomorphism, cytoplasmic vacuolization, loss o nuclear
is broad and includes conditioning regimen-related polarity, and varying degrees o centrilobular cholestasis.
Table 193 Acute GVHD Staging & Grading
Skin (Active Erythema Upper Gastrointestinal Lower Gastrointestinal

Stage Only) Liver (Bilirubin) Tract Tract (Stool Output/Day)
0 No active (erythematous) <2 mg/dL No or intermittent nausea, Adult: <500 mL/day or <3
GVHD rash vomiting, or anorexia episodes/day
Child: <10 mL/kg/day or
<4 episodes/day
1 Maculopapular rash 2–3 mg/dL Persistent nausea, Adult: 500–999 mL/day or
<25% BSA vomiting, or anorexia 3–4 episodes/day
Child: 10–19.9 mL/kg/
day or 4–6 episodes/
day
2 Maculopapular rash 3.1–6 mg/dL — Adult: 1000–1500 mL/day
25–50% BSA or 5–7 episodes/day
Child: 20–30 mL/kg/day
or 7–10 episodes/day
3 Maculopapular rash 6.1–15 mg/dL — Adult: >1500 mL/day or
>50% BSA >7 episodes/day
Child: >30 mL/kg/day or
>10 episodes/day
4 Generalized erythroderma >15 mg/dL — Severe abdominal pain
(>50% BSA) plus bullous with or without ileus,
ormation and or grossly bloody stool
desquamation >5% BSA (regardless o stool
volume).
Overall clinical grade (based on most severe target organ involvement):
• Grade 0: No stage 1–4 o any organ;
• Grade I: Stage 1–2 skin without liver, upper GI, or lower GI involvement;
• Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI;
• Grade III: Stage 2–3 liver and/or stage 2–3 lower GI, with stage 0–3 skin and/or stage 0–1 upper GI; and
• Grade IV: Stage 4 skin, liver, or lower GI involvement, with stage 0–1 upper GI.
a
As per the Mount Sinai Acute GVHD International Consortium (MAGIC), reported by Harris et al.191
BSA, body surace area.
Chapter 19
Other eatures such as portal or central vein endotheli- those treated with systemic corticosteroids 1 mg/kg
itis, centrilobular necrosis, hepatocellular ballooning, per day (50% vs 33%, P = .0005).201
and eathery degeneration are less common and may Any other aGVHD (grade II–IV) requires systemic
be noticed in advanced cases.200 There is no universally treatment. Corticosteroids 2 mg/kg per day is the stan-
accepted histologic grading system and we do not ascribe dard o care, which leads to responses in 40% to 60%
a histologic grade to patients with liver GVHD. o patients.202,203 A randomized phase 3 trial compared
Because this is the most common error made by the saety and ecacy o using prednisone 1 mg/kg
trainees and non-HCT physicians, it is worth empha- per day versus 2 mg/kg per day among patients with
sizing yet again that aGVHD staging and grading is grades II or higher GVHD.204 The study ound no
based on the clinical presentation, not by histology, as signicant dierences in the risk o progression to
noted in Table 19–3. grade III–IV aGVHD, cGVHD, NRM, relapse, or OS
between the arms. However, a signicantly higher
proportion o patients treated with lower-dose predni-
Treatment sone required secondary systemic immunosuppressive
Limited-stage isolated skin aGVHD (overall grade I, therapy than in the standard-dose arm (41% vs 7%; P
with <50% body surace area involvement) can be = .001). Furthermore, the use o lower-dose prednisone
treated with topical or systemic corticosteroids or was not associated with any meaningul advantage, as
observation alone.201 Although patients with disease suggested by similar risk o invasive inections, hyper-
managed by observation have a signicantly lower risk glycemia, hypertension, degree o myopathy, and
o bacterial inections (12% vs 25%; P = .04) and less quality-o-lie between the arms.204 The addition o
severe ungal inections, they also carry a signicantly other immunosuppressants to corticosteroids, includ-
higher risk o progression to grade II–IV aGVHD than ing MMF,205,206 pentostatin,206 denileukin dititox,206
etanercept,206 daclizumab,207 anti–IL-2 receptor mono- ollicular helper T (Th) cells, and ollicular regulatory T
clonal antibody,208 infiximab,209 or ATG210 have not (Tr) cells, and brosis-promoting actors in the patho-
shown additional benets in multiple randomized physiology o cGVHD.
trials. Chronic GVHD typically presents insidiously, with
Most recently, sirolimus was tested as a steroid- a median time to onset o about 4 to 6 months, although
sparing strategy or patients with standard-risk GVHD about 5% to 10% o cases can present beyond the rst
(mostly skin ± upper GI GVHD).211 In the BMT-CTN year o transplantation. The diagnosis and staging o
1501 clinical trial, patients with standard-risk GVHD cGVHD is based on the 2014 NIH Chronic GVHD
(per the Minnesota score212 plus Ann Arbor biomarker Diagnosis and Staging Consensus criteria.223 As elabo-
score 1–2213) were randomly assigned to receive either rated in Table 19–4, the signs and symptoms o cGVHD
sirolimus or prednisone (or prednisone dose equivalent) are consider either “diagnostic” (that establish the pres-
2 mg/kg per day. The sirolimus level was kept thera- ence o cGVHD without need or urther testing) or
peutic (10–14 ng/mL until aGVHD resolution, and then “distinctive” (not sucient in isolation to establish an
5–10 ng/mL ater resolution until at least day 56) with unequivocal diagnosis o cGVHD; these are not com-
concurrent CNI (tacrolimus, 3–7 ng/mL or cyclosporine, monly seen in aGVHD). In certain cases, additional
120–200 ng/mL). Overall response rates (ORRs) were testing such as a biopsy is needed to make a diagnosis.
comparable or sirolimus and corticosteroids at day The common sites o involvement include skin/
28 (65% vs 73%, respectively), with no dierences in ascia (~75%–80%), mouth (50%–85%), eyes (20%–
the risk o steroid-reractory aGVHD, cGVHD, serious 33%), liver (10%–50%), GI tract (20%–45%), lung
inections, NRM, relapse, or OS. However, there was a (bronchiolitis obliterans, 5%–20%), muscles/joints,
higher proportion o nonresponders in the sirolimus arm and genitalia.224–227 At MDACC, patients benet rom
by day 56 (with an ORR o 64% vs 79%, respectively), comprehensive cGVHD care provided through a mul-
and the risk o TMA within 6 months was also signi- tidisciplinary team that includes a dermatologist, oral
cantly higher in the sirolimus than in the steroid arm health specialist, physical therapist, and occupational
(10% vs 1.5%, respectively). therapist, who all generally evaluate patients jointly
Steroid-reractory aGVHD responds poorly to sec- with a HCT physician. In addition, dedicated ophthal-
ond-line therapies and is associated with increased mologists and pulmonologists skilled in the diagnosis
mortality.202 Multiple therapies have been tried with and management o ocular and lung cGVHD, respec-
varying success, including extracorporeal photother- tively, are available on site.
apy, MMF, methotrexate, basiliximab, daclizumab, It is crucial to recognize that the treatment o
inolimomab, denileukin dititox, alemtuzumab, horse cGVHD that requires systemic immunosuppression
ATG, etanercept, infiximab, sirolimus, or pentostatin, generally lasts or at least one year, with the median
to name a ew (reviewed by Martin et al202). Other duration o therapy being about 2 to 3 years, and about
agents being tested include brentuximab vedotin,214 15% o patients require treatment or more than 5 to
Chapter 19
α-1 antitrypsin,215 mesenchymal stem cells,216–218 and 7 years.226,228 Treatment generally includes corticoste-
vedoluzumab219 (specically or lower GI tract GVHD). roids (prednisone 0.5–1 mg/kg/day), which are tapered
Among these, ruxolitinib became the rst and only slowly at a rate that varies considerably rom practice to
drug so ar to have received FDA approval (May 2019) practice. One approach is to taper the dose by approxi-
or steroid-resistant aGVHD based on the results o an mately 25% every 2 weeks to reach an average dose
open-label, single-arm, multicenter REACH1 clinical o about 0.25 mg/kg per day (or 0.4–0.5 mg/kg every
trial (n = 71).220 The day 28 ORR in this study was 55% other day) within 3 months ater starting treatment,
(complete response rate o 27%) and the median time ollowed by much smaller dose reductions toward the
to response was 7 (range, 6–49) days.221 end o the taper, until the adrenal replacement dose is
reached (roughly 0.10 mg/kg/day).226 Despite lack o
any randomized trial showing benet, additional ther-
CHRONIC GRAFT-VERSUS-HOST apy is generally added to the corticosteroids with hopes
DISEASE to minimize toxicities rom prolonged corticosteroid
use.229 Multiple agents have been tried as adjuncts to
The pathophysiology o cGVHD is incompletely under- corticosteroids, including CNI, sirolimus, extracorpo-
stood and involves complex interactions between the real phototherapy, ultraviolet light therapy, ruxolitinib,
innate, humoral, and cell-mediated immunity, leading ibrutinib, rituximab, imatinib, pentostatin, MMF, low-
to brosis and other syndromes that resemble autoim- dose IL-2, bortezomib, thalidomide, pomalidomide,
mune or other immune-mediated disorders. A review hydroxychloroquine, infiximab, and etanercept, to
by Zeiser and Blazer222 highlights the key role o B-cell name a ew.224,226 O these, ibrutinib is the rst and only
signaling, naïve T-cell dierentiation into type 17 helper drug that received FDA approval (August 2017) or
T (Th17) cells, and type 17 cytotoxic T (Tc17) cells, treatment o SR-cGVHD based on a single-arm study
Table 194 Signs and Symptoms o Chronic GVHD
Diagnostic
(Sufcient to Distinctiveb (Seen in
Establish the Chronic GVHD, But Commond (Seen
Diagnosis o Insufcient Alone to Other Features or with Both Acute and
Organ or Site Chronic GVHD) Establish a Diagnosis) Unclassied Entitiesc Chronic GVHD)
Skin Poikiloderma Depigmentation Sweat impairment Erythema
Lichen planus– Papulosquamous Ichthyosis Maculopapular rash
like eatures lesions Keratosis pilaris Pruritus
Sclerotic eatures Hypopigmentation
Morphea-like Hyperpigmentation
eatures
Lichen sclerosus–
like eatures
Nails Dystrophy
Longitudinal ridging,
splitting, or brittle
eatures
Onycholysis
Pterygium unguis
Nail loss (usually
symmetric, aects
most nails)
Scalp and New onset o scarring Thinning scalp hair, typically
body hair or nonscarring patchy, coarse, or dull (not
scalp alopecia explained by endocrine or
(ater recovery rom other causes)
chemoradiotherapy) Premature grey hair
Loss o body hair
Scaling
Mouth Lichen planus–like Xerostomia Gingivitis
changes Mucoceles Mucositis
Mucosal atrophy Erythema
Ulcers Pain
Chapter 19
Pseudomembranes
Eyes New-onset dry, gritty, Photophobia
or painul eyes Periorbital
Cicatricial hyperpigmentation
conjunctivitis Blepharitis (erythema o
Keratoconjunctivitis the eyelids with edema)
sicca
Conuent areas o
punctate keratopathy
Genitalia Lichen planus–like Erosions
eatures Fissures
Lichen sclerosus– Ulcers
like eatures
Females Vaginal scarring
or clitoral/labial
agglutination
Males Phimosis or urethral/
meatus scarring
or stenosis
(Continued)
Table 194 Signs and Symptoms o Chronic GVHD (Cont.)
Diagnostic
(Sufcient to Distinctiveb (Seen in
Establish the Chronic GVHD, But Commond (Seen
Diagnosis o Insufcient Alone to Other Features or with Both Acute and
Organ or Site Chronic GVHD) Establish a Diagnosis) Unclassied Entitiesc Chronic GVHD)
GI tract Esophageal web Exocrine pancreatic Anorexia
Strictures or insufciency Nausea
stenosis in the Vomiting
upper to mid- Diarrhea
third o the Weight loss
esophagus Failure to thrive
(inants and children)
Liver Total bilirubin, alkaline
phosphatase >2×
upper limit o normal
ALT >2× upper limit
o normal
Lung Bronchiolitis Air trapping and Cryptogenic organizing
obliterans bronchiectasis on pneumonia
diagnosed with chest CT Restrictive lung disease
lung biopsy
Bronchiolitis
obliterans
syndromee
Muscles, ascia, Fasciitis Myositis or Edema
joints Joint stiness polymyositisg Muscle cramps
or contractures Arthralgia or arthritis
secondary
to asciitis or
sclerosis
Hematopoietic Thrombocytopenia
and immune Eosinophilia
Lymphopenia
Chapter 19
Hypo- or
hypergammaglobulinemia
Autoantibodies (AIHA, ITP)
Raynaud phenomenon
Other Pericardial or pleural
eusions
Ascites
Peripheral neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction
abnormality or
cardiomyopathy
a
As per the National Institutes o Health Consensus Development Project on Criteria or Clinical Trials in Chronic Grat-versus-Host Disease.
b
In all cases, inection, drug eect, malignancy, or other causes must be excluded.
c
Can be acknowledged as part o the chronic GVHD maniestations i diagnosis is conrmed.
d
Commonly reers to shared eatures by both acute and chronic GVHD.
e
BOS can be diagnostic or lung chronic GVHD only i distinctive sign or symptom present in another organ (see text).

Pulmonary entities under investigation or unclassied.
g
Diagnosis o chronic GVHD requires biopsy.
AIHA, autoimmune hemolytic anemia; ALT, alanine aminotranserase; ITP, idiopathic thrombocytopenic purpura.
Reproduced with permission rom Jagasia MH, Greinix HT, Arora M, et al: National Institutes o Health Consensus Development Project on Criteria or Clinical Trials in
Chronic Grat-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report, Biol Blood Marrow Transplant 2015 Mar;21(3):389-401.e1.
(n = 44) in that population.225 The trial showed an ORR o azacytidine (n = 93) versus observation (n = 94)
o 67% (21% complete and 65% partial responses), in patients with AML/MDS. Azacytidine dose was
which was sustained or at least 20 weeks in a majority 32 mg/m2 per day given subcutaneously or 5 days,
or patients. However, about one-third o patients had every 28 days or 12 cycles, with the rst cycle started
grade 3 or higher inections, about one-third required between days +42–100. About 93% o patients in the
dose reductions because o toxicities, and about one- azacytidine arm started the maintenance at a median
third discontinued treatment because o toxicities, o about 2 months post-HCT, but about 75% could not
most commonly atigue or pneumonia.225 complete the planned 12 cycles. The median number
In addition to systemic treatment, skilled ancillary o cycles received was our; the most common reason
and supportive care are the keys to the management o or discontinuation was the relapse/death in about
cGVHD to target specic organs involved, such as oral one-hal o the patients (47%) ollowed by toxicity in
mucosa (topical steroids, sialogogues), genital (topical about one-quarter (26%). The trial was stopped early
steroids and dilators), ocular (articial lubricant tears, because o slow accrual and showed no dierence in
punctal plugs, scleral lenses, or prosthetic replace- DFS between the arms.245 Many other clinical trials are
ment o the ocular surace ecosystem [PROSE] lenses), underway at MDACC to assess the saety and ecacy
lungs (inhaled corticosteroids, pulmonary rehabilita- o novel higher-potency hypomethylating agents (such
tion), and ascia/joint (physical/occupational therapy, as guadecitabine), novel combinations (such as aza-
stretching, casting, weight-bearing exercises, compres- cytidine plus BCL-2 inhibitor venetoclax) or patients
sion stockings or peripheral edema).226 with high-risk myeloid malignancies, and bispecic
monoclonal antibodies (such as blinatumomab246) or
patients with ALL.
RELAPSE
Treatment o Relapsed Disease
Role o Maintenance Therapy Post-
Although a small minority o “relapsed” disease post-
Transplantation or Relapse Prevention HCT can be donor derived, a majority o relapses are
Multiple studies suggest a potential benet o post- the result o residual host malignant cells that survive
HCT maintenance in specic situations, such as in the conditioning regimen and escape the GVT eect.
patients with FMS-like tyrosine kinase 3 (FLT3)/ This may be caused by loss or reduced expression o
internal tandem duplication (ITD; FLT3/ITD), tumor-related antigens, loss o mismatched HLA hap-
mutated AML, and Philadelphia chromosome–posi- lotype leading to the development o mutant leukemic
tive (Ph+ve) ALL/CML. The pivotal randomized, cells,247,248 or development o tolerance in the donor-
double-blind, placebo-controlled phase 2 multicenter derived T-cells.249 The management o relapsed disease
Chapter 19
(SORMAIN) trial230 assessed the ecacy o soraenib post-HCT is complicated and depends on several ac-
maintenance post-HCT but was terminated early tors, including time rom HCT to relapse, several dis-
because o slow accrual. Nevertheless, it did provide ease-related actors (impending relapse as assessed by
an indication o improved survival in patients who the loss o donor myeloid chimerism, detection o new
received maintenance. Ater a median ollow-up o minimal/measurable residual disease, overt/prolierative
almost 42 months post-randomization, 2-year DFS relapse), and patient characteristics (perormance sta-
was 53% versus 85% in the placebo versus soraenib tus, comorbidities, presence or absence o GVHD, etc).
groups, respectively (HR 0.39, 95% CI, 0.18–0.85; Broadly, the options include withdrawal o immunosup-
P = .0135). Besides soraenib,230,231 many other oral pression (with close monitoring because o a high risk o
FLT3/ITD inhibitors are being evaluated, including GVHD), immunotherapy (DLI, chimeric antigen recep-
quizartinib, 232,233 midostaurin (RADIUS trial),234 cre- tor cells, use o checkpoint inhibitors or other immuno-
nolanib,235 and gilteritinib.236,237 In patients with Ph+ modulatory drugs), chemotherapy, or subsequent HCT.
acute or chronic leukemias, several tyrosine kinase The prognosis o relapsed leukemia post-HCT is dismal.
inhibitors (TKIs), including imatinib238–240 or newer- A study by the CIBMTR in patients with relapsed AML
generation TKIs (dasatinib or ponatinib),241 have been showed that the median time to relapse ater HCT was
demonstrated to be sae or post-HCT maintenance. 7 months.250 O these, 29% o patients attained CR with
Besides these targeted agents, there is no estab- subsequent treatment (chemotherapy, DLI, or second
lished role o maintenance post-HCT, although this HCT), resulting in 1-year OS o 23%. Time to relapse
has been an area o investigation in multiple trials, ater rst HCT was the single most important predictor
most commonly using DNA hypomethylating agents, o survival. Three-year OS was 4% or patients whose
eg, azacitidine or decitabine or AML/MDS.242–244 The disease relapsed within the rst 6 months o rst HCT,
largest o these was a phase 3 randomized trial con- 12% or those whose disease relapsed between 6 and 12
ducted at MDACC,245 which assessed the ecacy months, 26% or those with disease relapse between 2
and 3 years, and 38% or those whose disease relapsed 3 CONCLUSIONS
or more years ater rst HCT.250
Allogeneic HCT remains an important therapeutic
technique or the management o various malignant
LATE COMPLICATIONS and nonmalignant disorders. Over the past decade,
better disease risk stratication, identication o high-
Among long-term survivors o HCT, many patients risk comorbidities, and advances in transplantation
experience delayed toxicities,251 which could be a techniques, conditioning therapy, GVHD prophylaxis,
sequela o the conditioning regimen, GVHD, and/or and supportive care have advanced the eld o trans-
its treatment. These include endocrine abnormalities plantation immensely. With a wider use o alternative
such as hypothyroidism, hypogonadism, or growth donors, no patient should now be denied transplanta-
hormone deciency in younger patients, pulmonary tion or lack o a donor. Further, with an increasing use
toxicities such as restrictive or obstructive lung dis- o RIC and innovative MAC regimens, older patients
ease, cardiac toxicities such as hypertension, dyslip- and those with high comorbidities can now be trans-
idemia, late inectious complications, impaired bone planted saely. Yet, relapse o the underlying disease,
health (osteopenia, osteoporosis, or avascular necrosis) GVHD, and inections remain the Achilles heels that
and secondary malignancies, to name a ew.252–255 The contribute to a vast majority o transplantation ailure.
intensive treatment and prolonged recovery rom allo- Although tremendous strides have been made since
geneic transplantation can also have proound psycho- that rst human BMT perormed in the late 1950s to
social as well as nancial implications or patients and now, we are yet to completely decipher the “Holy
their amilies. At MDACC, patients are routinely ol- Grail” o transplantation—which is to maximize the
lowed by a dedicated survivorship program to screen GVT eect while minimizing the GVHD.
or and to address these late eects o HCT.

J Whenever possible, allogeneic HCTs are perormed multidisciplinary team o HCT physicians, advanced
in the context o clinical trials that are assessing care providers, nutritionists, physical and occupa-
novel conditioning regimens and GVHD prophylaxis tional therapists, pharmacists, rehabilitation phy-
strategies. Patients who are ineligible or clinical tri- sicians, and geriatricians to address railty issues
als because o insurance issues or other reasons are beore HCT, with an aim to improve post-HCT
discussed in HCT team meetings to ormulate the outcomes.
Chapter 19
standard o care plan. J Allogeneic HCT patients are also assessed in a “sur-
J Most standard o care myeloablative condition- vivorship clinic” around 3 months post-HCT or
ing regimens include busulan and udarabine screening and counseling about long-term compli-
(mostly using the ractionated approach), whereas cations o HCT.
udarabine and melphalan are commonly used J Patients with GVHD benet rom care at dedicated
or reduced-intensity conditioning. Post-trans- GVHD multidisciplinary clinics that includes HCT
plantation cyclophosphamide is being used more physicians, dermatologists, oral health specialists,
commonly in almost all types o HCT or GVHD pro- physical and occupational therapists, pulmonolo-
phylaxis, except CBT. gists, and ophthalmologists.
J Older and/or rail patients benet rom reerral to J Patients are encouraged to participate in current
the MDACC HCT “Enhanced Recovery program,” clinical trials that are evaluating the use o strate-
which entails comprehensive assessment by a gies to reduce the relapse risk post-HCT.
18. Bertaina A, Andreani M. Major histocompatibility complex

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initial therapy, survival, and transplant-related mortality. Biol plete remission. Br J Haematol. 2016;175(3):496-504.
Blood Marrow Transplant. 2015;21(4):761-767. 232. Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus
213. Hartwell MJ, Ozbek U, Holler E, et al. An early-biomarker salvage chemotherapy in relapsed or reractory FLT3-ITD
algorithm predicts lethal grat-versus-host disease and survival. acute myeloid leukaemia (QuANTUM-R): a multicentre, ran-
JCI Insight. 2017;2(3): e89798. domised, controlled, open-label, phase 3 trial. Lancet Oncol.
214. DeFilipp Z, Li S, Kempner ME, et al. Phase I trial o brentux- 2019;20(7):984-997.
imab vedotin or steroid-reractory chronic grat-versus-host 233. Sandmaier BM, Khaled S, Oran B, et al. Results o a phase 1 study
disease ater allogeneic hematopoietic cell transplantation. Biol o quizartinib as maintenance therapy in subjects with acute
Blood Marrow Transplant. 2018;24(9):1836-1840. myeloid leukemia in remission ollowing allogeneic hematopoi-
215. Magenau JM, Goldstein SC, Peltier D, et al. alpha1-Antitrypsin etic stem cell transplant. Am J Hematol. 2018;93(2):222-231.
inusion or treatment o steroid-resistant acute grat-versus- 234. Maziarz RTT, Patnaik MM, Scott BL, et al. Radius: a phase 2
host disease. Blood. 2018;131(12):1372-1379. randomized trial investigating standard o care ± midostau-
216. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells or rin ater allogeneic stem cell transplant in FLT3-ITD-mutated
treatment o steroid-resistant, severe, acute grat-versus-host AML. Blood. 2018;132(suppl 1):662.
disease: a phase II study. Lancet. 2008;371(9624):1579-1586. 235. Oran B, Ciurea SO, Marin D, et al. Saety analysis o intra-
217. Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem patient dose-study o crenolanib maintenance therapy in
cells or treatment o therapy-resistant grat-versus-host dis- patients with FLT3 mutant AML ollowing allogeneic hemato-
ease. Transplantation. 2006;81(10):1390-1397. poietic stem cell transplant. Blood. 2018;132(suppl 1):3426.
218. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment o severe 236. Levis MJ, Hamadani M, Logan B, et al. A phase 3, trial o gilteri-
acute grat-versus-host disease with third party haploidentical tinib, as maintenance therapy ater allogeneic hematopoietic
mesenchymal stem cells. Lancet. 2004;363(9419):1439-1441. stem cell transplantation in patients with FLT3-ITD+ AML. J
219. Floisand Y, Lazarevic VL, Maertens J, et al. Saety and eective- Clin Oncol. 2018;36(suppl 15).
ness o vedolizumab in patients with steroid-reractory gastro- 237. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemo-
intestinal acute grat-versus-host disease: a retrospective record therapy or relapsed or reractory FLT3-mutated AML. N Engl J
review. Biol Blood Marrow Transplant. 2019;25(4):720-727. Med. 2019;381(18):1728-1740.
238. Chen H, Liu KY, Xu LP, et al. Administration o imatinib hematopoietic cell transplantation or acute lymphoblastic leu-
ater allogeneic hematopoietic stem cell transplantation may kemia. Blood. 2019;134(suppl 1):1298.
improve disease-ree survival or patients with Philadelphia 247. Villalobos IB, Takahashi Y, Akatsuka Y, et al. Relapse o leuke-
chromosome-positive acute lymphobla stic leukemia. J Hematol mia with loss o mismatched HLA resulting rom uniparental
Oncol. 2012;5:29. disomy ater haploidentical hematopoietic stem cell transplan-
239. Wassmann B, Peier H, Stadler M, et al. Early molecular tation. Blood. 2010;115(15):3158-3161.
response to posttransplantation imatinib determines outcome 248. Vago L, Perna SK, Zanussi M, et al. Loss o mismatched HLA
in MRD+ Philadelphia-positive acute lymphoblastic leukemia in leukemia ater stem-cell transplantation. N Engl J Med.
(Ph+ ALL). Blood. 2005;106(2):458-463. 2009;361(5):478-488.
240. Anderlini P, Sheth S, Hicks K, et al. Re: imatinib mesylate 249. Barrett AJ, Battiwalla M. Relapse ater allogeneic stem cell
administration in the rst 100 days ater stem cell transplanta- transplantation. Expert Rev Hematol. 2010;3(4):429-441.
tion. Biol Blood Marrow Transplant. 2004;10(12):883-884. 250. Bejanyan N, Weisdor DJ, Logan BR, et al. Survival o patients
241. DeFilipp Z, Langston AA, Chen Z, et al. Does post-trans- with acute myeloid leukemia relapsing ater allogeneic hema-
plant maintenance therapy with tyrosine kinase inhibitors topoietic cell transplantation: a center or international blood
improve outcomes o patients with high-risk Philadelphia and marrow transplant research study. Biol Blood Marrow Trans-
chromosome-positive leukemia? Clin Lymphoma Myeloma Leuk. plant. 2015;21(3):454-459.
2016;16(8):466-471, e461. 251. Battiwalla M, Tichelli A, Majhail NS. Long-term survivorship
242. de Lima M, Oran B, Champlin RE, et al. CC-486 maintenance ater hematopoietic cell transplantation: roadmap or research
ater stem cell transplantation in patients with acute myeloid and care. Biol Blood Marrow Transplant. 2017;23(2):184-192.
leukemia or myelodysplastic syndromes. Biol Blood Marrow 252. Majhail NS. Long-term complications ater hematopoi-
Transplant. 2018;24(10):2017-2024. etic cell transplantation. Hematol Oncol Stem Cell Ther.
243. Pusic I, Choi J, Fiala MA, et al. Maintenance therapy with 2017;10(4):220-227.
decitabine ater allogeneic stem cell transplantation or acute 253. Bevans M, El-Jawahri A, Tierney DK, et al. National Institutes
myelogenous leukemia and myelodysplastic syndrome. Biol o Health Hematopoietic Cell Transplantation Late Eects
Blood Marrow Transplant. 2015;21(10):1761-1769. Initiative: The Patient-Centered Outcomes Working Group
244. de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with Report. Biol Blood Marrow Transplant. 2017;23(4):538-551.
low-dose azacitidine ater allogeneic hematopoietic stem cell 254. Mohty B, Mohty M. Long-term complications and side eects
transplantation or recurrent acute myelogenous leukemia or ater allogeneic hematopoietic stem cell transplantation: an
myelodysplastic syndrome: a dose and schedule nding study. update. Blood Cancer J 2011;1(4):e16.
Cancer. 2010;116(23):5420-5431. 255. Kolb HJ, Socie G, Duell T, et al. Malignant neoplasms in
245. Oran B, Lima MD, Garcia-Manero G, et al. Maintenance with long-term survivors o bone marrow transplantation. Late
5-azacytidine or acute myeloid leukemia and myelodysplastic Eects Working Party o the European Cooperative Group
syndrome patients. Blood. 2018;132(suppl 1):971. or Blood and Marrow Transplantation and the European
246. Kebriaei P, Banerjee PP, Ganesh C, et al. Blinatumomab is Late Eect Project Group. Ann Intern Med. 1999;131(10):
well tolerated maintenance therapy ollowing allogeneic 738-744.
Chapter 19
20 Alternative Donor Transplants:
Cord Blood Transplant
Hind Rafei
Amanda Olson
Rohtesh S. Mehta
Betul Oran
Katayoun Rezvani
Elizabeth J. Shpall
KEY CONCEPTS
 Cord blood is a valuable alternative donor source or stem cell  High-intensity myeloablative regimens are used in young
transplant, oering a number o advantages: ease o collec- and t patients, whereas reduced-intensity regimens are
tion, availability or urgent need, less stringent human leuko- used in older or unt patients.
cyte antigen (HLA)-matching requirement, and lower risk o  Inections are the leading cause o early nonrelapse mor-
grat-versus-host disease. tality ater cord blood transplant, and grat-versus-host
 Data are evolving about the dierence in outcomes o disease is the leading cause o late mortality.
stem cell transplant using dierent grat sources, but more  Novel strategies to improve cord blood transplant
recent data suggest that there is no survival advantage o outcomes include improving cell collection, homing
a matched unrelated grat over cord blood. and engratment, ex vivo expansion, and in vivo
 To overcome the limitation o low cell doses in single enhancement.
cord blood units, double cord blood transplant has been
adopted or many patients.
BACKGROUND Cord blood is a valuable alternative donor source

or allogeneic SCT, oering many logistic advantages;
The number o allogeneic stem cell transplants (SCTs) CB units are easy to collect with little or no risk to the
perormed in the United States has steadily increased, mother or newborn. CB units can be obtained rapidly
rom more than 8000 per year in 2013 to 8839 in 2017 or 80% to 95% o the patients 20 years or older across
and an estimated 9028 transplants in 2018.1 Donor all races, and in almost 100% o younger patients.4
identication has always been a challenge, and only This is particularly advantageous in cases where urgent
25% to 30% o patients who need allogeneic SCT transplant is needed. Owing to the rapid procurement
have a matched-sibling donor available.2 The National o CB units, patients can receive CB transplantation
Marrow Donor Program (NMDP) and its cooperative (CBT) in 2 to 4 weeks rom the initiation o search com-
international registries have more than 19 million vol- pared with 3 to 6 months or unrelated donor sources.5
unteer donors, but the majority o them are White; Further, CBT is associated with a low risk o inection
other ethnicities are underrepresented in these large transmission, requires less stringent human leukocyte
registries, which poses a signicant challenge in nd- antigen (HLA) matching criteria, and has a relatively
ing donors or them.3 Mismatched related (oten hap- lower risk o grat-versus-host disease (GVHD) with
loidentical), cord blood (CB), or mismatched unrelated preserved grat-versus-malignancy eects.6,7 However,
donors (MMUD) with either peripheral blood (PB) or it has been historically associated with a greater risk
bone marrow (BM) grat sources are potential options o grat rejection, delayed engratment, and delayed
or patients in need o SCT but who lack a matched immune reconstitution, leading to a heightened risk
related (MRD) or unrelated donor (MUD). o inection or nonrelapse mortality (NRM).8–11 Many
427
428 Scion III Stem Cell Transplantation
o the adverse outcomes noted ater CBT are attrib- CELL DOSE, UNIT QUALITY, AND HLA
uted to the naïvety o CB T lymphocytes, and the low MATCHING
numbers o total nucleated cells (TNCs) and CD34+
cells in the grat. The outcomes o CBT depend on the impact o cell
It is important to note, however, that the evolution dose and the degree o HLA match.17 The TNC dose
o transplantation techniques and the optimization is a well-established parameter associated with suc-
o practices o unrelated donor transplants including cessul engratment and survival ater CBT. However,
CBT in the past 2 decades have led to the improve- the adequate TNC dose o a CB unit remains con-
ment o outcomes and survival o CBT, as was shown troversial. The randomized phase 3 trial BMT CTN
in a recent large study rom the European Society 0501 dened a sucient cryopreserved TNC dose in
or Blood and Marrow Transplantation registry that a single unit as >2.5 × 107/kg.18 On the other hand, in
included 106,188 patients between 2001 and 2015, a large registry study o more than 1500 myeloabla-
among them more 3000 CBT recipients, demonstrat- tive single-unit CBTs, a TNC <3.0 × 107/kg was ound
ing an improvement in the 3-year overall survival to be associated with an increased transplant-related
(OS) rom 36% between the years 2006 and 2010 to mortality (TRM).19 Moreover, an analysis o more
44% between the years 2010 and 2015, which owes than 1000 recipients o CBT rom a single bank, the
primarily to a decrease in the incidence o relapse.12 National Cord Blood Program o the New York Blood
Comparison o outcomes between CBT, MUD, and Center, suggested that a higher TNC dose is required
MMUD was undertaken by a large, retrospective sin- to oset the eect o increasing HLA mismatch. 17 It is
gle-institution study in patients with acute leukemia or important to note that the CD34+ cell dose is a criti-
myelodysplastic syndrome (MDS) who received a rst cal actor to be considered in unit selection along with
myeloablative SCT and showed that among patients the TNC dose. Purtill et al demonstrated the essential
with pretransplantation minimal residual disease, the role that the dominant unit–inused viable CD34+
probability o OS ater receipt o a CBT was at least cell dose plays in determining the speed and success
as avorable as that ater receipt o a transplant rom o neutrophil engratment ater double CBT (dCBT). 20
a MUD and was signicantly higher than that ater A dominant unit–inused viable CD34+ cell dose
MMUD. Furthermore, the probability o relapse was <0.5 × 105/kg was associated with marked impair-
lower in the CBT group than in either o the other ment o neutrophil engratment. 20
groups.13 Moreover, the post-thaw CD34+ viability, which
A recent prospective study also investigated the denes the unit quality, is another important consid-
outcomes o MUD (91 transplants) and CBT (119 eration.6 A number o studies have shown the impor-
transplants) in adults with acute leukemia and MDS tance o post-thaw colony-orming unit dose or
and demonstrated in multivariate analysis that the successul engratment.21,22 CB units with a low pro-
Chapter 20
grat source was not a signicant risk actor or OS, portion o post thaw–viable CD34+ cells have been
cumulative incidences o NRM and relapse, and dis- associated with very poor engratment potential.23
ease-ree survival (DFS). In adjusted analyses, MUD The HLA-matching criteria between the CB units
and CBT were shown to lead to similar OS, NRM, and the recipient have traditionally been less strin-
and relapse, again proving the importance o CB as an gent compared with other donor sources. Thereore,
alternative source o transplant.14 Moreover, the kinet- although unrelated adult donors are selected to be
ics o immune reconstitution post-CBT might actually closely matched to recipients at HLA-A, -B, -C, and
yield better outcomes ater CBT. In a retrospective -DRB1 by high-resolution testing,24,25 CB units are
analysis o immune reconstitution kinetics ater SCT selected using lower-resolution HLA typing (antigen-
rom BM, PB, or CB, mature B cells and dierentiated level) or HLA-A and -B and at the allele level or HLA-
natural killer (NK) cells signicantly increased ater DRB1.26 In a study o single CBT, Barker et al showed
CBT.15 A multivariate analysis showed that a higher that recipients o 6/6 matched CB units had the lowest
CD16+ CD57– NK cell count correlates with a lower TRM regardless o the dose, ollowed by 5/6 matched
incidence o relapse, whereas higher CD20+ B-cell and CB units with TNC dose >2.5 × 107/kg or 4/6 matched
CD8+ CD11b– T-cell counts are associated with lower units with TNC dose >5.0 × 107/kg, and 5/6 matched
NRM. This suggests that the collective contribution o units with lower TNC dose (<2.5 × 107/kg).17,27 These
grat source–specic and event-related immune recon- ndings support the notion that both TNC dose and
stitution might yield better outcomes ater CBT.15 Sim- HLA-matching level should be taken into account or
ilar results were observed in another recent study o CB unit selection.
immune recovery in 106 adults undergoing CBT, dem- Although the standard HLA-matching criteria do
onstrating a robust thymus-independent CD4+ T-cell not require high-resolution typing at class I antigen in
recovery, which in turn is associated with reduced risk CBT, a study by the Center or International Blood and
o mortality (Table 20–1).16
tbl 20–1 Results of Comparative Studies of Cord Blood Transplant and Other Donor Types in Adults With Hematologic Malignancies
Engraftment GVHD
Cumulative Acute
Donor Patients PLT neutrophil 24 Chronic Infection Relapse TRM
Reference type (n) ANC (day) (day) recovery (%) (%) (%) (%) (%) (%) Survival
8 a b
Eapen et al UCB 165 24 52 80 30 24 27 26 33 2-year DFS: 59%
PBPCs 888 14 19 96a 49 46 17b 31 27 2-year DFS: 48%
a b
BM 472 19 28 93 41 39 22 33 17 2-year DFS: 57%
9 d
Jacobson et al dUCB 42 21.5 41.5 NS 21 24 69 40 NS 2-year PFS: 49%
2-year OS: 66%
MUD 102 N/Ac N/Ac NS 12 54 33 32d NS 2-year PFS: 57%
2-year OS: 68%
Mahjail et al10 UCB 43 NS NS 89e 49 17e 19h NS 28g 3-year PFS: 34%
3-year OS: 34%
MRD 47 NS NS 100e 42 40 13h NS 23g 3-year PFS: 30%
3-year OS: 43%
Brunstein et al11 dUCB 128 26 53 ~85i 60 26j ~30h 15k NS 5-year DFS: 51%
C 20 Alternative Donor Transplants: Cord Blood Transplant

MRD 204 16 20 ~100i 65 47j ~10h 43k NS 5-year DFS: 33%
i j h k
MUD 152 19 21 ~100 80 43 ~7.5 37 NS 5-year DFS: 48%
MMUD 52 18.5 21 ~100i 85 48j ~7.5h 35k NS 5-year DFS: 38%
12(l) h m
Shouval et al MRD 16,362 NS NS NS 22 14 25 37 NS 3-year PFS: 45%
3-year OS: 55%
MUD 15,556 NS NS NS 28 12 27h 31m NS 3-year PFS: 44%
3-year OS: 52%
MMUD 4,089 NS NS NS 29 11 30h 32m NS 3-year PFS: 34%
3-year OS: 41%
Haplo 3,009 NS NS NS 25 7 34h 33m NS 3-year PFS: 40%
3-year OS: 44%
UCB 1,327 NS NS NS 34 8 31h 29m NS 3-year PFS: 38%
3-year OS: 44%
Milano et all3 UCB 140 NS NS NS 18n NS NS 15o NS 4-year unadjusted
rate o survival:
71%
MUD 344 NS NS NS 14n NS NS 24o NS 4-year unadjusted
rate o survival:
63%
MMUD 98 NS NS NS 26n NS NS 25o NS 4-year unadjusted
rate o survival:
49%
429
(Continued)
Chapter 20
Chapter 20
430
Scion III
tbl 20–1 Results of Comparative Studies of Cord Blood Transplant and Other Donor Types in Adults With Hematologic Malignancies (Cont.)
Engraftment GVHD
Cumulative Acute

Donor Patients PLT neutrophil 24 Chronic Infection Relapse TRM
Reference type (n) ANC (day) (day) recovery (%) (%) (%) (%) (%) (%) Survival
14 p
Terakura et al UCB 119 21 38 89 NS NS NS 31 NS Median OS: 66 mo
2-year OS: 62%
2-year DFS: 58%
UDT 91 15 26 95 NS NS NS 25p NS Median OS: 62 mo
2-year OS: 61%
2-year DFS: 56%
Ando et al15 UCB 136 NS NS NS 40 28 34q 27p NS 2-year OS: 76%
PBSC 55 NS NS NS 45 45 15q 40p NS 2-year OS: 67%
q p
BM 119 NS NS NS 54 43 31 33 NS 2-year OS: 62%
Marks et al47 UCB 116 NS NS 57r/91s 27 39 NS 22m 42t 3-year OS: 44%
r s m t
7/8-HLA 140 NS NS 96 /97 41 45 NS 28 39 3-year OS: 43%
matched
8/8-HLA 546 NS NS 95r/97s 47 42 NS 25m 31t 3-year OS: 44%
matched
Rodrigues et al52 UCB 104 18 35 81s 29 26u NS 28m NS 3-year PFS: 41%
3-year OS: 56%
MUD 541 14 14 97s 32 52u NS 35m NS 3-year PFS: 36%
3-year OS: 49%
a
Day 42 neutrophil recovery rate.
b
Inection as early cause o death.
c
Patients did not experience count nadir.
d
Two-year relapse rate.
e
Sustained donor engratment at 42 days.

Chronic GVHD at 1 year.
g
180-day TRM.
h
Inection as primary cause o death.
i
Day 45 cumulative incidence o neutrophil engratment.
j
Chronic GVHD at 2 years.
k
Relapse at 5 years.
l
Data taken or Epoch 3 (2011–2015) only.
m
3-year relapse incidence.
n
Incidence o severe acute GVHD (grade 3–4).
o
4-year unadjusted risk o relapse.
p
2-year cumulative incidence o relapse.
q
Incidence o inection in the rst 100 days post-transplant.
r
Day 28 cumulative incidence o neutrophil recovery.
s
t
3-year cumulative incidence o TRM.
u
ANC, absolute neutrophil count >500; BM, bone marrow; DFS, disease-ree survival; dUBC, double umbilical cord blood; GVHD, grat-versus-host disease; Haplo, haploidentical; MMUD, mismatched unrelated donor; MRD, matched
related donor; MUD, matched unrelated donor; NS, not stated; OS, overall survival; PBPCs, peripheral blood progenitor cells; PBSCs, peripheral blood stem cells; PFS, progression-ree survival; PLT, platelets >20,000; TRM, transplant-
related mortality; UCB, umbilical cord blood; UDT, unrelated donor transplant.
C 20 Alternative Donor Transplants: Cord Blood Transplant 431
Marrow Transplantation Research (CIBMTR) and the studies34 demonstrated the role o dCBT in extending
Eurocord reported better outcomes in single CBT ater the application o CBT to adults with inadequate sin-
myeloablative conditioning (MAC) with improved gle units. In addition, some other studies have sug-
allele-level matching or 4 HLA loci (-A, -B, -C, gested that dCBT may be associated with a reduced
and -DRB1).19 The investigators showed that the re- risk o relapse,35–38 with one analysis proving that
quency o neutrophil recovery was lower or recipients dCBT is more cost eective than single CBT.39
o mismatches at 3–5 but not at 1–2 alleles compared A unique eature ater dCBT is evidence o mixed
with those o HLA-matched units. NRM was higher chimerism rom both CB units observed during the
with units mismatched at 1–5 alleles compared with initial post-transplant period.40 In the early post-
matched units. This retrospective study conrmed dCBT period (day +21), both CB units contribute to
the clinical importance o selecting better HLA hematopoiesis in 40% to 50% o patients, but by day
allele–matched units or single CBT, an observation +100, one unit predominates in a vast majority.41,42
already well described or BM and PB progenitor cell Although the nonengrating unit does not contribute
transplantation. Data rom our institution have also to hematopoiesis, it may have a acilitatory eect on
demonstrated increased TRM with increasing HLA engratment. In act, an analysis o 129 dCBT recipi-
mismatch.28 In contrast, other studies rom the Univer- ents has shown that in patients receiving a low-dose
sity o Minnesota,29 Memorial Sloan Kettering Cancer dominant unit (dened as an inused viable CD34+
Center,30 and others18,31 reported that a high degree cell dose <1.2 × 105/kg), a higher TNC dose in the
o HLA mismatch did not adversely aect transplant nondominant unit is associated with improved neu-
outcomes. Further studies to establish the relative con- trophil recovery.43 The actors leading to unit domi-
tribution o the TNC dose, the CD34+ dose, and the nance are not well-dened. It is however recognized
HLA match to the success o engratment and survival that there is no association with the TNC or CD34+
post-CBT are warranted. cell doses, HLA match, gender match, ABO typing,
or the order in which CB units are inused. 32,41,42,44,45
Moreover, there are no sucient data to support
SINGLE VERSUS DOUBLE CBT interunit HLA matching when selecting double-
unit grats.46 This current lack o evidence is a major
The relatively low number o progenitor cells in a limitation to dCBT, and identiying predictive ac-
single CB unit resulting in delayed hematopoietic tors or unit dominance would optimize CB-unit
recovery and engratment ailure limited the use o selection algorithms by allowing or the selection o
CBT in adults. Most adults do not have access to a two CB units with a high probability o long-term
single CB unit containing the recommended nucle- engratment.
ated cell dose o 2.5 × 10 7 TNCs/kg. 32 To overcome
the cell-dose limitation, investigators pioneered an
Chapter 20
approach where two partially HLA-matched CB CONDITIONING REGIMENS
units are used to augment the progenitor cell dose
in circumstances in which a single unit was con-
sidered inadequate, and conrmed its easibility.32
Myeloablative Conditioning Regimens
A CIBMTR analysis investigated the relative High-intensity MAC regimens are reserved or young
risks and benets o transplanting double CB and otherwise t patients who can tolerate the asso-
units compared with an adequately dosed single ciated regimen morbidity. Such regimens are associ-
CB unit. The investigators observed no dierences ated with a low risk o relapse at the expense o a high
in clinical outcomes ater dCBT or adequately dosed TRM compared with reduced-intensity conditioning
single CBT. Both transplant approaches led to com- (RIC) regimens. One o the largest registry studies
parable outcomes with 78% (95% CI, 72–83) versus comparing single-unit CB (n = 165) with PB (n = 888)
81% (95% CI, 74–88; P = .83) probabilities o neu- or BM (n = 472) transplants in adults with acute leu-
trophil engratment by day 42, and 68% (95% CI, kemia using MAC regimens rom 2002 through 2006
62–74) versus 63% (95% CI, 53–72; P = .34) prob- showed promising outcomes with CBT. Total body
abilities o platelet recovery at 6 months, respec- irradiation (TBI) constituted part o the preparative
tively. There were no dierences in grade III–IV regimen in about hal o patients in the CB group and
acute GVHD ([18% (95% CI, 11%–26%) versus 14% about two-thirds in the comparative groups. Despite
(95% CI, 10–19%); P = .64]), 2-year probabilities o a signicantly higher number o patients with ully
chronic GVHD (31% [95% CI, 26–37] versus 24% HLA-matched PB or BM grats (70%) compared with
[95% CI, 15–34]; P = .27), TRM (hazard ratio [HR], CB grats (6%), the rates o DFS and relapse were
0.91; P = .63), risk o relapse (HR, 0.90; P = .64), and similar among the groups, whereas the risks o acute
overall mortality (HR, 0.93; P = .62).33 This and other or chronic GVHD were signicantly lower with CBT.
Also, TRM was similar with CBT compared with CBT compared with 8/8-matched and 7/8-matched PB
mismatched PB or BM grats, but higher in contrast or BM transplants, respectively.47
to ully matched PB (HR, 1.62 [95% CI, 1.18–2.23]; The major concern with MAC regimens remains
P = .0030) or BM transplants (HR, 1.69 [95% CI, their associated toxicity, which was shown in more
1.19–2.39]; P = .003). This was oset by a signi- recent studies. A prospective multicenter study o
cantly lower incidence o chronic GVHD compared high-dose myeloablative dCBT in adults with high-
with ully matched PB (HR, 0.38 [95% CI, 0.27–0.53]; risk acute leukemia and MDS between 2007 and 2011
P = .001) or BM transplants (HR, 0.63 [95% CI, 0.44– demonstrated 89% neutrophil engratment at day 100,
0.90]; P = .01].8 Thereore, in the absence o matched grade II–IV acute GVHD incidence at day 180 o 64%,
PB or BM donors, CBT potentially oers better out- and a 3-year incidence o chronic GVHD o 36%. At
comes compared with mismatched alternative donor 3 years post-transplant, the TRM was 39% (95% CI,
transplants. 26%–52%), and the 3-year relapse incidence was 11%
Similar encouraging results were noted in a study (95% CI, 4%–21%). With a median ollow-up o 37
that compared 4–6/6 matched dCBT exclusively months, the 3-year DFS was 50% (95% CI, 37%–
(using the MAC regimen including fudarabine 63%). This study again shows the importance o CBT
75 mg/m 2, cyclophosphamide 120 mg/kg, and TBI as an alternative therapy or high-risk acute leukemia/
1200–1320 cGy Flu/Cy/TBI) to 8/8 MRD or MUD, MDS in patients lacking a MUD with a low incidence
or 1 allele–MMUD donors. 11 This study also noted o relapse. Yet the TRM risk remains high and strate-
lower risk o relapse, higher NRM, lower GVHD, gies to ameliorate toxicities are warranted.48
and comparable DFS ater CBT compared with other
groups. The risk o relapse was signicantly lower
ater dCBT (15%, 95% CI, 9–22%) compared with
Reduced-Intensity Conditioning Regimens
MRD (43%, 95% CI, 35%–52%) or MUD (37%, The advent o RIC regimens extended the utility o
95% CI, 29%–46%) transplants. Higher NRM was CBT to older patients and those with comorbid condi-
noted ater dCBT (34%, 95% CI, 25%–42%) com- tions that otherwise restrict the use o the MAC regi-
pared with MRD (24%, 95% CI, 17%–39%) or MUD mens. A majority o trials o MRD or MUD transplants
(14%, 95% CI, 9%–20%) transplants, which resulted used an arbitrary age denition o older than 55 to 60
in comparable 5-year DFS between CB (51%, 95% years (to dene “older patients”) as a threshold o using
CI, 41%–59%), MRD (33%, 95% CI, 26%–41%), a RIC regimen. However, age more than 40 to 45 years
and MUD (48%, 95% CI, 40%–56%) transplants. is generally chosen as a threshold or RIC in the CBT
The cumulative incidence o grade II–IV GVHD at setting.
day 100 ater dCBT, MRD, and MUD was 60% (95% Barker et al reported that the RIC with fudarabine
CI, 50%–70%), 65% (95% CI, 57%–73%), and 80% 200 mg/m2, cyclophosphamide 50 mg/kg, and 2 Gy
Chapter 20
(95% CI, 70%–90%). The rate o chronic GVHD at TBI (Flu/Cy/2 Gy TBI) was well tolerated, with rapid
2 years was 26% (95% CI, 15%–35%), 47% (95% neutrophil recovery, a sustained donor engratment
CI, 39%–55%), and 43% (95% CI, 34%–52%), rate o 94%, and a low incidence o TRM.49 This regi-
respectively. 11 men is associated with signicantly better DFS com-
In adults with high-risk acute lymphoblastic leuke- pared with other RIC regimens (51% vs 28%, HR,
mia (ALL), CBT leads to similar OS, TRM, and relapse 0.53; P = .0002).50 Multiple studies supporting the use
risk, with signicantly lower risk o acute or chronic o RIC CBT in patients who would not be able to tol-
GVHD, compared with PB or BM transplants. This erate more intensive preparative regimens have subse-
was demonstrated in a registry study that compared quently been reported.10,41,42,51–53
outcomes ater single or double 4–6/6 matched CB A retrospective single-center study compared the
(n = 116) and 7–8/8 matched PB (n = 546) or BM outcomes in patients older than 55 years who under-
(n = 140) transplants ater MAC regimens.47 More than went CB and MRD SCT with RIC (primarily o Flu/
hal o the patients in the CBT group received Flu/ Cy/2 Gy TBI). There were no dierences in TRM at
Cy/TBI as the conditioning regimen, and about 75% 180 days (28%, 95% CI, 14%–41% vs 23%, 95% CI,
o the patients in the PB or BM groups received TBI/ 11%–36%), 3-year DFS (34%, 95% CI, 19%–48% vs
Cy-based regimens. There were no dierences in the 30%, 95% CI, 16%–44%), or 3-year OS (34%, 95%
3-year OS rates (44%, 44%, and 43%), relapse risk CI, 17%–50% vs 43%, 95% CI, 29%–58%) between
(22%, 25%, and 28%), or TRM (42%, 31%, and 39%) the groups.10 These ndings were conrmed by a reg-
among the groups. However, the risk o acute grade II– istry analysis o patients with acute leukemia com-
IV GVHD (27%, 47%, and 41%) or grade III–IV acute paring the outcomes ater CB (n = 161), 8/8-matched
GVHD (9%, 16%, 24%) was appreciably lower ater (n = 313), and 7/8-matched PB (n = 111) transplant with
RIC regimens. Patients who underwent CBT ater the that in adults who have AML relapse ater CB or MRD
Flu/Cy/2 Gy TBI regimen had comparable results with transplants, DLI in the latter group did not aect OS
8/8 HLA-matched PB donors. However, higher TRM (19% CB vs 28% MRD at 1 year; P = .36), and patients
and lower OS and DFS were observed in recipients o with disease relapse had a poor prognosis independent
CBT i they were treated with alternative RIC regi- o the donor source.55
mens including busulan plus melphalan, or cyclophos- In the CBT setting, inections are the leading cause
phamide with fudarabine and in vivo T-cell depletion o early 100-day NRM (27%), whereas GVHD con-
with antithymocyte globulin (ATG).53 Similar ndings tributes to most (20%) o the delayed NRM (beyond
were reported by Eurocord and the EMBT in patients 100 days).8 The reported probabilities o acute grade
with lymphoid malignancies. When patients with CB III–IV GVHD at day 100 (10%–40%), and chronic
units (n = 104) were compared with 8/8-matched PB GVHD (25%–35%), TRM (20%–50%), risk o relapse
MUD (n = 541) transplants, no dierence was noted in (10%–50%), DFS (15%–60%), and OS (20%–70%)
NRM (29% vs 28%), PFS (41% vs 36%), or OS (56% at 2 to 5 years vary, depending on conditioning regi-
vs 49%) at 3 years. Further, the risk o chronic GVHD mens, study population, HLA matching, and other
was signicantly lower in the CBT group (26% vs 52% actors.11–14,33,42,47,48,50,53,54 The rates o post-transplant
at 3 years; P = .0005).52 complications are comparable ater the use o dCBT
More recently, intensication o the standard RIC and single CBT.56
regimen was investigated in a retrospective analysis o Early inections (within 100 days) are primarily
adult recipients o rst dCBT comparing standard RIC caused by neutropenia and mucosal damage caused by
regimen with an intensied regimen o fudarabine conditioning regimens. Delayed inections are related
150 mg/m2, cyclophosphamide 50 mg/kg, thiotepa 10 to the speed o cell-mediated immune reconstitution
mg/kg, and 400 cGy TBI (intensied RIC). The cumu- and use o immunosuppressants. Most early inections
lative incidence o relapse was signicantly lower are bacterial; more than hal o the invasive ungal
with intensied RIC compared with standard RIC inections and 45% o cytomegalovirus (CMV) occur
(P = .0013). TRM was comparable between the two beyond day +100.57
groups (P = .99), whereas OS was signicantly better The heightened risk o inections in CBT is partly
ater intensied RIC compared with standard RIC explained by the naïvety o CB T-cells, and delayed
(P = .03); median OS was 17 months ater standard RIC T-lymphocyte immune reconstitution and neutrophil
but was not reached ater intensied RIC. Grade II–IV engratment in contrast to other donor sources.8,11,53,58,59
acute GVHD was signicantly higher in the intensied Although signicant B-cell recovery starts within 3 to
RIC cohort compared with the standard RIC cohort 4 months and may approach normal numbers by 6
(P = .007), whereas the incidence o grade III–IV acute months ater transplant, T-cell reconstitution is sub-
GVHD, any chronic GVHD, and moderate-to-severe stantially prolonged.59 The CD4+ and CD8+ T-cell
chronic GVHD was comparable between the two counts are strikingly reduced ater CBT, remain low
Chapter 20
cohorts (P = .20, P = .21, and P = .61, respectively).54 or up to 6 months, and approach normal values by one
These studies support the use o CBT with RIC as a year. The PB T-cells ater CBT are more dysunctional
suitable alternative or patients who may benet rom as compared with other types o allogeneic SCTs.
RIC SCT and who do not have a suitable related or Patients also do not recover thymic unction ater CBT
unrelated volunteer donor in the period in which trans- in contrast to other allogeneic SCT recipients.60
plantation is needed, with the possibility o intensiy- A retrospective registry analysis rom the CIBMTR
ing the RIC regimen when appropriate in higher-risk comparing CB (n = 150) with matched (n = 367) or
patients (Table 20–2). antigen-mismatched (n = 83) BM transplants reported
higher risk o early (within 100 days) inection-related
deaths ater CBT compared with other groups (45%,
POST-TRANSPLANT 21%, and 24%, respectively; P = .01).56 In another
COMPLICATIONS study, the risk o severe inection, especially bacterial
inections in the rst 100 days, was signicantly higher
Disease relapse is the most common cause o mortality ater CBT in contrast to BM or PB grat (85% vs 69%;
ater allogeneic SCT, whereas GVHD and inections P < .01). The risk o inection-related mortality did not
are the two leading causes o NRM. Treatment options dier at day 100 or at 3 years. In a multivariate analy-
post-SCT relapse include withdrawal o immunosup- sis o a CMV-seropositive recipient who received CBT,
pression, chemotherapy, or donor lymphocyte inu- prolonged neutropenia beyond day 30 and low cell
sion (DLI). Although DLI is currently unavailable or dose (<2 × 107/kg) were the predictors or inection-
CBT patients outside clinical trials, a study showed related mortality.57
Chapter 20
434
Scion III
tbl 20–2 Outcomes of Cord Blood Transplant After Myeloablative Conditioning and ReducedIntensity Conditioning in Adult Patients With
Hematologic Malignancies
Engraftment GVHD

Cumulative
Conditioning Patients ANC PLT neutrophil Acute Chronic Infection Relapse TRM
Reference regimen (n) (day) (day) recovery (%) 24 (%) (%) (%) (%) (%) Survival
a b
Eapen MAC 165 24 52 80 30 24 27 26 33 2-year DFS: 59%
et al8
Mahjail RIC 43 NS NS 89j 49 17k 19c NS 28t 3-year PFS: 34%
et al10 3-year OS: 34%
Brunstein MAC 128 26 53 ~85d 60 26e ~30c 15 NS 5-year DFS: 51%
et al11
Ballen RIC 21 20 41 NS 40 31 NS NS 14n 1-year DFS: 67%
2-year DFS: 55%
2-year OS: 71%
Brunstein RIC 110 12 49 92 59 23o 27c 31l 26i 3-year EFS: 38%
Marks MAC 116 NS NS 57g/91h 27 39 NS 22l 42i 3-year OS: 44%
et al47
Barker MAC 56 22 49 89j 64 36k 5c 11l 39i 1-year OS: 57%
1-year DFS: 55%
3-year DFS: 50%
Barker RIC Bu/Flu/TBI 18 26 NS 76m 44% or 21% or NS NS 48n 100-day DFS: 38%
et al49 the the 1-year DFS: 24%
RIC Cy/Flu/TBI 21 9.5 NS 94m entire entire NS NS 28n 100-day DFS: 68%
group group 1-year DFS: 41%
at 1
year
Miyakoshi RIC 30 17.5 39 87 27 23 40 NS 27n 1-year OS: 33%
et al51 1-year EFS: 22%
Rodrigues RIC 104 18 35 81h 29 26p NS 28l NS 3-year PFS: 41%
(Continued)
tbl 20–2 Outcomes of Cord Blood Transplant After Myeloablative Conditioning and ReducedIntensity Conditioning in Adult Patients With
Hematologic Malignancies (Cont.)
Engraftment GVHD
Cumulative
Conditioning Patients ANC PLT neutrophil Acute Chronic Infection Relapse TRM
Reference regimen (n) (day) (day) recovery (%) 24 (%) (%) (%) (%) (%) Survival
a e c q p
Brunstein RIC Cy/Flu/TBI 121 9 NS 93 50 34 16 49 19 2-year DFS: 31%
RIC other 40 20 NS 90a 33 36e 29c 35q 52p 2-year DFS: 15%
2-year OS: 19%
Sharma Intensied RIC 47 21 38 ~90a 55 22o 85 inections 8r 22s Median OS: not reached
et al54 Standard RIC 52 13 37 ~90 a
29 13 o
60 inections 36 r
18 s
Median OS: 17 mo
a
Day 42 neutrophil recovery rate.
b
Inection as early cause o death.
c
d
e

Relapse at 5 years.

g
h
i
j
Sustained donor neutrophil engratment at 100 days.
k
l
3-year relapse incidence.
m
Sustained donor neutrophil engratment at 42 days.
n
TRM at day 100.
o
Chronic GVHD at 1 year.
p
q
2-year relapse rate,
r
1-year relapse rate.
s
t
180-day TRM
ANC, absolute neutrophil count >500; Bu, busulan; Cy, cyclophosphamide; DFS, disease-ree survival; EFS, event-ree survival; Flu, fudarabine; GVHD, grat-versus-host disease; NS, not stated; OS, overall survival; PFS, progression-
ree survival; PLT, platelets >20,000; TBI, total body irradiation; TRM, transplant-related mortality.
435
Chapter 20
MD ANDERSON APPROACH TO CBT with donor health or availability, a prompt decision is

made about whether to abandon the unrelated donor
At MDACC, patients with various hematologic malig- search in avor o CB.
nancies who do not have a MRD or MUD but require To maximize the chance o identiying optimal CB
SCT are considered or CBT, and a search or a CB unit unit(s), we conduct a global search while being aware
is initiated (Fig. 20–1). that there is no global regulatory oversight o CB bank-
ing standards. It is important to know which banks are
included in the NMDP consortium o banks, in the
Unit Selection Netcord, and in the NMDP Cooperative Registries. We
Within the rst days to weeks o the initial donor give equal consideration to domestic and international
search, coordinators determine the likelihood o units as the primary units o the grat, whereas we pre-
obtaining a suitably matched donor based on the er domestic units or backup.
patient’s ancestry, the preliminary search results, and Our current institutional policy is to use a double-
review o the HLA typing. I the likelihood o nding a unit grat in an eort to augment engratment and
matched donor is deemed to be low, we proceed with reduce TRM. Given that either unit may engrat ater a
conrmatory HLA typing o CB units. Alternatively, dCBT, each unit o a double-unit grat is equally impor-
we may delay typing o CB units i multiple 10/10 tant. We give a strong priority to HLA match over a
HLA-A, -B, -C, -DRB1, or -DQ allele–MUD are prob- pre-cryopreservation TNC threshold o ∼2.0 × 107/kg
able, or i the transplantation is not urgent. I an unre- or each unit o a double-unit grat. This approach
lated donor collection is delayed because o problems gives strong priority to HLA match but augments the
Patients without matched related or matched unrelated donors
Consider for cord blood transplant
Evaluate for ex-vivo graft manipulation protocol eligibility

(MSC expansion/fucosylation)
Chapter 20
HLA typing1
(antigen level for HLA-A, and B, allele level for HLA-DRB1)
4/6 match 5/6 match 6/6 match
Cell dose (TNC)2 ≥0.25 × 108 TNCs/kg
Age < 45-50 years and no significant

Age > 45-50 years, or co-morbidities
co-morbidities
Myeloablative Conditioning Reduced Intensity Conditioning
1Avoid HLA-DRB1 mismatch

2Preferhigher TNC dose for lower
degree of match
FIGURE 20–1 Approach to a patient for cord blood transplant.

chance o engratment by inusing two units with at Filgrastrim is administered rom day 0 until neutro-
least an adequate dose in each. phil engratment and blood products are transused as
We use novel ex vivo grat manipulation techniques indicated. Standard inectious disease prophylaxis with
pioneered at MDACC, such as ex vivo CB expansion antibacterial (levofoxacin), antiviral (valacyclovir), and
with mesenchymal stromal cells (MSCs)61 and ex vivo antiungal (voriconazole, posaconazole, or caspoun-
CB ucosylation.62 With these techniques, remarkable gin—the choice depending on risk actors) and against
improvement in engratment is noted compared with his- Pneumocystis jiroveci pneumonia (PCP) are also provided
torical controls. The median time to neutrophil engrat- or all CBT patients. The surveillance or cytomega-
ment is 15 days (range, 9–42) with MSC expansion61 and lovirus using quantitative polymerase chain reaction
14 days (range, 12–28) with ucosylation, which is sig- (or antigenemia assay i absolute neutrophil count is
nicantly aster than the 24 days (range, 12–52) noted >1 × 109/L) is perormed routinely, twice weekly or the
in the CIBMTR controls, (P ≤ .001).62 Similarly, platelet rst 100 days ater CBT or longer i any complications
engratment is 42 days (range, 15–62) with MSC expan- are present. We routinely perorm Epstein-Barr virus
sion and 33 days (range, 18–100) with ucosylation, testing using quantitative polymerase chain reaction
compared with 49 days (range, 18–264) in the CIBMTR every 2 weeks rom day +30 until day +100. Testing
controls (P = .03).61,62 We are investigating the impact o or other viruses including adenovirus, BK virus, respi-
CB-unit killer cell immunotype receptor (KIR) genotype ratory syncytial virus, infuenza, human herpesvirus 6,
on transplant outcomes with an aim to integrate KIR and parainfuenza is done as clinically indicated.
inormation into a CB-unit selection algorithm.
Conditioning Regimens NOVEL STRATEGIES TO IMPROVE

CBT OUTCOMES
We have investigated various MAC regimens or CBT,
which include combinations o (1) melphalan, fuda- Improving Cell Collection
rabine, and thiotepa; (2) busulan and fudarabine; (3)
busulan, cloarabine, fudarabine, and low-dose TBI Despite the availability o automated methods to
given 9 days ater chemotherapy; and (4) busulan, cloar- increase the recovery o hematopoietic progenitor cells
abine, fudarabine, and low-dose TBI given immediately rom banked CB units,64 optimization o the number
ater the chemotherapy.63 The most avorable outcomes o cells collected remains a necessity. The BM environ-
appear to be associated with the latest regimen, which is ment where hematopoietic stem cells expand is very
well tolerated and associated with prompt engratment hypoxic, with oxygen levels as low as 1%–5%, and
and eective disease control. This regimen consists o hypoxia is involved in stem cell regulation pathways.65
fudarabine 10 mg/m2 per day (days −7 through −4), clo- The immediate exposure o collected CB cells to the
arabine 30 mg/m2 per day (days –7 through –4), busulan high oxygen content o the ambient air grossly alters
Chapter 20
at a dose calculated to deliver a daily area under the curve the numbers and unction o stem and progenitor cells,
o 4000 µmol/min or 4 days (days –7 through –4) based a phenomenon reerred to as “extra physiologic oxy-
on an outpatient test dose o 32 mg/m2, and 2 Gy TBI on gen shock/stress (EPHOSS).”66,67 Strategies to mitigate
day –3. Our preerred RIC regimen consists o fudara- the oxygen shock have been investigated, such as the
bine 40 mg/m2 per day (days –5 through –2) and melpha- immediate collection and procession o the CB cells in
lan 140 mg/m2 (day –2) in addition to the Flu/Cy/2 Gy the presence o cyclosporine A, which was shown to
TBI or patients older than 50 years and/or those who are lead to an increase in the yield o hematopoietic stem
not medically t to tolerate the MAC regimen. cells.66,67 However, this strategy necessitates more
optimization and standardization. More recent in vivo
studies showed that combinations o antioxidants and/
Prophylaxis or o epigenetic enzyme inhibitors allow or enhanced
Prophylaxis against GVHD is provided with mycophe- collection o mouse BM hematopoietic stem cells in
nolate moetil (MMF) and tacrolimus. We start MMF ambient air,68 although these procedures remain to be
rom day –3 at a dose o 15 mg/kg (maximum o 1 g validated or human CB-unit collections. Research in
orally twice daily) and continue it through day +100. this eld is ongoing and aims to enhance the proce-
Tacrolimus is started rom day –2 and taper is started dures used to collect CB or the best stem cell yield.
at day 180 in the absence o GVHD. We use rabbit
ATG, 3 mg/kg inused over 2 days on days –4 and –3 Improving Homing and Engraftment
in all patients. Patients taking azole antiungals require
appropriate dose adjustments or adding tacrolimus. To enhance the engratment o hematopoietic stem cells
Other drug interactions and creatinine clearance need ater their administration, researchers have attempted
to be considered while calculating the dosage. to improve their capability to home to the BM. Dierent
methods have been tested, such as ucosylation o progenitor cells when used as a puried recombinant
the CB progenitor cells62,69,70; the use o prostaglan- protein and hence was shown to act as a hematopoi-
din E2 derivatives71 or dipeptidyl peptidase-4 (DPP4) etic cytokine with potential clinical applicability.90
inhibitors72; short-term treatment o cells with hyper- N6-methyladenosine (m6A) is the most abundant
thermia73; short-pulse glucocorticoid hormone stimula- epigenetic modication on eukaryocytic messenger
tion74; inhibition o the negative epigenetic regulation RNAs, has been implicated in the regulation o a
by histone deacetylase 5 (HDAC5)75; the pharmaco- wide range o biological processes, and is recognized
logic activation o nitric oxide signaling76; or a combi- by its reader YTH domain amily members. A recent
nation o strategies.77 Many o these techniques have work showed that the knockdown o YTHDF2
demonstrated signicantly improved time to neutrophil results in increased numbers o hematopoietic stem
engratment (13–17 days) comparable with other donor cells rom CD34+ CB cells and could be a promising
types. strategy or clinical application in the ex vivo expan-
sion o CB.91,92
Apart rom augmenting the cell dose, ex vivo
Ex Vivo Expansion grat manipulation techniques are being increasingly
To increase CB cell dose, a variety o ex vivo expan- explored, which has permitted the generation and
sion techniques have been developed, which yield sig- clinical use o antiviral and antitumor adoptive immu-
nicantly higher nal numbers o TNC. These include notherapies, as well as cellular therapies or GVHD
coculturing the CB cells with cytokine support and or prevention.93,94 A variety o “designer” CB lympho-
MSCs to simulate the BM “hematopoietic niche” ex cytes can now be engineered and expanded ex vivo—
vivo61 or using nicotinamide analogs,78–80 copper chela- or instance, T-cells with specic cytotoxicity against
tors (such as tetraethylenepentamine),81,82 and target- tumors and or viruses,95–98 chimeric antigen recep-
ing the Notch signaling pathway,83 all o which block tor (CAR) T-cells,99 NK cells,100 CAR-NK cells,101 and
the dierentiation o early progenitor cells leading to regulatory T-cells, 102 which are being tested in clinical
expansion o hematopoietic stem cells. trials.
Other approaches include the use o small mol-
ecules such as StemRegenin 1 (SR1) in combination
with cytokines, which was investigated in a phase 1/2
In Vivo Enhancement
study, leading to a 330-old increase in CD34+ cells The means to enhance the ecacy o CBT by acceler-
and engratment in all 17 patients who underwent ating the renewal and dierentiation o already trans-
dCBT at a median o 15 days or neutrophils and 49 planted CB cells have also been investigated. Such
days or platelets, signicantly aster than in patients methods include the administration o growth actors
treated with unmanipulated CB.84 A more recent study and the use o DPP4 inhibitors such as sitagliptin beore
Chapter 20
investigated the use o UM171, a hematopoietic stem and ater the engratment process has started.72,103,104
cell sel-renewal agonist,85 in a phase 1/2 study o 27 Other groups have investigated the use o hyperbaric
patients undergoing single CBT, which showed prom- oxygen or the recipient to enhance engratment.105,106
ising results. UM171 led to the successul expansion Research to enhance the yield o collected CB, its
o 26 (96%) o 27 CB units. Among the 22 patients ex vivo expansion, and engratment is very active and
who received single UM171-expanded CBT, the continues to evolve to eventually help elucidate the
median time to engratment was 18 days, median optimal means or ex vivo CB expansion. However,
time to platelet recovery was 42 days, and no grat guidelines such as those published by an international
ailure occurred. At one year, the incidence o TRM group o clinical investigators associated with the
was 5% and the incidence o relapse was 21%. Over- Cord Blood Association have now been published to
all survival, progression-ree survival, GVHD-ree and standardize CB banking and procedures and provide
relapse-ree survival, and chronic GVHD-ree relapse- guidance on means to enhance the eciency o CBT
ree survival at 12 months were 90%, 74%, 64%, and (Table 20–3, Fig. 20–2).107
74%, respectively.86
Other small molecules such as antagonists o
peroxisome prolieration-activated receptor (PPAR)- CONCLUSION
gamma,87 structural analogs o SB20358 (p38-map
kinase inhibitor),88 and OAC1 that activates the plu- CB transplantation is an attractive option or patients
ripotent transcription actor Oct489 have been used who lack a matched PB or BM donor. We and other
to enhance cytokine-mediated ex vivo expansion researchers and investigators continue to work on
o CB hematopoietic stem cells. DEK is a secreted improving our understanding o the biology and regu-
nuclear protein that was demonstrated to enhance lation o the CB progenitor and stem cells. The out-
the ex vivo expansion o hematopoietic stem and comes o alternative donor transplantation with CBT
tbl 20–3 Clinicl advncs in Cod Blood tnsln in adul pins Wi hmologic Mlignncis
Engraftment GVHD
Cumulative
Patients ANC PLT neutrophil Acute 24 Chronic Infection Relapse TRM
Reference Clinical advance (n) (day) (day) recovery (%) (%) (%) (%) (%) (%) Survival
b c
de Lima Expansion ex vivo 31 15 42 96 42 45 35 13 55 1-year OS: 32%
et al61 in cocultures
with allogeneic
mesenchymal
stromal cells
Popat Fucosylation o 22 17 35 86a 41 5 NS 14 41 8-month OS: 45%

et al62 CB progenitor
cells
Cutler Use o PGE2 12 (cohort 18 43 100b 17 8 NS 25 33 1-year PFS: 62%
et al71 derivatives 2) 2-year PFS: 31%
1-year OS: 75%
2-year OS: 39%
Farag et al72 High dose o 15 19 NS 100b 0 NS 53c NS 47d NS
DPP4 inhibitor
Horwitz Expansion with 11 13 33 NS 42 17 NS 17 8 1-year OS: 82%
et al79 nicotinamide 1-year PFS: 73%
Sti Expansion 101 21 54 ~90b 32 18 NS NS NS 100-day OS: 84%
et al81 with copper
chelatore
Wagner Expansion with 17 15 49 86 29 (grade NS NS NS 45 45%
et al84 SR-1 3–4)
(Continued)
439
Chapter 20
Chapter 20
440
Scion III
tbl 20–3 Clinicl advncs in Cod Blood tnsln in adul pins Wi hmologic Mlignncis (Cont.)
Engraftment GVHD
Cumulative
Patients ANC PLT neutrophil Acute 24 Chronic Infection Relapse TRM
Reference Clinical advance (n) (day) (day) recovery (%) (%) (%) (%) (%) (%) Survival
h g
Cohen Expansion with 27 18 42 100 64 17 ADV: 9% 21 5 1-year OS: 90%
et al86 UM171 (part 1) (1-year) Asp: 9% 1-year PFS: 74%
23 Bacteremia:
(part 2) 41%
BK: 9%
C. di: 5%
CMV: 23%
Device-
related:
9%
EBV: 14%
HHV-6: 5%
PCP: 9%
UTI: 5%
a
b
c
d
At 6 months.
e
Tetraethylenepentamine (carlecortemcel-L).

g
h
1-year relapse rate.
ADV, adenovirus cystitis (with adenovirus viremia); ANC, absolute neutrophil count >500; Asp, Aspergillus pneumonia; BK, BK virus–associated cystitis; C. di, Clostridium difcile colitis; CB, cord blood; DPP4, dipeptidyl peptidase 4;
EBV, Epstein-virus viremia; GVHD, grat-versus-host disease; HHV-6, human herpesvirus-6 reactivation; OS, overall survival; PCP, Pneumocystis jiroveci pneumonia; PGE2, prostaglandin E2; PLT, platelets >20,000; SR-1, StemRegenin-1;
TRM, transplant-related mortality; UTI, urinary tract inection.
*
Avoid HLA-DRB1 mismatch
**
Preer higher TNC dose or lower degree o match
Cell collection Homing and engraftment Ex-vivo expansion In-vivo enhancement
MSCs
Fucosylation
Nicotinamide
PGE2 derivatives Copper chelators
Notch signaling
Cyclosporine A DPP4 inhibitors DPP4
SR-1
Hyperthermia UM171
Combinations of PPAR-gamma
antioxidants and/or Hyperbaric
epigenetic enzyme Glucocorticoids oxygen
inhibitors Structural analogs of SB20358
OAC1
HDAC5
DEK
Activation of NO
Knockdown YTHDF2
PGE2: Prostaglandin E2; DPP4: Dipeptidyl peptidase-4; HDAC5: Histone deacetylase 5; NO: Nitric oxide; MSCs: Mesenchymal
stromal cells; SR-1: StemRegenin 1; PPAR: Peroxisome proliferation-activated receptor.
FIGURE 20–2 Strategies to improve cord blood transplant.
Chapter 20
have signicantly improved over the past decade, lead- vivo expansion or homing and to enhance immune
ing to survival and relapse rates comparable with those reconstitution with the inusion o CB-derived NK
with other donor sources while oering the advan- cells and cytotoxic T lymphocytes with antiviral and
tage o being logistically more practical and aster. To antileukemic specicities have been investigated. The
overcome the limitation o low cell doses in single CB unmet need as o this writing remains instituting more
units, dCBT has been adopted or many patients, and prospective multicenter clinical trials to determine the
promising strategies to improve engratment with ex ecacy o these promising technologies.

J Within the rst days to weeks ater donor search is J Our preerred RIC regimen consists o ludarabine
initiated, the likelihood o nding a matched donor is 40 mg/m 2/day (days –5 through –2) and melpha-
determined. I this likelihood is deemed to be low, we lan 140 mg/m 2 (day –2) in addition to the Flu/
proceed with conrmatory HLA typing o CB units. Cy/2 Gy TBI or patients older than 50 years and/
J Our current institutional policy is to use a double- or those not medically it to tolerate the MAC
unit grat in an eort to augment engratment and regimen.
reduce TRM. We give a strong priority to HLA match J Prophylaxis against GVHD is provided with
over a pre-cryopreservation TNC threshold o ~2.0 × MMF and tacrolimus. We use rabbit ATG 3 mg/
107/kg or each unit o a double-unit grat. kg inused over 2 days on days –4 and –3 in all
J We use novel ex vivo grat manipulation techniques patients.
pioneered at MDACC, such as ex vivo CB expansion J Filgrastrim is administered rom day 0 until neu-
with MSCs and ex vivo CB ucosylation. trophil engratment and blood products are trans-
J Our preerred MAC regimen consists o fudarabine used as indicated.
10 mg/m2 per day (days −7 through −4), cloarabine J Standard inectious disease prophylaxis with anti-
30 mg/m2 per day (days –7 through –4), busulan at bacterial (levofoxacin), antiviral (valacyclovir),
a dose calculated to deliver a daily area under the and antiungal (voriconazole, posaconazole, or
curve o 4000 µmol/min or 4 days (days –7 through caspoungin—the choice depending on risk ac-
–4) based on an outpatient test dose o 32 mg/m2, tors) and against PCP are also provided or all CBT
and 2 Gy TBI on day –3. patients.
Chapter 20
17. Barker JN, Scaradavou A, Stevens CE. Combined eect o total

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68. Cai Q, Capitano M, Huang X, et al. Combinations o anti- 86. Cohen S, Roy J, Lachance S, et al. Hematopoietic stem cell
oxidants and/or o epigenetic enzyme inhibitors allow or transplantation using single UM171-expanded cord blood: a
enhanced collection o mouse bone marrow hematopoietic single-arm, phase 1-2 saety and easibility study. Lancet Hae-
stem cells in ambient air. Blood Cells Mol Dis. 2018;71:23-28. matol. 2020;7(2):e134-e145.
69. Robinson SN, Thomas MW, Simmons PJ, et al. Fucosylation 87. Guo B, Huang X, Lee MR, et al. Antagonism o PPAR-γ signal-
with ucosyltranserase VI or ucosyltranserase VII improves ing expands human hematopoietic stem and progenitor cells
cord blood engratment. Cytotherapy. 2014;16(1):84-89. by enhancing glycolysis. Nat Med. 2018;24(3):360-367.
70. Xia L, McDaniel JM, Yago T, et al. Surace ucosylation o 88. Bari S, Zhong Q, Fan X, et al. Ex vivo expansion o CD34(+)
human cord blood cells augments binding to P-selectin and CD90(+) CD49(+) hematopoietic stem and progenitor cells
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2004;104(10):3091-3096. pounds. Stem Cells Transl Med. 2018;7(5):376-393.
71. Cutler C, Multani P, Robbins D, et al. Prostaglandin-modulated 89. Huang X, Lee M-R, Cooper S, et al. Activation o OCT4
umbilical cord blood hematopoietic stem cell transplantation. enhances ex vivo expansion o human cord blood hematopoi-
Blood. 2013;122(17):3074-3081. etic stem and progenitor cells by regulating HOXB4 expres-
72. Farag SS, Nelson R, Cairo MS, et al. High-dose sitagliptin sion. Leukemia. 2016;30(1):144-153.
or systemic inhibition o dipeptidylpeptidase-4 to enhance 90. Capitano ML, Mor-Vaknin N, Saha AK, et al. Secreted nuclear
engratment o single cord umbilical cord blood transplanta- protein DEK regulates hematopoiesis through CXCR2 signal-
tion. Oncotarget. 2017;8(66):110350-110357. ing. J Clin Invest. 2019;129(6):2555-2570.
73. Capitano ML, Hangoc G, Cooper S, Broxmeyer HE, et al. 91. Li Z, Qian P, Shao W, et al. Suppression o m(6)A reader
Mild heat treatment primes human CD34(+) cord blood cells Ythd2 promotes hematopoietic stem cell expansion. Cell Res.
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NSG mouse model. Stem Cells. 2015;33(6):1975-1984. 92. Huang X, and Broxmeyer HE. m6A reader suppression bolsters
74. Guo B, Huang X, Cooper C, Broxmeyer HE. Glucocorticoid HSC expansion. Cell Res. 2018;28(9):875-876.
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hematopoietic stem cell homing and engratment. Nat Med. blood grat engineering: challenges and opportunities. Bone
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75. Huang X, Guo B, Liu S, et al. Neutralizing negative epigen- 94. Mehta RS, Dave H, Bollard CM, et al. Engineering cord blood
etic regulation by HDAC5 enhances human haematopoietic to improve engratment ater cord blood transplant. Stem Cell
stem cell homing and engratment. Nat Commun. 2018;9(1): Investig. 2017;4:41.
p. 2741. 95. Hanley P, Leen A, Gee AP, et al. Multi-virus-specic T-cell ther-
76. Xu D, Yang M, Capitano M, et al. Pharmacological activation apy or patients ater hematopoietic stem cell and cord blood
o nitric oxide signaling promotes human hematopoietic stem transplantation. Blood. 2013;122(21):140.
cell homing and engratment. Leukemia. 2020;35(1):229-234. 96. Weber G, Gerdemann U, Caruana I, et al. Generation o multi-
77. Broxmeyer HE, Pelus LM. Inhibition o DPP4/CD26 and leukemia antigen-specic T cells to enhance the grat-versus-
dmPGE2 treatment enhances engratment o mouse bone leukemia eect ater allogeneic stem cell transplant. Leukemia.
marrow hematopoietic stem cells. Blood Cells Mol Dis. 2013;27(7):1538-1547.
2014;53(1-2):34-38. 97. Micklethwaite KP, Savoldo B, Hanley PJ, et al. Derivation o
Chapter 20
78. Saber W, Cutler CS, Nakamura R, et al. Impact o donor human T lymphocytes rom cord blood and peripheral blood
source on hematopoietic cell transplantation outcomes or with antiviral and antileukemic specicity rom a single culture
patients with myelodysplastic syndromes (MDS). Blood. as protection against inection and relapse ater stem cell trans-
2013;122(11):1974-1982. plantation. Blood. 2010;115(13):2695-2703.
79. Horwitz ME, Chao NJ, Rizzieri DA, et al. Umbilical cord blood 98. Hanley PJ, Melenhorst JJ, Nikiorow S, et al. CMV-spe-
expansion with nicotinamide provides long-term multilineage cic T cells generated rom naïve T cells recognize atypi-
engratment. J Clin Invest. 2014;124(7):3121-3128. cal epitopes and may be protective in vivo. Sci Transl Med.
80. Islam P, Horwitz ME. Small-molecule nicotinamide or 2015;7(285):285ra63.
ex vivo expansion o umbilical cord blood. Exp Hematol. 99. Kebriaei P, Huls H, Singh H, et al. First clinical trials employing
2019;80:11-15. Sleeping Beauty gene transer system and articial antigen pre-
81. Sti PJ, Montesinos P, Peled T, et al. Cohort-controlled com- senting cells to generate and inuse T cells expressing CD19-
parison o umbilical cord blood transplantation using carlecor- specic chimeric antigen receptor. Blood. 2013;122(21):166.
temcel-L, a single progenitor-enriched cord blood, to double 100. Shah N, Martin-Antonio B, Yang H, et al. Antigen presenting
cord blood unit transplantation. Biol Blood Marrow Transplant. cell-mediated expansion o human umbilical cord blood yields
2018;24(7):1463-1470. log-scale expansion o natural killer cells with anti-myeloma
82. de Lima M, McMannis J, Gee A, et al. Transplantation o ex activity. PLoS One. 2013;8(10):e76781.
vivo expanded cord blood cells using the copper chelator tet- 101. Liu E, Marin D, Banerjee P, et al. Use o CAR-transduced natu-
raethylenepentamine: a phase I/II clinical trial. Bone Marrow ral killer cells in CD19-positive lymphoid tumors. N Engl J Med.
Transplant. 2008;41(9):771-778. 2020;382(6):545-553.
83. Delaney C, Heimeld S, Brashem-Stein C, et al. Notch- 102. Brunstein CG, Miller JS, Cao Q, et al. Inusion o ex vivo
mediated expansion o human cord blood progenitor expanded T regulatory cells in adults transplanted with umbili-
cells capable o rapid myeloid reconstitution. Nat Med. cal cord blood: saety prole and detection kinetics. Blood.
2010;16(2):232-236. 2011;117(3):1061-1070.
84. Wagner JE Jr, Brunstein CG, Boitano AE, et al. Phase I/II trial o 103. Farag SS, Srivastava S, Messina-Graham S, et al. In vivo DPP-4
StemRegenin-1 expanded umbilical cord blood hematopoietic inhibition to enhance engratment o single-unit cord blood
stem cells supports testing as a stand-alone grat. Cell Stem Cell. transplants in adults with hematological malignancies. Stem
2016;18(1):144-155. Cells Dev. 2013;22(7):1007-1015.
104. Vélez de Mendizábal N, Strother RM, Farag SS, et al. Model- 106. Mina A, Shune L, Abdelhakim H, et al. Long-term results
ling the sitagliptin eect on dipeptidyl peptidase-4 activity in o a pilot study evaluating hyperbaric oxygen therapy to
adults with haematological malignancies ater umbilical cord improve umbilical cord blood engratment. Ann Hematol.
blood haematopoietic cell transplantation. Clin Pharmacokinet. 2019;98(2):481-489.
2014;53(3):247-259. 107. Broxmeyer HE. Long-overdue guidelines or the cord
105. Aljitawi OS, Paul S, Ganguly A, et al. Erythropoietin modulation is blood banking community. Stem Cells Transl Med. 2019;
associated with improved homing and engratment ater umbili- 8(4):320-322.
cal cord blood transplantation. Blood. 2016;128(25):3000-3010.
Chapter 20
21 Alternative Donor Transplants:
Haploidentical Hematopoietic
Samer A. Srour
Richard E. Champlin
Stefan O. Ciurea
KEY CONCEPTS
 Allogeneic stem cell transplantation (allo-SCT) remains  Fully matched related donors remain the preerred grat
the only curative intervention or a variety o high-risk source or allo-SCT. However, several transplant registry
hematologic malignancies. Haploidentical grats rom a studies in United States and Europe have conrmed com-
rst-degree related mismatched donor extends the appli- parable survival outcomes between matched unrelated
cability o this liesaving treatment to a large proportion and haploidentical transplants.
o patients who otherwise do not have a suitable human  The results o the large phase 3 randomized Bone and
leukocyte antigen–matched donor. Marrow Transplant Clinical Trials Network multicenter clin-
 Breakthrough advances achieved over past decade in ical trials were reported recently conrming superiority
controlling the bidirectional alloreactivity and in grat o haploidentical transplant over double cord transplant
engineering have led to a decreased incidence o com- in terms o improved overall survival and decreased NRM.
plications, including grat-versus-host disease and non-  Several actors are considered when choosing the best
relapse mortality (NRM), without compromising the haploidentical donor. The donor-specic antibodies
grat-versus-tumor eect. remain one o the most important actors to consider
 The use o haploidentical transplantation continues to because the presence o antibodies is associated with a
increase with growing evidence or its eectiveness in high risk o grat ailure. Younger donors, male donors,
several myeloid and lymphoid neoplasms. Haploidenti- athers rather than mothers, and rst-degree to second-
cal use has taken precedence compared with some other degree donors are preerred grat sources or recipients o
alternative donor sources given its immediate availability haploidentical transplants.
and cost-eectiveness.
Haploidentical stem cell transplantation (HaploSCT) to transplantation (median, 3–4 months), which makes
rom a rst-degree related mismatched haplotype it dicult to treat patients with more advanced disease
donor (siblings, children, parents) extends the applica- in rapid need or a transplant. The ethnicity or race o
tion o this liesaving treatment to a large proportion o the recipient can have great impact as well in identiy-
patients with high-risk hematologic malignancies who ing a suitable MUD because approximately 30%, 70%,
otherwise do not have a suitable human leukocyte and 90% o the white, Hispanic, and Arican Ameri-
antigen (HLA)–matched donor.1 As the average am- can population do not have a MUD in the worldwide
ily size continues to shrink, the likelihood o nding registries.3 In contrast to unrelated donor grats, hap-
an HLA-matched related sibling donors continues to loidentical (or “hal-matched”) donors can be immedi-
decrease.2 Moreover, with aging o the United States ately available, and there are no costs associated with
population, nding a young healthy sibling donor an unrelated donor search, grat acquisition, maintain-
becomes increasingly less likely. The use o matched ing a registry, or coordinating logistics with distant
unrelated donors (MUDs) is limited by a longer time donor centers. This is an especially valuable option or
447
448 Sci III Stem Cell Transplantation
nonwhite and mixed-race individuals who requently CD34+-selected grats. Complete T-cell depletion
have no available matched donors to proceed with has been associated with much lower incidence o
transplantation.3 This approach might also be particu- acute GVHD (aGVHD). However, this came at the
larly useul in developing countries that may not have expense o markedly delayed immune recovery ater
the resources to procure unrelated donor transplants transplant and was associated with high nonrelapse
or maintain complex unrelated donor registries. More- mortality (NRM) rom inections, higher disease
over, haploidentical donors oer the advantage o ad relapse rates, given the decreased grat-versus-leu-
hoc availability to quickly collect donor cells or cel- kemia eect, and high rates o grat rejection.7–9
lular therapy interventions ater transplant. Over the Although grat rejection was partially overcome
recent decade, signicant breakthrough advances in with “mega” doses o CD34+ cells (typically >10 7
controlling alloreactivity have been made, and impor- CD34+ cells/kg) and a myeloablative conditioning
tant steps have been taken toward grat engineering regimen (including total body irradiation, cyclo-
and posttransplant cellular therapy, approaches that phosphamide, thiotepa), severe T-cell depletion o
may urther change landscape o HaploSCT in the the grat delayed immune recovery led to an unac-
uture. Improved haploidentical transplant outcomes ceptably high incidence o inectious complications
represent a major advancement in transplantation, and increased NRM in excess o 40%.10 We have
which has practically eliminated the limitation o used this approach with our conditioning regimen
donor availability or allogeneic stem cell transplanta- (fudarabine, melphalan, and thiotepa) and showed
tion (allo-SCT). that most patients died o NRM related to inectious
complications. 11 Improved outcomes with selected
α-β T-cell depletion has been subsequently adopted
Complete t-Cell depletIon: mostly in children with better results. 12 During the
past decade, several advances have enabled investi-
Control of graft-verSuS- gators to selectively deplete alloreactive T-cells and
hoSt dISeaSe but wIth a hIgh successully control GVHD rates while maintaining
treatment-related mortalIty memory T-cells in the grat to accelerate immune
rate recovery and prevent signicant inectious compli-
cations post transplant. Table 21–1 summarizes the
Historically, the use o unmanipulated T-cell-replete major contemporaneous approaches to HaploSCT.
HaploSCT grats with conventional grat-versus- These advances have signicantly improved the
host disease (GVHD) prophylaxis in the late 1970s treatment outcomes o patients receiving haploiden-
was associated with intense bidirectional alloreac- tical donor transplants, which are now comparable
tivity and unacceptably high morbidity and mor- to matched transplants. In the ollowing sections,
Chapter 21
tality rates because o hyperacute GVHD and grat we aim to summarize the recent developments with
rejection. 4–6 This led in the 1980s to the develop- this type o transplant ocusing on advances made at
ment o complete ex vivo depletion o T-cells using MD Anderson Cancer Center (MDACC).
table 211 C acs  hiic S C tsi
Approach Rationale Stage of Clinical Development

High-dose Eliminating the only the alloreactive T-cells. Phase II/III
posttransplantation Rapid immune recovery with low inectious complications
cyclophosphamide Acceptable rates o GVHD
Lower cost
Selective αβ T-cell Removing αβ T-cells that are most responsive or aGVHD Phase I/II
depletion Remaining γδ T-cells are thought to have an innate immune-
like response capability without inducing GVHD
Photodepletion Ex vivo depletion o alloreactive T-cells with TH9402 that Phase I/II
accumulates in activated T-cells
Selective CD45RA+ T-cell Elimination o CD45RA+ naïve T-cells thought to play a Phase I
depletion major role in GVHD
Preserves memory T-cells that are active against inections
aGVHD, acute grat-versus-host disease; GVHD, grat-versus-host disease.
C 21 Alternative Donor Transplants: Haploidentical Hematopoietic Stem Cell Transplantation 449
balanCIng graft-verSuS- changed to 2-Gy TBI). Dose o thiotepa was decreased

hoSt dISeaSe, Immune because o higher gastrointestinal toxicity in combina-
tion with melphalan, and melphalan dose was subse-
reCovery, and the ConCept quently decreased or older patients and patients with
of SeleCtIve allodepletIon: lymphoma. Initial results were very promising and
poSttranSplant proved to be very eective in inducing remission in
CyClophoSphamIde the great majority o patients with leukemia, includ-
ing those with advanced disease.11,19 The results o our
The introduction o high-dose posttransplant cyclo- phase 2 clinical trial in 60 patients, the majority with
phosphamide (PTCy) or GVHD prevention rep- myeloid leukemias, showed 2-year progression-ree
resented a major turning point or HaploSCT. The survival (PFS) and overall survival (OS) rates o 53%
concept o inducing immune tolerance with PTCy and 55%, respectively, with 2-year NRM and relapse
was introduced by Berenbaum and Brown in 1963, rates o 23% and 24%, respectively.20 More recently,
who showed that the lie o a skin allograt can be pro- outcomes o 25 patients with lymphoma who under-
longed with the use o PTCy administered 1 to 3 days went HaploSCT at our institution were reported with
ater the allograt.13 Moreover, Mayumi et al demon- 3-year NRM, PFS, and OS o 31%, 49%, and 52%,
strated that microchimerism and robust tolerance to respectively.21 Patients with acute myeloid leukemia
minor histocompatibility antigens can be achieved in (AML) and lymphoma receiving haploidentical trans-
mice receiving allogeneic splenic cells by intraperito- plants had similar outcomes with other donor types,
neal high-dose cyclophosphamide administered on but older patients and those with lymphoma appeared
days 2 or 3 posttransplant.14 This concept ound its to benet rom a reduced-intensity melphalan-based
best applicability in allogeneic transplantation, particu- conditioning with lower doses o melphalan (100 mg/
larly in haploidentical transplantation, in which PTCy m2),21–23 with one exception— patients with Hodgkin
induces bidirectional immune tolerance by selectively lymphoma not in remission at transplant, who had
eliminating the highly dividing alloreactive donor and better survival with the more intense regimen (140
recipient T-cells generated early ater transplant in mg/m2).24
the setting o an HLA-mismatched transplant, which With HaploSCT outcomes signicantly improved,
has led to decreased rates o GVHD and grat rejec- we and others have subsequently compared trans-
tion.15 Interestingly, preclinical and clinical studies plant outcomes o patients treated with a haploidenti-
have shown that stem cells are resistant to high-dose cal versus MUD, mismatched MUD, matched related
PTCy (because o high levels o aldehyde dehydroge- donors, or cord transplants (Table 21–2).20,25–27 All
nase present in these cells) and likewise the memory these single-institution studies uniormly showed at
T-cells are spared, leading to excellent hematopoietic least comparable outcomes between patients treated
engratment and a better immune reconstitution with with a haploidentical transplant with PTCy and those
Chapter 21
relatively lower rates o inections.16–18 Our group has received HLA-matched donors or cord transplants with
demonstrated that this approach was superior to com- conventional GVHD prophylaxis and or mismatched
plete T-cell depletion approaches because o a signi- MUD received PTCy-based GVHD prophylaxis.20,25–27
cantly lower NRM and risk o inectious complications In addition, the nal results o the Bone and Marrow
ater transplant.19 Transplant Clinical Trials Network (BMTCTN) phase
We rst used PTCy-based GVHD prophylaxis or 3 randomized trial comparing double cord transplant
HaploSCT in 2009 in a phase 2 clinical trial shortly ater with HaploSCT were recently reported.28 A total o
the rst clinical trials in humans showed the saety o 368 patients were enrolled, and with a an approximate
this approach.17 Initial studies used a nonmyeloablative median ollow-up o 24 months, there were signi-
conditioning regimen with fudarabine, cyclophospha- cantly better outcomes or HaploSCT in regards to OS
mide, and 2-Gy TBI, which was associated with a low (57% vs 46% or cord transplant; P = .037) and NRM
incidence o grades 2 to 4 aGVHD and NRM at 1 year (11% vs 18% or cord transplant; P = .039), albeit com-
(35% and 15%, respectively); however, a remarkably parable PFS rates (41% or HaploSCT vs 35% or cord
high relapse rate o 51% at 1 year was observed partic- transplant; P = .409) and with no dierence in relapse
ularly or patients with acute leukemia.17 We hypoth- rates.28 Several retrospective registry studies have been
esized that a more intense but tolerable conditioning reported since conrming that haploidentical trans-
is needed, particularly or these patients; hence, we plants have similar survival with MUD transplants (see
used our melphalan-based conditioning platorm, pre- Table 21–2).29–34 Among the rst and largest reports,
viously used in T-cell-depleted HaploSCT,11,19 which that o Ciurea et al compared outcomes o patients
includes fudarabine 160 mg/m2, melphalan 100 to with AML receiving HaploSCT with MUD transplants
140 mg/m2, and thiotepa 5 to 10 mg/kg (subsequently using the Center or International Blood and Marrow
table 212 Sc ts ris Sis Ci hiic S C
tsi i mc u d S C tsi
Patients aGVHD cGVHD TRM Relapse 3-Year PFS

Disease Subtype (n) (%) (%) (%) (%) (%) GRFS
29
AML
MAC —
Haplo —
MUD 104 16 30 14 44 45
RIC 1245 33 53 20 39 50
Haplo
MUD 88 19 34 9 58 46
Lymphomas30
Haplo 737 28 52 23 42 44
MUD with ATG 185 27 13 11 36 47 —
MUD without ATG 241 40 33 13 36 38 —
491 49 51 20 28 49 —
Hodgkin lymphoma31
Haplo 98 33 26 17 39 43a -
MUD 273 30 41 21 32 45a
DLBCL32
Haplo 132 34 18 22 41 38 36
MUD TCD+ 403 32 27 17 38 36 33
MUD TCD- 378 42 57 26 34 37 19
ALL33
Haplo 136 28 44 23 28 49 44
MUD 809 32 39 19 28 53 39
ALL34b
Haplo 487 33 30 24 37 39 31
Chapter 21
MUD 974 32 28 24 34 41 32
a
Two-year survival is reported.
b
Haploidentical recipients were matched (1:2) with matched unrelated donor (MUD) control participants.
aGVHD, acute grat-versus-host disease; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ATG, antithymocyte globulin; DLBCL, diuse large B-cell
lymphoma; GRFS, GVHD-ree relapse-ree survival; GVHD, grat-versus-host disease, Haplo, haploidentical stem cell transplantation; MAC, myeloablative conditioning;
PFS, progression-ree survival; RIC, reduced-intensity conditioning; TCD, T-cell depletion; TRM, transplant-related mortality.
Transplant Registry (CIBMTR) database.29 Results o on these ndings, we have proposed a prospective mul-
this retrospective analysis o 2174 patients showed ticenter observational study comparing the two donor
similar 3-year OS between these two donor sources sources (BMTCTN 1702), which will help answer some
(45% or HaploSCT vs 50% or MUD with myeloab- o the questions not addressed to date in the retrospec-
lative conditioning; P= .38 and 46% vs 44% with tive studies.
reduced-intensity conditioning [RIC] or HaploSCT
and MUD, respectively; P = .71). The incidence o grade
2 to 4 aGVHD was lower or haploidentical compared graft engIneerIng
with MUD transplants (16% vs 33% or myeloablative
and 19% vs 28% or RIC transplants), likely related to Several research strategies are being investigated
the use o PTCy and the predominant receipt o bone to optimize the haploidentical grat, maximize the
marrow grat in the haploidentical group.29 Table 21–2 immune recovery, and minimize GVHD ater trans-
summarizes key ndings rom selected large transplant plant. A very promising approach is selective deple-
registry studies comparing HaploSCT versus MUD tion o αβ T-cells that capable o eliciting GVHD while
transplants in myeloid and lymphoid neoplasms. Based preserving in the grat the memory T-cells and gδ T
table 213 ps s C tis ai  dcsi diss rs i
hiic hiic S C tsi
Approach Rationale Pitfalls

Unmodied DLI To ght disease relapse via harnessing Limited experience in HaploSCT
grat-versus-malignancy eect Potential or GVHD precipitation
Not targeted to specic antigen(s)
Engineered donor lymphocytes To ght disease relapse via harnessing Not targeted to specic antigen(s)
with a saety suicide switch grat-versus-malignancy eect Clinical ecacy not yet demonstrated
Saety switch allows T-cell suicide in case o
GVHD development
g-δ DLI Inusion o selected g-δ T-cells Grat-versus-malignancy eect not yet
No GVHD potential demonstrated
CAR T-cells T-cells engineered to recognize specic Clinical ecacy ater HaploSCT not yet
antigens (eg, CD19) that provide grat- demonstrated
versus-malignancy eect without GVHD
Inusion o ex vivo expanded NK Potential grat-versus-malignancy eect Clinical ecacy demonstrated in a
cells without GVHD phase II study
CAR, chimeric antigen receptor; DLA, donor lymphocyte inusion; GVHD, grat-versus-host disease; HaploSCT, haploidentical hematopoietic stem cell transplantation;
NK, natural killer.
cells.12 gδ T-cells possess innate and adaptive immune investigation at our institution to prevent and treat dis-
responses, and similar to natural killer (NK) cells, can ease relapse ater transplant (Table 21–3).
unction without requiring antigen presentation by
the HLA system, which makes them unlikely to gen-
erate GVHD.35 Accordingly, methods to deplete αβ Unmodifed Donor Lymphocyte Inusion
T-cells, leaving the gδ subsets intact, are being investi- The readily available haploidentical donors can be use-
gated with encouraging results especially in children.36 ul sources o lymphocytes or posttransplant donor
Another approach involves depletion o naïve T-cells lymphocyte inusion (DLI), which could be inused
(CD45RA+) thought to play a major role in the devel- to prevent or treat early relapse. Although there is a
opment o GVHD in mouse models.37–39 A phase 1 theoretical higher risk o inducing severe aGVHD with
Chapter 21
saety study testing saety o this approach in haploi- the use o haploidentical DLI, the incidence o GVHD
dentical donor transplants at MDACC has been com- was not shown to be higher than in HLA-matched
pleted, and preliminary results demonstrated excellent transplants,41–43 possibly in part because o the toler-
control o GVHD. Another approach to mitigate izing eect o PTCy. In one o the earliest reports,
risks o complete T-cell depletion is administration o 40 patients with various hematologic malignancies
T-regulatory cells along with conventional T-cells to received unmodied haploidentical DLI or relapsed
prevent GVHD; in a preliminary report, this approach disease ater HaploSCT with PTCy-based GVHD pro-
was shown to reduce the risk o GVHD and leuke- phylaxis.41 Most patients received a dose o 1 ° 106/
mia relapse.40 Future clinical trials will explore these kg CD3+ T-cells. Acute GVHD developed in 25%
approaches at MDACC because they may control o patients, and 15% o patients had grade III to IV
GVHD and acilitate a rapid immune recovery without aGVHD. Interestingly, most o these patients received
the need or posttransplant immunosuppression. cytoreductive therapy beore the DLI inusion, and one
third o patients achieved a complete response with a
median duration o response o 12 months. Two more
poSttranSplant Cellular recent studies reported similar outcomes.42,43 Because
therapy to prevent dISeaSe DLIs are expected to be more eective in patients with
relapSe low tumor burden, such as patients with minimal
residual disease,44 preemptive DLI has been explored
With signicant improvements in NRM, relapse in the HaploSCT setting with encouraging results.45,46
remains the major cause o treatment ailure, not Prophylactic DLIs rom haploidentical donors are also
only in HaploSCT patients but also in HLA-matched being explored or patients with high-risk o relapse
transplants. Several approaches are currently under ater transplant.47 These reports suggest that cellular
therapy with haploidentical DLI and other therapeutic with relapsed reractory ALL and achieved complete
cells can be applied saely ater transplant, and uture remission in 90% o patients.52 Subsequently, 75
approaches should ocus on improving the saety and patients were enrolled in a phase 2 clinical trial that
ecacy o this therapeutic strategy.48 conrmed an overall remission rate o 81% at 3 years,
with 1-year PFS and OS rates o 50% and 76%, respec-
tively.53 Likewise, CD19 CAR T-cell therapy showed
Modifed Donor Lymphocyte Inusion impressive results in patients with relapsed or rerac-
Using T-Cells with a Saety Switch (Suicide toryDLBCL.54,55 Our group has been exploring the use
Gene) o CAR T-cells in the peritransplant setting to improve
Improved control o GVHD posttransplant can be outcomes ater autologous and allogeneic transplanta-
achieved by inserting a suicide gene in the haploiden- tion.56,57 Results rom the phase 1 clinical trial showed
tical donor T-cells. I signicant aGVHD develops, a very encouraging outcomes, including in HaploSCT
“saety o switch” can be used to “turn o” these T-cells recipients (n = 8), with 1-year PFS and OS rates o 75%
and avoid excessive aGVHD. This approach has so ar and 100%, respectively, and with no increased risk
been investigated to boost posttransplant immune o GVHD.56 These preliminary results suggested that
recovery ater T-cell-depleted haploidentical grats. allogeneic CAR T-cells can be saely given peritrans-
Ciceri et al inused DLI engineered T-cells to express plant without signicant GVHD to decrease relapse
herpes simplex virus–thymidine kinase suicide gene that can posttransplant. Future studies should explore the use
be triggered by ganciclovir to induce apoptosis.49 This o CAR T-cells ater allo-SCT or dierent diseases.
was used to boost posttransplant immune reconstitu-
tion by adding back T-cells ater a complete or par- Natural Killer Cells and Killer
tial T-cell-depleted HaploSCT. Grade 1 to 4 aGVHD Immunoglobulin-like Receptor Mismatch
developed in 20% o the patients, and GVHD was suc-
cessully controlled by inducing the suicide gene with NK cells are part o the innate immune system and
ganciclovir. However, ganciclovir may not be the ideal normally are involved in identiying and killing tumor
drug in this setting because it is commonly used ater cells or virally inected cells. NK cells recognize and
transplantation to control cytomegalovirus reactiva- target “oreign” cells that lack one or more HLA class I
tion. Another approach developed by the Baylor group alleles specic to the inhibitory receptors (killer immu-
used modied DLIs engineered to express an inducible noglobulin-like receptors [KIRs]).58 NK cells, which
caspase-9 transgene.50 This gene can be induced by a target malignantly transormed or virally inected cells,
synthetic dimerizing drug leading to rapid cell death. do not contribute to the development o GVHD, mak-
GVHD, which occurred in our o the ve HaploSCT ing them ideal to use to decrease relapse in the post-
patients ater inusing the saety switch-modied transplant setting. Prior studies in T-cell-depleted
Chapter 21
T-cells, was rapidly reversed by administering the haploidentical transplants showed a lower incidence
dimerizing drug.50 Long-term outcomes were reported o relapse when patients had a KIR-ligand mismatched
or 10 HaploSCT pediatric patients inused with same (KIR-LM) donor.59 Several studies suggest a lower risk
product, showing persistence o these modied cells o relapse with donors who possess specic activat-
or over 2 years and potentially contributing to oppor- ing KIR genes such as KIR2DS1, KIR2DS2, or the KIR
tunistic inection control and promoting endogenous “B” haplotype.60–62 Although no denitive role or a
T-cell recovery.51 This approach could be explored in KIR-LM donor has been conrmed to date, our group
the uture using preemptive DLI in patients who have explored the use o high doses o ex vivo expanded and
advanced disease beore transplant. activated NK cells beore and ater transplant with very
encouraging results. In a phase 1 dose-escalation stud,63
using the mb-IL21 method as developed at MDACC,64
Chimeric Antigen Receptor T-Cells 13 patients with high-risk myeloid malignancies were
Although DLI oers nonspecic antitumor activity, inused with mb-IL21–expanded donor NK cells on days
its eect is nontargeted. Recently, the introduction o -2, +7, and +28 o HaploSCT. The study demonstrated
chimeric antigen receptor (CAR) T-cells that can rec- easibility o inusing high doses o ex vivo expanded
ognize a specic antigen on cancer cell surace has NK cells without signicant toxicities or increased risk
demonstrated excellent activity in CD19-expressing o GVHD and with notable low posttransplant relapse
lymphoid malignancies. The Food and Drug Admin- rates and incidence o viral inections.63 Preliminary
istration granted accelerated approval or treatment o results rom a subsequent phase 2 study conrmed the
relapsed or reractory B-cell acute lymphoblastic leuke- ndings, and in a matched-pair analysis independently
mia (ALL) and diuse large B-cell lymphoma (DLBCL). perormed with a CIBMTR cohort, NK cell–treated
In the initial pilot studies, Maude et al used autolo- patients showed a signicantly lower relapse and
gous CARs against CD19 (CTL019) in 30 patients improved PFS than patients who did not receive NK
cells.65 Based on these data, a multicenter phase 2 study are preerred or recipients o haploidentical trans-
was initiated by the BMTCTN (BMTCTN 1803). plants with PTCy.66,67 In addition, ABO-matched or
minor mismatched grats are preerred to major ABO-
mismatched grats.66 There is controversy whether
donor SeleCtIon for patients should be selected based on NK cell alloreac-
haploIdentICal Stem Cell tivity; more studies are needed to clariy this aspect.68
tranSplantatIon and rISkS
from donor-SpeCIfIC antI– ConCluSIonS and future
human leukoCyte antIgen dIreCtIonS
antIbodIeS
The eld o HaploSCT has signicantly grown over the
Unlike matched related donor transplants, in whom past decade with the introduction o PTCy and novel
the number o matched donors is usually small, mul- methods o partial T-cell depletion. These newer tech-
tiple donors are usually available to choose rom in niques eectively control strong alloreactive reactions
the HaploSCT. Several actors are considered when in HaploSCT and are associated with robust immune
choosing the best donor.66 One o the rst and most recovery, translating into ewer inectious complica-
important actors is to evaluate is the presence o tions and lower NRM. Data rom several studies suggest
donor-specic anti-HLA antibodies (DSAs).67,68 that haploidentical transplants have similar outcomes
Patients may develop antibodies against oreign HLA to MUD transplants, but when aster transplantation
antigens, particularly parous women and multiply is needed, haploidentical grats may be preerred.70
transused patients. We have shown or the rst time Because o these, the use o this type o transplant con-
that patients with high levels o complement-xing tinues to expand worldwide. Prospective controlled
anti-HLA antibodies against donor HLA antigens are clinical trials are needed to address important questions
at high risk o engratment ailure.68 Routine evalua- in dierent clinical settings and impact o donor choice
tion o all donors with HLA mismatches has now been and time to transplant on outcomes because approxi-
incorporated into standard practice worldwide. Crite- mately hal o patients do not get to transplant in time.
ria to optimize donor selection to improve outcomes In addition, exploration o various cellular therapy inter-
have been developed.62,66,69 Patients with high DSAs ventions in the peritransplant setting, particularly NK
should be avoided as donors but i not possible should cell therapy, represents a great opportunity to improve
be treated to decrease risk beore transplant.66 Younger the grat-versus-malignancy eect and decrease relapse
donors, male donors, athers rather than mothers, and posttransplant, which is the next most important next
rst-degree to second-degree haploidentical donors step in improving transplant outcomes.
Chapter 21
J Haploidentical transplantation use at MDACC has J Incorporation o donor NK cell into haploidenti-
increased signicantly over past decade, and it is a cal transplant or patients with high-risk myeloid
preerred alternative donor source in the absence o malignancies has led to signicantly deceased
a ully matched donor. relapse and viral inections and improved survival
J There are no prospective randomized clinical trials outcome in our experience. A multicenter phase 2
comparing haploidentical with matched unrelated study is initiated by the BMTCTN based on our data.
transplants. Haploidentical transplant is preerred J The DSAs remain one o the most important actors
over double cord transplant. MDACC is a lead in the to consider or best haploidentical donor because
ongoing multicenter BMTCTN prospective obser- the presence o antibodies is associated with high
vational clinical trial comparing the outcomes o risk o grat ailure. Patients with high DSAs should
alternative donors in the absence o a ully matched be avoided as donors but i not possible should be
sibling donor. treated to decrease risk beore transplant.
J The introduction o PTCy or GVHD prevention repre- J Prospective controlled clinical trials are a priority
sented a major turning point or improving outcomes to address important questions in dierent clinical
o haploidentical transplants. The concept was rst settings, impact o donor choice, and time to trans-
adopted at MDACC in 2009, incorporated into our plant on outcomes because approximately hal o
fudarabine–melphalan conditioning platorm, and patients do not get to transplant in time.
since has become our standard o care option.
haploidentical hematopoietic stem cell transplantation. Biol

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cal donor lymphocyte inusions or patients with relapsed natural killer cell alloreactivity in mismatched hematopoietic
hematologic malignancies ater related HLA-haploidentical transplants. Science. 2002;295(5562):2097-2100.
bone marrow transplantation. Biol Blood Marrow Transplant. 60. Cooley S, Trachtenberg E, Bergemann TL, et al. Donors with
2014;20(3):314-318. group B KIR haplotypes improve relapse-ree survival ater unre-
42. Ghiso A, Raiola AM, Gualandi F, et al. DLI ater haploidenti- lated hematopoietic cell transplantation or acute myelogenous
cal BMT with post-transplant CY. Bone Marrow Transplant. leukemia. Blood. 2009;113(3):726-732.
2015;50(1):56-61. 61. Sivori S, Carlomagno S, Falco M, et al. Natural killer cells express-
43. Goldsmith SR, Slade M, DiPersio JF, et al. Donor-lymphocyte ing the KIR2DS1-activating receptor eciently kill T-cell blasts
inusion ollowing haploidentical hematopoietic cell transplan- and dendritic cells: implications in haploidentical HSCT. Blood.
tation with peripheral blood stem cell grats and PTCy. Bone 2011;117(16):4284-4292.
Marrow Transplant. 2017;52(12):1623-1628. 62. Chen DF, Prasad VK, Broadwater G, et al. Dierential impact o
44. Tan Y, Du K, Luo Y, et al. Superiority o preemptive donor lym- inhibitory and activating killer Ig-like receptors (KIR) on high-
phocyte inusion based on minimal residual disease in acute risk patients with myeloid and lymphoid malignancies under-
leukemia patients ater allogeneic hematopoietic stem cell trans- going reduced intensity transplantation rom haploidentical
plantation. Transfusion. 2014;54(6):1493-1500. related donors. Bone Marrow Transplant. 2012;47(6):817-823.
45. Yan CH, Liu DH, Liu KY, et al. Risk stratication-directed donor 63. Ciurea SO, Schaer JR, Bassett R, et al. Phase 1 clinical trial using
lymphocyte inusion could reduce relapse o standard-risk acute mbIL21 ex vivo-expanded donor-derived NK cells ater haploi-
leukemia patients ater allogeneic hematopoietic stem cell trans- dentical transplantation. Blood. 2017;130(16):1857-1868.
Chapter 21
plantation. Blood. 2012;119(14):3256-3262. 64. Denman CJ, Senyukov VV, Somanchi SS, et al. Membrane-bound
46. Mo XD, Zhang XH, Xu LP, et al. Salvage chemotherapy ol- IL-21 promotes sustained ex vivo prolieration o human natural
lowed by granulocyte colony-stimulating actor-primed donor killer cells. PLoS One. 2012;7(1):e30264.
leukocyte inusion with grat-vs.-host disease control or 65. Stean O, Ciurea RS, Soebbing D, et al. Enhanced antitumor eect
minimal residual disease in acute leukemia/myelodysplastic and lower viral reactivation with high doses o ex vivo expanded
syndrome ater allogeneic hematopoietic stem cell transplanta- NK cells administered ater haploidentical transplantation. Paper
tion: prognostic actors and clinical outcomes. Eur J Haematol. presented at: American Society o Clinical Oncology; 2019.
2016;96(3):297-308. 66. Ciurea SO, Champlin RE. Donor selection in T cell-replete hap-
47. Dholaria B, Savani BN, Labopin M, et al. Clinical applications o loidentical hematopoietic stem cell transplantation: knowns,
donor lymphocyte inusion rom an HLA-haploidentical donor: unknowns, and controversies. Biol Blood Marrow Transplant.
consensus recommendations rom the Acute Leukemia Working 2013;19(2):180-184.
Party o the EBMT. Haematologica. 2020;105(1):47-58. 67. Yoshihara S, Maruya E, Taniguchi K, et al. Risk and prevention
48. Kongtim P, Lee DA, Cooper LJ, et al. Haploidentical hema- o grat ailure in patients with preexisting donor-specic HLA
topoietic stem cell transplantation as a platorm or post- antibodies undergoing unmanipulated haploidentical SCT. Bone
transplantation cellular therapy. Biol Blood Marrow Transplant. Marrow Transplant. 2012;47(4):508-515.
2015;21(10):1714-1720. 68. Ciurea SO, de Lima M, Cano P, et al. High risk o grat ailure
49. Ciceri F, Bonini C, Stanghellini MT, et al. Inusion o suicide- in patients with anti-HLA antibodies undergoing haploidentical
gene-engineered donor lymphocytes ater amily haploidenti- stem-cell transplantation. Transplantation. 2009;88(8):1019-1024.
cal haemopoietic stem-cell transplantation or leukaemia (the 69. Wang Y, Chang YJ, Xu LP, et al. Who is the best donor or a
TK007 trial): a non-randomised phase I-II study. Lancet Oncol. related HLA haplotype-mismatched transplant? Blood.
2009;10(5):489-500. 2014;124(6):843-850.
50. Di Stasi A, Tey SK, Dotti G, et al. Inducible apoptosis as 70. Ciurea SO, Bittencourt MCB, Milton DR, et al. Is a matched
a saety switch or adoptive cell therapy. N Engl J Med. unrelated donor search needed or all allogeneic transplant can-
2011;365(18):1673-1683. didates? Blood Adv. 2018;2(17):2254-2261.
51. Zhou X, Di Stasi A, Tey SK, et al. Long-term outcome ater
haploidentical stem cell transplant and inusion o T cells
expressing the inducible caspase 9 saety transgene. Blood.
2014;123(25):3895-3905.
22 Cellular Therapy in Allogeneic
Hematopoietic Cell
Transplantation
Amanda Olson
Jeremy Ramdial
Uri Greenbaum
Paul Lin
Katayoun Rezvani
Partow Kebriaei
KEY CONCEPTS
 The ecacy o allogeneic hematopoietic cell transplanta-  The pathogenesis o GVHD is complex and includes the
tion (HCT) is based on the grat-versus-tumor eect, by dierentiation o naïve donor T-cells into eector cells
which the donor immune system achieves immunologic that attack host tissues. Increasing numbers o HLA misma
control o the tumor via the human leukocyte antigen tches are associated with higher incidence o GVHD and
(HLA) system. transplant-related mortality. Grades II to IV acute GVHD
 Three key barriers to successul HCT are relapse caused by occur in 25% to 60% o cases with matched related donors
ailure o immunologic control o the underlying disease, and 45% to 70% o cases with matched unrelated donors.
grat-versus-host disease (GVHD), and inectious compli- Recent improvements in GVHD include the approval o
cations, and studies are underway to improve on these ruxolitinib or steroid-reractory acute GVHD and the use
complications. o posttransplant cyclophosphamide to decrease the inci-
dence o GVHD.
 Strategies to mitigate relapse include using prophylactic
donor lymphocyte inusions, chimeric antigen receptor  Viral inection is a major cause o death ater HCT, result-
modifed T-cells derived typically rom the patient, and ing rom cellular and humoral immune defciency. Viral
natural killer (NK) T-cells. inections o particular relevance ater HCT are cytomega-
lovirus, Epstein-Barr virus, the polyoma viruses BK and JC,
 In contrast to B and T lymphocytes, NK T-cells do not
adenovirus, and human herpesvirus 6. Pharmacotherapy
express rearranged, antigen-specifc receptors and as a
or these inections has limited ecacy. Viral-specifc
consequence have a low risk or GVHD, allowing the use
T-cells directed against these inections is easible to gen-
o allogeneic NK cells. An allogeneic product is advanta-
erate and eective.
geous because it is readily available and urthermore uses
healthy immune cells or product production.
The ecacy o allogeneic hematopoietic cell transplan- antigen-presenting cells (APCs), such as macrophages,
tation (HCT) in hematologic malignancies can in large dendritic cells, and B cells.
part be attributed to a grat-versus-tumor (GVT) eect, Peptides derived rom microbes are presented on
by which the donor immune system achieves immu- class I HLAs to CD8+ T-cells and result in immu-
nologic control o the tumor. As such, it is the proto- nologic destruction o inected cells; class II HLAs
type o cellular therapy. The human leukocyte antigen are recognized by CD4+ T-cells. T-cell activation
(HLA) system is undamental to transplant biology. requires costimulatory signals rom the APC, speci-
The HLAs are highly polymorphic proteins that have cally CD80/86 binding to CD28 or LFA-3 binding to
a key role in antigen presentation and immune regu- CD2.1 Absence o a costimulatory signal results in
lation. Class I HLAs are expressed on the suraces o T-cell anergy, which is a key mechanism o peripheral
all nucleated cells; class II are expressed on specialized immune tolerance to sel-antigen in normal immune
457
458 Secion III Stem Cell Transplantation
Conditioning: tissue damage
1. Host APC Small

activation Host
intestine
tissues
TNFα
IL1
LPS
LPS
Mϕ
Host
APC
IFNγ TNFα
IL1
Donor
T-reg
T-cell
Target cell
apoptosis
T-reg
CD4 TNFα
Th1 CTL IL1
2. Donor T-cell CD8

activation CTL 3. Cellular and
CD8
CTL infammatory
eectors
FIGURE 22–1 Pathogenesis o grat-versus-host disease (GVHD). In phase I, chemotherapy or radiotherapy as part o trans-
plant conditioning causes host tissue damage and release o inammatory cytokines such as tumor necrosis actor α (TNF-
ChaptER 22
α), interleukin (IL)-1, and IL-6, with resulting priming o host antigen-presenting cells (APCs). In phase II, host APCs activate
mature donor cells, which subsequently prolierate and dierentiate; release o additional eector molecules, such as TNF-α
and IL-1, mediates urther tissue damage. Lipopolysaccharide (LPS) that has leaked through damaged intestinal mucosa trig-
gers additional TNF-α production. The TNF-α can damage tissue directly by inducing necrosis and apoptosis in the skin and
gastrointestinal tract through either TNF receptors or the Fas pathway. TNF-α plays a direct role in intestinal GVHD damage,
which urther amplifes damage in the skin, liver, and lung in a “cytokine storm.” The process culminates in death o host cells
through CD8-positive cytotoxic T-cell-mediated apoptosis. (Reproduced with permission rom Ferrara JL, Levine JE, Reddy P, et
al: Grat-versushost disease, Lancet 2009 May 2;373(9674):1550-1561)
regulation. Early ater transplantation, there is a subsequently occurs, resulting in immunologic attack
“cytokine storm”; release o proinfammatory cyto- on host tissues and the potential development o
kines, such as tumor necrosis actor α (TNF-α) and grat-versus-host disease (GVHD). 2 Increasing num-
interleukin-6 (IL-6), is induced by tissue damage rom bers o HLA mismatches are associated with higher
the conditioning regimen, activating the host innate incidence o GVHD and transplant-related mortality
immune system (Fig. 22–1). Donor T-cells interact (TRM) rate.3 However, even in a ully HLA matched
with host APCs and recognize oreign peptides; helper HCT, GVHD still occurs because o donor T-cells
T-cells produce urther cytokines, especially IL-2, and directed against minor histocompatibility antigens
prime host APCs via CD40–CD40L interaction. Di- (MiHAs), polymorphic peptides displayed on host
erentiation o naïve donor T-cells into eector cells HLA molecules.
Cer 22 Cellular Therapy in Allogeneic Hematopoietic Cell Transplantation 459
There are three key barriers to successul HCT: • Induction o co-inhibitory molecules
relapse caused by ailure o immunologic control o • Induction o myeloid-derived suppressor cells in the
the underlying disease, GVHD, and inectious com- microenvironment that inhibit immune responses
plications. Herein, we review these issues in greater through multiple mechanisms.
detail with an emphasis on recent cellular therapeutic • Invasion o immunologically privileged sites
approaches to address these complications.
Cellular therapeutic approaches are designed with the
intent to abrogate these escape mechanisms.
ENhaNCING GRaFt-VERSUS-
tUMOR EFFECt tO OVERCOME Cellular Therapy to Induce Grat-Versus-
RElapSE Tumor Eect
Donor Lymphocyte Inusions
Pathophysiology o the Grat-versus-
Tumor Eect Donor lymphocyte inusion (DLI) may induce remis-
sions in patients with molecular or overt low volume
The GVT eect occurs because o a predominantly relapse o their malignancy and can reverse CD8+ T-cell
T-cell-mediated immunologic attack on tumor cells. exhaustion.5 However, the likelihood o success varies
In HLA-identical transplants, GVT eect is mediated signicantly according to the underlying disease. Chronic
by naïve T-cells; or development o eector unction, myelogenous leukemia is most sensitive; ollicular lym-
these must rst be primed by host APCs. This requires phoma (FL) and Hodgkin lymphoma (HL) are also highly
the ollowing: presentation o MiHAs or tumor-specic responsive.6,7 Responses to DLI in AML or myelodys-
antigens on HLA; appropriate costimulatory molecules, plastic syndrome (MDS) are less requent, and durability
including CD28, OX40, CD40L, and 41BB; and an is oten poor. Acute lymphoblastic leukemia (ALL) is the
appropriate “third signal,” provided by IL-12, intereron least responsive to DLI. Reported response rates are 60%
g (IFN-g) or adjuvant.4 Restraining infuences limiting the to 73% in CML, 15% to 29% in AML, and 0% to 18% in
degree o immune activation are present to protect the ALL.8 Limitations to DLI therapy include most notably,
host rom an excessive immune response and include development o GVHD, which occurs in 40% to 60%
expression o CTLA4 (which competes with CD28 or o patients.8 The GVHD rates may be reduced by reduc-
binding to CD80/86) and programmed cell death pro- ing the T-cell dose; a dose–response relationship exists
tein 1 (PD-1) and its interactions with its ligand PDL1, or both GVT and GVHD eects. Additionally, i there
which limit T-cell activation and expansion during nor- is insucient residual donor hematopoiesis beore DLI,
mal, pathogen-directed immune responses. eradication o host hematopoiesis by the inused lym-
Soon ater transplant, there are activation and expan- phocytes can result in marrow aplasia; chimerism stud-
sion o MiHA-reactive T-cells ollowed by a decline,
ChaptER 22
ies should thereore be perormed beore DLI to ensure
similar to that seen in pathogen-directed immune reac- adequate donor hematopoiesis.9 Finally, responses to
tions. This may in part relate to the development o DLI may not be seen or up to 2 months.8
peripheral tolerance or anergy and to replacement o In eorts to enhance the response to DLI in AML,
host hematopoiesis, with resulting loss o host APCs. combination therapy with hypomethylating agents
For tumor-associated antigen presentation to continue, (HMAs) has been studied. Based on preclinical stud-
there must be cross presentation on donor APCs. In ies that azacitidine increases T-regulatory (T-reg) cells,
addition, the initial allogeneic response to MiHAs suppressing GVHD while sparing GVT, Ghobadi and
results in recruitment o T-cells targeting either tumor- colleagues reported on a phase I trial testing three
associated antigens or nonpolymorphic genes, which escalating doses o azacitidine (30 mg/m2,45 mg/m2,
are either overexpressed or aberrantly expressed by 75 mg/m2) administered ater DLI.10 With a median
the tumor.4 ollow-up period o 5.2 months, 6 o 8 treated patients
responded, with no grades III or IV GVHD noted.10
Tumor Escape From Immunologic Schroeder and colleagues reviewed the outcomes o 36
Destruction patients with relapsed AML (n = 29) or MDS (n = 7) ater
HCT and treated with DLI and median two cycles o
Tumors use numerous mechanisms to escape immu-
decitabine.11 The median duration o complete remis-
nologic destruction, including the ollowing:
sion (CR) was 10 months or the group, with acute and
• Induction o regulatory T-cells chronic GVHD rates o 19% and 5%, respectively; the
• Production o inhibitory cytokines 2-year survival rate was only 11%,11 underscoring the
• Downregulation o costimulatory molecules and limited impact o DLI, even with the addition o other
HLA class I agents.
Prophylactic Donor Lymphocyte Inusion in High- were 31.5% and 53%, respectively, suggesting that this
Risk Patients may be a reasonable strategy in high-risk patients.13
The limited benet o DLI in overt relapse ater trans-
plant has led investigators to study the potential o DLI Cellular Therapy to Prevent Relapse: Chimeric
or the prevention o relapse. In a study by Kothari Antigen Receptor T-Cells
and colleagues, 75 patients with high-risk hemato- Chimeric antigen receptor (CAR) T-cells have become
logic malignancies underwent an alemtuzumab-based, one o the new and promising treatment modalities
T-cell-deplete transplant with matched related donors or hematologic malignancies. They are genetically
(MRDs n = 46) or matched unrelated donors (MUDs; modied T-cells, transected with a viral vector or a
n = 29) with planned early withdrawal o immune plasmid coding or a chimeric receptor (Fig. 22–2). The
suppression (WOI) and DLI in eorts to decrease extracellular portion o the receptor is a single-chain
relapse.12 Twenty-eight patients with MRDs were able variable ragment (scFv) o an antibody, acting as the
to undergo early WOI, and 93% received at least one antigen recognition domain. First-generation con-
DLI; only seven patients with MUDs were able to structs contained only the extracellular scFv domain
undergo WOI and 57% received at least one DLI. The coupled with an activating intracellular CD3 ζ com-
estimated 2-year progression-ree survival (PFS) and ponent. because o limited in vivo prolieration and
overall survival (OS) rates or all patients were 41% persistence o CAR T-cells, second-generation CAR
and 51%, respectively; or patients who received at includes an additional costimulatory domain (eg,
least one prophylactic DLI, 2-year PFS and OS were CD28 or 4-1BB), resulting in improved CAR T proli-
57% and 67%. In addition, patients who received DLI eration and persistence in vivo, and third-generation
had aster immune reconstitution and improved donor CAR constructs have two costimulatory domains (eg,
chimerism. This novel approach may be an eective both CD28 and 4-1BB), with potential or even bet-
strategy in patients undergoing MRD transplants. ter expansion and longer persistence. This advantage
In another study, low-dose azacitidine and DLI or third-generation CAR was shown in a study in
was tested in a prophylactic ashion in patients with which both second- and third-generation CARs were
AML (n = 20) or MDS (n = 10) deemed at high risk or inused simultaneously in the same patient.14 Since
relapse ater allogeneic HCT.13 The median number o second-generation CAR T-cells were approved by the
azacitidine cycles was 5 (range, 1–12) with 33% com- Food and Drug Administration (FDA) in 2017, they are
pleting the 12 intended cycles; 17 patients received 1-3 becoming more widely available and used as standard
inusions o DLI. At a median ollow-up period o 49 o care therapy or patients with relapsed or rerac-
months (range, 27–63 months), the OS and disease-ree tory B-cell non-Hodgkin lymphoma (NHL) or ALL.
survival (DFS) rates were 65.5% at 2 years; the rates or CAR T therapy induce high rates o responses, up to
2-year grades I to III acute GVHD and chronic GVHD
ChaptER 22
74% in NHL and 90% in ALL, but are also associated
A B C
Tumor
antigen
recognition
Intracellular
signaling
FIGURE 22–2 Schematic o chimeric antigen receptor (CAR) constructs. A. The frst-generation CAR consists o an antigen
recognition domain (usually a single-chain monoclonal antibody [scFv]) targeting a tumor-associated antigen), coupled via
an extracellular hinge domain and transmembrane domain to an intracytoplasmic signaling domain, typically the CD3ζ chain.
B. C. In second- and third-generation CAR constructs, the intracellular component includes costimulatory domains, typically
4-1BB, CD28, or both, that enhance persistence and prolieration.
with rates o serious toxicity in the orm o cytokine Chimeric Antigen Receptor T-Cell Therapy
release syndrome (CRS) o up to 44% and severe neu- Combined with Allogeneic Transplant
rotoxicity o up to 42%.15 With a longer ollow-up
period, up to 50% o ALL patients and 60% o NHL Combining CAR T therapy with allogeneic HCT is
patients relapse, sometimes with an antigen-negative also under investigation. The transplant preparative
relapse.16,17 In many ALL studies, despite a CR rate regimen may have a deleterious eect on any remain-
o 70% to 90% ater CAR T therapy, more than hal ing circulating CAR T-cells and impair their immune
relapse within 1 year without consolidative allogeneic surveillance. Furthermore, CAR T-cell therapy and
HCT.18–25 Thus, studies are underway to investigate its associated toxicity may impact transplant-related
the ideal sequence or these therapies and i there is toxicities, such as increasing GVHD. Currently, the
any benet to combining with transplant. available data regarding the saety and possible ben-
et or allogeneic HCT ater CAR T therapy comes
rom retrospective series, largely without preplanned
Chimeric Antigen Receptor T-Cell Therapy
consolidation with transplant (Table 22–1). The data
Combined with Autologous Transplant
in aggregate indicate that transplant consolidation
Several studies have looked at CAR T administration may coners protection against relapse at the expense
combined with autologous HCT or NHL. Sauter and o greater TRM, thus not providing a survival benet
colleagues reported on 15 patients with relapsed or or all patients. Zhang et al reported on the outcomes
reractory NHL who had positron emission tomogra- o 52 adult patients with ALL who received treat-
phy–positive disease beore HCT and showed a 2-year ment with either CD19 or CD22 autologous CAR T
PFS o 30% when CAR T-cells were administered ollowed by planned allogeneic HCT with reduced-
on days 2 and 3 o the transplant.26 Furthermore, 10 intensity conditioning therapy.22 At 1 year, the relapse
o 15 patients experienced high-grade neurotoxicity, rate was 24.7%, TRM was very low at 2.2% with-
perhaps because o the intense chemotherapy during out excess GVHD, and there was an excellent 1-year
the transplant. A study conducted at MD Anderson OS o 87.7%. More studies will need to be conducted
Cancer Center (MDACC) used the Sleeping Beauty with planned consolidation o allogeneic HCT ater
transposon–transposase system (as opposed to a viral CAR T to conrm these highly encouraging results.
platorm) to produce CD19 CAR T-cells, which were Similarly, in children, data or consolidation with
inused 2 days ater autologous HCT in seven patients HCT ater CAR T-cell therapy is mainly reported rom
with relapsed or reractory B-cell NHL.27 In this trial, retrospective studies without planned transplant con-
the 5-year PFS and OS rates were 71% and 86%, solidation.30 A retrospective study o 15 pediatric or
respectively. Interestingly, 4 o 6 evaluable patients had adolescent and young adult patients with relapsed or
persistence o the CAR T-cells at last ollow-up, at a reractory B-cell ALL who went on to an allogeneic
median o 4.5 years. HCT ater achieving an MRD-negative remission
ChaptER 22
Current CAR T trials in multiple myeloma with CAR T-cells, reported OS o 80% at 24 months
(MM) are mainly using the B-cell maturation anti- and relapse and TRM rates at 16% and 20%, respec-
gen (BCMA) as the target and are usually enrolling tively.31 In this study, patients were treated with mye-
relapsed or reractory patients who have had prior loablative conditioning regimens ollowed by either a
autologous transplant. However, one o the rst trials CD34-selected T-cell-depleted allogeneic grat (n = 9)
used a CD19-directed CAR as an adjunct to a second or unmanipulated grat (n = 6); TRM and OS were 0
transplant and compared each patient’s PFS ater the and 100% versus 50% and 50% or the manipulated
CAR T + HCT strategy to the previous PFS attained versus unmanipulated groups, respectively. This very
with transplant only.28 The use o CD19, not usually small study hints at the possibility that a T-cell-replete
present on mature plasma cells, was thought to target grat may not be necessary i transplant is used as con-
the myeloma-propagating cells. In this study, among solidation in this setting, sparing patients some degree
10 patients treated, only two had longer PFS ater the o toxicity, such as GVHD. As we continue to investi-
CAR T + HCT versus transplant alone. Interestingly, gate the role o CAR T therapy and its sequence in the
these two patients eventually progressed with iso- treatment o dierent diseases and patient populations,
lated extramedullary plasmacytomas, and the authors we will be able to rene the role o transplant consoli-
suggested this may hint at continuing bone marrow dation. The patient’s disease characteristics, the CAR
immune surveillance. Another trial reported on inu- T construct, and the patient’s response to therapy will
sion o both CD19- and BCMA-directed CAR T-cells help to delineate who may benet rom this approach.
14 to 20 days ater HCT in nine patients.29 The overall One such example o this approach was investigated
response (OR) rate was 100% with all patients achiev- by Summers and colleagues, in which patients with
ing CR or very good partial response ater CAR T-cell B-cell aplasia o less than 63 days ater CAR T treat-
therapy, although response duration was not reported. ment were oered a transplant. Among 50 evaluable
taBlE 221 Oucomes in Sudies wi piens wi BCe acue lymobsic leukemi Wo
Received aogeneic hemooieic Ce trnsnion afer Cimeric anigen Receor tCe
tery
Allogeneic HCT Ater CAR T Inusion

Reerence Structure o CAR T Yes No
25
Park et al (n = 43) CD19–28z (n = 17) (n = 26)
Relapse, 6 o 17 (35%); TRM, 6 o 17 (35%) Relapse, 17 o 26 (65%)
Lee et al110 (n = 51) CD19–28z (n = 21) (n = 7)
Relapse, 2 o 21 (9%) Relapse, 6 o 7 (86%)
LFS not reached (P = .0006) LFS, 4.9 months
Pan et al20 (n = 45) CD19-4-1BBz (n = 27) (n = 18)
Relapse, 2 o 27 (P = .023); TRM, 2 o 27 Relapse, 9 o 18
6-mo LFS, 81.3%
Pan et al19 (n = 23) CD22-4-1BBz (n = 11) (n = 7)
Relapse, 1 o 11 (9%); TRM, 2 o 11 Relapse, 4 o 7
LFS at 1 year, 71.6%
Jacoby et al18 (n = 20) CD19–28z (n = 14) (n = 4)
Relapse, 2 o 14 Relapse, 2 o 4
1-year EFS, 73%; OS, 90%
Shalabi et al111 CD19–28z (n = 52) 43 achieved MRD-negative CR N/A
(n = 85) CD22-4-1BBz (n = 33) 25 went on to allo-HCT
2-year relapse, 13.5%
Zhang et al (n = 52)22 CD19/CD22-4-1BB z 1-year OS, 87.8% N/A
1-year EFS, 73.%
1-year TRM, 2·2%
Fabrizio et al31 19–28z/19-BBz 24-month relapse, 16%
24-month TRM 20%
24-month OS 80%
Summers et al32 CD-19- 41BBz-EGFRt No prior HCT: 2 o 14 relapsed, 1 TRM No prior HCT: 3 o 3 relapsed
No prior HCT (n = 17) Prior HCT: 5 o 10 relapsed Prior HCT: 15 o 23 relapsed
Prior HCT (n = 33)
ChaptER 22
allo-HCT, allogeneic hematopoietic cell transplantation; CAR, chimeric antigen receptor; CR, complete remission; EFS, event-ree survival; LFS, leukemia-ree survival;
MRD, minimal residual disease; N/A, not applicable. OS, overall survival; TRM, transplant-related mortality.
patients, 15 had B-cell aplasia o less than 63 days, and and only two patients had GVHD that responded to
nine o these patients proceeded to transplant. Among therapy. In another trial o 20 patients with relapsed
the transplanted patients, only two relapsed, and all B-cell malignancies ater allogeneic HCT who received
six patients with early reconstitution o B cells who CAR T inusion, eight o the patients had a CR or
did not proceed to transplant relapsed.32 partial response.34 These patients did not receive any
lymphodepletion beore CAR T inusion, and impor-
tantly, no patients developed GVHD, despite 70% o
Chimeric Antigen Receptor T-Cell Therapy Ater patients having had a prior history o GVHD with their
transplant. Similar ndings have been reported rom
Allogeneic Transplant
smaller series, importantly all without excess rates o
Finally, sequencing CAR ater an allogeneic HCT GVHD.35,36 A recent report o donor-derived cytokine-
allows the production o donor-derived CAR T-cells induced killer T-cells engineered with the Sleeping
i the patient remains chimeric. This allows the use Beauty transposon to express CD19 CAR showed
o healthy T-cells or CAR production and provides a responses in our o ve patients with reractory ALL,
strategy to address relapse in these patients. A report with no GVHD reported ater treatment.37
on 18 patients with relapsed CD19+ ALL ater allo- Although most donor-derived CAR T trials investi-
HCT had 13 o 18 patients achieving a CR (72%) and gated the use o CAR T-cells as therapy or relapse ater
11 o these not requiring urther therapy at a median transplant, a ew have studied CAR T-cells as prophy-
ollow-up period o 7 months.33 Importantly, ull donor lactic therapy. Kebriaei et al used a nonviral approach
chimerism was restored or the responding patients, or the production o CD19-directed CAR T-cells using
the Sleeping Beauty transposon–transposase system T-cells is to downregulate their HLA class I molecules.
to incorporate the vector into the genome; this con- Because HLA class I molecules are some o the stron-
struct was tested in phase 1 clinical trials in 26 patients gest inhibitors o NK cells, the lack o these molecules
with B-cell malignancies in combination with alloge- consequentially leads to NK cell activation, thus pro-
neic (n = 19) or autologous (n = 7) transplant.38 Six o viding a balance to T-cell surveillance.41 NK cells can
seven patients who had an autologous HCT ollowed also be activated by ligands such as major histocom-
by CAR T were in remission ater a median ollow- patibility complex class I polypeptide-related sequence
up period o 25.5 months; 11 o 19 patients receiving A (MICA), MICB, and UL16 binding proteins (ULBPs)
an allogeneic HCT were in remission ater a median that are upregulated in cells that have DNA damage or
ollow-up period o 7.5 months, with reported 1-year are stressed or inected, including cancer cells. Finally,
PFS and OS rates o 53% and 63%, respectively.38 In NK cells can be activated by binding to the Fc portion
another small study o two patients using a similar o antibodies through its CD16 receptor and thus are
strategy o prophylactic donor-derived CAR T-cells involved in the body’s antibody-dependent cellular
ater allogeneic HCT, investigators reported prolonged cytotoxicity immune deense. This is believed to be
CAR T persistence, absence o GVHD, and continued integral, or example, in the ecacy observed with the
remission at a ollow-up period o 1 year.39 anti-CD38 antibody therapy daratumumab in mul-
tiple myeloma.42 Ater being activated, NK cells can
directly kill cancer cells via secretion o granzymes and
NatURal KIllER CEllS perorins, and they can also modulate the surround-
ing microenvironment by secreting cytokines such as
Natural killer (NK) cells have a number o advantages IFN-g and TNF-α (Fig. 22–3).
over T-cell therapy in the treatment o patients with Early NK cell recovery (within 30 days) ater allo-
cancer. Unlike T and B lymphocytes, NK cells do not geneic stem cell transplant has been associated with
express rearranged, antigen-specic receptors and as a reduced rates o both relapse and acute GVHD
consequence have a low risk or GVHD. This allows (aGVHD), with resultant improved survival.43 This
the use o allogeneic NK cells, thus providing an o- dual benet makes allogeneic NK cells an attractive
the-shel product that decreases the cost and delay to option or adoptive cellular therapy peritransplant.
treatment seen with autologous CAR T therapy. Fur- Adoptive transer o NK cells has previously been
thermore, there is evidence that autologous immune limited by the small numbers o circulating NK cells
cells are dysunctional in cancer,40 and thus it might be (5%–15% o the total lymphocytes) and consequently
ideal to use allogeneic cells. the low numbers obtained in an apheresis procedure.44
NK eector unction is dictated by an integration Thus, techniques that have been used to expand NK
o activating and inhibitory signals received through cells ex vivo rom hematopoietic or induced pluripo-
germline-encoded receptors that can recognize ligands tent stem cell–derived NK cells45 or to use an immortal-
ChaptER 22
on their cellular targets. This interplay between ized NK cell line.46 At MDACC, we have developed a
receptors is complex because certain ligands, such as novel method to expand cord blood NK cells in vitro
CD155, can bind to both activating and inhibitory by using engineered K562 “eeder cells” with IL-2 and
receptors, and certain receptors can be either activat- are able to obtain clinically relevant cell numbers.47 Fur-
ing or inhibitory.41 thermore, cord blood NK cells appear to have higher
NK cells serve an important role in cancer immune expression o genes or cell cycle and replication than
surveillance. One method that cancer cells use to evade peripheral blood (PB) NK cells.48
HLA I
NK
NK
Normal Cancer
Activating Activating
NK ligand NK ligand
FIGURE 22–3 Selective killing o transormed cells by natural killer (NK) cells. In normal cells, the inhibitory signals triggered
by killer cell immunoglobulin-like receptor (KIR)–human leukocyte antigen (HLA) I molecule engagement overrides activating
signals. In the context o cancer, expression o stress ligands or activating receptors, in conjunction with low expression o HLA
I molecules, attenuates the triggering o inhibitory receptors and results in an activating signal.
Optimizing Natural Killer Cell Ecacy overall response rate (ORR) o 87%53; these striking
preliminary results were conrmed in larger trials54
NK cells have a class o highly polymorphic recep- and led to the FDA approval o nivolumab or patients
tors called killer cell immunoglobulin-like receptor with relapsed HL.
(KIR) that can be divided into inhibitory and activat- The potential importance o immune checkpoints
ing subtypes. The KIRs are inherited as haplotypes in AML has been demonstrated in preclinical studies,55
(KIR-A and KIR-B). The KIR-A haplotypes, ound in and clinical studies are currently underway. Zeidner et
one third o adults o European descent, have one al reported an ORR o 46% or patients with relapsed
activating receptor, but the KIR-B haplotypes have or reractory AML treated with high-dose cytarabine
two or more. Transplantation in AML rom a KIR-B ollowed by pembrolizumab.56
haplotype donor is associated with lower relapse rates
and superior survival.49 Donor KIR2DS1 (an activat-
ing KIR) and recipient HLA-C type infuence relapse REDUCING GRaFt-VERSUS-hOSt
risk. The KIR2DS1-associated reduction in the rate o DISEaSE
AML relapse is restricted to donors with HLA-C1/C1
or C1/C2, in whom KIR2DS1-expressing NK cells are Cellular Therapy or Treatment o Grat-
presumed to be “educated,” and the benet was elimi- versus-Host Disease
nated in transplants rom donors with HLA-C2/C2,
in whom KIR2DS1-expressing NK cells are expected Grades II to IV aGVHD occur in 25% to 60% o
to be tolerized in the setting o sel HLA-C2.50 Selec- MRDs and 45% to 70% o MUDs.57 Corticosteroid-
tion o adult or cord blood donors or ex vivo NK based therapy or grades II to IV aGVHD is unsatis-
cell expansion based on KIR genotype may thereore actory, with ewer than 50% o patients showing
enhance NK cell ecacy. a durable complete response. 58 Increasing severity
Similar to T-cells, NK cells can be modied with a o aGVHD is associated with incremental TRM and
CAR to enhance their activation and specicity. This inerior survival. Corticosteroid-reractory GVHD has
led to the rst-in-human phase I/II trial o CAR-trans- a poor prognosis. Numerous additional agents have
duced NK cells at MDACC in which cord blood NK been studied in combination with corticosteroids or
cells were modied to express a CAR against CD19 as second-line therapies and showed uniormly poor
and to secrete IL-15 to support their in vivo proliera- response rates and numerous complications, particu-
tion and persistence.51 In a heavily pretreated popularly viral reactivation.58 Although mesenchymal stro-
lation o patients with B-cell malignancies who had mal cells (MSCs) appear to show benet in smaller,
received a median o our prior lines o therapy, 8 o 11 single-center trials or steroid-reractory GVHD,59
(73%) patients responded ater only a single inusion, there did not appear to be a clear benet in the only
including patients with high-risk eatures such as Rich- phase 3 randomized controlled trial.60 Some benet
ChaptER 22
ter transormation or deletion 17p CLL. The inused was noted in post-hoc subset analyses o high-risk
CAR NK cells were detected as long as 1 year ater patients (day 28 OR, 58% MSC vs 37% placebo; P =
treatment. The therapy was well tolerated, and the .03) and pediatric patients (day 28, OR 64% MSC vs
only grade 4 toxicity observed was neutropenia and 23% placebo; P =.05), suggesting that MSCs may be
leukopenia rom the initial lymphodepleting chemo- a viable option or some patients. Further investiga-
therapy. Unlike CAR T-cells, no CRS or neurotoxicity tions are underway.60
were observed, and there were no cases o GVHD. A
phase II multicenter trial is planned. T-Cell Depletion or Prevention o Grat-versus-
Host Disease
Programmed Cell Death Protein 1 and A T-cell-replete transplant usually contains 1 to 5 ×

107 T-cells/kg recipient weight.61 T-cell depletion is
Programmed Cell Death Protein Ligand 1
the most potent method o preventing aGVHD but
Antibodies is associated with increased rates o grat rejection;
The interaction o PD-1 and PDL1 induces T-cell dys- delayed immune reconstitution; inectious complica-
unction, and manipulation o this pathway has oered tions, including Epstein-Barr virus (EBV)–driven post
a treatment strategy in a variety o malignancies. These transplant lymphoprolierative disease (PTLD); and
therapies have been most extensively studies in meta- increased relapse risk.62 T-cell depletion can be accom-
static solid tumors as monotherapy and in combina- plished ex vivo immunologically (T-cell antibodies,
tion with the anti-CTLA4 antibody ipilimumab.52 In positive CD34 selection) or by the use o physical sep-
one o the rst studies in hematologic malignancies, aration (eg, density gradients) or in vivo by the use o
23 patients with reractory or relapsed HL received the anti-T-cell antibodies such as antithymocyte globulin
PD-1–blocking antibody nivolumab with a reported (ATG) or alemtuzumab. In vivo T-cell depletion with
ATG reduces severe aGVHD and extensive cGVHD they have been used or GVHD prevention, as well
without increasing relapse but does not reduce TRM as treatment. In a study o 23 adult patients receiv-
or improve survival,62 likely because o increased inec- ing double-unit cord blood–derived grats, T-reg cells
tion risk. Alemtuzumab-based GVHD prophylaxis were administered or prevention o acute GVHD
achieves low rates o severe aGVHD and extensive with a reduction in risk o grades II to IV aGVHD
cGVHD but results in high rates o mixed chimerism relative to historical control participants (43% vs
and viral inections, particularly cytomegalovirus 61%; P = .05) and, importantly, similar DFS rates.70
(CMV) reactivation.63 A later report on 11 additional patients with higher
The alkylating agent cyclophosphamide is now being dose levels showed very low incidence o 9% o
used more requently as a method to eliminate cGVHD. acute GVHD and no patients with chronic GVHD at
Cyclophosphamide is metabolized by liver cytochrome 1 year ater transplant.71 In a small case series with
P450 into phosphoramide mustard and acrolein and pre- ve patients receiving T-reg cells or as treatment or
vents cell division by crosslinking DNA strands. HSCs chronic GVHD, two patients had clinical improve-
benet rom having a higher level o the enzyme alde- ment o symptoms, and three had a stable disease.72
hyde dehydrogenase, used to convert phosphoramide However, two o the patients developed skin cancers
mustard into the inactive metabolite carboxycyclophos- within 1 year o T-reg transusion. Larger clinical tri-
phamide. Administering cyclophosphamide a ew days als are needed to validate these results and address
ater transplant was rst introduced into clinical prac- saety issues as well as this therapy’s impact on the
tice on trials with haploidentical donor grat transplants grat-versus-leukemia eect.
at Johns Hopkins University64 in an eort to reduce Adoptive transer o other immune-modulating
GVHD but has now extended across donor types as a cells, such as “veto” cells capable o inducing immune
mechanism to eliminate grat alloreactive CD4+ cells tolerance, are also being explored in preliminary clini-
in donor grats65 and donor grat sources.66 In a recent cal trials. These may also allow or more ecient “o-
report o patients with AML or MDS who had check- the-shel” CAR T-cell therapy by inducing tolerance
point inhibitor therapy beore proceeding with HCT, and preventing rejection o these allogeneic cells.73
the use o posttransplant cyclophosphamide reduced
severe acute GVHD and improved PFS.67
pREVENtING aND tREatING
Adoptive Transer o Regulatory T-Cells INFECtION WIth VIRal-SpECIFIC
The level o CD4+CD25+FOXP3+ T-reg cells in the t-CEllS
grat and ater HCT correlates inversely with aGVHD
and cGVHD.68 Thereore, adoptive transer o T-reg Delayed recovery o cellular and humoral immunity
cells could ameliorate GVHD. Ater sorting and expan- results in morbidity and mortality rom inection.
ChaptER 22
sion, adoptive transer o T-reg cells has been shown in Figure 22–4 shows the approximate time course o
murine xenogenic GVHD models to prevent and treat numeric recovery o immune cells ater HCT; Figure
GVHD, improving survival.69 22–5 shows the time course o inections.
Early-phase clinical trials have shown posttrans- Viral inection is a major cause o death ater HCT,
plant adoptive transer o T-reg cells to be sae, and resulting rom cellular and humoral immune deciency;
140
↓ Graft infusion
120
100
80
60 Neutrophils, monocytes, NK cells

B cells, CD8 T-cells
40 CD4 T-cells
Plasma cells, Dendritic cells
20 Upper normal limit
Lower normal limit
0
Weeks Months Years post transplant
FIGURE 22–4 Time course o numeric cellular immune recovery posttransplant. (Reproduced with permission rom Mackall C,
Fry T, Gress R, et al. Background to hematopoietic cell transplantation, including post transplant immune recovery, Bone Marrow
Transplant 2009 Oct;44(8):457-462.)
Phase I: pre- Phase II: post- Phase III: late phase

engraftment engraftment
Chronic
Graft-versus-host-disease: acute
Impaired cellular and

Neutropenia, barrier Impaired cellular and
humoral immunity; NK cells
breakdown (mucositis, humoral immunity; B cell
recover first, CD8 T-cell
central venous access and CD4 T-cell numbers recover
numbers increasing but
devices) slowly and repertoire diversifies
restricted T-cell repertoire
Less common
Gram negative bacilli
Bacterial
Gram positive organisms Encapsulated bacteria

Gastrointestinal streptococci species
Herpes simplex virus

Cytomegalovirus Varicella zoster virus
Viral
Respiratory and enteric viruses (seasonal/intermittent)
More common
Other viruses, eg, HHV
EBV PTLD
Aspergillus species Aspergillus species

Fungal
Candida species
Pneumocystis
Day 0 Day 15-45 Day 100 Day 365 and beyond
FIGURE 22–5 Time course o inections ater transplant. (Reproduced with permission rom Mackall C, Fry T, Gress R, et al.
Background to hematopoietic cell transplantation, including post transplant immune recovery, Bone Marrow Transplant 2009
Oct;44(8):457-462.)
risk actors include umbilical CB transplantation, T-cell can be generated rom naïve CB cells by genetically
depletion, and GVHD requiring systemic immunosup- modiying EBV lymphoblastoid cell lines transduced
pression. Viral inections o particular relevance ater with an adenoviral vector expressing the CMVpp65
ChaptER 22
HCT are CMV, EBV, the polyoma viruses BK and JC, transgene.76 These are highly active against virus
adenovirus, and human herpesvirus 6 (HHV-6). Pharma- despite recognition o noncanonical CMV and EBV
cotherapy or these inections has limited ecacy and epitopes,76 and clinical results are encouraging.77,78
substantial toxicity. Consequently, adoptive immuno- Third-party, banked VSTs rom adult donors can
therapy or the prevention and treatment o viral reacti- also be used to treat viral reactivation in patients with-
vation or inection ater transplant is attractive. out an available adult donor or in whom rapid disease
Generation o viral-specic T-cells (VSTs)s is most progression precludes waiting or generation o VSTs
straightorward rom an immune-experienced adult rom their donor. Suitable lines (which are dependent
donor who has viral-specic memory T-cells specic on the recipient expressing immune dominant viral
in the PB. The VSTs rom such donors can be gener- peptides on an HLA antigen shared by a donor VST
ated in two ways74: line) are available in approximately 90% o patients
and can be rapidly identied and made available.
1. T-cell co-culture, in the presence o specic cyto-
VSTs demonstrated high response rates in patients
kines, with an articial APC modied to express the
with reractory CMV, adenovirus, and EBV-related
immune dominant antigens o the target virus and
PTLD.78–80
costimulatory molecules
In a recent review o 229 patients who received
2. Rapid selection strategies without ex vivo culture.
VST or viral inections occurring ater transplant, the
These rely on the presence o sucient numbers o
response rate was 91.3%.81 Interestingly, despite the
VSTs in the donor PB and hence are limited to CMV
theoretical risk o inducing GVHD due to HLA mis-
and EBV.75
match, no severe cases o de novo aGVHD were seen
Generation o VSTs rom immunologically naïve in initial studies, and retreatment was successul in
donors (eg, CB) is more challenging. However, multivi- several cases despite initial immunologic rejection o
rus-specic T-cells against EBV, CMV, and adenovirus the transerred cells.78,79
Treatment o Specifc Inections with ganciclovir prophylaxis or preemptive therapy.92 In

Viral-Specifc T-Cells 2017, letermovir, which targets the HCMV DNA
terminase complex, was licensed or prophylaxis o
Epstein-Barr Virus Reactivation and HCMV inections in HCT recipients and has lowered
Posttransplant Lymphoprolierative Disorder the rate o reactivation. Use o letermovir is limited
PTLD related to EBV occurs in the setting o severe by emerging drug resistance and drug expense. 93 Gas-
transplant-related immunosuppression when the trointestinal disease, pneumonia, and retinitis are
EBV-specic T-cell response is insucient to con- the most common maniestations; pneumonia has a
trol latent EBV inection within recipient or donor high mortality rate despite treatment with ganciclo-
B cells. Risk actors or inection predominantly relate vir or oscarnet and CMV immunoglobulin.92 Given
to the degree o immunosuppression in recipients o the toxicity and expense associated with pharmaco-
T-cell-depleted transplants. Patients typically present logic interventions and their imperect ecacy, cel-
with high ever and lymphadenopathy with elevated lular therapy as treatment or prophylaxis o CMV in
serum lactate dehydrogenase levels. Initial therapy high-risk patients is attractive. In one study, 40 o 47
or EBV reactivation is reduction in immunosuppres- patients with CMV inection or disease reractory
sion. However, there are no randomized studies to to antiviral therapy were treated with CMV CTLs
guide the best therapy o established EBV-associated and cleared the virus ater one or two inusions. In
PTLD. In patients with rank PTLD, the largest study82 another study, 110 patients received CMV CTLs as a
showed a 70% complete response/complete response prophylaxis 28 to 115 days ater HCT. Reactivation
undened rate with our weekly doses o rituximab o CMV in patients receiving CMV CTLs was 16%
monotherapy, but there were poor responses to subse- while reactivation in the control cohort was 66%.
quent treatment (chemotherapy, DLI, or both) in non- No statistically signicant severe de novo GVHD has
responders. Chemotherapy is associated with greater been reported ater CMV CLT inusion. 94–99
toxicity in HCT recipients and may increase inec-
tion risk. Cellular therapy shows great promise in the Adenovirus Inection
management o EBV-related PTLD. Unmanipulated
donor T-cell inusions can control established PTLD in Adenovirus inection occurs in up to 21% o transplant
approximately 70% o patients but can induce severe recipients, with maniestations o adenovirus disease
or atal GVHD.83 Thereore, when available, VSTs are in 20% to 89% o inected patients.100 Four clinically
preerred. The EBV-specic or polyvirus-specic cyto- signicant syndromes are seen: pneumonitis, nephritis,
toxic T lymphocytes (CTLs) have proven successul hemorrhagic colitis, and hemorrhagic cystitis. Dissemi-
in overt PTLD in 77.5% o patients, including patients nated disease with multiorgan ailure also occurs and
with rituximab-reractory disease.84 EBV CTLs have has a poor outcome despite antiviral therapy; most suc-
ChaptER 22
been administered in the prophylactic setting in more cessully treated cases are respiratory or urinary tract
than 100 patients, and no patient has developed EBV- inections. Adenovirus-specic T-cells can now be gen-
PTLD with up to 15-year ollow-up.75,85–91 erated rom both CB76,77 and adult donors,77 with a high
clinical response rate in cidoovir-reractory cases.101
Donor-derived adenovirus-specic T-cells have been
Cytomegalovirus Inection used recently in a high-risk pediatric trial with a 100%
response rate with no serious toxicity noted.91,102
Risk actors or CMV reactivation and disease
ater HCT include receiving umbilical CB grats,
BK and JC Virus Inections
T-cell-depleted grats, T-cell antibody therapy or
GVHD prophylaxis, or high-dose steroids. 92 In addi- BK virus reactivation occurs in 5% to 68% o HCT
tion, CMV-seropositive patients with seronega- recipients. It can cause severe hematuria, urinary
tive donors are at particularly high risk because o obstruction, renal ailure, and increased mortality.
the lack o memory T-cells against CMV rom the It is more requent in patients with grades III and IV
seronegative donor.92 Although ganciclovir prophy- aGVHD and CB transplants.103 Pharmacologic therapy
laxis reduces the risk o CMV disease, it prolongs is toxic and poorly ecacious. JC virus–associated
neutropenia, increases invasive bacterial and ungal progressive multiocal leukoencephalopathy (PML)
inections, and does not improve survival.92 Close occurs in immunosuppressed individuals and car-
monitoring or CMV reactivation in blood, ollowed ries a grim prognosis with limited treatment options,
by preemptive therapy with ganciclovir when assays although PD-1 inhibition does show some prom-
in blood become positive, reduces the incidence o ise.104,105 Because o the homology in immunogenic
CMV disease. Overall, rates o CMV disease have proteins between BK and JC, BK-0specic CTLs have
declined rom 30% to 35% to 8% to 10% with been used in the treatment o patients with PML with
good response rates.106 BKV CTLs have been included BKV, and HHV-6) viruses included or use in both the
in multivirus-specic T-cell clinical trials with response prophylactic and treatment setting. Clinical studies
rates approaching 100%.91 have shown response rates rom 67% to 100% with
no increase in incidence o severe GVHD or other
Human Herpes Virus 6 Inection toxicity.108,109
Inection with HHV-6 is virtually universal beore

age 2 years.107 Reactivation occurs in more than 50% CONClUSION
o allograt recipients and can result in encephalitis,
delayed engratment, and increased rate o GVHD, Allogeneic HCT, initially perormed in a twin patient
with increased mortality rates.107 A response rate o with leukemia by Dr. E. Donnall Thomas in the late
67% was reported in a clinical study in which HHV-6 1950s, was one o the rst elegant demonstrations o
was included in a multivirus-specic T-cell inusion.91 the power o cellular therapy. Much has been learned
since then, and our increased understanding o the
Multivirus Viral-Specifc T-Cells immune system has translated into exciting new thera-
peutic approaches, especially relevant to transplanta-
Some investigators have generated multiple-virus spe- tion and its complications, leading to continued better
cic T-cells, with 2 ,3, 4, and 5 (EBV, CMV, adenovirus, outcomes or patients.

J Allogeneic HCT is curative or a subset o patients J The incorporation o post transplant cyclophospha-
with hematologic malignancies. mide has led to decreased rates o GVHD.
J Adoptive inusion o CAR T-cells have shown J Ruxolitinib is the frst approved agent or steroid-
remarkable ecacy or patients with reractory ALL reractory acute GVHD.
and NHL; CAR T-cells in conjunction with transplant J VSTs can be very eective in patients with specifc
is under investigation. viral inections such as CMV, EBV, polyoma viruses
J Inusion o allogeneic NK T-cells provide a readily BK and JC, adenovirus, and HHV-6.
available source o eective immunotherapy; trials
are underway.
ChaptER 22
lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2

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ChaptER 22
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80. Vasileiou S, Turney AM, Kuvalekar M, et al. Rapid genera- macotherapy ater allogeneic stem cell transplantation. Blood.
tion o multivirus-specic T lymphocytes or the prevention 2013;121(18):3745-3758.
and treatment o respiratory viral inections. Haematologica. 98. Koehne G, Hasan A, Doubrovina E, et al. Immunotherapy with
2020;105(1):235-243. donor T Cells sensitized with overlapping pentadecapeptides
81. Qian C, Wang Y, Reppel L, et al. Viral-specic T-cell transer or treatment o persistent cytomegalovirus inection or vire-
rom HSCT donor or the treatment o viral inections or dis- mia. Biol Blood Marrow Transplant. 2015;21(9):1663-1678.
eases ater HSCT. Bone Marrow Transplant. 2018;53(2):114-122. 99. Bao L, Cowan MJ, Dunham K, et al. Adoptive immunother-
82. Fox CP, Burns D, Parker AN, et al. EBV-associated post-trans- apy with CMV-specic cytotoxic T lymphocytes or stem cell
plant lymphoprolierative disorder ollowing in vivo T-cell- transplant patients with reractory CMV inections. J Immuno-
depleted allogeneic transplantation: clinical eatures, viral load ther. 2012;35(3):293-298.
correlates and prognostic actors in the rituximab era. Bone 100. Chakrabarti S, Mautner V, Osman H, et al. Adenovirus inec-
Marrow Transplant. 2014;49(2):280-286. tions ollowing allogeneic stem cell transplantation: incidence
83. Heslop HE, Leen AM. T-cell therapy or viral inections. Hema- and outcome in relation to grat manipulation, immunosup-
tology Am Soc Hematol Educ Program. 2013;2013:342-347. pression, and immune recovery. Blood. 2002;100(5):1619-1627.
84. Mika T, Strate K, Ladigan S, et al. Reractory Epstein-Barr virus 101. Geyeregger R, Freimuller C, Stemberger J, et al. First-in-man
(EBV)-related post-transplant lymphoprolierative disease: cure clinical results with good manuacturing practice (GMP)-com-
by combined brentuximab vedotin and allogeneic EBV-specic pliant polypeptide-expanded adenovirus-specic T cells ater
T-lymphocytes. Front Med. 2019;6:295. haploidentical hematopoietic stem cell transplantation. J Immu-
85. Heslop HE, Slobod KS, Pule MA, et al. Long-term outcome o nother. 2014;37(4):245-249.
EBV-specic T-cell inusions to prevent or treat EBV-related 102. Ip W, Silva JMF, Gaspar H, et al. Multicenter phase 1/2 appli-
lymphoprolierative disease in transplant recipients. Blood. cation o adenovirus-specic T cells in high-risk pediatric
2010;115(5):925-935. patients ater allogeneic stem cell transplantation. Cytotherapy.
86. Gustasson A, Levitsky V, Zou JZ, et al. Epstein-Barr virus (EBV) 2018;20(6):830-838.
load in bone marrow transplant recipients at risk to develop 103. Rorije NM, Shea MM, Satyanarayana G, et al. BK virus disease
posttransplant lymphoprolierative disease: prophylactic inu- ater allogeneic stem cell transplantation: a cohort analysis. Biol
sion o EBV-specic cytotoxic T cells. Blood. 2000;95(3):807-814. Blood Marrow Transplant. 2014;20(4):564-570.
104. Walter O, Treiner E, Bonneville F, et al. Treatment o Progres- patients undergoing allogeneic hematopoietic stem cell trans-
sive Multiocal Leukoencephalopathy with Nivolumab. N Engl plantation. Cytotherapy. 2015;17(10):1406-1420.
J Med. 2019;380(17):1674-1676. 109. Papadopoulou A, Gerdemann U, Katari UL, et al. Activ-
105. Cortese I, Muranski P, Enose-Akahata Y, Ha et al. Pembroli- ity o broad-spectrum T cells as treatment or AdV, EBV,
zumab Treatment or Progressive Multiocal Leukoencepha- CMV, BKV, and HHV6 inections ater HSCT. Sci Transl Med.
lopathy. N Engl J Med. 2019;380(17):1597-1605. 2014;6(242):242ra83.
106. Mutuoglu M, Olson A, Marin D, et al. Allogeneic BK virus- 110. Lee DW, Kochenderer JN, Stetler-Stevenson M, et al. T cells
specic T cells or progressive multiocal leukoencephalopathy. expressing CD19 chimeric antigen receptors or acute lympho-
N Engl J Med. 2018;379(15):1443-1451. blastic leukaemia in children and young adults: a phase 1 dose-
107. Gerdemann U, Keukens L, Keirnan JM, et al. Immunothera- escalation trial. Lancet. 2015;385(9967):517-528.
peutic strategies to prevent and treat human herpesvirus 6 111. Shalabi H, Delbrook C, Stetler-Stevenson M, et al. Chimeric
reactivation ater allogeneic stem cell transplantation. Blood. antigen receptor T-cell (CAR-T) therapy can render patients
2013;121(1):207-218. with ALL into PCR-negative remission and can be an eec-
108. Ma CK, Blyth E, Clancy L, et al. Addition o varicella zoster tive bridge to transplant (HCT). Biol Blood Marrow Transplant.
virus-specic T cells to cytomegalovirus, Epstein-Barr virus and 2018;24(suppl 3):S25-S26.
adenovirus tri-specic T cells as adoptive immunotherapy in
ChaptER 22
SECTION IV Lung Cancer
23 Small Cell Carcinoma of the Lung
24 Non–Small Cell Lung Cancer: General Principles, Management

of Localized Disease, and Treatment of Metastatic Disease
without Oncogene Drivers
25 Targeted Therapies in Non–Small Cell Lung Cancer

23 Small Cell Carcinoma of the Lung
Jeremy A. Ross
Lauren A. Byers
Carl M. Gay
KEY CONCEPTS
 Small cell lung cancer (SCLC) is an aggressive malignancy  Numerous clinical trials have established the eectiveness
or which outcomes remain poor. The majority o patients o prophylactic cranial irradiation (PCI) in decreasing the
present with metastatic disease, and ew patients are incidence o intracranial disease, although its impact on
cured, even among those that present with early-stage survival has been variable. All patients with limited-stage
disease. There is an urgent need or more eective thera- disease who respond to treatment should receive PCI. The
pies or this disease. use o PCI in patients with extensive-stage disease remains
 For patients with stage I disease, surgical resection should controversial.
be considered i mediastinal staging is negative. Adjuvant  First-line chemoimmunotherapy has recently been shown
chemotherapy with our cycles o etoposide–cisplatin to improve survival in patients with extensive-stage dis-
(EP) should be considered or all patients with surgically ease. The development and understanding o biomarkers
resected SCLC and no lymph node metastases ound at or response to immunotherapy is progressing and may
the time o resection. improve outcomes or some patients.
 Most patients with limited-stage disease are treated with  Treatment options are limited or patients with recur-
concurrent chemoradiotherapy. Although carboplatin is rent disease, and clinical trials are recommended when
requently used in patients with extensive-stage disease, easible. There are no approved targeted agents or SCLC
EP with twice-daily radiation therapy remains the standard despite a plethora o trials.
o care in patients without contraindications to cisplatin.
Small cell lung cancer (SCLC) is an aggressive broncho- staging o SCLC.2 Clinically, the limited- and exten-
genic carcinoma representing 14% o all lung cancers, sive-stage classication is practical given that most
accounting or approximately 30,000 new cases annu- patients present with advanced disease (stages III–IV)
ally in the United States.1 It is distinguished rom non– and are rarely candidates or resection or other deni-
small cell lung cancer (NSCLC) by its rapid doubling tive therapies.
time and early metastatic dissemination. Regional Standard treatment or patients with LD (stages I–
lymph node involvement or distant metastasis is pres- IIIB) includes both chemotherapy and radiation; che-
ent in 90% or more o patients at diagnosis. Histori- motherapy is the mainstay o treatment or ED (stage
cally, SCLC has been staged as limited disease (LD), IV). Although a dramatic response to initial therapy is
which is conned to the ipsilateral thorax o origin usually observed, more than 95% o patients with ED
and regional nodes, versus extensive disease (ED). The and 80% to 90% o those with LD eventually have a
recent International Association or the Study o Lung relapse and die o their disease.
Cancer (IASLC) staging project and American Joint Despite extensive research, ew substantive
Committee on Cancer/International Union Against advances in the systemic treatment o patients
Cancer (AJCC/UICC), eighth edition, suggest use o with SCLC have been made or decades. However,
the tumor, node, metastasis (TNM) system or the molecular proling and preclinical models o SCLC
475
476 Scion IV Lung Cancer
have increased our understanding o the biology and NATURAL HISTORY

genomic changes in the pathogenesis o SCLC. The
use o immune checkpoint inhibitors has improved The natural history o SCLC was documented in the
survival, and the translation o preclinical research to placebo arm o a randomized trial rom the Veterans
the clinic has brought promising data with targeted Administration Lung Cancer Study Group (VALSG)
therapies, providing hope that urther improvements reported in 1969, testing the eect o three doses o
in outcomes or patients are on the horizon. intravenous (IV) cyclophosphamide.7 In this trial, the
median survival periods or patients in the placebo
arm were 6 weeks or those with ED and 12 weeks or
EPIDEMIOLOGY those with LD, based on the primitive staging studies
that were available at that time. Because o the avail-
SCLC is uncommon in never smokers, who consti- ability o modern staging techniques, outcomes in
tute only 3% to 5% o cases, and is commonly asso- both groups would be likely better today. Cyclophos-
ciated with intense tobacco exposure.3,4 However, phamide increased the median survival by 75 days in
transormation to SCLC has been documented in both groups, tripling the survival time o patients with
never smokers with epidermal growth actor recep- metastases and doubling that o patients with LD. This
tor (EGFR) mutation–positive adenocarcinoma o the was the rst observation oretelling the important role
lung, in the setting o resistance to tyrosine kinase chemotherapy would come to play in management o
inhibitors. 5 The original EGFR mutation is main- patients with SCLC.
tained in the SCLC, supporting the notion that the The use o eective combination chemotherapy
tumor evolved rom transormation and is not a sec- and, in the case o patients with tumor amenable to
ond primary cancer. denitive radiation, the use o multimodality treat-
The incidence o SCLC has steadily declined, as ment have improved survival o patients with SCLC.1
illustrated by an analysis o the Surveillance, Epide-
miology, and End Results (SEER) database, 1 in which
the proportion o SCLCs decreased rom 17% in PROGNOSTIC FACTORS
1986 to 13% in 2002. However, this decrease was
accompanied by an increase in SCLC cases arising The most important prognostic actor or SCLC is the
in women (28% in 1973 vs 50% in 2002), attributed stage because patients with LD have improved survival
to increasing tobacco use among women starting in compared with those with ED.8 Among patients with
the 1960s. The reduced incidence is primarily due to LD, good perormance status (PS), age younger than
decreased smoking in men and may also be due in 70 years, emale gender, and normal lactate dehydro-
part to changes in the pathologic criteria leading to genase (LDH) levels are predictive o a avorable out-
the classication o cases as large cell neuroendocrine come.8 Among these patients, a small subgroup with
carcinoma (LCNEC) that would have been previously very LD (no mediastinal involvement) was ound to
classied as SCLC. have a longer median survival time when treated with
surgery.9 In patients with ED, normal LDH, multidrug
regimen treatment, and a single metastasis predicted
better outcomes. Liver or cerebral metastases coner
RISK FACTORS signicantly shorter survival compared with bone, sot
tissue, or bone marrow involvement.10 Paraneoplastic
O all lung cancer subtypes, SCLC shows the stron- syndromes (PNSs) may also predict outcome. Patients
gest association with tobacco exposure, which rep- with the syndrome o ectopic corticotrophin (ACTH)
resents the most important risk actor.4 The risk is secretion producing clinical Cushing syndrome have a
related to both duration (>40 years) and intensity o dismal prognosis, with a low response to chemotherapy
tobacco use (>30 cigarettes/day). This risk is lower and poor control o hypercortisolism ater treatment.8
in ormer smokers versus current smokers, although Lambert-Eaton myasthenic syndrome (LEMS), an auto-
the risk in ormer smokers still exceeds that o nonimmune PNS, coners a more avorable prognosis, pre-
Chapter 23
smokers. 4 Additional risk actors include exposure to sumably because o immunity against the cancer.11
asbestos, benzene, coal tar, and radon gas, usually
as co-carcinogens with tobacco. Smoking cessation
should be encouraged as primary prevention. Patients PATHOBIOLOGY
with LD who continue to smoke during or ater
chemoradiation experience increased toxicity, have SCLC is dened by light microscopy as a malignant
a high risk o second lung cancers, and have shorter epithelial tumor consisting o small cells, with a round
survival times than those who quit.6 to usiorm shape, scant cytoplasm, nely granular
C 23 Small Cell Carcinoma of the Lung 477
as low-grade, well-dierentiated NETs do, such as car-

cinoids. In 10% o cases, all neuroendocrine marker
results may be negative, and the diagnosis can still be
established i the morphology is diagnostic. Thyroid
transcriptase actor 1 (TTF-1) is expressed in 70% to
90% o SCLCs; however, this marker may also be
expressed in extrapulmonary small cell carcinomas
and thus does not refect lung origin.15 The expres-
sion o TTF-1 may refect molecular dierences that
could help guide treatment.16 The Ki-67 staining index,
refecting prolieration, is generally greater than 50%
in SCLC and can be used to dierentiate SCLC rom
lower-grade NETs.17
FIGUre 23–1 Light microscopic images of small cell lung MOLECULAR FEATURES
cancer. Note the small, round, and spindle-shaped cells with
hyperchromic nuclei and scant cytoplasm. SCLC is characterized by genomic alterations, biology,
and clinical behavior that are distinct rom the interme-
diate- and low-grade pulmonary NETs. Loss o unc-
nuclear chromatin, and absent or inconspicuous nucle- tion alterations in the tumor suppressors tumor protein
oli.12 Nuclear molding and necrosis are requent, and 53 (TP53) and the retinoblastoma 1 (RB1) gene at 13q14
mitotic rates are high (Fig. 23–1). Tumors usually grow occur in virtually all patients with SCLC.18,19 Haploin-
in diuse sheets, but rosettes, peripheral palisading, suciency caused by allele loss in multiple areas on
organoid nesting, streams, ribbons, and rarely, tubules chromosome 3p, including 3p21.3,3p12,3p14.2, and
or ductules may be present. Typically, the diagnosis 3p24.4, leads to absent or lower expression o several
is made rom small biopsies and cytology specimens tumor-suppressor genes in more than 90% o SCLCs
because surgery is rarely perormed. Because o signi- and is an early event in tumorigenesis.13
cant crush artiact, biopsies are sometimes more prob- In addition to near-ubiquitous TP53 and RB1 inacti-
lematic in diagnosis than cytology specimens. vation, genomic proling o SCLC tumors revealed re-
SCLC is a “small, round, blue cell tumor” using a quent (25%) inactivating mutations in NOTCH amily
hematoxylin and eosin stain, and the dierential diag- genes (PMID:26168399). Along with NOTCH amily
nosis includes other small, round, blue cell tumors, mutations, additional mutually exclusive alterations
including lymphomas and small cell sarcomas. Histo- are requent among histone acetyltranserase genes
logically, identical tumors can arise in other organs (eg, such as CREB-binding protein (CREBBP) and E1A
nasopharynx, larynx, genitourinary or gastrointestinal binding protein P300 (EP300), as well as several genes
tract, and cervix) and are termed extrapulmonary small related to TP53 and RB1 (tumor protein 73 (TP73),
cell carcinomas. Both pulmonary and extrapulmonary retinoblastoma-like 1 (RBL1), and retinoblastoma-like
small cell carcinomas have similar biological eatures 2 (RBL2) ((PMID:26168399)). Amplication o MYC
and clinical behavior, with high potential or wide- amily members (v-myc avian myelocytomatosis
spread disease. However, malignant cells rom extra- viral oncogene homolog, MYC, MYCL1, and MYCN)
pulmonary small cell carcinomas do not exhibit 3p is detected in 20% o SCLCs.18 Loss o phosphatase
deletions, which are common in SCLCs, indicating, at and tensin homolog (PTEN) is observed in 2% to 4%
least in part, dierences in carcinogenesis.13 o tumors20; however, the phosphoinositide 3-kinase
Immunohistochemical (IHC) markers are valuable (PI3K) pathway alteration rate be overall higher and
in dierential diagnosis o SCLC. Positive pancytoker- promote SCLC tumorigenesis in preclinical models.
atin (AE1/AE3) staining helps to identiy the tumor as a Dierential patterns o gene expression underlie sig-
carcinoma rather than a lymphoma or sarcoma.12 Neu- nicant inter-tumoral diversity among SCLC (PMID:
Chapter 23
ral cell adhesion molecule (CD56), chromogranin, and 20926931). The neuroendocrine-high (previously clas-
synaptophysin are the most useul markers. Whereas sic) SCLC subtype, now reerred to as SCLC-A, is driven
CD56 expression is detectable in approximately 90% largely by the expression o the transcription actor
to 100% o cases, SCLC may be negative or expres- achaete-scute homolog 1 (ASCL1) and its transcrip-
sion o neuroendocrine markers, such as chromogranin tional targets (PMID: 2985258,27452466). Meanwhile,
and synaptophysin.14 SCLC is a primitive undieren- neuroendocrine-low (previously variant) SCLC is com-
tiated high-grade neuroendocrine tumor (NET) and posed o several unique subtypes, including a neuro-
does not typically express these proteins as intensely nal dierentiation 1 (NEUROD1)-regulated subtype
TABLE 23-1 Representative List of Common or CLINICAL PRESENTATION

Potentially Targetable Genomic and Proteomic
Alterations According to Percentage in Small Cell SCLC typically arises in the central airways and inl-
Lung Cancer trates the submucosa, with a tendency to narrow the
bronchial lumen through extrinsic or endobronchial
Gene Mutation Frequency (Type of Mutation) spread, in contrast to squamous cell carcinomas, in
TP53 75%–90% which polypoid luminal occlusion is common. Rapid
Loss o unction (mutation, LOH, deletion) intrathoracic tumor growth, lymphatic and distant
RB1 ~100% spread, and maniestation o PNSs can cause severe
Loss o unction (mutation, LOH, deletion) and progressive symptoms that lead to diagnosis gen-
PTEN ~5% erally within 3 months rom onset. Common clini-
Loss o unction (mutation, LOH, deletion) cal maniestations include cough, dyspnea, weight
MYC 18%–31% MYC amily alterations overall
loss, and debility. Hemoptysis and postobstructive
Gain o unction (amplifcation or pneumonia are relatively uncommon because o
transcriptional dysregulation) the submucosal growth pattern o the tumor. Bulky
involvement o mediastinal lymph nodes is a hall-
SOX2 27%
Gain o unction (amplifcation) mark o SCLC, and syndromes resulting rom mass
eects are commonly seen, including superior vena
FGFR1 <10%
cava syndrome, hoarseness (rom recurrent laryngeal
Gain o unction (amplifcation, mutation)
nerve compression), phrenic nerve palsy, dysphagia
CCNE1 <10% (rom esophageal compression), and stridor (rom
Gain o unction (amplifcation)
tracheal compression). SCLC is the most common
EPHA7 <10% malignant cause o superior vena cava obstruction.
Gain o unction (amplifcation) Radiographically, a large hilar mass with bulky medi-
PARP1 >50% astinal adenopathy is commonly observed (Fig. 23–2),
(overexpression o protein target) although occasional peripheral satellite nodules may
CCNE1, cyclin E1; EPHA7, ephrin receptor A; FGFR1, fbroblast growth actor be ound.
receptor 1; MYC, v-myc avian myelocytomatosis viral oncogene homolog; PARP, Most patients (60%–70%) present with overt met-
poly(ADP-ripose) polymerase 1; PTEN, phosphatase and tensin homolog; RB1,
retinoblastoma 1; SOX2, sex-determining region Y box 2; TP53, tumor protein 53. astatic disease; common sites o metastasis include
liver, adrenals, bone, bone marrow, and brain. Symp-
toms o metastatic disease can include bone or abdom-
inal pain, headache, seizures, atigue, and anorexia.
(SCLC-N) and a subtype originating in pulmonary tut Occasionally, patients may present with PNSs, such
cells driven by the expression o POU domain, class 2, as syndrome o inappropriate antidiuretic hormone
transcription actor 3 (POU2F3, SCLC-P) (PMID: 2985 (SIADH) or LEMS.
258,27452466,28089889,29945888).
At the protein level, increased expression o cKit,
and its ligand stem cell actor, is detected in up to 80%
to 90% o SCLC surgical specimens.21 The BCL-2 am-
ily proteins exert an antiapoptotic eect and may be
upregulated in 75% to 95% o SCLCs.18 More compre-
hensive proteomic proling by reverse phase protein
array has identied dierences in protein expression
between SCLC or LCNEC and other NSCLC cancers,
including the DNA repair protein poly(ADP-ribose)
polymerase 1 (PARP1).22
Alterations in epigenetic regulation o the genome
may be involved in SCLC biology. Sequencing o SCLC
Chapter 23
exomes has led to the identication o histone modi-

cation as a major eature. Mutations in CREBBP and
EP300 are common in SCLC and may clustered around
the histone acetyltranserase (HAT) domain, signi-
cantly impacting the activity o these genes, and sup-
ports a role or the loss o their unction in SCLC.23,24 FIGUre 23–2 Bulky involvement of mediastinal adenopa-
Table 23–1 describes common genomic and proteomic thy (black arrow) at computed tomography scan of chest in a
alterations that occur in SCLC. patient with extensive-stage small cell lung cancer.
STAGING patients with LD who are candidates or denitive

therapy. In the presence o obvious ED, staging may be
The two-stage system originally proposed by the clinically directed. Brain imaging should be obtained
VALSG in the late 1950s and later modied by the in all patients, given the morbidity o uncontrolled
IASLC is currently used or simplicity and practicality. central nervous system (CNS) disease.27 Imaging o
LD is dened as a tumor conned to one hemithorax, the CNS reveals brain metastases in 10% to 15% o
with involvement o regional nodes, including contra- patients at diagnosis, with 30% o these individuals
lateral mediastinal or ipsilateral supraclavicular nodes, asymptomatic.
that can be included in a single tolerable radiother- In patients with apparent stage I disease (T1-2N0),
apy (RT) port (TNM stages I–IIIB). ED is dened as a surgical resection should be considered i mediastinal
tumor beyond the boundaries o LD, including distant staging results are negative9 by conventional mediasti-
metastases, malignant pericardial or pleural eusions, noscopy, transesophageal endoscopic ultrasound-guided
and contralateral supraclavicular and contralateral ne-needle aspiration, endobronchial ultrasound-guided
hilar node involvement (TNM stage IV, any T, any transbronchial needle aspiration, or video-assisted tho-
N, M1a/b). More recently, IASLC proposed changes racoscopy. I a pleural eusion is present in a patient
to the TNM NSCLC staging system, mainly in T and with otherwise LD, thoracentesis should be perormed
M descriptors and stage groupings. These changes and fuid sent or cytology. I the fuid is exudative or i
have been incorporated into the AJCC seventh and malignant cells are present, the patient should be consid-
eighth editions, which recommend TNM staging or ered to have ED (stage IV: M1a). Although most pleural
SCLC and NSCLC.25 However, the two-stage system eusions in lung cancer are related to the malignancy,
continues to be used in clinical practice because most there may be a ew instances in which multiple cyto-
patients present with advanced disease (stages III and pathological examinations are negative or malignancy
IV) and are only rarely candidates or surgery. This and the pleural fuid is not an exudate. When these ele-
system has prognostic signicance and clinical impli- ments and clinical judgment indicate that a pleural eu-
cations because patients with LD are candidates or sion is not malignant, the eusion should be excluded
chemoradiation with curative intent, but patients with as a staging element. Pericardial eusion is classied
ED receive chemotherapy with or without immuno- according to the same criteria.
therapy and palliative radiation as clinically indicated. Sampling o cerebrospinal fuid is indicated i lep-
Approximately 30% to 40% o patients with SCLC tomeningeal spread is suspected. Pulmonary unction
present with LD; the remainder have ED.1 tests should be perormed in patients who are candi-
The initial clinical evaluation should include his- dates or denitive chemoradiation therapy. Severe
tory and physical examination; chest radiography; anemia, nucleated red blood cells on peripheral smear,
pathology review; baseline laboratory tests, including neutropenia, or thrombocytopenia, in the absence o
complete blood cell count, a comprehensive metabolic other obvious causes are selection criteria or bone
prole, and LDH ;, computed tomography (CT) scans marrow aspiration and biopsy.10,26 The presence o
o the chest and abdomen with IV contrast; and brain tumor cells in a marrow biopsy identies ED. Treat-
magnetic resonance imaging (MRI) or CT scan with IV ment should be initiated as quickly as possible ater
contrast. Brain MRI is more sensitive than CT in iden- diagnosis is conrmed, given the rapid rate o progres-
tiying metastases and is preerred. I LD is suspected, sion. I the patient is signicantly symptomatic or the
a positron emission tomography (PET)–CT scan may staging evaluation prolonged, staging should be com-
be indicated because it can identiy distant disease and pleted while chemotherapy is started.
guide mediastinal evaluation. For most metastatic sites,
a PET-CT scan is superior to other imaging modalities;
however, it is inerior to MRI or CT o the brain or TREATMENT
detection o brain metastases. Even though PET-CT
may improve staging accuracy o SCLC, pathologic Limited Disease
conrmation is still recommended or lesions depicted
at PET-CT scan that may alter staging. I PET-CT scan Patients with SCLC rarely survive more than a ew
Chapter 23
is not available or is equivocal, bone imaging with a months without treatment. The disease is highly
whole-body bone scan should be used to stage the responsive to both chemotherapy and radiation, and
skeleton.26 patients with LD are treated with curative intent.
Staging should not ocus only on symptomatic sites In LD, the overall response rates (RRs) to combined
o disease or on altered laboratory data. For example, chemoradiation are typically 80% to 90%, including
bone scans may be positive in up to 30% o asymp- 50% to 60% complete RRs. Median overall survival
tomatic patients without abnormal alkaline phospha- (OS) is approximately 17 months, and the 5-year sur-
tase levels. The goal o complete staging is to identiy vival rate is approximately 12%.
Surgery 9.7 months; P = .001). In patients with ED, no survival

dierence was noted.
An autopsy series on patients who died rom postop-
The addition o other chemotherapeutic agents to
erative complications revealed that 90% o patients
the EP regimen—either as a triplet with paclitaxel or
with SCLC had mediastinal metastasis within 30 days
alternating therapy with cyclophosphamide, doxoru-
ater surgical resection. 28 A randomized trial evalu-
bicin, and vincristine—has also been studied, but to
ating surgery versus thoracic RT (TRT) in patients
date a new standard in the treatment o LD has not
with resectable disease revealed that the TRT group
emerged.33,34
had signicantly longer OS,29 suggesting that even in
absence o diagnosed metastases, surgery alone is an
inadequate therapeutic strategy. However, surgery Radiation Intensity
may play a role in multimodality therapy or patients Based on the radiobiology o SCLC, the Intergroup
(5%) with early T stage and without nodal involve- (INT) trial 0096 studied accelerated hyperractionated
ment (T1-T2N0M0, very LD). A 5-year survival rate RT (AHRT) compared with conventional ractionation
o 48% has been reported in patients with very LD in a phase III trial.35 More than 400 patients were ran-
when surgery was ollowed by adjuvant chemo- domized between the two arms. All patients received
therapy.9 Adjuvant chemotherapy with our courses our cycles o EP, and TRT was administered concur-
o etoposide–cisplatin (EP) should be considered or rently, starting with the rst cycle o chemotherapy.
all patients with surgically resected SCLC. I nodal All patients received 45 Gy, either in once-daily 1.8-Gy
involvement is ound at the time o surgery, chemo- ractions or 5 weeks or twice-daily 1.5-Gy ractions
radiation and chemotherapy are recommended. or 3 weeks. Patients in the twice-daily RT group had
an improved median OS (23 vs 19 months) and 5-year
Combined Chemoradiation Therapy survival (26% vs 16%), at the cost o increased weight
loss and grade 3 esophagitis (27% vs 11%). Local ail-
Based on the results o a British Medical Research ure rates were lower in the twice-daily RT arm, pre-
Council trial demonstrating surgery to be inerior to sumably the major reason or improved survival.
RT or the treatment o LD,29 TRT became standard o Intergroup trial 0096 convincingly showed an OS
care or local control or these patients. Although early benet to concurrent chemoradiation with hyper-
studies indicated that RT could increase local control ractionation. However, because o concerns or
compared with chemotherapy alone, these studies did side eects and the logistical diculties involved in
not consistently show signicant survival benets to twice-daily treatment, the regimen was not widely
combination therapy over chemotherapy.30 Because o adopted.36 The control arm o the INT 0096 study used
this controversy, randomized trials were perormed. a relatively low total RT dose, and since the results o
Two meta-analyses were perormed that showed a INT 0096 have become available, conventionally rac-
signicant 2-year survival benet o 5.4% with the tionated radiation in higher doses has also been stud-
addition o RT to systemic chemotherapy or patients ied. The Cancer and Leukemia Group B (CALGB) trial
with LD.30,31 Notably, the best outcomes rom these tested the regimen paclitaxel and topotecan or two
older trials included concurrent as opposed to sequen- cycles ollowed by TRT with 70 Gy in 35 daily rac-
tial approaches; in addition, the regimens used in this tions with concurrent carboplatin–etoposide (CE; total
era were anthracycline- and alkylator-based therapies o three cycles) in a phase II study.37 Median OS was
and were associated with excessive in-eld toxicity 22.4 months, comparable to that ound with AHRT in
when administered with concurrent radiation. The the INT 0096 study.
development o the EP regimen was critical to improv- Another schedule o TRT tested was concomitant
ing the tolerance and easibility o concurrent chemo- boost, in which patients received once-daily radia-
radiation. EP can be given at ull dose with RT, leading tion through most o their course and then received
to improved disease control. hyperractionated therapy at the end o treatment so
An anthracycline-based regimen (cyclophospha- that RT was accelerated without the need or twice-
mide, epirubicin, and vincristine [CEV]) was compared daily administration throughout the treatment course.
Chapter 23
in a phase III trial with EP in patients with SCLC.32 The Radiation Therapy Oncology Group (RTOG)
Patients received RT concurrently with the third cycle tested this approach in the phase II trial 0239. Patients
o chemotherapy, and prophylactic cranial irradiation received 61.2 Gy over 5 weeks, with twice-daily RT in
(PCI) was administered to those who achieved com- the nal 9 days.38 RT started on day 1 o chemotherapy
plete remission (CR). The results showed that, in with our cycles o EP. The two-year survival rate was
patients with LD, EP was superior to CEV or survival 37%, somewhat less than that ound in both INT 0096
rates at 2 and 5 years (14% and 5% vs 6% and 2%, and the CALGB trial (2-year survival rates o 41% and
respectively; P = .0001), as well as median OS (14.5 vs 48%, respectively).
In the phase III CONVERT trial, patients were ran- best 5-year survival rate has been observed in LD, EP
domized to receive either 45-Gy RT in twice-daily should be given unless there is a signicant contraindi-
ractions o 1.5 Gy over 19 days or 66-Gy RT in 33 cation to cisplatin use. Notably, the dose o cisplatin in
once-daily ractions o 2 Gy over 45 days while receiv- INT 0096 was only 60 mg/m.2 Figure 23–3 illustrates
ing EP chemotherapy. The primary endpoint was OS, the treatment algorithm or management o limited-
and there was no signicant dierence between the stage SCLC.
groups. Toxicities were similar between the groups,
and twice-daily chemoradiotherapy continues to be
the standard o care.39
Extensive Disease
Systemic chemotherapy represents the primary ther-
Timing of Chemotherapy apeutic modality or patients with ED, although the
addition o immunotherapy to rst-line chemotherapy
Sequential, concurrent, and alternating chemotherapy has been shown to improve survival.44 Currently, TRT
have all been tested with TRT. Early studies did not is used or symptom palliation; however, a potential
show a survival benet to concurrent chemotherapy, role or radiation in patients with limited systemic dis-
likely because o the increased toxicity when using ease and a good response to initial therapy has been
cyclophosphamide- or doxorubicin-based chemother- suggested. Chemotherapy prolongs survival compared
apy. EP is better tolerated than these earlier regimens with best supportive care (BSC).7 From the time o
when administered concurrently with RT. diagnosis, the median OS or patients with ED is 8
The National Cancer Institute o Canada reported to 13 months, the 5-year survival rate is 1% to 2%,
a phase III trial o alternating CAV (cyclophospha- and the 2-year survival rate is 4% to 5%. 1 Figure 23–4
mide, anthracycline, and vincristine)–EP with TRT in shows representative coronal PET-CT images in a
either the second or sixth cycle o chemotherapy.40 patient with extensive-stage SCLC (ED).
The patients receiving early RT experienced improved
OS (21.2 vs 16 months). The Japan Clinical Oncology
Group compared RT (45 Gy in twice-daily 1.5-Gy Chemotherapy
ractions) starting with either the rst cycle o EP or In an early study, patients with SCLC had a highly
ater completion o the chemotherapy course.41 More signicant improvement in survival with IV cyclo-
myelosuppression was noted in the patients in the phosphamide compared with placebo, increasing the
concurrent arm, but there was a signicant reduction median period survival rom 12 weeks to almost 5
in risk o death or early concurrent therapy, with a months.7 As new cytotoxins became available, com-
hazard ratio (HR) o 0.70 (P = .02). Although not all bination therapy was studied, and the CAV regimen
trials have consistently shown a benet or concurrent became the standard o care or patients with ED. EP
chemoradiation, the data strongly support this and its was initially evaluated in patients who had recurrent
early integration in treatment when the regimen is EP. disease ater or ailed to respond to CAV, with RRs o
Furthermore, ecacy outcomes are consistently better 55%.45 It was later evaluated as a rst-line treatment
with EP in the treatment o LD. in patients unable to tolerate CAV, demonstrating a
Given that SCLC is such a rapidly dividing malig- median OS o 39 weeks in ED, with less toxicity.46 In
nancy, it has been hypothesized that accelerated pro- a phase III trial, the equivalent ecacy o EP and CAV
lieration o tumor clonogens can aect outcome and was conrmed by randomizing 437 patients to receive
that treatment should be delivered in a condensed our cycles o EP, six cycles o CAV, or alternation o
ashion.42 A meta-analysis examined the impact o a these two regimens or 18 weeks (CAV/EP, three cycles
novel parameter, time rom the start o any treatment each).47 The RRs (61%, 51%, 59%, respectively) and
to the end o RT (SER), on OS in LD. A shorter SER median OS (8.6, 8.3, and 8.1 months, respectively)
was ound to be a signicant predictor o better out- were equivalent across the arms. Myelosuppression
come. For each week that the SER was lengthened, was the dose-limiting toxicity, and our cycles o EP
OS at 5 years showed an absolute decrease o almost were better tolerated. Similar results were seen in a
2%.42 The data rom INT 0096 had a strong infuence Japanese trial.33
Chapter 23
on this result.
Carboplatin is requently used in ED because o a
Chemoimmunotherapy
more avorable toxicity prole, whereas cisplatin is
preerred in patients with LD with curative intent. The The high mutation rate in SCLC led to the hypothesis
ecacy o cisplatin versus carboplatin regimens in LD that the addition o immunotherapy to chemother-
was evaluated in a meta-analysis o our trials,43 which apy could enhance the antitumor immune response.
revealed no signicant dierence in terms o ecacy. However, early trials o immune checkpoint inhibition
Nevertheless, because o its use in trials or which the did not improve outcomes. In a phase II study o 45
Adjuvant
chemotherapy
pN0
Surgery
Negative pN1–N3
Adjuvant
Tl–T2, NO Mediastinoscopy
chemoradiation
Positive
Staging pN1–N3 Chemoradiation
T3–T4, NO Chemoradiation PR or CR Prophylactic cranial

Any T, N1–N3 and chemotherapy irradiation
PD <PR
Second-line PD
Surveillance
chemotherapy
FIGUre 23–3 Treatment algorithm for management of patients with limited-stage small cell lung cancer. CR, complete remis-
sion; M, metastasis; N, node; PD, progressive disease; PR, partial remission; T, tumor.
Chapter 23
A B
FIGUre 23–4 Representative positron emission tomography (PET)–computed tomography images in a patient with exten-
sive-stage small cell lung cancer. Coronal PET (A) and fused coronal (B) images are shown.
patients with ED who had a response or stable disease will be claried as data mature. As the development
with induction chemotherapy received maintenance and understanding o biomarkers or response to
therapy with pembrolizumab, a monoclonal antibody immunotherapy progress, outcomes may continue
directed at programmed cell death protein 1 (PD-1). to improve or some patients.
The median PFS was 1.4 months (95% condence
interval [CI], 1.3–2.8), which was not improved com-
Thoracic Radiation Therapy
pared with historical data. However, 13% o patients
had PFS o at least 1 year, and 37% o patients had OS Prospective trials have evaluated the role o consolida-
o at least 1 year, suggesting that an unknown subset tive TRT in patients with ED who initially respond to
o patients could have benetted rom this therapy.48 systemic chemotherapy. In a single-center study, 206
Ipilimumab, a monoclonal antibody directed against patients received three cycles o EP,52 and complete
CTLA-4 (cytotoxic T lymphocyte-associated antigen responders at distant sites and those with intrathoracic
4), was given in sequential combination with car- partial remission (PR) or CR (n = 109) were randomized
boplatin–paclitaxel in a randomized phase II o 130 to thoracic AHRT (54 Gy, 36 ractions over 18 days) com-
untreated patients with SCLC. There was improved bined with CE or our additional cycles o EP. Patients
PFS (HR, 0.64; P = .03) but not OS (median, 12.5 vs 9.1 with brain metastases, stable disease, progressive dis-
months or the sequential combination vs chemother- ease, or only PR outside the thorax were not random-
apy alone; P = .13).49 In a subsequent phase III study ized. The addition o TRT to chemotherapy improved
o more than 1110 patients with newly diagnosed ED, median OS (17 vs 11 months; 5-year survival rate, 9%
the regimen o EP plus ipilimumab was compared with vs 4%, respectively; P = .041). There was a trend toward
EP plus placebo. The addition o ipilimumab did not reduced local recurrence in the radiation arm but no di-
improve the median OS, which was approximately 11 erence in metastasis-ree survival. Acute high-grade
months in both treatment groups.50 toxicity was higher in the chemotherapy arm.
More recently, the IMpower133 study combined In the phase III multicenter European CREST trial,
atezolizumab with chemotherapy in newly diagnosed patients with ED were initially treated with our to six
ED. In this double-blind, placebo-controlled, phase III cycles o platinum-based chemotherapy. Patients with
trial, patients were randomly assigned to receive EP plus any response were then randomized to TRT (30 Gy
atezolizumab ollowed by maintenance atezolizumab in 10 ractions) plus PCI (n = 247) or to PCI alone (n =
compared with EP plus placebo ollowed by mainte- 248).53 The study did not meet the primary end point
nance placebo. The median OS was 12.3 months in o 1-year survival improvement (33% with thoracic
the atezolizumab group compared with 10.3 months RT vs 28% without; P = .07). However, 2-year sur-
in the placebo group (HR, 0.70, P = 0.007).44 The results vival and PFS rates were signicantly longer or those
o this study represented the rst signicant improve- receiving TRT ater prolonged ollow-up (2-year OS,
ment in OS or patients with ED in multiple decades, 13% vs 3%; P = .004; PFS, 24% vs 7%, respectively,
and this regimen is now the standard-o-care regimen at 6 months). The most common grade 3 toxicities in
or the rst-line treatment o ED. the TRT group compared with the control group were
The therapeutic value o immunotherapy as atigue (4.5% vs 3.2%) and dyspnea (1.2% vs 1.6%).
shown in the IMpower133 study was conrmed in Patients most likely to benet were those with residual
another recent phase III clinical trial, the CASPIAN disease in the thorax.
study. In this study, patients were randomly assigned The RTOG 0937 phase II study (NCT 01055197)
to receive durvalumab, an inhibitor o PD-L1, plus comparing PCI alone versus PCI with consolidative
platinum–etoposide, durvalumab plus tremelim- RT to residual locoregional and metastatic disease in
umab, an inhibitor o CTLA-4, plus platinum–eto- patients with ED who responded to platinum-based
poside or platinum–etoposide alone. At a median chemotherapy was closed early due to excess grade 5
ollow-up period o 14.2 months, the median OS toxicity in the experimental arm. Currently, it is our
was 13.0 months with durvalumab plus chemother- practice to consider consolidative TRT in selected
apy (95% CI, 11.5–14.8) and 10.3 months (95% CI, patients with ED with excellent control o extrathoracic
9.3–11.2) with chemotherapy alone. Furthermore, disease, residual disease in the thorax, and retained PS
Chapter 23
the objective RR was higher with durvalumab plus ater chemotherapy. Thoracic RT should be limited to
chemotherapy (79% vs 70%), although there was palliative dosing and conventional ractionation, and
no dierence in the median duration o response.51 concurrent chemotherapy should not be given.
This trial is ongoing, and results or the durvalumab Figure 23–5 demonstrates metabolic response on
plus tremelimumab plus chemotherapy group have PET in a patient with ED and extensive bone metas-
not yet been reported. The impact o the addition tases ater our cycles o CE. Figure 23–6 shows the
o immune checkpoint inhibitors to conventional treatment algorithm or the management o extensive-
chemotherapy on the survival o patients with ED stage SCLC.
A B
FIGUre 23–5 Response of extensive-stage small cell lung cancer following treatment with platin–etoposide at positron
emission tomography (PET)–computed tomography imaging. Baseline (A) and restaging coronal PET (B) images are shown.
Recurrent Disease recurrent disease is less responsive, and survival is lim-

ited, with the median survival period ranging rom 2
Chemotherapy and Immunotherapy to 6 months ater relapse. The response to initial treat-
ment and the time to relapse ater induction chemo-
Despite initial response to chemoradiation, approxi- therapy are both important determinants o response
mately 11% o patients with LD and only 1% to 2% to second-line chemotherapy. Patients with objective
o those with ED are alive at 5 years, with the vast response to initial treatment and PFS at least 60 to 90
majority succumbing to recurrent SCLC.1 Historically, days ater completion o induction chemotherapy are
Painful Local radiotherapy

Chemotherapy
metastases to bone metastases
Brain Whole brain

Chemotherapy
metastasis radiation
Acute local tumor
issues
SVC Thoracic
Chemotherapy
syndrome radiotherapy
Consider PCI/
None Chemoimmunotherapy
Chapter 23
consolidation
thoracic
PD CR or PR radiotherapy
Second-line
Surveillance
therapy
FIGUre 23–6 Treatment algorithm for management of patients with extensive-stage small cell lung cancer. CR, complete
remission; PCI, prophylactic cranial irradiation; PD, progressive disease; PR, partial remission; SVC, superior vena cava.
more likely to respond to additional chemotherapy and Temozolomide (TMZ) is a well-tolerated oral alkyl-
are considered to have “sensitive” disease. Those who ating agent with an overall response rate (ORR) o 16%
do not achieve disease regression with initial chemo- in a small phase II study.61 In this study, the RRs were
therapy or with shorter duration o response ater che- 23% in patients with platinum-sensitive disease, 13%
motherapy is discontinued are considered reractory.54 in patients reractory to platinum, and 38% in brain
Reintroduction o the chemotherapy regimen used metastases.
or induction has been a therapeutic strategy or relapse The CheckMate 032 study evaluated the ecacy and
in patients with prolonged PFS ater rst-line therapy. saety o nivolumab and nivolumab plus ipilimumab in
The rst evidence to support this was suggested in a patients with recurrent disease ater the ailure o plati-
series o six patients who had achieved a greater than num-based chemotherapy.62 Patients were randomized
2-year remission ater induction chemotherapy.55 Five to receive nivolumab or nivolumab plus ipilimumab
o these patients received some or all o the agents or our cycles ollowed by nivolumab maintenance.
o their induction regimen, with our responses, last- The objective RR was 21.9% in patients receiving
ing up to 18 months. Other studies also suggested nivolumab plus ipilimumab compared with 11.6% with
responses when rst-line therapy was reintroduced at nivolumab alone. However, the median OS was similar
relapse i patients had either a CR or a response lon- between the two groups (5.7 months vs 4.7 months).
ger than 34 weeks ater induction.56,57 In the modern This study has led to the inclusion o nivolumab with
era, when many patients receive just our courses o or without ipilimumab to the National Comprehensive
induction chemotherapy, retreatment with EP could be Cancer Network SCLC Guidelines as an option or the
considered i initial response was dramatic and main- treatment o recurrent, platinum-reractory disease. Fur-
tained PFS or 3 months or more. thermore, nivolumab monotherapy is FDA approved
Topotecan and irinotecan have been studied in or use in the third-line setting. Pembrolizumab is also
recurrent disease. Topotecan is the only drug or approved in the third-line setting based on the results
which there are several randomized trials in this set- o the KEYNOTE-158 study,63 in which the ORR was
ting and is the only agent approved by the Food and 19%. Among patients that responded, the durations o
Drug Administration (FDA) in the second-line setting response were greater than or equal to 18 months and
or recurrent SCLC. Oral topotecan was ound to have 18 months in 56% and 63%, respectively.
similar ecacy to IV topotecan, with less toxicity and
ease o administration.58 A phase III trial showed that
IV topotecan had similar ecacy to the CAV regi- BRAIN METASTASIS
men in patients with sensitive relapse, with an RR o
24% versus 18%, with a similar median TTP (13 vs The brain is a common site o metastasis in patients
12 weeks) and OS (25 vs 24.7 weeks) or topotecan with SCLC, with 10% o patients presenting with
versus CAV, respectively.54 The topotecan group had brain involvement at diagnosis and an additional 40%
better symptom control, with less-severe neutropenia. to 50% developing CNS metastasis during the course
The improvement in symptom control led to its FDA o disease.
approval. In a phase III registration trial, oral topotecan
was compared with BSC in patients who had relapsed Whole-Brain Radiation Therapy
45 days or more ater achieving a response to rst-line
therapy and were not candidates to receive IV topo- Whole-brain radiation therapy (WBRT) rapidly
tecan.59 Topotecan signicantly improved OS (25.9 vs resolves symptoms o brain involvement rom SCLC.
13.9 weeks), including signicant benet in patients RT with 30 Gy in 10 daily ractions has been shown
who relapsed 60 days or less ater initial treatment, and equally eective as altered ractionation to a higher
was associated with a slower deterioration in quality dose (54 Gy in 34 ractions) in the phase III trial RTOG
o lie. In a phase III trial, 304 patients with sensitive 9104,64 which evaluated these WBRT regimens in 429
relapse were randomized to oral (2.3 mg/m2 daily or 5 patients with unresected brain metastases, including
days) or IV (1.5 mg/m2 daily or 5 days) topotecan every 39 patients with SCLC. Median OS was 4.5 months
3 weeks.58 The RRs and the median and 1-year sur- in both arms; the 1-year survival rate was also similar,
Chapter 23
vival rates as well as the toxicity proles were similar at 19% with accelerated ractionation and 16% on the
between the two arms (18% vs 22%, 33 vs 35 weeks, control arm.
and 33% vs 29%, respectively). Topotecan is typically Reirradiation o the CNS may be considered (20
administered on days 1 to 5 o a 3-week cycle. Irino- Gy in 10 ractions) or symptom palliation in recurrent
tecan has not been directly compared with topotecan, intracranial disease.65 Stereotactic radiosurgery (SRS)
and phase III trials have not been perormed; phase II represents a therapeutic option or progressive brain
studies suggested similar ecacy compared with topo- metastases ollowing WBRT. The technique uses exter-
tecan in the recurrent setting.60 nal irradiation beams that deliver a single high dose
o radiation to a small volume o tissue with minimal The risk o developing brain disease in patients alive
invasion o and injury to healthy tissue. SRS or brain at 2 years ater diagnosis who did not receive PCI is
metastases ater WBRT rom SCLC (ewer than our between 50% and 80%.68 PCI has been investigated
sites) is sae and achieves 1-year local control o 60% as a means to control brain metastatic disease ater
to 90%, especially in lesions smaller than 2 cm66; how- chemotherapy beore it becomes clinically evident, in
ever, regional CNS recurrence risk approaches 60%. an eort to prevent morbidity and mortality. Numer-
ous clinical trials have established the eectiveness
Chemotherapy o PCI in decreasing the incidence o intracranial dis-
ease in patients who have responded to initial treat-
In general, RRs to chemotherapy in brain metastases ment or LD and ED, although its impact on survival
mirror those in extracranial disease sites, with higher has been variable.
rates in therapy-naïve patients. In a meta-analysis,
a 36% RR in the CNS was revealed in the results o
ve trials in which 135 patients with brain metastases Prophylactic Cranial Irradiation in Limited
were treated ater initial therapy with single-agent eto- Disease
poside or carboplatin. Pooled data rom another ve The PCI Overview Collaborative Group meta-analy-
studies conducted in 64 patients with brain metastases sis evaluated seven randomized trials comparing PCI
at diagnosis treated with various combination regi- (treatment group) versus no PCI (control group) in
mens showed a RR o 66%.67 987 patients with SCLC who achieved CR to initial
In summary, or treatment-naïve patients who pres- therapy. Approximately 85% o the patients enrolled
ent with CNS involvement and are asymptomatic or in both groups had LD. The PCI provided a 5.4%
minimally symptomatic, chemotherapy should be improvement in 3-year survival rate (15.3% vs 20.7%
given initially, and i brain disease is controlled, WBRT in control vs treatment group, respectively), increased
may be given ater completion o our cycles o chemo- disease-ree survival (P <.001), and decreased the risk
therapy. Brain irradiation should ultimately be admin- o developing brain disease (33% vs 59%, HR 0.46;
istered given that it is associated with higher CR o P <.001).68 A second meta-analysis evaluated 1547
brain metastases compared with chemotherapy alone. patients rom 12 randomized studies, ve o whom
Symptomatic CNS involvement or progression o brain required CR status or randomization.69 The results o
metastases during chemotherapy is an indication or the second analysis conrmed the reduced rate o brain
WBRT. The approach o combining WBRT and induc- metastasis or all patients but improvement in OS only
tion chemotherapy must be considered in situations or patients in CR (HR, 0.82; 95% CI, 0.71–0.96). Based
in which brain disease is bulky and symptomatic and on these data, PCI became standard o care or patients
there is also signicant extracranial disease requiring with LD and disease control ater chemoradiation.
urgent treatment. Myelosuppression is increased with Two large, randomized trials have investigated the
concurrent modalities, and this should be expectantly eect o RT doses above 25 Gy. A multinational phase
managed. For patients who develop CNS involvement III trial randomized 720 patients with LD and CR ater
ater initial chemotherapy, WBRT is indicated, and induction therapy to receive PCI at 25 Gy in 10 rac-
chemotherapy may have a palliative role in those who tions or 36 Gy (18 ractions o 2 Gy each or 24 ractions
progress ater receiving WBRT. Occasionally, previ- o 1.5 Gy twice daily).70 No signicant dierences were
ously irradiated patients with SCLC are candidates or noted in the 2-year incidence rates o brain metastasis,
SRS; however, the rate o brain ailure is high. and an increased mortality rate was noted with higher
PCI doses (2-year survival rate 37% vs 42%; HR, 1.20).
The phase II randomized RTOG 0212 study similarly
PROPHYLACTIC CRANIAL showed no dierences in the incidence o brain metas-
IRRADIATION tasis or OS benet in patients with LD and CR ater
initial chemoradiation comparing PCI with 25 Gy to
Despite only 10% o patients with SCLC initially 36 Gy.71
presenting with CNS involvement, there is a signi-
Chapter 23
cant rate o occult brain disease in patients who lack

neurologic symptoms; thus, staging o the brain is
Prophylactic Cranial Irradiation in
indicated in all patients. Approximately 15% to 20% Extensive Disease
o patients with LD SCLC who initially respond to An early European Organization or Research and
therapy will develop brain metastases as the sole site Treatment o Cancer (EORTC) study suggested a
o relapse, suggesting that brain radiation early in the benet to PCI in ED, but this study had limitations
treatment course might be curative in this group.68 in its design, and its conclusions were not supported
by a more recent study. The EORTC study random- OLDER ADULT AND INFIRM PATIENTS
ized patients with ED with response to initial che-
motherapy to either PCI (choice o three schedules) Approximately 25% o patients with SCLC are older
or observation.72 Baseline imaging o the brain was than the age o 70 years. These patients have oten
required only or symptomatic patients. Overall, 286 been excluded rom clinical trials because o concerns
patients were randomized. Patients in the PCI group or greater toxicity because o lowered organ reserves,
had a lower risk o brain metastases (15% vs 40%; especially myelosuppression and requently lowered
HR, 0.27; P <.001) and a longer median OS rom unctional status because o comorbidities. However,
time o randomization versus the observation group retrospective studies have shown that older adult
(6.7 vs 5.4 months, respectively). It is notable that patients with retained PS have improved outcomes
more patients in the PCI group received second-line with more aggressive treatment. 75 In a Canadian
chemotherapy (68% vs 45%), possibly accounting analysis, older adult patients 70 years o age or older
or the OS improvement. Fatigue was signicantly who received our or more cycles o CAV or EP had a
worse on the PCI arm in the rst 24 weeks. Global median survival time o 10.7 months; those patients
health status and cognitive unctioning were assessed who received three or ewer cycles had a median
only up to 9 months rom randomization and were survival time o 3.9 months; and untreated patients
a mean o 8 points less (scale o 0–100) at 6 weeks survived a median time o 1.1 months.76 Multivari-
and 3 months on the PCI arm. 73 These results are di- ate analysis showed that neither increasing age nor
cult to interpret given the lack o brain imaging at comorbidities was an adverse prognostic actor. This
baseline and heterogeneity in both chemotherapy review reported that PS, stage, and treatment were
and PCI schedules. Furthermore, the 1.3-month OS the most important prognostic eatures. Additional
improvement could be attributed to an imbalance in studies have conrmed these conclusions, whereas
subsequent chemotherapy use, which is known to only one retrospective Australian review reported
infuence survival. that the complications rom therapy adversely
The more recent Japanese trial evaluated the e- aected outcome in older adults. 77 In a retrospective
cacy o PCI versus observation in 224 patients with cohort study examining the impact o chemotherapy
SCLC who had response to induction chemotherapy on survival among patients 65 years and older with
with either etoposide or irinotecan and cisplatin.74 SCLC selected rom the SEER database,7867% o the
Beore randomization, brain MRI was perormed to patients received chemotherapy, mainly EP or CE,
rule out occult metastases, and patients on both arms which provided a 6.5-month improvement in median
were ollowed postrandomization with serial brain survival (P < .001), even in patients older than 80
imaging. PCI was given as 25 Gy in 10 ractions. The years o age.
accrual was stopped early or utility when analy- With regard to radiation tolerance in the case o
sis ater 111 deaths revealed a trend toward shorter LD, older adult patients have been reported to have
median survival with PCI (10.1 vs 15.1 months; HR, increased toxicity. Analysis o the patients older than
1.38; P = .091). As expected, decreased incidence o 70 years o age in the INT trial 0096 (EP with conven-
brain metastases with PCI at 1 year (32% vs 58%; tional TRT vs AHRT) showed that they experienced
P <.001) was observed, and ewer patients treated with a higher rate o treatment-related death (older than
PCI required RT or symptomatic brain involvement 70 years vs 70 years or younger: 10% vs 1%, respec-
(31% vs 80%). The high rate o brain metastases in tively).79 However, the 5-year OS rate or older adult
both arms o this study (48% with PCI; 69% with patients was 16%, similar to that in the control arm
observation) supports the need or MRI surveillance in overall. Altered ractionation did not appear to benet
all patients with ED. the older adult subgroup.
In summary, PCI clearly decreased the incidence o In summary, patients with good PS and no signi-
symptomatic brain disease in SCLC, but the impact on cant organ dysunction should receive ull-dose chemo-
OS in patients with ED was variable. It is reasonable therapy and RT. Their higher risk o treatment-related
to discuss PCI in patients with ED who have a CR or death implies a need or close monitoring and intense
very good PR to initial treatment and good PS. The lack supportive care. Patients with severe comorbidities, a
Chapter 23
o denite survival benet and the potential or at least worse PS beore diagnosis, or the very old may require
short-term toxicity should be discussed. It should be a change in strategy rom standard o care. A meta-
used with caution in older adults and in patients with analysis o randomized trials evaluating patients with
signicant ischemic cerebrovascular disease because o “poor-risk” SCLC (generally ED) has shown a benet
a concern or increased acute and late brain toxicity. It o combination chemotherapy over single-agent oral
is important to separate PCI rom chemotherapy and etoposide.80 These trials reported that IV combination
to use radiation regimens that are sae in regard to late regimens palliated symptoms better and improved
neurotoxic eects (e.g., 25 Gy in 10 daily ractions). median PFS and OS. Thereore, in patients with a poor
PS, initial treatment should be combination chemo- plus paclitaxel and 4.5 months with placebo plus
therapy. EP is recommended over cyclophosphamide- paclitaxel. Median PFS was also improved in patients
or doxorubicin-based regimens in the older adult with c-MYC expression.89
population because it is less myelosuppressive.75 Sev-
eral studies have evaluated the CE regimen in the older
adult population.81,82 With the exception o the trial Poly(ADP-Ribose) Polymerase Inhibitors
reported by Samantas et al,81 which used low doses o Proteomic proling o a large panel o SCLC cells
both agents, studies using CE have shown good RRs showed high expression o PARP1 and other repair
and tolerance in older adult patients. proteins. Several PARP inhibitors have shown single
In conclusion, carboplatin (area under the curve, 5) activity in in vitro and in vivo models o SCLC.90
and etoposide (100 mg/m2 or 3 days) can be recom-
BMN-673 is the most potent PARP1/2 inhibitor,
mended or most patients with SCLC considered “high inducing synthetic lethality in tumors decient in
risk” on the basis o age, comorbidities, or reduced homologous recombination. In a phase I trial o
unctional status. The time o highest risk or treat- BMN-673,2 o 11 patients with recurrent SCLC had
ment-related mortality is in the rst cycle. Prophylactic PR. Veliparib, another PARP inhibitor, was studied
use o bone marrow growth actors such as peglgras- in with TMZ in the second- or third-line setting in a
tim is recommended in this group when chemother- randomized phase II study.91 Patients were random-
apy is given alone. The use o marrow growth actors ized to receive veliparib or placebo in combination
is contraindicated during concurrent chemoradiation; with TMZ. There was no signicant dierence in
thus, modest dose reduction and conventional rac- the median PFS or OS between the groups. How-
tionation should be considered. Continued research in ever, there was an improvement in the objective
this area, especially in the very old, is needed. RR in patients receiving veliparib plus TMZ (39%)
compared with placebo plus TMZ (14%). In patients
who were positive or Schlaen-11 (SLFN11), a DNA/
TARGETED AGENTS RNA helicase that regulates replication stress at sites
o DNA damage, PFS was prolonged (5.7 months vs
There are no approved targeted agents or SCLC despite 3.6 months) as was OS (12.2 months vs 7.5 months)
a plethora o trials over the past 15 years. Angiogenesis with veliparib plus TMZ. This study provided ur-
inhibitors, tyrosine kinase and other signal transduc- ther evidence that a biomarker-driven selection o
tion inhibitors, and BH3 mimetics targeting apoptosis patients could improve outcomes in urther clinical
have not demonstrated substantial promise in early- trials and suggested that SLFN11 may be predictive
phase trials, and none has been validated in phase III o response to PARP inhibitors.92
studies.83–86 However, early experience with the Aurora
A kinase inhibitor alisertib and inhibitors o poly(ADP-
ribose) polymerase (PARP) showed promise. Delta-like Protein 3–Targeted Therapy
Delta-like protein 3 (DLL3) is a member o the NOTCH
receptor ligand amily and has been identied as a
Aurora A Kinase Inhibitors potential therapeutic target or SCLC and other high-
Data in SCLC cell lines and xenograts indicate that grade neuroendocrine carcinomas. Rovalpituzumab
expression o MYC is correlated with sensitivity to tesirine is an antibody–drug conjugate targeting DLL3
Aurora A kinase inhibition.87 In a phase II study o that showed promising ecacy in a phase I clini-
alisertib (50 mg by mouth twice a day or 14 days cal trial. The objective RRs were 18% in assessable
every 21 days) in solid tumors, a partial RR o 15% patients and 38% in those with DLL3 expression in
was observed in 47 patients with relapsed SCLC.88 50% or more o tumor cells.93 Unortunately, the phase
In a randomized, double-blind, phase II study o III TRINITY showed only modest activity, including
alisertib plus paclitaxel as second-line treatment or in patients with high DDL3 expression.94 Furthermore,
SCLC, patients were randomized to alisertib plus serious adverse events were seen in 63% o patients,
paclitaxel or placebo plus paclitaxel. The median PFS and rovalpituzumab tesirine is unlikely to be tested
Chapter 23
was 3.3 months with alisertib plus paclitaxel com- urther in SCLC.
pared with 2.17 months with placebo plus paclitaxel
in the intent-to-treat population. However, among
patients with cell cycle regular mutations, median PFS PARANEOPLASTIC SYNDROMES
was improved to 3.68 months with the addition o
alisertib compared with 1.80 months. In this group PNSs are a complex spectrum o symptoms secondary
o patients, median OS was 7.2 months with alisertib to hormones secreted rom tumor cells not related to
their tissue or organ o origin or to immune-mediated P/Q-type voltage-gated calcium channels on the
tissue destruction through the production o autoan- tumor cells and at presynaptic nerve terminals. These
tibodies against tumor cells. SCLC is one o the most antibodies impair acetylcholine release rom the pre-
common cancer types associated with such phenom- synaptic motor terminal at the neuromuscular junc-
ena. Ectopic hormone production has been associated tion and cause transient cranial nerve palsies, upright
with ED and a poorer outcome, whereas the antibody- presyncopal symptoms, proximal muscle weakness
mediated PNSs are associated with more avorable with lower extremity predominance, and depressed
outcomes.8,11 It is critical to recognize the maniesta- tendon refexes.11 The electromyographic ndings
tions o PNSs because this may lead to the diagnosis o decreased baseline muscle action potential that
o an underlying, previously unsuspected malignancy increases with repeated stimulations are characteris-
and be useul in monitoring the course o the underly- tic and allow or clear-cut diagnosis. LEMS represents
ing disease. a avorable prognostic actor presumably based on
antitumor immunity.11 Unortunately, these patients
requently experience progressive neurologic decline
Endocrine Paraneoplastic Syndromes despite tumor control with treatment because by the
Hyponatremia o malignancy occurs in 15% o patients time neurologic symptoms and decits emerge, per-
with SCLC. This disorder is caused by ectopic produc- manent neuronal damage has occurred.
tion o antidiuretic hormone rom tumor cells, resulting Additional paraneoplastic CNS disorders are asso-
in the SIADH.95 Fluid restriction, saline inusion with ciated with infammation and neuronal loss. The
urosemide diuresis, hypertonic saline, and demeclo- most common syndromes in this group are paraneo-
cycline are options or acute management depending plastic cerebellar degeneration, limbic encephalitis,
on the severity o symptoms. Chemotherapy should opsoclonus-myoclonus, and diuse encephalitis with
be started urgently. multiocal neurologic symptoms.95 It remains unclear
The incidence o ectopic Cushing syndrome in whether these syndromes or the presence o antibod-
SCLC is approximately 5%. Patients with SCLC ies can serve as predictive markers o tumor response
with such a syndrome commonly present with signs or progression.
and symptoms o rapid-onset hypercortisolism,
including weight loss (83%), hypokalemia (87%),
abnormal glucose tolerance (73%), and edema THE SPECTRUM OF
(58%) compared with the classic Cushingoid ea- NEUROENDOCRINE CARCINOMAS
tures o moon acies, central obesity, or hirsutism,
which are more commonly seen in patients with Neuroendocrine carcinomas are a wide spectrum o dis-
carcinoid tumors. 95 This may be attributable to the eases, including low-grade typical carcinoid (TC),
slower growth rate o carcinoids, which causes a intermediate-grade atypical carcinoid (AT), and high-
gradual, rather than acute, increase in ACTH levels. grade neuroendocrine carcinomas (small cell carci-
Patients with SCLC with Cushing syndrome have noma and LCNEC).96 Carcinoid tumors are more oten
higher hydroxycorticosteroid (17-OHCS) and ACTH ound in the gastrointestinal system than in the lungs.
plasma levels than those seen in the Cushing disease The behavior o these tumors is oten dependent on
o pituitary origin. These patients are immunosup- grade o dierentiation. The histopathological eatures
pressed and at high risk or opportunistic inections o these tumors are identical regardless o their ana-
rom hypercortisolism; thereore, cortisol-suppress- tomic location; thus, the determination o a primary
ing agents, such as metyrapone or ketoconazole, site oten requires careul clinical evaluation.
are recommended beore initiating myelosuppres- Many o the same IHC markers are used to dene
sive antineoplastic therapy. RT can also be used in NETs, regardless o primary site. Some IHC stains
these cases to palliate and temporize until hypercor- appear to be expressed in tumors in certain locations.
tisolism has been controlled. Endocrine syndromes For example, whereas TTF-1 is commonly positive in
parallel cancer control, subsiding with cytoreduction thoracic tumors, CDX2 is more commonly expressed
o tumor and recurring with progression. in gastrointestinal tumors. On limited biopsies, deni-
Chapter 23
tive tumor grading may be challenging, especially in

Neurologic Paraneoplastic Syndromes tumors o low and intermediate grade.
Pulmonary NETs comprise approximately 20% o
Neurologic PNS disorders occur as the result o onco- all invasive lung malignancies. Ater SCLC, LCNEC
neuronal antibodies recognizing tumor and neuronal accounts or 3% o resected lung cancers in surgical
cell antigens; thus, they are autoimmune in mecha- series, and TCs account or 1% to 2% o lung can-
nism. LEMS, seen in 1% to 3% o patients with cers. AT is the rarest lung NET because it comprises
SCLC, is caused by autoantibodies directed against approximately 10% o all lung carcinoids, accounting
taBLe 23-2 Gding Cii nd hisologic Fus of pulmony Nuondocin tumos
Grade Histology Conventional Nomenclature

Low grade (well dierentiated) • < 3 mitotic fgures × 10 hp Carcinoid
• Absent or only ocal punctate necrosis
• Absent or mild nuclear atypia
Intermediate grade (moderately • 3–10 mitotic fgures × 10 hp Atypical carcinoid
dierentiated) • Comedonecrosis present
• Moderate nuclear atypia
High grade, poorly dierentiated • >10 mitotic fgures × 10 hp Small cell carcinoma
(small cell carcinoma) • Necrosis present
• Prominent nuclear atypia with or without positive
NE markers
High grade, poorly dierentiated • >10 mitotic fgures × 10 hp Large cell neuroendocrine
(large cell neuroendocrine • Necrosis present carcinoma
carcinoma) • Prominent nuclear atypia with positive NE
morphologic eatures and positive or negative NE
markers
hp, high-power feld; NE, neuroendocrine.
Data rom Moran CA, Suster S, Coppola D, et al. Neuroendocrine carcinomas o the lung: a critical analysis, Am J Clin Pathol. 2009;131(2):206-221.
or 0.1% to 0.2% o invasive lung cancers. LCNEC or chemotherapy is recommended (one or two cycles
has similar biology, behavior, and natural history to o EP concurrent with RT ollowed by additional che-
SCLC.12 Table 23–2 shows the grading criteria and the motherapy to complete a total o our courses). For
histopathological eatures or pulmonary NETs.97 The stage IV disease, our to six cycles o EP and palliative
dierent types o NETs possess diverse epidemiologic, RT, i clinically indicated, are recommended. PCI can-
clinical, pathologic, and molecular eatures.98 not be routinely recommended because o limited data
Surgical resection is recommended or localized on the incidence o brain metastases in patients with
pulmonary NETs i pulmonary reserve is adequate. LCNEC.96
For surgically unt patients or or exceptional low-
grade cases, transbronchoscopic resection may be
considered. Approximately 5% to 20% o bronchial SUMMARY
TCs and 30% to 70% o ATs metastasize to lymph
nodes; thus, a complete mediastinal lymph node SCLC is a very aggressive malignancy, aecting
sampling or dissection at the time o surgery is rec- 30,000 or more individuals annually in the United
ommended. The 5-year survival rates o surgically States. Most patients present with widespread dis-
resected pulmonary TCs and ATs range between ease at diagnosis, and despite the initial high sensi-
87% and 100% and 30% and 95%, respectively. 98 tivity to chemotherapy and RT, resistance emerges
Patients with TCs are unlikely to benet rom adju- rapidly. Extensive research over the past ew decades
vant systemic therapy even i lymph node involve- has not signicantly impacted the therapeutic para-
ment is present. The ATs have higher recurrence digm o SCLC. The standard o care or both LD and
rates; thereore, despite the lack o consensus, adju- ED is etoposide–platin chemotherapy or a minimum
vant EP with or without RT or patients with stage II o our courses. Early integration o concurrent TRT
or III may be considered.99 is indicated or LD. PCI can be oered to patients
Because o the rarity o LCNEC, most o the data who have excellent disease control ater initial ther-
Chapter 23
regarding treatment are retrospective in nature. In apy. Major advances in treatment will require greater
general, there is a worse prognosis or patients with understanding o the drivers o the pan-resistant
resected LCNEC compared with those with stage- phenotype that characterizes recurrent disease and
matched other NSCLC. Treatment recommendations development o therapy to which these cells will be
or this entity are extrapolated rom treatment para- vulnerable. Recent discoveries rom bench research
digms or SCLC. For resected stage I and II LCNEC, and early-phase clinical investigation uel the hope
our cycles o adjuvant EP are recommended. For locally that outcomes or patients with SCLC will continue
advanced disease (stage III), concurrent chemoradiation to improve in the next decade.

J Clinical trials should be considered or all patients this treatment modality or appropriate patients
with SCLC, especially ater relapse. treated with chemoimmunotherapy.
J The use o PCI in extensive-stage patients with SCLC J As with all malignancies, but especially true in light
should be restricted to highly selected cases, such as o SCLC’s poor prognosis, early establishment o
patients with low burdens o metastatic disease; realistic prognostic expectations and goals o care
good PS; and a complete, or near-complete, meta- is critical.
bolic response to rontline systemic therapy. All J Although nivolumab and pembrolizumab are FDA
patients with extensive-stage disease should have approved or third-line treatment o relapsed SCLC,
surveillance brain imaging. we do not recommend repeat use o immune check-
J Consider the use o the TMZ or patients with point blockade in patients who ailed rontline che-
relapsed disease, which is a convenient (oral) agent moimmunotherapy unless within a clinical trial. On
with good tolerability and excellent blood–brain the other hand, i a newly relapsed patient did not
barrier penetration. In particular, this agent is useul previously receive immunotherapy, o-label use o
or patients with a history o CNS metastases. nivolumab or pembrolizumab even in the second
J Although both the IMpower133 and CASPIAN trials line should be considered, in light o durable, albeit
excluded use o consolidative thoracic irradiation rare, responses.
ater chemoimmunotherapy, we continue to deploy
Chapter 23
21. Tamborini E, Bonadiman L, Negri T, et al. Detection o over-

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Chapter 23
radiotherapy is easible concurrent with chemotherapy or

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Chapter 23
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Chapter 23
24 Non–Small Cell Lung Cancer:
General Principles, Management o
Localized Disease, and Treatment
o Metastatic Disease without
Oncogene Drivers
Mehmet Altan
Joshua M Gulvin
George Simon
Bonnie Glisson
KEY CONCEPTS
 Lung cancer is the leading cause o cancer-related death in  Immune checkpoint therapies, particularly therapies
the United States. However, patients with early lung can- targeting the programmed cell death protein 1–pro-
cer have lower lung cancer–related mortality, and screen- grammed cell death ligand 1 pathway are now the stan-
ing with low-dose computed tomography in high-risk dard (as a single agent or as a part o combination) therapy
groups correlates with a reduction in overall mortality. or rst-line treatment o metastatic NSCLC that does not
 Multidisciplinary evaluation, including early integration harbor targetable mutations and should be considered or
o palliative care, or patients with locally advanced or all patients i there are no contraindications.
metastatic non–small cell lung cancer (NSCLC), improves
patient outcomes and quality o lie.
Lung cancer is the second most common cancer in absence o comorbidities, stage, tumor characteristics,
women (ater breast cancer) and in men (ater prostate and perormance status as discussed in this chapter.
cancer) but is the most common cause o cancer-related Lung cancer is broadly divided into small cell lung can-
death.1 Every year, more than 1.7 million patients die cer (SCLC) and NSCLC. Approximately 85% o lung can-
o lung cancer worldwide.2 About 70% o patients are cers are NSCLC. This chapter describes the epidemiology,
diagnosed in advanced stages o disease, when the etiology, histology, prevention, and molecular biology o
probability o cure is low. Over the years, lung cancer NSCLC. The multidisciplinary management o stages I to
screening eorts and technological advancements in III is described ollowed by treatment o stage IV NSCLC
imaging studies have increased the detection o lung without an oncogene driver. Chapter 25 ocuses on treat-
cancer in earlier stages; advances in minimally invasive ment o patients with NSCLC with a targetable mutation.
techniques or diagnosis, radiation therapy, and mul- We will review current clinical knowledge in these areas,
timodality approaches in locally advanced disease in with an emphasis on our approach at the University o
non–small cell lung cancer (NSCLC) have improved Texas MD Anderson Cancer Center (MDACC).
clinical outcomes. Furthermore, in the metastatic set-
ting, advances in targeted therapies in patients with
actionable mutations and introduction o immune EPIDEMIOLOGY
checkpoint inhibitors (ICIs) used as single agents or in
combination have contributed to signicant improve- Lung cancer is rarely diagnosed in people younger than
ments in overall survival (OS). The eventual survival 35 years old. Indeed, the median age or lung cancer
o a patient depends on actors such as presence or in the United States in 70 years o age. Incidence and
495
496 Section IV Lung Cancer
death rates rise exponentially until age 75 years, when Tobacco smoke is a complex mixture o chemi-
a plateau is reached. NSCLC accounts or the great- cals that includes multiple carcinogens, most impor-
est number o deaths rom cancer in both men and tant, the N-nitrosamines (nicotine-derived nitrosamino
women over age 60 years. ketone and N′-nitrosonornicotine [NNN]) and poly-
The geographic, social, and temporal trends o the cyclic aromatic hydrocarbons [benzo(a)pyrene and
incidence o NSCLC are closely related to tobacco con- dimethylbenz(a)anthracene]. They are activated through
sumption. In developed Western countries, the inci- hydroxylation by the P450 enzyme system and exert
dence o NSCLC has been declining; however, it has their action through the ormation o DNA adducts.
been increasing in Asia, Eastern Europe, and develop- Smokeless tobacco is requently advocated as a
ing countries.3 saer alternative. There has not been a clear association
Worldwide, NSCLC is more common in men, and between smokeless tobacco and lung cancer; however,
this dierence has been attributed to higher tobacco it increases the risk o head and neck, pancreatic, and
consumption. In some regions, such as Eastern Europe gastric cancer. E-cigarettes deliver water vapor with
and South America, there was an uptake o smok- scents and dierent amounts o nicotine, which is addic-
ing by women in the 1980s, and these areas are cur- tive and contains nitrosamines. They also contain high
rently experiencing a rise in NSCLC cases in women. levels o propylene glycol and glycerin, and their long-
In the United States, the incidence has been declining term eects on health are unknown. Their use should
or both men and women as tobacco use declines; the not be recommended to nonsmokers, and use as part
male-to-emale ratio rom 2007 to 2011 was 1.4 to 1.4 o a smoking cessation approach needs urther study.6
Approximately 15% o cases o NSCLC occur
in never smokers, corresponding to approximately
ETIOLOGY 20,000 deaths annually. In addition to secondhand
smoke exposure, several other agents have also been
Smoking linked to the development o lung cancer (Table 24–2).
The causal relationship between tobacco smoke and
lung cancer was established in the 1950s in case-con- Asbestos
trol and cohort studies. This led to the 1964 report o Asbestos exists in many natural orms. The silicate ber
the US Surgeon General, concluding that smoking can has been implicated in carcinogenesis, is chemically
cause lung cancer. Currently, it is estimated that 83% inert, and can remain in a person’s lungs or a lietime.
to 85% o lung cancers in the United States are caused Epidemiologic studies have conrmed the association
by smoking. Nonsmokers who are exposed to second- between asbestos exposure and certain lung diseases,
hand smoke are also at an increased risk. There is a such as pulmonary brosis, mesothelioma, and lung
dose–response relationship between smoking and lung cancer.7 Most exposure occurs in the workplace. When
cancer risk, and smoking cessation leads to a signi- smoking is combined with asbestos exposure, the rela-
cant risk reduction (Table 24–1).5 tive risk o lung cancer is strikingly increased.7
TABLE 241 Approximate 10-Year Risk o Developing Lung Cancera
Duration o Smoking
25 Years 40 Years 50 Years
Age (years) Quit (%) Still Smoking (%) Quit (%) Still Smoking (%) Quit (%) Still Smoking (%)
One-Pack-Per-Day Smokers
55 <1 1 3 5 NA NA
65 <1 2 4 7 7 10
75 1 2 5 8 8 11
ChAPTER 24
Two-Packs-Per-Day Smokers
55 <1 2 4 7 NA NA
65 1 3 6 9 10 14
75 2 3 7 10 11 15
a
This table assumes that people who have quit smoking will continue to abstain or the next 10 years and those who are still smoking will keep smoking the same
amount or the next 10 years.
NA, not available.
Adapted with permission rom Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers, Cancer 2003 Mar 19;95(6):470-478.
Capter 24 Non–Small Cell Lung Cancer: General Principles, Management o Localized Disease 497
TABLE 242 Relative Risk o Developing Lung Cancer
Risk Factor Relative Risk Reerence

Cigarette smoking in males 17.4 (Garnkel & Silverberg, 1991)
Cigarette smoking in emales 10.8 (Garnkel & Silverberg, 1991)
Passive smoking 1.5 (Samet et al., 2009)
Asbestos 1.2–2.6 (Bach et al., 2003; Hodgson & Jones, 1986)
Asbestos and smoking 28.8 (Kjuus, Skjaerven, Langård, Lien, & Aamodt, 1986)
Mining 3–8 (Harley et al., 1986; Samet et al., 2009)
Radon (residential) 1.1–2 (Samet et al., 2009)
Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst. 2003;95:470-478. doi:10.1093/jnci/95.6.470
Garnkel L, Silverberg E. Lung cancer and smoking trends in the United States over the past 25 years. CA Cancer J Clin. 1991;41(3):137-145. doi:10.3322/canjclin.41.3.137
Harley N, Samet JM, Cross FT, Hess T, Muller J, Thomas D. Contribution o radon and radon daughters to respiratory cancer. Environ Health Perspect. 1986;70:17-21.
doi:10.1289/ehp.867017
Hodgson JT, Jones RD. Mortality o asbestos workers in England and Wales 1971-81. Br J Ind Med. 1986;43(3):158-164. doi:10.1136/oem.43.3.158
Kjuus H, Skjaerven R, Langård S, Lien JT, Aamodt T. A case-reerent study o lung cancer, occupational exposures and smoking. II. Role o asbestos exposure. Scand J
Work Environ Health. 1986;12(3):203-209. doi:10.5271/sjweh.2157
Samet JM, Avila-Tang E, Boetta P, Hannan LM, Olivo-Marston S, Thun MJ, Rudin CM. Lung cancer in never smokers: clinical epidemiology and environmental risk
actors. Clin Cancer Res. 2009; 15(18):5626-5645. doi:10.1158/1078-0432.Ccr-09-0376
Radon correction or smoking, and this risk seems to be inher-

ited in a Mendelian co-dominant ashion.11
Radon is a naturally occurring decay product o ura- Many studies describe weak but consistent associa-
nium. It is a colorless, odorless, chemically inert gas tions between some polymorphisms and lung cancer
that can penetrate the earth’s crust and accumulate risk. The cytochrome P450 (CYP) amily is responsible
in buildings. It emits heavy ionizing alpha particles, or the metabolism o tobacco smoke, and the poly-
which may damage DNA. It was shown that many morphism CYP1A1 Ile462Val is associated with a higher
households in Europe, Canada, and the United States risk in Asians (odds ratio [OR], 1.61).12 The glutathione
have some degree o radon radiation that may increase S-transerase enzyme prevents oxidative damage, and
NSCLC risk among smokers and nonsmokers.8 the polymorphism GSTM1 increases risk in Asians
(OR, 1.17).13 Finally, individuals with impaired DNA
Diet repair capacity are at higher risk o developing lung
cancer, even i they are nonsmokers, and the polymor-
The majority o studies that have examined vegetable
phism Lys751Gln in the DNA-repairing enzyme ERCC2
consumption in relation to lung cancer have shown a
is associated with lung cancer (OR, 1.15).14
protective eect,9 but there are inherent biases in these
Large genome-wide association studies (GWAS)15
population studies. There is also epidemiologic evi-
have identied three loci strongly associated with
dence that dietary intake o certain vitamins decreases
lung cancer risk in dierent populations: 15q25, 5p15,
lung cancer risk; however, trials o vitamin supple-
and 6p21. The 15q25 susceptibility region encodes
mentation or cancer prevention have ultimately been
three cholinergic nicotine receptor genes (CHRNA3,
unsuccessul (see later Chemoprevention section).
CHRNA5, CHRNB4), and alterations in those regions
have been associated with a higher risk or nicotine
Other Factors dependence and higher smoking burden. In nonsmok-
Environmental or industrial exposure to arsenic, chro- ers, they have also been associated with impaired
mium, chloromethyl ether, vinyl chloride, and polycy- healing o the respiratory mucosa, suggesting a higher
clic aromatic hydrocarbons increases lung cancer risk.10 sensitivity to toxin-induced airway damage. The 5p15
Preexisting lung disease such as tuberculosis, silicosis, region encodes the TERT gene, responsible or telom-
pulmonary brosis, and chronic obstructive pulmo- erase unction, which is altered in many cancers.16
nary disease are also associated with an increased lung
ChAPTER 24
cancer incidence even when correcting or the degree PREVENTION OF LUNG CANCER
o cigarette consumption. This suggests that common
pathways to these conditions, such as chronic infam-
Smoking Cessation and Prevention
mation, may drive the tumorigenic process.
The most eective method o preventing lung cancer
is reducing tobacco exposure, either through encour-
Genetic Predisposition aging smoking cessation or preventing young people
Family history o lung cancer is associated with a two- rom starting to smoke. In the United States, cam-
to threeold increase in lung cancer risk, even ater paigns to reduce smoking rates have been successul.
The estimated percentage o Americans who actively women over a 10-year period.19 Based on these results,
smoke decreased rom 42.4% in 1965 to 25% in 1990 the US Preventive Services Task Force currently rec-
and to 18.1% in 2012.17 However, ormer smokers ommends lung cancer screening with yearly low-dose
retain an increased risk o lung cancer, and there are CT or current or past smokers, age 55 to 80 years,
still a considerable number o smokers, highlighting with a smoking history o at least 30 pack-years. (In
the need or better education and prevention strate- late 2020. this screening recommendation is expected
gies, especially those targeted to youths. to revise and to be extended to include adults ages 50
to 80 years who have a 20 pack-year smoking history
and currently smoke or have quit within the past 15
Early Detection and Screening years.20) Screening should be discontinued when a per-
Previous studies examined the role o chest radiog- son has not smoked or 15 years.
raphy, with or without cytologic analysis o sputum, Despite recent developments, low-dose CT screen-
to screen or lung cancer, and none showed a clear ing still has signicant limitations, including high alse-
benet. Most o them were conounded by lead time, positive ratios and the development o interval lung
length time, and overdiagnosis biases. cancers, which can be aggressive. Positron emission
Spiral computed tomography (CT)—also called tomography (PET)–CT scan, epigenetic markers, and
helical CT or low-dose CT—is much more sensitive cell-ree tumor DNA are additional approaches under
to detect early NSCLC than chest radiography. In investigation, which are only recommended in the set-
2011, the results o the National Lung Screening Trial ting o a clinical trial.
were published.18 In this trial, 53,454 current or or-
mer smokers ages 55 to 74 years old with at least a
30-pack-year smoking history and no symptoms that Chemoprevention
could be related to lung cancer were randomized to Cigarette smoking has an eect o eld cancerization,
undergo yearly chest radiographs or low-dose CT or with the accumulation o genetic mutations and other
3 years. Ater a median ollow-up o 6.5 years, the premalignant changes throughout the lung and the
low-dose CT group had a 20% reduction in the rate aerodigestive tract lining. Patients treated and cured o
o lung cancer–specic mortality, rom 309 to 247 per early-stage lung cancer have a high risk o developing
100,000 person-years, as well as a 6.7% reduction in second primary tumors. Thereore, a series o chemo-
overall mortality. In the CT group, 39% o patients prevention trials has ocused on smokers and survivors
had suspicious lung nodules (vs 16% in the control o lung and head and neck cancers.
arm), and the majority o these (96%) were consid- Multiple studies evaluated supplementation with
ered alse-positive results. Sensitivity and specicity vitamins and oligo-elements, but none showed a ben-
o low-dose CT were 93.8% and 73.4%, respectively, et to supplementation, and several studies showed
compared with 73.5% and 91.3% or chest radiogra- risk, with increased lung cancer incidence and mortal-
phy. Cost-eectiveness analysis showed a median cost ity (Table 24–3).21–27
o $43,000 per quality-adjusted lie-year gained or Given the potential connection between infam-
current smokers assigned to the low-dose CT group. mation and tumorigenesis, phase II studies have used
Another trial that supported the surveillance with CT anti-infammatory agents, such as celecoxib, and pros-
scans had been conducted in Belgium and the Neth- taglandin analogues, such as iloprost. These agents
erlands (the NELSON study) looking at the 10-year have been able to reduce prolieration and dysplasia
impact o lung cancer screening using low-dose CT o oral and bronchial epithelium in smokers and or-
scan. In this study, A total o 13,195 male participants mer smokers, but their benet in cancer prevention
at high risk or lung cancer were randomly assigned to remains to be proven. There are currently no proven
either the screening group (6583 men) or the control agents or the chemoprevention o lung cancer.
group (6612 men). CT screening perormed at baseline,
year 1, year 3, and year 5.5 or no screening. At 10 years
o ollow-up, the incidences o lung cancer were 5.58
cases per 1000 person-years in the screening group hISTOLOGY AND MOLECULAR
ChAPTER 24
and 4.91 cases per 1000 person-years in the control PAThOLOGY

group; lung cancer mortality was 2.5 deaths versus 3.3
deaths per 1000 person-years, respectively. The cumu- NSCLCs include three major types: adenocarci-
lative rate ratio or death rom lung cancer at 10 years noma, squamous cell carcinoma (SCC), and large cell
was 0.76 (95% condence interval [CI], 0.61–0.94; P carcinoma.
= .01) in the screening group compared with the con- The most current histologic classication o
trol group. CT scanning decreased the mortality rate NSCLC was proposed by the International Associa-
by 26% in high-risk men and up to 61% in high-risk tion or the Study o Lung Cancer/American Thoracic
TABLE 243 Large Randomized Lung Cancer Cemoprevention Trials
Study Intervention Population Size Endpoint Outcome

21
ATBC β-Carotene; Male smokers 29,133 Lung cancer Harmul
α-tocopherol incidence
CARET22 β-Carotene; retinol Current and ormer 18,314 Lung cancer Harmul
smokers incidence
Intergroup Lung Trial23 Isotretinoin Resected NSCLC 1166 Second malignancies Harmul
Euroscan24 Retinol, Resected NSCLC and 2592 Second malignancies Negative
N-acetylcysteine head and neck cancer
ECOG 559725 Selenium Resected NSCLC 1772 Second malignancies Negative
Physicians’ Health Vitamin C and vitamin Healthy male physicians 14,641 Cancer incidence Negative
Study II26 E
NORVIT and WENBIT27 Vitamin B12 and olic Patients with ischemic 6845 Cancer incidence Harmul
acid heart disease
ATBC, The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study; CARET, The Beta-Carotene and Retinol Ecacy Trial (CARET); ECOG, Eastern Cooperative
Oncology Group; NORVIT, The Norwegian Vitamin (NORVIT) trial; NSCLC, non–small cell lung cancer; WENBIT, Western Norway B Vitamin Intervention Trial (WENBIT).
Society/European Respiratory Society in 201128 and sarcoma (RAS)–Rapidly Accelerated Fibrosarcoma

uses immunohistochemistry (IHC) to identiy sub- (RAF) pathway, including mutations in the ErbB amily
groups with dierent molecular proles and clinical member EGFR (ErbB1).The prevalence o EGFR muta-
behaviors (Tables 24–4 and 24–5). Adenocarcinomas tions ranges rom 5% to 10% in smokers to 40% to
usually stain positive or cytokeratin 7, thyroid tran- 50% in nonsmokers in the Western population.33 The
scription actor 1 (TTF-1), and Napsin A and are nega- alterations are usually in the tyrosine kinase domain
tive or cytokeratin 20. TTF-1 is a marker to determine o the gene within exons 18 to 24, most specically in
i a tumor is arising rom the lung or thyroid origin the intracellular adenosine triphosphate (ATP)-binding
and is expected to be negative i adenocarcinoma is domain.33–35
originating rom other organ systems.29 All carcinoids Frequencies o EGFR, KRAS, ALK, ROS1, and other
and most SCLCs stain positive or chromogranin and driver genetic alterations commonly ound in lung ade-
synaptophysin, whereas NSCLC is usually negative nocarcinoma samples are listed in Table 24–6.32,33,36–40
or these two markers. Mesothelioma is distinguished This is a rapidly changing landscape that is dening
rom adenocarcinoma by the presence o calretinin, the many molecular subsets o this heterogeneous
WT-1, and cytokeratin 5/6 staining and the absence o disease.
carcinoembryonic antigen (CEA), B72.3, Ber-EP4, and
MOC-31.29,30
Squamous Cell Carcinoma
SCC is now the second most requent histology,
Adenocarcinoma accounting or 30% o cases o NSCLC in men and
Adenocarcinoma is the most common subtype o 20% in women. This tumor arises most requently
NSCLC in the United States, representing 40% o in the proximal bronchi and has the stronger asso-
cases in men and 50% in women. It is predominant in ciation with smoking than adenocarcinomas. Patho-
nonsmokers, and its incidence has been rising. These logically, it is characterized by visible keratinization,
tumors are classically peripheral and, on histologic with prominent desmosomes and intercellular bridges
examination, demonstrate gland ormation, papillary (Fig. 24–2).
structures, or mucin production (Fig. 24–1). SCCs requently have amplications in chromo-
NSCLC is one o the cancer types with the highest some 3q, which contains genes involved in squamous
ChAPTER 24
mutation burden, with an average o 360 exonic muta- dierentiation (SOX2 and TP53) and cell prolieration
tions per sample.31 However, the patterns o mutations (PI3K). About 81% to 90% o patients with SCCs
are dierent or adenocarcinomas and SCCs. have TP53 mutations, and 47% have alterations in
About 75% o lung adenocarcinomas have altera- the PI3K–AKT–mTOR pathway, whereas only 26%
tions in driver genes that activate intracellular path- o SCCs have activations o the RTK/RAS/RAF path-
ways leading to prolieration, cell survival, and way.31 Whereas the prevalence o EGFR mutations is
oxidative stress response.32 Up to 79% o those altera- 1% to 3%, 6% o patients have EGFR amplications,
tions are in the Receptor Tyrosine Kinase (RTK)–Rat and 1% to 6% have KRAS mutations.31
TABLE 244 Te 2011 International Association CLINICAL PRESENTATION

or te Study o Lung Cancer/American Toracic
Society/European Respiratory Society histologic NSCLC is oten asymptomatic at diagnosis and may be
Classication o Invasive Malignant Epitelial ound incidentally on imaging perormed or other rea-
Tumors sons. I symptoms are present, they are oten related to
the specic locations o tumor masses and the occur-
Squamous cell carcinoma rence o paraneoplastic syndromes. The symptoms
o centrally located lesions include cough, hemopty-
Small cell carcinoma
sis, wheezing, stridor, dyspnea, and postobstructive
Adenocarcinoma pneumonia. Peripheral lesions can cause pain because
Lepidic predominant (ormerly nonmucinous o pleural or chest wall invasion, cough, or restrictive
bronchoalveolar carcinoma pattern with >5 mm
dyspnea. Loss o appetite, loss o weight, and bone
invasion)
Acinar predominant
pain are other common systemic symptoms.
Papillary predominant The involvement o thoracic and cervical structures
Micropapillary predominant can also lead to classical clinical presentations:
Solid predominant with mucin production • Pancoast syndrome: shoulder pain radiating to
Variants o invasive adenocarcinoma the arm in an ulnar distribution caused by invasion
Invasive mucinous adenocarcinoma (ormerly mucinous o the eighth cervical and rst thoracic nerves in the
bronchoalveolar carcinoma) superior sulcus
Colloid • Horner syndrome: enophthalmos, ptosis, miosis,
Fetal (low and high grade) and ipsilateral dyshidrosis caused by involvement
Enteric o the paravertebral sympathetic nerves, typically
Large cell carcinoma rom a superior sulcus tumor
Variants: large cell neuroendocrine; large cell • Hoarseness: compression or invasion o the let
neuroendocrine (NE) carcinoma (positive NE markers); recurrent laryngeal nerve as it passes through the
large cell carcinoma with NE morphology (morphology
aortopulmonary window by metastatic adenopathy
suggestive o NE carcinoma but negative stains)
• Elevation of the hemidiaphragm: involvement o
Adenosquamous carcinoma or NSCLC with squamous cell phrenic nerve rom mediastinal adenopathy
and adenocarcinoma patterns
• Superior vena cava syndrome: swelling o the
Carcinomas with pleomorphic, sarcomatoid, or ace and arm and supercial venous engorgement
sarcomatous elements caused by compression o the superior vena cava
Carcinoma with spindle or giant cells
either directly by the primary tumor or by meta-
Pleomorphic carcinoma
static adenopathy
Spindle cell carcinoma
Giant cell carcinoma The production o hormones or hormone-like sub-
stances can lead to paraneoplastic syndromes:
Carcinosarcoma
Blastoma (pulmonary blastoma) • Cancer cachexia: The most common paraneo-
Others plastic syndrome, characterized by weight loss,
Carcinoid tumor impaired immune unction, and weakness that are
Typical carcinoid not completely explained by poor oral intake. The
Atypical carcinoid exact mechanism or development o cachexia is
Carcinomas o salivary gland type unknown, but tumor-elaborated cytokines have
Mucoepidermoid carcinoma been implicated.
Adenocystic carcinoma, others • Hypercalcemia: The second most common paraneo-
Unclassied carcinoma plastic syndrome in NSCLC, hypercalcemia is caused
by ectopic production o a parathyroid hormone–
NSCLC, non–small cell lung cancer.
Adapted with permission rom Travis WD, Brambilla E, Noguchi M, et al. related protein or bone metastases. Ectopic secretion
International Association or the Study o Lung Cancer/American Thoracic is more common in the squamous cell subtype.
Society/European Respiratory Society international multidisciplinary
• Hypertrophic pulmonary osteoarthropathy:
ChAPTER 24
classication o lung adenocarcinoma, J Thorac Oncol 2011 Feb;6(2):244-285.

Arthropathy and clubbing o the ngers and toes
with evidence o periostitis o the long bones (Fig.
Large Cell Carcinoma 24–4). Its cause is unknown, and it is more common
The least common subtype o NSCLC, large cell carci- in adenocarcinomas and large cell carcinoma.
noma, accounts or approximately 8% o all NSCLCs NSCLC is requently metastatic at diagnosis, and
(Fig. 24–3). Renements in histopathologic techniques symptoms secondary to metastases are common. The
have led to the diagnosis o adenocarcinoma or SCC most common sites or metastases are intrathoracic
in cases previously diagnosed as undierentiated large nodes, pleura, contralateral lung, liver, adrenal glands,
cell carcinoma. bone, and brain.
TABLE 245 Adenocarcinoma histologic Subtypes and Molecular and Radiologic Associations
Predominant Computed Tomography Relative Risk o Recurrence

Histologic Subtype Molecular Features Scan Appearance Ater Resection
Lepidic TTF-1 positive: 100% Ground glass or solid 1.0
EGFR amplication: 20%–50% nodule
EGFR mutation (nonsmokers): 10%–30%
KRAS mutations (smokers): 10%
BRAF mutations: 5%
Papillary TTF-1 positive: 90%–100% Solid nodule 2.7 (95% CI, 1.1–6.8)
EGFR amplication: 20%–60%
EGFR mutation: 10%–30%
KRAS mutations: 3%
BRAF mutations: 5%
ERBB2 mutations: 3%
P53 mutations: 30%
Acinar TTF-1 positive or negative Solid nodule 2.3 (95% CI, 0.9–5.7)
EGFR amplication: 10%
EGFR mutation (nonsmokers): <10%
KRAS mutation (smokers): 20%
P53 mutation: 40%
EML4/ALK translocation: >5%
Micropapillary EGFR mutation: 20% Unknown 4.4 (95% CI, 1.8–11.2)
KRAS mutation: 33%
BRAF mutation: 20%
Solid TTF-1 positive: 70% Solid nodule 5.7 (95% CI, 2.2–14.7)
MUC1 positive
EGFR amplication: 20%–50%
EGFR mutation (nonsmokers): 10%–30%
KRAS mutation (smokers): 10%-30%
EML4/ALK translocations: >5%
P53 mutations: 50%
LRP1B mutations
INHBA mutations
Invasive mucinous TTF-1 negative (0%–33% positive) Consolidation; air Unknown
adenocarcinoma No EGFR mutation bronchograms
KRAS mutation: 80%–100%
MUC5, MUC6, MUC2, CK20 positive
CI, condence interval; TTF-1, thyroid transcription actor 1.
Adapted with permission rom Travis WD, Brambilla E, Noguchi M, et al. International Association or the Study o Lung Cancer/American Thoracic Society/European
Respiratory Society international multidisciplinary classication o lung adenocarcinoma, J Thorac Oncol 2011 Feb;6(2):244-285.
DIAGNOSIS
Solitary Pulmonary Nodule
A solitary pulmonary nodule is a single asymptomatic
mass that is surrounded by lung tissue, is well circum-
scribed, measures less than 3 cm, and does not show
evidence o mediastinal or hilar adenopathy. The di-
ChAPTER 24
erential diagnosis includes primary cancer, metastatic

cancer, inection, benign tumors (eg, hamartomas),
vascular abnormalities, and infammation (eg, granulo-
matous disease). The American College o Chest Phy-
sicians and National Comprehensive Cancer Network
(NCCN) have issued guidelines on the evaluation o
solitary lung nodules, based on their size, the clinical
FIGURE 24–1 Adenocarcinoma. Photomicrograph o
adenocarcinoma o the lung stained with hematoxylin and
probability o malignancy, and the patient’s surgical
eosin. (Used with permission rom Cesar Moran, MD.) risk41 (Table 24–7 and Fig. 24–5).
TABLE 246 Common Driver Genes Altered in Lung Adenocarcinoma
Name Alteration Main Eects Incidence

KRAS mutations Multiple; usually in codons 12 Activation o RAS–RAF–MEK–ERK 30%–35% (mostly in
and 13; most common, G12D pathway smokers)33
(nonsmokers) and G12C
(smokers)
EGFR mutations Several alterations in the ATP- Activation o RAS/RAF/MEK and 10%–15% (40%–50%
binding domain o the receptor PI3K–AKT–mTOR pathways in nonsmokers)36
BRAF mutations ~50% are the V600E mutation Activation o RAS–RAF–MEK–ERK 7%–10%32
also described in other cancers pathway
MET mutations Exon 14 skipping; can occur with Activation o MET 7%32
or without MET amplication
PIK3CA Many activating mutations AKT, TSC, and mTOR 7%32
EML4/ALK and other ALK Inversion within chromosome 2p Constitutively activates the 1%–4%37,38
translocations anaplastic lymphoma
kinase (ALK) gene leading to
downstream activation o RAS
and PI3K
ROS1 usions Multiple rearrangements o the Related to the ALK protein, also 1%–2%37
ROS1 gene with dierent genes activates RAS and PIK3CA
RET usions Multiple rearrangements o the Activation o the RET proto- 1%39
RET gene with dierent genes oncogene and RAS pathway
ERBB2 (HER2) mutations Various mutations; in ~50% o Activation o RAS–RAF–MEK and 2%–4%40
cases co-occurrence with HER2 PI3K–AKT–mTOR pathways
amplication
AKT, Protein kinase B (PKB); ERK: extracellular signal-regulated kinase; MEK, Mitogen-activated protein kinase kinase; mTOR, mammalian target o rapamycin; PI3K,
phosphoinositide 3-kinase; RAS, Rat sarcoma; RAF, Rapidly Accelerated Fibrosarcoma; TSC, Tuberous Sclerosis Complex.
A detailed description o the management o soli- Pulmonary Mass

tary pulmonary nodules is beyond the scope o this
book chapter. Readers reerred to the updated Fleis- Lesions that are large (>3 cm), multiple, or with enlarged
chner Society guidelines (2017)42 and the NCCN hilar, mediastinal, and/or supraclavicular lymph nodes
guidelines.43 should undergo complete lung cancer staging and a
ChAPTER 24
FIGURE 24–2 Squamous cell carcinoma. Photomicrograph o FIGURE 24–3 Large cell carcinoma. Photomicrograph o
squamous cell carcinoma o the lung stained with hematoxy- large cell carcinoma o the lung stained with hematoxylin
lin and eosin. (Used with permission rom Cesar Moran, MD.) and eosin. (Used with permission rom Cesar Moran, MD.)
FIGURE 24–4 Hypertrophic pulmonary osteoarthropathy (HPO). This 62-year-old man with non–small cell lung cancer
reported a 1-month history o fnger clubbing and arthritic lower extremity pain. Plain radiographs o the lower extremities
show a periosteal reaction in both emora as well as in bilateral tibias and fbulas that is consistent with HPO.
TABLE 247 Clinical Probability o Malignancy o Solitary Lung Nodules
Intermediate
Low Probability (<5%) Probability (6%–65%) High Probability (>65%)
Patient Young, low smoking burden, Mixture o low- and Older, heavy smoker, previous
no previous history o high-probability cancer
cancer eatures
Nodule (CT scan) Small, regular margins, non–upper Mixture o low- and Large, irregular or spiculated,
lobe location, enhancement <15 high-probability upper lobe location;
HU in the contrast phase eatures enhancement >15 HU in the
contrast phase
FDG-PET results Low or moderate clinical probability Weak or moderate PET Intense hypermetabolic
with low PET probability activity nodule
Nonsurgical biopsy Specic benign diagnostic Nondiagnostic Suspicious or malignancy
results (bronchoscopy
or transthoracic
biopsy)
Behavior on CT Progressive decrease in size or NA Clear evidence o growth
surveillance resolution; no growth over ≥2
years (solid nodules) or over ≥3
ChAPTER 24
years (semisolid nodules)

CT, computed tomography; FDG-PET, 18F-fuorodeoxyglucose–positron emission tomography; NA, not applicable.
nonsurgical biopsy. Fiberoptic bronchoscopy is appro- percutaneous transthoracic biopsies can be consid-
priate or central lesions and is able to establish the ered. Because o the tissue requirements or IHC and
diagnosis in 97% o cases. For peripheral lesions, the molecular marker testing o lung cancers, at MDACC,
diagnostic yield o bronchoscopy is only 55%, and we usually perorm an image-guided core-needle
New solitary nodule on chest CT (8-30 mm, solid, indeterminate)
Low/moderate surgical risk High surgical risk
Evaluate clinical probability of cancer Nonsurgical CT

(Table 18-8) biopsy surveillance
Low Intermediate High Benign or Non

Malignant
(<5%) (5%-65%) (>65%) diagnostic
Full staging
PET
evaluation (+/– PET)
Moderate/intense
Negative/mild uptake T1-3 N0M0 T4NX, TX N1-3; M1
uptake
CT surveillance at 3-6; Surgical resection/SBRT or Core biopsy and

Nonsurgical biopsy
9-12; 18-24 months RFA for high surgical risk standard treatment
FIGURE 24–5 Management algorithm or individuals with solitary nodules (8–30 mm). CT, computed tomography; PET, pos-
itron emission tomography; RFA, radiorequency ablation; SBRT, stereotactic body radiotherapy. (Adapted with permission
rom Gould MK, Donington J, Lynch WR, et al. Evaluation o individuals with pulmonary nodules: when is it lung cancer? Diag-
nosis and management o lung cancer, 3rd ed: American College o Chest Physicians evidence-based clinical practice guide-
lines., Chest 2013 ;143(5 suppl):e93S-120S.)
biopsy. Mediastinoscopy or bronchoscopic endobron- be encouraged as a part o the initial evaluation in the
chial ultrasound (EBUS) can be used to obtain biopsy preoperative setting and preradiation settings (stages
samples rom mediastinal and hilar nodes. I–III) In one series, occult N2 disease was ound in
20% o patients with T1 to T2 NSCLC, node nega-
tive by PET-CT.44
Staging Ater completion o the staging evaluation, the dis-
Ater the histologic diagnosis o NSCLC has been ease is assigned a TNM stage as outlined in Tables
established, the extent o disease must be determined. 24–8, 24–9. The eighth edition TNM staging a was
The stage o disease dictates therapy and prognosis adopted in 2017.45
(Tables 24–8 and 24–9). All patients must undergo
a complete history and physical examination, PET-
CT, a complete blood count, and blood chemistry Key T Descriptors (Fig. 24–6)
tests that assess renal and hepatic unction, electro- Primary Tumor
lytes, and calcium levels. All patients with stage II
T1 disease: T1 tumors are divided into T1a (≤1 cm),
to IV disease should have evaluation o the brain,
T1b (>1 to ≤2 cm), and T1c (>2 to ≤3 cm).
with magnetic resonance imaging (MRI) i possible.
Central nervous system imaging may also be consid- T2 disease: T2a is larger than 3 cm to 4 cm, and T2b
ered or patients with stage I disease. For stage I to is larger than 4 cm but not larger than 5 cm. Or it is a
IV NSCLC,18F-fuorodeoxyglucose (FDG)-PET should tumor with any o the ollowing eatures. involvement
ChAPTER 24
be perormed to evaluate mediastinal nodes and or o the mainstem bronchus, regardless o the distance
distant metastases. Because the involvement o medi- rom the carina; visceral pleura involvement; and par-
astinal lymph nodes will infuence surgical decisions tial or total atelectasis that extends to the hilar region
(see the Treatment section), the presence o FDG-avid either involving part o the lung or the entire lung.
mediastinal lymph nodes in a PET-CT scan should be T3 disease: T3 is larger than 5 to 7 cm. Or the tumor
conrmed with either mediastinoscopy or EBUS. In directly invades any o the ollowing: chest wall,
the setting o a normal-appearing mediastinum on phrenic nerve, parietal pericardium, or associated
PET-CT, invasive mediastinal assessment should also spate tumor nodule(s) in the same node as the primary.
TABLE 248 Denitions or Tumor (T), Node (N), and Metastasis (M) Descriptors (Stage Grouping or
te TNM Classication or Lung Cancer)
Descriptor Subgroup Defnition

T Primary tumor
Tx Primary tumor cannot be assessed or tumor proven by the presence o malignant cells in
sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0 No evidence o primary tumor
Tis Carcinoma in situ
T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without
bronchoscopic evidence o invasion more proximal than the lobar bronchus (ie, not in the
main bronchus)a
T1mi Minimally invasive adenocarcinomab
T1a Tumor ≤1 cm in greatest dimensiona
T1b Tumor >1 cm but not >2 cm in greatest dimensiona
T1c Tumor >2 cm but not >3 cm in greatest dimensiona
T2 Tumor >3 cm but not >5 cm or tumor with any o the ollowing eaturesc
• Involves main bronchus regardless o distance to the carina but without involving the
carina
• Invades the visceral pleura
• Associated with atelectasis or obstructive pneumonitis that extends to the hilar region,
either involving part o the lung or the entire lung
T2a Tumor >3 cm but not >4 cm in greatest dimension
T2b Tumor >4 cm but not >5 cm in greatest dimension
T3 Tumor >5 cm but not >7 cm in greatest dimension or one that directly invades any o
the ollowing: chest wall (including superior sulcus tumors), phrenic nerve, or parietal
pericardium; or associated separate tumor nodule(s) in the same lobe as the primary
T4 Tumor >7 cm or one that invades any o the ollowing: diaphragm, mediastinum, heart, great
vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate
tumor nodule(s) in a dierent ipsilateral lobe to that o the primary
N Regional lymph nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial or ipsilateral hilar lymph nodes and intrapulmonary
nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene,
or supraclavicular lymph node(s)
M Distant metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or
malignant pleural or pericardial eusiond
M1b Single extrathoracic metastasis in a single organe
ChAPTER 24
M1c Multiple extrathoracic metastasis in one or several organs

a
The uncommon supercial spreading tumor o any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is
also classied as T1a.
b
Solitary adenocarcinoma (≤3 cm), with a predominantly lepidic pattern and ≤5 mm invasion in the greatest dimension in any one ocus.
c
T2 tumors with these eatures are classied T2a i ≤4 cm or i size cannot be determined and T2b i >4 cm but not >5 cm.
d
Most pleural (pericardial) eusions with lung cancer are due to tumor. In a ew patients, however, multiple microscopic examinations o pleural (pericardial) fuid are
negative or tumor, and the fuid is nonbloody and is not an exudate. When these elements and clinical judgement dictate that the eusion is not related to the tumor,
the eusion should be excluded as a staging descriptor.
e
This includes involvement o a single distant (nonregional) node.
Reproduced with permission rom Goldstraw P, Chansky K, Crowley J, et al: The IASLC Lung Cancer Staging Project: Proposals or Revision o the TNM Stage Groupings
in the Forthcoming (Eighth) Edition o the TNM Classication or Lung Cancer, J Thorac Oncol 2016 Jan;11(1):39-51.
TABLE 249 Staging Grouping or te 8t separate tumor nodule(s) in a dierent ipsilateral lobe
Edition o te Tumor (T), Node (N), and to that o the primary.
Metastasis (M) Classication or Lung Cancer
Regional Lymph Nodes (Fig. 24–7):
Stage T N M N0: no nodal metastases
Occult carcinoma Tx N0 M0 N1: metastasis in ipsilateral peribronchial or ipsilateral
0 Tis N0 M0 hilar lymph nodes and intrapulmonary nodes, includ-
IA1 T1mi N0 M0 ing involvement by direct extension
T1a N0 M0 N2: metastasis in ipsilateral mediastinal or subcarinal
IA2 T1b N0 M0 nodal disease
IA3 T1c N0 M0 N3: metastasis in contralateral mediastinal, contralat-
IB T2a N0 M0 eral hilar, ipsilateral, or contralateral scalene or supra-
clavicular lymph node(s)
IIA T2b N0 M0
IIB T1a N1 M0 Distant Metastasis (Fig. 24–8)
T1b N1 M0 M1a: metastatic disease conned to the chest is
T1c N1 M0 classied as M1a, which includes contralateral lung
T2a N1 M0 nodule(s) (notably, nodules in the ipsilateral lung are
classied as T3 disease i they are in the same lobe as
T2b N1 M0
the primary or T4 disease i they are in a dierent lobe
T3 N0 M0
as the primary), malignant pleural or pericardial eu-
IIIA T1a N2 M0 sions, or pleural or pericardial nodules. MIa disease is
T1b N2 M0 grouped as stage IVA disease.
T1c N2 M0 M1b: a solitary metastasis outside the chest. M1b dis-
T2a N2 M0 ease is grouped as stage IVA.
T2b N2 M0 M1c: multiple metastases outside the chest in one or
T3 N1 M0 several organs. M1c disease is grouped as stage IVB.
T4 N0 M0 Please see Table 24–10 or stage groupings and prog-
nosis by stage.45
T4 N1 M0
Clinical staging has inherent inaccuracies and there-
IIIB T1a N3 M0 ore typically underestimates the true extent o disease.
T1b N3 M0 In patients who undergo surgical tumor resection, sur-
T1c N3 M0 gical or pathologic staging should be done to predict
T2a N3 M0 recurrence and to evaluate the need or adjuvant ther-
apy. Patients’ 5-year survival rates by tumor stage per
T2b N3 M0
American Joint Committee on Cancer (AJCC) eighth
T3 N2 M0
edition are shown in Table 24–10.
T4 N2 M0
IIIC T3 N3 M0
T4 N3 M0 TREATMENT
IVA Any T Any N M1a
Any T Any N M1b Stage I and II Disease
IVB Any T Any N M1c Surgery
Reproduced with permission rom Goldstraw P, Chansky K, Crowley J, et al: The
IASLC Lung Cancer Staging Project: Proposals or Revision o the TNM Stage Surgery is standard treatment or stage I and II NSCLC
Groupings in the Forthcoming (Eighth) Edition o the TNM Classication or Lung
Cancer, J Thorac Oncol 2016 Jan;11(1):39-51. i there are no contraindications (Figs. 24–9 and 24–10).
ChAPTER 24
For patients who cannot be saely operated on or reuse

surgery, radiation therapy can be considered.
The extent o lung resection is dictated by the size
and location o the tumor. The entire tumor must be
T4 disease: T4 is larger than 7 cm. Or the tumor that removed, with margins negative or cancer. Wedge
invades any o the ollowing: diaphragm, mediasti- resection and segmentectomy are associated with
num, heart, great vessels, trachea, recurrent laryngeal higher rates o local recurrence than lobectomy and
nerve, esophagus, vertebral body, or carina or it is a pneumonectomy and are not considered standard o
care, although they may be an option or patients who diusing capacity o the lungs or carbon dioxide less
cannot tolerate a larger surgery due to poor pulmonary than 40% to 60%.48
unction.46 All patients should also undergo complete
ipsilateral mediastinal lymph node dissection or sys- Radiation Therapy
tematic mediastinal sampling or accurate pathologic
staging.47 For patients with early-stage lung cancer who cannot
Any patient who is being considered or surgery undergo surgery because o poor pulmonary reserve or
must undergo pulmonary unction tests to assess the medical comorbidities, stereotactic radiosurgery (SRS)
ability to withstand pulmonary resection. Split-lung is a reasonable and even a desirable option with local
unction studies can urther help to predict lung unc- control rates o 90% and a cancer-specic survival rate
tion ater the planned resection. There is no single o 88% at 3 years.49
accepted value, criterion, or cuto or pulmonary There is controversy regarding whether SRS should
resection. Published criteria that have been shown to be considered in patients who are candidates or sur-
predict high risk or lung resection include estimated gery and who have small primary tumors and no
posttreatment orced vital capacity less than 2 L, lymph node involvement. Retrospective series suggest
orced expiratory volume in 1 second less than 1 L, and that outcomes with radiation may be similar to those
T1a, T1b T1c

Tumor:
Tumor: ≤1 cm >2 cm, ≤3 cm
Superficial spreading tumor

of any size with its invasive
component limited to the
bronchial wall, which may
extend proximal to the main
bronchus is T1
Tumor:
>1 cm, Tumor ≤3 cm; any associated
≤2 cm bronchoscopic invasion
should not extend proximal
to the lobar bronchus
Tumor in the main bronchus

<2 cm from the carina (without T2a T2b
Tumor:
involvement of the carina) and/ >3 cm, ≤4 cm
or associated atelectasis or
obstructive pneumonitis Tumor ≤4 cm,
of the entire lung invasion of the
visceral pleura
Tumor involves
main bronchus, Tumor:
regardless of >4 cm,
distance from ≤5 cm
carina but (with or
without carinal without
involvement other T2
Associated descriptors)
atelectasis or
ChAPTER 24
obstructive
pneumonitis that extends to the hilar
region, either involving part of the
lung or the entire lung
FIGURE 24–6 Lung cancer staging or tumor (T). SVC, superior vena cava.
(Continued)
T3 Chest wall invasion, including pancoast

tumors without invasion of vertebral
body or spinal canal, encasement of
the subclavian vessels, or unequivocal
Tumor: involvement of the superior branches of
>5 cm, ≤7 cm the brachial plexus (C8 or above)
Invasion
of parietal
Phrenic nerve pleura
or parietal
pericardium
invasion
Separate tumor
nodule(s) in the
lobe of the primary
Pancoast tumors with invasion of

one or more of the following structures:
T4 - Vertebral body or spinal canal
- Brachial plexus (C8 or above)
Tumor invades - Subclavian vessels
trachea and/or Tumor invades aorta
SVC or other and/or recurrent
great vessel laryngeal nerve
Tumor
involves
carina Tumor >7 cm
Tumor accompanied
by ipsilateral,
separate
Diaphragmatic tumor nodules,
invasion different lobe
Tumor invades
Tumor invades esophagus, mediastinum,
adjacent and/or heart
vertebral body
FIGURE 24–6 (Continued)
o surgery.49 Surgery, however, remains the standard o benet in 5-year survival rate o about 5%.54 In a
care or patients who can tolerate it. pooled analysis o ve largest trials o cisplatin-based
Concurrent chemotherapy and radiotherapy are rec- chemotherapy in patients with completely resected
ommended or patients who are medically inoperable NSCLC showed that this benet is greater with
with stage II (node-positive) and stage III NSCLC.50–53 increasing stage, with a hazard ratio (HR) or stage II
o 0.83; (95% CI, 0.73–0.95) and HR or stage III o
0.83; (95% CI, 0.72–0.94).55 Thus, adjuvant chemo-
Adjuvant Chemotherapy
therapy should be oered to all patients with good
Even ater complete resection, rates o recurrence o perormance status, with completely resected stage II
ChAPTER 24
NSCLC are high, prompting the study o adjuvant and III NSCLC (Table 24–11).55–60 For patients with no
chemotherapy in this disease. The potential benet lymph node involvement and a primary tumor smaller
o adjuvant chemotherapy is the eradication o micro- than 4 cm, adjuvant chemotherapy is not recom-
metastatic disease beore it becomes clinically evident, mended. For node-negative tumors larger than 4 cm,
thus potentially increasing cure rates. For patients with the Cancer and Leukemia Group B 9633 trial suggested
completely resected stage II or III NSCLC, multiple a benet o adjuvant platinum-based chemotherapy,
meta-analyses demonstrate that adjuvant platinum- and it should be considered particularly in the setting
based chemotherapy is associated with an absolute o high-risk actors such as vascular invasion, visceral
N0 N1
Metastasis in
ipsilateral
intrapulmonary,
peribronchial, or
No regional hilar lymph node(s),
lymph node including nodal
metastases involvement by
direct extension
N2
Metastasis in
ipsilateral mediastinal Metastasis in
and/or subcarinal ipsilateral
lymph node(s), mediastinal
including “skip” and/or subcarinal
metastasis without lymph node(s)
N1 involvement associated with
N1 disease
N3
Metastasis in
ipsilateral scalene
or supraclavicular
lymph node(s)
Metastasis in
contralateral
hilar, mediastinla,
scalene, or
supraclavicular
ChAPTER 24
lymph node(s)
FIGURE 24–7 Lung cancer staging or node (N).

M1a
Contralateral,
Primary tumor separate
tumor nodule(s)
M1b
This includes
involvement of a single
distant (nonregional)
lymph node
Malignant Malignant
pleural effusion or nodule(s) pericardial effusion or nodule(s)
M1c
M1b
Brain
This includes
multiple extrathoracic
metastases in one
Lymph or several organs
nodes
Bone
Single
extrathoracic
metastasis
Liver Adrenal
Liver
FIGURE 24–8 Lung cancer staging or metastasis (M).
TABLE 2410 Five-Year Survival or NonSmall

Cell Lung Cancer by Patologic Clinical Stage pleural involvement, wedge resection, poorly dier-
entiated tumors, and unknown lymph node status56,61
Stage MST 24 Months (%) 60 Months (%) (see Table 24–11).
Cisplatin–vinorelbine is the most studied regimen
IA1 NR 97 92
or adjuvant chemotherapy; in practice, other cispla-
IA2 NR 94 83 tin-based doublets are requently used. Acceptable
IA3 NR 90 77 second agents include pemetrexed (or nonsquamous
IB NR 87 68 NSCLC), docetaxel, paclitaxel, etoposide, and gem-
IIA NR 79 60 citabine. Cisplatin is preerred over carboplatin, but
i cisplatin is not easible, carboplatin–paclitaxel is an
IIB 66.0 72 53
appropriate alternative.56 Neoadjuvant chemotherapy
ChAPTER 24
IIIA 29.3 55 36 oers several real and theoretical advantages over

IIIB 19.0 44 26 postoperative therapy, including better patient compli-
IIIC 12.6 24 13 ance, improved tumor resectability, earlier treatment
IVA 11.5 23 10 o micrometastatic disease, and earlier assessment o
IVB 6.0 10 0
clinical and pathologic response. There has been one
randomized trial and one meta-analysis62 that sug-
MST, median survival time in months; NR, not reached.
Data rom Goldstraw P, Chansky K, Crowley J, et al: The IASLC Lung Cancer gest the equivalence o the neoadjuvant and adju-
Staging Project: Proposals or Revision o the TNM Stage Groupings in the vant approaches. Adjuvant treatment is the standard
Forthcoming (Eighth) Edition o the TNM Classication or Lung Cancer, J Thorac
Oncol 2016 Jan;11(1):39-51. o care, but neoadjuvant chemotherapy could be
Surgical Surgical
candidate? candidate?
Yes No
Yes No
Consider Combined modality

Radiotherapy neoadjuvant therapy with
Surgery chemotherapy and
alone chemotherapy
thoracic irradiation
followed by 1 year
of consolidative
Surgical therapy with
margins Surgery Surgery margins Durvalumab
Consider
Positive Negative adjuvant Negative Positive
Yes
chemo
followed by
radiotherapy
N2 disease or N2 disease or Consider adjuvant
Adjuvant
involvement of involvement of Yes radiotherapy
radiotherapy
multiple levels multiple
Consider
of nodes No levels of nodes
adjuvant
chemo if N + No
Consider adjuvant
chemotherapy
FIGURE 24–9 Treatment algorithm or stage I non–small
cell lung cancer. See text or details.
FIGURE 24–10 Treatment algorithm or stage II, incidental
III non–small cell lung cancer. See text or details.
considered in special situations, such as or stage III Stage III Disease
disease when response to chemotherapy may help to
determine whether a patient should undergo surgery Patients with stage III disease have better outcomes
or chemoradiation. with multimodality rather than single-modality therapy,
Adjuvant radiation or chemoradiation or resected and their care should be managed by an experienced
stage I and II NSCLC has been shown to be detrimen- multidisciplinary team. For patients with stage IIIB dis-
tal and is not recommended.63 ease, chemoradiation represents the standard o care.
TABLE 2411 Cemoterapy Regimens or Adjuvant Treatment o Patients wit NonSmall Cell Lung
Cancer
Trial Regimen
57
IALT Cisplatin 80–120 mg/m2 every 3 o 4 weeks or three or our cycles, with
Vinorelbine 30 mg/m2 weekly or
Vinblastine 4 mg/m2 every week or 5 weeks; then every 2 weeks or
Etoposide 100 mg/m,2 days 1–3, with each cisplatin
58
ANITA Cisplatin 100 mg/m,2 day 1, every 4 weeks and vinorelbine 30 mg/m2 weekly or our cycles
NCIC-CTG JBR.1062 Cisplatin 50 mg/m,2 days 1 and 8, every 4 weeks or our cycles; vinorelbine 25 mg/m2 every week
or 16 cycles
TREAT60 (nonsquamous Cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks or our cycles
ChAPTER 24
histology)
CALGB 963356 Carboplatin AUC 6 and paclitaxel 200 mg/m2 every 3 weeks or our cycles
Others Cisplatin 75 mg/m2 and docetaxel 75 mg/m,2 day 1, every 3 weeks or our cycles
Cisplatin 75–80 mg/m,2 day 1; vinorelbine 25–30 mg/m,2 days 1 and 8, every 3 weeks or our cycles
Cisplatin 75 mg/m,2 day 1, and gemcitabine 1250 mg/m,2 days 1 and 8, every 3 weeks or our cycles
Carboplatin AUC 6 and pemetrexed 500 mg/m2 every 3 weeks or our cycles (nonsquamous
histology)
ANITA, Adjuvant Navelbine International Trialist Association [ANITA); AUC, area under the curve; CALGB, Cancer and Leukemia Group B; NCIC-CTG JBR.10, National
Cancer Institute o Canada Clinical Trials Group JBR.10; NSCLC, non–small cell lung cancer; TREAT, Trial on Renement o Early Stage Lung Cancer Adjuvant Therapy.
Chemoradiation is oten used or patients with stage higher rates o locoregional ailure (44% vs 35.3%;
IIIA disease as well, but surgery with adjuvant treat- P =.04) and worse median survival times (19.5 vs 28.7
ment can be considered or careully selected patients. months; P =.0007) than those receiving standard-dose
In a randomized trial o chemoradiation alone ver- radiation (60 Gy).66 Proton therapy is a newer tech-
sus chemoradiation ollowed by resection, the patients nique that is able to deliver a higher dose to the tumor
who beneted rom the surgical approach were those while delivering lower doses to normal surrounding
with stage IIIA disease who had limited involvement tissue; it is currently being compared with standard
o mediastinal lymph nodes and who underwent radiation in a randomized phase III trial.
lobectomy (as opposed to pneumectomy).64 Neoad- Multiple concurrent chemotherapy regimens have
juvant chemoradiation ollowed by surgery has been been tested against radiation alone with proven ben-
compared with neoadjuvant chemotherapy ollowed et53; however, these regimens have not been directly
by surgery and adjuvant radiation65 and was associ- compared with each other, and multiple regimens are
ated with more toxicity with no survival benet. At considered acceptable (Table 24–12). At MDACC, we
MDACC, we consider surgical treatment in patients avor carboplatin and paclitaxel based on our experi-
with stage IIIA disease with good perormance status ence and retrospective data that suggest that this regi-
and without multistation or bulky (>2 cm) mediastinal men is less toxic than cisplatin and etoposide.67
adenopathy. These patients are typically treated with ICI therapy is standard as consolidation ater CRT
neoadjuvant chemotherapy ollowed by consideration based on a landmark study, the A Phase III, Ran-
o surgery. Adjuvant radiation therapy is typically given domised, Double-blind, Placebo-controlled, Multi-
i there is evidence o mediastinal node involvement centre, International Study o MEDI4736 as Sequential
based on assessment o surgical pathology (Fig. 24–11). Therapy in Patients With Locally Advanced, Unresect-
Patients with stage IIIA disease and extensive medi- able Non-Small Cell Lung Cancer (Stage III) Who Have
astinal involvement or IIIB disease should be treated Not Progressed Following Denitive, Platinum-based,
with concurrent chemoradiation and ollowed by con- Concurrent Chemoradiation Therapy (PACIFIC) trial.
solidative ICI therapy. Concurrent chemoradiotherapy For patients with unresectable, stage III NSCLC with-
(CRT), when compared with sequential radiotherapy out progression ater CRT, durvalumab demonstrated
and chemotherapy, is associated with higher survival increased survival rates versus placebo leading to its
rates (23.8% vs 18.1% at 3 years; HR, 0.84; P =.004) approval by the Food and Drug Administration (FDA).
with increased, but manageable, acute esophageal Patients included in the PACIFIC study had stage III
toxicity (grade 3–4 rom 4% to 18% vs 4%; relative unresectable disease, received two or more cycles o
risk [RR], 4.9; P =.001) without a signicant dierence platinum-based chemotherapy (containing etoposide,
regarding acute pulmonary toxicity.50 vinblastine, vinorelbine, paclitaxel, docetaxel, peme-
Standard radiotherapy or stage III NSCLC consists trexed) concurrently with denitive radiation, without
o radiation given once daily or 6 weeks (30 rac- progression.68 Patients previously treated with pro-
tions) to a total dose o 60 Gy. Attempts to increase grammed cell death (ligand) 1 (PD-(L)1 inhibitors or
ecacy through increased radiation dose have ailed. grade 2 or greater pneumonitis rom previous chemora-
In The Radiation Therapy Oncology Group 0617 trial, diation were excluded.68 Patients were enrolled irrespec-
patients receiving high-dose radiation (74 Gy) had tive o PD-L1 status. Patients were randomized within
Concurrent
chemoradiotherapy
Followed by a year of
B consolidative therapy
with Durvalumab
Yes
Stage III
• Multiple N2 nodal
ChAPTER 24
levels Consider
A No
• Medically inoperable neoadjuvant Surgery
• Technically chemotherapy
inoperable
pN2
Consider Consider
adjuvant adjuvant
chemotherapy radiotherapy
FIGURE 24–11 Treatment algorithm or stage III non–small cell lung cancer. See text or details.
TABLE 2412 Cemoradiation Regimens or Stage III NonSmall Cell Lung Cancer
Adjuvant Treatment Ater the

Regimen Histology Doses Completion o Chemoradiation
Cisplatin + All NSCLC Cisplatin 50 mg/m2 days 1, 8, 29,36 No
etoposide Etoposide 50 mg/m2 days 1–5, 29–33
Cisplatin + All NSCLC Cisplatin 100 mg/m2 days 1 and 29 No
vinblastine Vinblastine 5 mg/m2 weekly × 5
Carboplatin + Adenocarcinoma Carboplatin AUC 5 day 1 every 21 days × 4 Yes; continue carboplatin +
pemetrexed Pemetrexed 500 mg/m2 day 1 every 21 days × 4 pemetrexed to a total o our
cycles
Cisplatin + Adenocarcinoma Cisplatin 75 mg/m2 day 1 every 21 days × 3 Yes; continue cisplatin +
pemetrexed Pemetrexed 500 mg/m2 day 1 every 21 days × 3 pemetrexed to a total o three
cycles
Carboplatin + All NSCLC Carboplatin AUC 2 weekly during radiation Yes; two cycles o carboplatin AUC
paclitaxel Paclitaxel 45–50 mg/m2 weekly during 6 + paclitaxel 200 mg/m2 every
radiation 21 days ater the completion o
chemoradiation
AUC, area under the curve; NSCLC, non–small cell lung cancer.
6 weeks o completing CRT to receive durvalumab 10 challenging. Patients with N0 to N1 tumors should
mg/kg intravenously every 2 weeks or placebo or up undergo preoperative concurrent chemoradiation ol-
to 12 months.68 They were stratied by age younger lowed by resection. For these patients, 5-year disease-
than 65 years vs 65 years and older), sex, and smoking ree survival rates are 40% to 50%.74 Patients with
status (current or ormer smoker vs never smoker). A N2 to N3 disease should be treated with concurrent
total o 473 patients were randomized to durvalumab, chemoradiation ollowed by durvalumab therapy.
and 236 patients were randomized to placebo.68
The addition o durvalumab improved progression- Stage IV Disease
ree survival (PFS) and OS; 12-, 24- and 36-month OS
rates with durvalumab and placebo were 83.1% versus The primary goals o systemic therapy in patients
74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, with metastatic NSCLC are to reduce symptom bur-
respectively, and therapy was generally tolerated den rom cancer, delay progression o symptoms, and
well with without compromising patient-reported improve survival while maintaining quality o lie.
outcomes.69,70 Beore palliative systemic therapy, a consideration
Ater radiation therapy to the involved lung, any should be made or palliative radiotherapy in patients
grade o pneumonitis was observed in nearly one with symptomatic brain or spinal cord metastases,
third o patients in the durvalumab arm, with 20% hemoptysis, postobstructiccmetastases. Early reer-
attributed to radiation pneumonitis and about 13% ral to specialized palliative care services has also been
attributed to durvalumab.71 Pneumonitis was the shown to improve OS.75
most common immune-related adverse event leading Advances in tumor analysis by next-generation
to treatment discontinuation, and our patients died sequencing (NGS) and other proling technologies
rom pneumonitis. This immune-related adverse event
needs to be ollowed closely in patients undergoing
A
this consolidative approach.
I patients have a contraindication to ICI therapy,
such as organ transplant or active autoimmune dis-
ChAPTER 24
ease, when the saety o immunotherapy has not been

well established, consolidative chemotherapy can be
considered. However, no level 1 randomized evidence
supports a survival benet with this treatment.72,73
Pancoast Tumors
Tumors in the lung apex invading apical structures,
termed pancoast tumors (Figs. 24–12 and 24–13), are FIGURE 24–12 Pancoast tumor.
B
option because compared with best supportive care,
chemotherapy had been associated with a modest
improvement in median OS (1.5 months) and signi-
cant gains in symptom control.81 Multiple platinum-
based doublets are eective with response rates rom
18% to 35%, PFS o 3 to 6 months, and OS o 8 to
12 months.77–80,82 A deeper understanding o tumor–
immune interactions and development o ICIs have
dramatically changed the therapeutic landscape o
NSCLC and other malignancies.83
Immunotherapy in Advanced Non–Small

Cell Lung Cancer
Immune checkpoints are the T-cell regulatory mecha-
nisms o co-stimulatory and inhibitory signals that
control the amplitude and quality o immune response.
The expression o inhibitory immune checkpoints can
be upregulated by tumors and serve as an adaptive
FIGURE 24–13 On magnetic resonance imaging, this non– immune evasion mechanism.84 Activation o the pro-
small cell lung cancer tumor at the right lung apex invades grammed cell death 1 (PD-1) receptor by its ligand (PD-
the second right rib and extends apically into the right apical L1) has been recognized as a major immune inhibitory
at, with a loss o the at plane between the tumor and the T1 mechanism in solid tumors.85,86 Antibodies that inhibit
nerve. The T2 nerve is also involved by the mass. the PD-1–PD-L1 and cytotoxic T-lymphocyte-associ-
ated protein (CTLA-4) pathway produce durable clinical
provide inormation on tumor diagnosis and prog- responses in various solid tumors, including NSCLC.87–90
nosis and provide therapy options or patients. At PD-(L)1 inhibitors improve clinical outcomes compared
MDACC, we recommend molecular proling with with traditional chemotherapy and are now standard
NGS or locally advanced, metastatic NSCLC when- with or without chemotherapy or NSCLC without
ever easible because multiplexed genetic sequencing oncogenic driver alterations (Table 24–13).
panels, such as NGS, not only enables the simultane- Several actors are taken into consideration when
ous assessment o multiple genomic alterations such selecting a rst-line treatment option or a patient with
as EGFR, ALK, BRAF, RET, ERBB2(HER2), and MET but metastatic NSCLC, including tumor histology, molecu-
also hundreds o other genes that may have potential lar prole, PD-L1 expression levels, preexisting autoim-
roles in cancer development and targets or investiga- mune diseases, and other comorbid conditions. Next
tional therapies. we discuss several o the available rst-line options
It is recommend that all adenocarcinomas, mixed and studies that inorm the choice o those options.
adenosquamous carcinomas, NSCLCs not otherwise
specied and all lung cancers occurring in nonsmok-
ers should undergo comprehensive molecular proling. Immune Checkpoint Inhibitor Monotherapy
Because o the importance o molecular testing, attempts Previous trials ocused on cancer vaccines in NSCLC,
should be made to obtain core biopsies rather than ne- which were shown to induce tumor-specic immune
needle aspirations to ensure sucient tissue or prol- responses but ailed to improve survival.91 Subse-
ing.76 Systemic therapy or NSCLC with actionable quently, identication and targeting immune check-
molecular alterations is reviewed in Chapter 25, and points has renewed the interest in immunotherapy
this chapter ocuses on systemic therapy or advanced approaches or NSCLC. Clinical studies showed clinical
NSCLC with no actionable mutations. benet with therapies targeting CTLA-4, PD-1–PD-L1
axis in melanoma, which led to studies in other solid
ChAPTER 24
First-Line Systemic Therapy for Advanced tumors, including metastatic NSCLC.92 Initial studies
Non–Small Cell Lung Cancer with no in previously treated metastatic NSCLC reported a sta-
tistically signicant improvement in OS with PD-(L)1
Actionable Tumor Mutation inhibitors compared with docetaxel in patients with
Until 2016, chemotherapy combinations o cisplatin platinum-reractory advanced NSCLC and revealed
or carboplatin with paclitaxel,77 docetaxel,77 peme- a relationship between higher tumor PD-L1 protein
trexed78,79 (nonsquamous only), gemcitabine,77 or nab- expression and greater ecacies.93–96 These observa-
paclitaxel80 were standard o care rst-line therapy tions led to clinical trials with PD-(L)1 inhibitors in the
TABLE 2413 Efcacy o Immune Ceckpoint Inibitor Monoterapy in te First-line Treatment o
Patients wit NonSmall Cell Lung Cancer
Patient Treatment Overall OS PFS

Trial Patients (n) Population Arm(s) Control Arm RR (months) (months)
KEYNOTE 305 NSCLC, PD-L1 Pembrolizumab Platinum 44.8% (P) 30 (P) vs 10.3 (P)
02498 TPS ≥50%, (P)a doublet vs 27.8% 14.2 (C) vs 6 (C)
with no chemotherapy (C) (HR, 0.60; (HR, 0.50;
EGFR or ALK (C) 95% CI, 95% CI,
genomic 0.41–0.89; 0.37–
tumor P = .005 0.68: P
aberrations <.001)
KEYNOTE 1274 NSCLC, PD-L1 Pembrolizumab Platinum 27% (P) vs 16.7 (P) vs 5.4 (P) vs
042100 TPS ≥1%, (P)a doublet 27% (C) 12.1 (C) 6.5 (C)
with no chemotherapy (HR, 0.81; (HR, 0.07;
EGFR or ALK (C) 95% CI, 95% CI,
genomic 0.71–0.93; 0.94–
tumor P = .0036). 1.21)
aberrations
IMpower 572 (high PD-L1 NSCLC whose Atezolizumab Platinum For high For high For high
11099 subgroup tumors (A)b doublet PD-L1 PD-L1 PD-L1
treatment arm express chemotherapy groupc: groupc: groupc:
(atezolizumab PD-L1 (TC (C) 38.3% 20.2(A) vs 8.1(A) vs
n = 107), ≥ 1% or IC (A) vs 13.1 (C) 5.1 (C)
control arm ≥ 1%), no 28.6% (HR, 0.59; (HR, 0.63;
(chemotherapy, EGFR or ALK (C) 95% CI, 95% CI,
n = 98) genomic 0.40–0.89; 0.45–
tumor P = .0106) 0.88)
aberrations
a
The recommended pembrolizumab dosage or this indication is 200 mg intravenously every 3 weeks.
b
The recommended atezolizumab dosage or treatment o patients with non–small cell lung cancer (NSCLC) is 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680
mg every 4 weeks
c
High programmed cell death ligand 1 (PD-L1) expression (PD-L1–stained ≥50% o tumor cells [≥50%] or PD-L1–stained tumor-inltrating immune cells [ICs] covering
≥10% o the tumor area [IC ≥ 10%]) by the VENTANA PD-L1 (SP142) Assay (Ventana Medical Systems, Inc.).
CI, condence interval; HR, hazard ratio; OS, overall survival; PFS, progression-ree survival; RR, Response rate; TPS, tumor proportion score.
rst-line setting with PD-L1 protein expression being a carboplatin plus pemetrexed.97 The median PFS with
stratication and/or an inclusion criteria. pembrolizumab in patients with PD-L1 TPS o 50%
In the KEYNOTE 024 (NCT02142738) trial, patients or greater was 10.3 months versus 6.0 months in the
with treatment-naïve NSCLC without EGFR or ALK chemotherapy group with an HR o 0.50 (95% CI,
gene aberrations and PD-L1 tumor proportion score 0.37–0.68; P <.001).97 In an updated analysis, median
(TPS) o 50% o higher (PD-L1 expression as deter- OSs were 30.0 months (95% CI, 18.3–months to not
mined by an IHC assay using the PD-L1 IHC 22C3 reached) with pembrolizumab and 14.2 months (95%
pharmDx Kit) were randomized to pembrolizumab CI, 9.8–19.0 months) with chemotherapy (HR, 0.63;
200 mg intravenously every 3 weeks or up to 35 95% CI, 0.47–0.86). Eighty-two patients assigned to
cycles or platinum-based chemotherapy or our to chemotherapy crossed over on study to receive pem-
six cycles.97 The chemotherapy regimens included brolizumab. When adjusted or crossover using the
platinum–pemetrexed or patients with nonsquamous two-stage method, the HR or OS or pembrolizumab
ChAPTER 24
NSCLC and platinum–paclitaxel or gemcitabine or versus chemotherapy was 0.49 (95% CI, 0.34–0.69).
those with squamous NSCLC. Pemetrexed mainte- Treatment-related grade 3 to 5 adverse events were
nance was allowed ater initial platinum-based ther- less requent with pembrolizumab compared with
apy. Crossover rom chemotherapy to pembrolizumab chemotherapy and were 31.2% vs 53.3%, respec-
was also allowed in the event o progression. A total tively.98 This trial demonstrated that in patients with
o 154 patients were assigned to pembrolizumab, NSCLC with PD-L1 TPS o 50% or greater, treatment
and 151 patients were assigned to chemotherapy, with pembrolizumab monotherapy in the rst-line
with the most common chemotherapy regimen being therapy o metastatic NSCLC showed improved PFS,
OS, response rate, duration o response, and saety no signicant dierence in OS compared with chemo-
prole compared with platinum-based chemotherapy, therapy with a median OS o 13.4 versus 12.1 months
leading to its approval in the rst-line setting. (HR, 0.92; 95% CI, 0.77–1.11). The grade 3 to 5 drug-
IMpower110 (NCT02409342), was a randomized, related adverse events were less requent at 18% with
open-label trial in patients with therapy-naïve patients pembrolizumab versus 41.0 % or chemotherapy.100
with stage IV NSCLC whose tumors expressed PD-L1 These ndings led to the FDA approval o pembroli-
(tumor cells [TCs] ≥1% or tumor-inltrating immune zumab monotherapy or tumors with PD-L1 TPS o
cells (ICs) ≥1% measured by VENTANA PD-L1 [SP142 1% or higher by a companion diagnostic test using
assay]). Patients were randomized (1:1) to receive PD-L1 IHC assay in the rst-line therapy o patients
atezolizumab 1200 mg every 3 weeks versus plati- with metastatic NSCLC.
num-based chemotherapy. Although there was no In a similar trial design, the PD-1 inhibitor nivolumab
statistically signicant dierence in OS between the ailed to demonstrate improved OS benet in the
arms or the lower PD-L1 subgroups (TC ≥5% or IC phase 3 CheckMate 026 (NCT02041533) study. This
≥5% and TC ≥1% or IC ≥1%), in the high PD-L1 sub- study compared nivolumab with histology-dependent
group (TC ≥50% or IC ≥10%), the median PFS was 8.1 platinum-based doublets in treatment-naïve meta-
months in the atezolizumab arm and 5.0 months in the static NSCLC. PD-L1 expression level o 5% or greater
platinum-based chemotherapy arm (HR, 0.63; 95% CI, on TCs was selected as a cuto or eligibility. In this
0.45–0.88). Median OS was 20.2 months or patients in study, nivolumab did not show OS benet compared
the atezolizumab arm compared with 13.1 months in with a platinum doublet.101 When comparing results
the chemotherapy arm (HR, 0.59; 95% CI, 0.40–0.89; o KEYNOTE-042 and CheckMate 026, it should be
P = .0106). Conrmed overall response rate (ORR) was noted that the chemotherapy arm in CheckMate 026
38% versus 29%, and grades 3 to 4 treatment-related permitted crossover to nivolumab ater disease pro-
adverse events were reported in 12.9% in the atezoli- gression, whereas KEYNOTE-042 did not. In Check-
zumab arm compared with 44.1% in chemotherapy.00 Mate 026,60% o patients in the chemotherapy arm
Subsequently eorts ocused on investigation o received subsequent ICI therapy at the time o their
clinical ecacy o immunotherapy in tumors with progression, but only 20% o patients in the chemo-
low or absent PD-L1 expression. The KEYNOTE 042 therapy arm received subsequent ICI therapy in the
(NCT02220894) study explored the use o pembroli- KEYNOTE 042 study, which might have contributed
zumab in the rst-line setting by using a PD-L1 TPS to a dierence in OS benet in these two studies.
1% or greater as the cuto. Patients were randomized Because o relative limited clinical activity in low
to receive pembrolizumab 200 mg intravenously every PD-L1–expressing tumors and generally nonoverlap-
3 weeks or investigator’s choice o a carboplatin-con- ping toxicity proles o PD-(L)1 inhibitors and che-
taining regimen with either pemetrexed or paclitaxel motherapy, subsequent eorts shited to combination
or their treatment-naïve locally advanced or meta- therapy strategies, which included chemotherapy,
static NSCLC.100 In addition to selection criteria, PD-L1 biologic agents, and other ICIs. Multiple therapy com-
protein expression was also used or patient stratica- binations have resulted in improved clinical outcomes
tion (TPS ≥50% vs TPS 1-49%). OS in the TPS 50% or rst-line therapy o patients with NSCLC com-
or greater NSCLC subgroup, the TPS 20% or greater pared with platinum doublets and have received FDA
NSCLC subgroup, and the overall population (TPS approvals (Table 24–14).
≥1%) were the major ecacy measures.100 KEYNOTE
042 demonstrated statistically signicant OS improve- Combination Therapies Containing Immune
ments or those randomized to pembrolizumab com-
Checkpoint Inhibitors s
pared with chemotherapy in all three populations.100
Although there was no signicant dierence in PFS or KEYNOTE 189 (NCT02578680) was a randomized
ORR between therapy arms in the TPS 1% or greater open-label study o rst-line treatment o metastatic
population (overall population), the median OS was nonsquamous NSCLC. Patients were randomized (2:1)
improved to 16.7 months in the pembrolizumab arm to receive pembrolizumab 200 mg given intravenously
compared with 12.1 months in chemotherapy arm every 3 weeks (or placebo) in combination with peme-
ChAPTER 24
(HR, 0.81; 95% CI, 0.71–0.93; P = .0036). It is impor- trexed and investigator’s choice o either cisplatin or
tant to point out that in this study, OS benet had been carboplatin every 3 weeks or our cycles ollowed by
largely driven by tumors that had high PD-l1 IHC TPS pembrolizumab (or placebo) and pemetrexed main-
score. In the TPS 50% or greater subgroup, the esti- tenance. Treatment with pembrolizumab continued
mated median OSs were 20 months in the pembroli- until disease progression, unacceptable toxicity, or a
zumab arm and 12.2 months or chemotherapy arm maximum o 24 months. The primary ecacy outcome
(HR, 0.69; 95% CI, 0.56–0.85; P = .0006). In contrast, measures were OS and PFS.101 The trial demonstrated
or patients with PD-L1 TPS o 1% to 49%, there was a statistically signicant improvement in PFS and OS
TABLE 2414 Efcacy o Immune Ceckpoint + Cemoterapy and/or Combination Immune

Ceckpoint Terapies in te First-Line Treatment o Patients wit NonSmall Cell Lung Cancer
Patients Patient Treatment Overall OS PFS

Trial (n) Population Arm(s) Control Arm RR (months) (months)
KEYNOTE 616 Nonsquamous Pembrolizumab, Cisplatin or 47.6% (T) 22 (T) vs 9 (T) vs 4.9 (C)
189103 cell NSCLC, cisplatin, or carboplatin vs 18.9% 10.7 (C) (HR, 0.48;
with no carboplatin, and and (C) (HR, 0.56; 95% CI,
EGFR or ALK pembrolizumab pemetrexed 95% CI, 0.40–0.58)
genomic tumor (triple [T]) (C) 0.45–0.70).
aberrations
KEYNOTE 559 Squamous cell Pembrolizumab, cisplatin OR 58% (T) vs 15.9 (T) vs 6.4 (T) vs
407104 NSCLC cisplatin, or carboplatin 35% (C) 11.3 (C) 4.8(C)
carboplatin and and paclitaxel (HR, 0.64; (HR, 0.56;
paclitaxel or or nab- 95% CI, 95% CI,
nab-paclitaxel paclitaxel (C) 0.49–0.85; 0.45–0.70;
(triple [T]) P = .0017) P <.0001)
IMpower 724 Nonsquamous Atezolizumab, Protein-bound 49.2% 18.6 (A) vs 7.2 (A) vs 6.5
130105 NSCLC protein-bound paclitaxel and 31.9% 13.9 (C) (C) (HR,
paclitaxel, and carboplatin (OR, 2.07) (HR, 0.80; 0.75; 95%
carboplatin ollowed by 95% CI, CI, 0.63–
ollowed by maintenance 0.64–0.99; 0.91;
maintenance pemetrexed P = .0384) P = .0024)
atezolizumab (A) (C)
IMpower 1202 Nonsquamous Atezolizumab, Carboplatin, 55% (ABCP) 19.2 (ABCP) 8.5 (ABCP)
150107 NSCLC carboplatin, paclitaxel, and vs 42% vs 14.7 vs 7(C)a
paclitaxel, and bevacizumab (C)a (C)a arm (HR, 0.71;
bevacizumab (C) (HR, 0.78; 95% CI
(ABCP); 95% CI, 0.59–0.85;
atezolizumab, 0.64–0.96; P = .0002)
carboplatin and P = .016)
paclitaxel (ACP)
CheckMate 793 NSCLC, PD-L1 Ipilimumab and Platinum 36% (I + N) 17.1 (I + N) 5.1 (I + N)
227108 tumor nivolumab doublet vs 30% vs 14.9(C) vs 5.6 (C)
expression (I + N)b chemotherapy (C) (HR, 0.79; (HR, 0.82;
≥1% by PD-L1 (C) 95% CI, 95% CI,
IHC 28-8 0.67–0.94; 0.69–0.97)
pharmDx, with P = 0.0066)
no EGFR or ALK
genomic tumor
aberrations
CheckMate 719 NSCLC with no Nivolumab plus Platinum 38% (4DR) 14.1 (4DR) 6.8 (4DR)
9LA110 EGFR or ALK ipilimumab doublet vs 25% vs 10.7 (C) vs 5 (C)
genomic tumor and two cycles chemotherapy (C) (HR, 0.69; (HR, 0.70;
aberrations o platinum- (C) (our 96.71% CI, 95% CI,
doublet cycles) 0.55–0.87) 0.57–0.86)
chemotherapy
(our-drug
regimen [4DR])c
ChAPTER 24
a
Comparative analysis or atezolizumab, carboplatin, paclitaxel, and bevacizumab arm versus platinum-based chemotherapy arm among patients with nonsquamous
non–small cell lung cancer (NSCLC) without an EGFR or ALK mutation.
b
The recommended dosages or metastatic NSCLC are nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks.
c
The recommended nivolumab dosage or this indication is 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and two cycles o platinum-doublet
chemotherapy. The nivolumab and ipilimumab is continued until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.
CI, condence interval; HR, hazard ratio; OS, overall survival; PFS, progression-ree survival; RR, Response rate.
or patients randomized to pembrolizumab plus che- maintenance or to receive protein-bound paclitaxel
motherapy. Median PFSs were 9.0 (95%Cl, 8.1–9.9) plus carboplatin ollowed by maintenance pemetrexed
months or pembrolizumab plus chemotherapy and at the investigator’s discretion (control). The primary
4.9 (95% Cl, 4.7–5.5) months or placebo plus chemo- ecacy outcome measures were PFS and OS.105 In the
therapy (HR, 0.48; 95% CI, 0.40–0.58), and the median primary analysis population (intention to treat, EGFR
OS was 22.0 (95% CI, 19.5–25.2) months versus 10.7 mutation, ALK translocation wild type n = 681), the
(95% Cl, 8.7–13.6) months, respectively (HR, 0.56; median PFS was 7.2 months (95% CI, 6.7–8.3) or the
95% CI, 0.45–0.70). OS and PFS benets with pembro- atezolizumab arm compared with 6.5 months (95%
lizumab were observed regardless o PD-L1 expression CI, 5.6–7.4) or the control arm (HR, 0.75; 95% CI,
or presence o liver or brain metastases. The incidence 0.63–0.91; P = .0024). Median OSs were 18.6 months
o therapy-related grade 3 to 5 adverse events was sim- (95% CI, 15.7–21.1) and 13.9 months (95% CI, 12.0–
ilar in the pembrolizumab–chemotherapy (71.9%) and 18.7), respectively (HR, 0.80; 95% CI, 0.64–0.99; P =
placebo–chemotherapy (66.8%) arms (HR, 0.49; 95% .0384). Treatment-related grade 3 to 4 adverse events
Condence interval (CI) 0.38-0.64; P <.00001).103 were reported in 381 (81%) o 473 patients in the
KEYNOTE 407 (NCT02775435) had a trial design atezolizumab plus chemotherapy arm and 164 (71%)
similar to KEYNOTE 189 but was conducted or meta- o 232 patients in the control arm.106
static squamous NSCLC, regardless o PD-L1 tumor IMpower150 (NCT02366143), was an open-label,
expression status, as a rst-line systemic therapy or randomized, three-arm study or rst-line treatment
metastatic disease. A total o 559 patients were ran- o patients with metastatic nonsquamous NSCLC and
domized to pembrolizumab 200 mg or placebo in was designed to conduct comparisons between atezoli-
combination with carboplatin and investigator’s choice zumab, carboplatin, paclitaxel, and bevacizumab
o either paclitaxel every 3 weeks or nab-paclitaxel (our-drug regimen); atezolizumab, carboplatin, and
weekly on a 3-week cycle or our cycles ollowed by paclitaxel three3-drug regimen); or carboplatin, pacli-
pembrolizumab or placebo. Patients continued pem- taxel, and bevacizumab (control arm). Ater comple-
brolizumab or placebo maintenance until disease pro- tion o our or six cycles o carboplatin and paclitaxel,
gression, unacceptable toxicity, or a maximum o 24 patients continued to receive bevacizumab in the our-
months. The main ecacy outcome measures were drug arm and the control arm and continued to receive
OS, PFS, and ORR.104 The trial demonstrated statisti- atezolizumab in the two experimental arms until dis-
cally signicant improvements in OS, PFS, and ORR or ease progression or unacceptable toxicity. In this study
patients receiving pembrolizumab plus chemotherapy atezolizumab was given at 1200 mg as an IV inusion
compared with those randomized to placebo plus che- every 3 weeks. The major ecacy measures were OS
motherapy. The median PFSs were 6.4 and 4.8 months and PFS.107
or the pembrolizumab plus chemotherapy and pla- Among patients with nonsquamous NSCLC with-
cebo plus chemotherapy arms, respectively (HR, 0.56; out an EGFR or ALK mutation, median PFSs were
95% CI, 0.45–0.70; P <.0001). The ORRs were 58% 8.5 months or patients receiving the our-drug regi-
and 35%, avoring the pembrolizumab-containing men and 7 months or those in the control arm (HR,
arm (95% CI, 9.9–36.4; P = .0008). The median OSs 0.71; 95% CI, 0.59–0.85; P = .0002). Median OSs were
were 15.9 and 11.3 months or the pembrolizumab 19.2 months or patients receiving the our-drug regi-
plus chemotherapy and placebo plus chemotherapy men and 14.7 months or the control arm (HR, 0.78;
arms, respectively (HR, 0.64; 95% CI, 0.49–0.85; P = 95% CI, 0.64–0.96; P = .016). The ORRs were 55%
.0017). Treatment-related adverse events o grade 3 or in the our-drug arm and 42% in the control arm. No
higher occurred in 69.8% o the patients in the pem- signicant dierences in interim OS or nal PFS were
brolizumab-combination group and in 68.2% o the observed between the three-drug arm and the con-
patients in the placebo-combination group. But discon- trol arm. The incidence o treatment-related adverse
tinuation o treatment because o adverse events was events was reported in 219 (55.7%) o 393 patients in
more requent in the pembrolizumab-combination the our-drug arm and 188 (47.7%) o 394 patients in
group than in the placebo-combination group (13.3% the control arm. The most common adverse reaction
vs 6.4%).104 resulting in discontinuation o atezolizumab was pneu-
ChAPTER 24
IMpower130 (NCT02367781) was a randomized, monitis (1.8%). With this study, the FDA approved
open-label trial or treatment-naïve stage IV nonsqua- the use o atezolizumab in combination with beva-
mous NSCLC. Patients with activating mutations were cizumab, paclitaxel, and carboplatin or the rst-line
allowed to receive prior EGFR or ALK kinase inhibitor treatment o patients with metastatic nonsquamous
i appropriate. The trial randomized 724 patients to NSCLC with no EGFR or ALK genomic tumor aberra-
receive atezolizumab 1200 mg as an intravenous (IV) tions. In a preplanned analysis, in patients with EFGR
inusion every 3 weeks plus protein-bound paclitaxel mutation (124 EGFR mutant, including 91 with sen-
and carboplatin ollowed by single-agent atezolizumab sitizing mutation), PFS was reported to be longer in
the our-drug arm than the control arm (median PFS, 4.1 to 6.3) in the nivolumab plus ipilimumab arm and
8.3 months vs 6.8 months; stratied HR, 0.61; 95% 5.6 months (95% CI, 4.6–5.8) in the chemotherapy
CI, 0.52–0.72). Although the number is small this sub- arm (HR, 0.82; 95% CI, 0.69–0.97). Median OSs were
group analysis provided evidence to use atezolizumab 17.1 months (95% CI, 15–20.1) versus 14.9 (95% CI,
plus bevacizumab and chemotherapy in patients with 12.7–16.7) (HR, 0.79; 95% CI, 0.67–0.94; P = .0066)
EGFR-mutant NSCLC who have ailed TKIs.107 How- avoring nivolumab plus ipilimumab arm over the che-
ever, use o this regimen in patients with EGFR-mutant motherapy arm. Conrmed ORRs were 36% (95%
adenocarcinoma is not yet FDA-approved. CI, 31–41) and 30% (95% CI, 26–35), avoring the
Eorts to spare toxicities o chemotherapy also led nivolumab plus ipilimumab arm. Median response
to exploration o non–chemotherapy-containing ICI durations were 23.2 months in the nivolumab plus
combinations. CheckMate-227 (NCT02477826) was a ipilimumab arm and 6.2 months in the chemotherapy
randomized multiarm study in patients with stage IV arm.108 Based on this study, the FDA approved the use
or recurrent NSCLC.108 As a part o this study, patients o ipilimumab and nivolumab combination as rst-line
with PD-L1 o 1% or higher (by using PD-L1 IHC 28-8 treatment or patients with metastatic NSCLC whose
pharmDx [Agilent Technologies, Inc.] platorm) were tumors express PD-L1 (≥1%), as determined by an
stratied according to histologic subtype (squamous FDA-approved test.109
NSCLC vs nonsquamous NSCLC) and were random- Addition o chemotherapy to ICI therapy has been
ized to nivolumab 3 mg/kg every 2 weeks plus ipi- considered particularly because o the early progres-
limumab 1 mg/kg every 6 weeks, platinum doublet sion and transient higher death rates compared with
(chemotherapy arm) every 3 weeks or up to our the chemotherapy arms or patients, particularly with
cycles, or nivolumab at a fat dose o 240 mg every 2 PD-L1 protein expression low or negative tumors
weeks. The median PFSs were 5.1 months (95% CI, (Fig. 24–14). This can be observed not only because
100
90
Overall survival rate (%)
80
70
60
50
40
Pembrolizumab
30
20
Chemotherapy
10
0
0 6 12 18 24 30 36 42
A Time since randomization (months)
100
Median overall survival:
90
Nivolumab + ipilimumab, 17.1 months (95% Cl, 15.0–20.1)
Patients who survived (%)
80 Chemotherapy, 14.9 months (95% Cl, 12.7–16.7)

70 P = .007
60
50
40
30 Nivolumab + ipilimumab
20 Chemotherapy
ChAPTER 24
10
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
B Months
FIGURE 24–14 Kaplan-Meier estimates o survival. A. KEYNOTE 042 in programmed cell death ligand 1 (PD-L1) tumor propor-
tion score (TPS) 1% or greater population. B. CheckMate 227 in the PD-L1 %1 or greater population. In both studies, there is a
crossover in overall survival because o early deaths with immune checkpoint inhibitors. CI, confdence interval.
o the lack o response to ICI in primary resistance to have been validated in prospective studies or patient
immunotherapy but also because o delayed responses selection o rst-line NSCLC therapy. In PD-L1 mono-
to ICI. Despite the OS benet with combined ICI clonal antibody clone 22C3 in Dako platorm, PD-L1
therapy in CheckMate 227, early progression and protein expression is evaluated by means o IHC with
transient higher death rates compared with the che- PD-L1 scoring system based on tumor PD-L1 expres-
motherapy arm led to studies exploring combination sion on TC membranes (TPS). This has been validated
ICIs with an abbreviated course o chemotherapy. The in the KEYNOTE 024, KEYNOTE 042, and KEY-
aim was to rapidly achieve disease control and prevent NOTE 189 studies.97,100,102 The PD-L1 IHC 28-8 phar-
early death while limiting the duration o cytotoxic mDx platorm has been prospectively tested in the
therapy. Ecacy o this strategy was investigated in CheckMate 227 study and received FDA approval.111
the CheckMate-9LA (NCT03215706) study, which With the IMPower110 study, the FDA also approved
randomized patients to receive standard platinum the VENTANA PD-L1 (SP-142) assay (Ventana Medi-
doublet vs nivolumab plus ipilimumab and two cycles cal Systems, Inc.) as a companion diagnostic test or
o platinum-doublet chemotherapy as rst-line treat- selecting patients with NSCLC or treatment with
ment or patients with metastatic or recurrent NSCLC, atezolizumab. It is important to note that the VEN-
unselected or PD-L1 expression and with no EGFR or TANA platorm is dierent compared with the PD-L1
ALK aberrations. Although these data are not yet pub- IHC 22C3 pharmDx Kit and PD-L1 IHC 28-8 pharmDx
lished in nal orm, early progression and death were because PD-L1 expression not only takes into account
not observed on the ICI–chemotherapy arm, which tumor cells but also tumor-inltrating ICs.99
was refected in improved median PFS o 6.8 months Dierent clones, protocol conditions, instruments,
(95% CI, 5.6–7.7) versus 5 months (95% CI, 4.3–5.6) and scoring or readout methods may pose challenges
(HR, 0.70; 95% CI, 0.57–0.86). Median OSs were 14.1 in introducing dierent PD-L1 assays or immunother-
months (95% CI, 13.2–16.2) versus 10.7 months (95% apy.112 Eorts to assess the easibility o harmonizing
CI, 9.5–12.5) (HR, 0.69; 96.71% CI, 0.55–0.87). Similar the clinical use o independently developed commer-
to other studies with combined ICI and chemotherapy, cial PD-L1 IHC assays led to the development o the
ORR was increased as well (38% (95% CI, 33–43) ver- Blueprint study, which assessed the comparability o
sus 25% (95% CI, 21–30), respectively).110 PD-L1 scoring in commercially available PD-L1 IHC
At MDACC, or patients with a good perormance platorms. FDA-approved monoclonal anti–PD-L1
status and with tumor PD-L1 expression less than antibodies clone, 22C3, 28-8, SP263; their platorms
50%, in patients with rapidly progressive disease or PD-L1 IHC 22C3 pharmDx, PD-L1 IHC 28-8 phar-
high disease burden regardless o the tumor PD-L1 mDx 28-8 and VENTANA PD-L1 (SP263), and their
status and in patients or whom tumor PD-L1 status respective protocols showed close similarity and were
is not readily available, we typically choose combined comparable. In contrast, the VENTANA PD-L1 SP142
ICI and chemotherapy based on KEYNOTE 189, KEY- assay showed less sensitivity (lower TPS scores).113 At
NOTE 407, IMpower 130, IMpower 150, and Check- MDACC, we use the 22C3 pharmDx qualitative IHC
Mate 9LA studies. For patients with tumor PD-L1 TPS assay and TPS scoring because it was the rst com-
score o 50% or greater and without high disease bur- panion diagnostic test to receive FDA approval or ICI
den, we oer anti–PD-(L)1 monotherapy (KEYNOTE monotherapy in PD-L1–positive tumors. It is important
024, IMpower 110). In patients with tumor PD-L1 1% to note that these assays were not compared in the set-
or greater, the nivolumab and ipilimumab combination ting o a prospective clinical trial; thereore, none can
is an acceptable alternative, particularly or patients be deemed “interchangeable” with another.112
who wish to avoid chemotherapy (CheckMate 227).
For rail patients with tumor PD-L1 1% or greater, Therapies in the Setting o Contraindications to
pembrolizumab alone is appropriate (KEYNOTE 042). Immune Checkpoint Inhibitor Therapy
I ICI therapy is contraindicated owing to the pres-
Programmed Cell Death Ligand 1 As a Biomarker
ence o autoimmune or infammatory diseases or in
In earlier studies with PD-(L)1 inhibitors, PD-L1 protein patients with organ transplants, cisplatin–carbopla-
ChAPTER 24
expression in the surace o the TCs correlated with tin–based combinations with paclitaxel,77 docetaxel,77
responses to PD-(L)1 inhibitors. Subsequently, prospec- pemetrexed78,79 (nonsquamous only) gemcitabine,77
tive trials validated the predictive utility o PD-L1 IHC. nab-paclitaxel,80 or vinorelbine114 remain standard o
Thus, tumor expression o PD-L1 was approved by the care therapy (Table 24–15).
FDA as a companion diagnostic beore ICI therapy. The addition o the vascular endothelial growth ac-
There are numerous PD-L1 monoclonal antibodies, tor (VEGF)monoclonal antibody bevacizumab to car-
and eorts to incorporate stromal cell PD-L1 protein boplatin–paclitaxel can be considered in patients with
expression are ongoing. Currently, three platorms nonsquamous NSCLC based on the phase III Eastern
TABLE 2415 Summary o Platinum-Based Cemoterapy Trials in Patients wit NonSmall Cell Lung
Cancer
Response PFS OS
Pivotal Trial Histology Drug Rate (%) (months) (months) Trial Interpretation
ECOG 1594 All NSCLC Cisplatin 75 mg/m2 day 1 + 21 3.4 7.8 No signicant
(2002)77 paclitaxel 135 mg/m2 over 24 dierence
hours day 2 every 3 weeks between the
our-drug
regimens
Cisplatin 100 mg/m2 day 1 + 22 4.2 8.1
gemcitabine 1000 mg/m2 day 1,
day 8 every 4 weeks
Cisplatin 75 mg/m2 + docetaxel 75 17 3.7 7.4
mg/m2 every 3 weeks
Carboplatin AUC 6 + paclitaxel 225 19 3.1 8.1
mg/m2 every 3 weeks
Socinski et al All NSCLC Carboplatin AUC 6 day 1 + nab- 33 6.3 12.1 Similar ecacy;
(2012)80 paclitaxel 100 mg/m2 days 1, 8, 15 nab-paclitaxel
every 3 weeks associated
with more
neutropenia and
less neuropathy
mg/m2 every 3 weeks
ECOG 4599 Nonsquamous Carboplatin AUC 6 + paclitaxel 35 6.2 12.3 Benet o adding
(2006)82 200 mg/m2 +bevacizumab 15 bevacizumab to
mg/kg every 3 weeks × 6; then the induction
maintenance bevacizumab every and maintenance
3 weeks phases; high
risk o bleeding
in squamous
histology
mg/m2 every 3 weeks × 6
Scagliotti et al Nonsquamous Cisplatin 75 mg/m2 + pemetrexed 29 5.5 12.6 Benet o
(2008)78,79 500 mg/m2 every 3 weeks pemetrexed in
nonsquamous
histology
Cisplatin 75 mg/m2 + gemcitabine 22 5.0 10.9
1250 mg/m2 day1, day 8 every 3
weeks
Squamous Cisplatin 75 mg/m2 + pemetrexed 23 4.4 9.4 Benet o
500 mg/m2 every 3 weeks gemcitabine in
squamous NSCLC
Cisplatin 75 mg/m2 + gemcitabine 31 5.5 10.8
1250 mg/m2 day 1, day 8 every 3
weeks
ChAPTER 24
AUC, area under the curve; ECOG, Eastern Cooperative Oncology Group; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-ree survival.
Cooperative Oncology Group (ECOG) 4599 trial.82 (P <.001), and improved OS at 12.3 months versus
Patients were randomized to carboplatin and paclitaxel 10.3 months (P =.003). However, there were higher
with or without bevacizumab. The bevacizumab-con- rates o adverse events in the bevacizumab-containing
taining arm a had better response rate o 35% vs 15% arm, including a higher risk o severe bleeding (4.4%
(P <.001), better PFS at 6.2 months versus 4.5 months vs 0.7%; P <.001). Patients with squamous histology,
hemoptysis, uncontrolled hypertension, and those older those continuing nivolumab treatment experienced an
than 70 years o age are at a higher risk or bleeding rom improvement in PFS (median PFS not reached [NR] vs
bevacizumab and are not candidates or bevacizumab. 10.3 months; HR, 0.42; 95% CI, 0.25–0.71), and there
Bevacizumab was also combined with pemetrexed was only a nonsignicant trend toward improvement
and carboplatin in the phase III PointBreak study and in OS (NR vs 23.2 months; HR, 0.63; 95% CI, 0.33–
compared with paclitaxel–carboplatin–bevacizumab 1.22).116 Although some clinical trials allowed therapy
(our cycles) ollowed by maintenance with peme- until progression or unacceptable toxicity occurs, some
trexed plus bevacizumab or bevacizumab alone. studies had 2 years o therapy with ICI; thereore, the
Although there was a very modest PFS improvement optimal treatment duration remains an open question.
or patients treated with pemetrexed (6 vs 5.6 months; It remains unclear i longer treatment duration leads
HR, 0.83; 95% CI, 0.71–0.96), there was no improve- to longer survivorship or increased risk o toxicity. At
ment in OS.115 No randomized data exist to substantiate MDACC, we generally continue treatment with ICIs
the precise benet o bevacizumab added to peme- at least 2 years or until progression or unacceptable
trexed–carboplatin and pemetrexed maintenance. toxicity occurs. Ater 2 years o therapy, depending on
At MDACC, or ICI-ineligible patients, we avor the patient’s tolerance and preerences, a recommen-
rst-line therapy with pemetrexed–carboplatin ol- dation is made to continue or discontinue therapy.
lowed by pemetrexed maintenance or patients with Beore the immunotherapy era, multiple trials stud-
lung adenocarcinoma and either gemcitabine or taxane ied maintenance chemotherapy—either continuation
with carboplatin or SCC o the lung. maintenance (continuing the same nonplatinum drug
or drugs) or switch maintenance (initiating a non–
cross-resistant nonplatinum drug) (Table 24–16).115,117–
Maintenance Therapy 122
Pemetrexed maintenance has been shown to
The triplet combination o carboplatin, pemetrexed, improve PFS and OS in two phase 3 studies in patients
and pembrolizumab has become a standard o care with nonsquamous NSCLC.118,123 For example, in the
or patients with nonsquamous NSCLC based on the PARAMOUNT study, 539 patients with an objective
KEYNOTE 189 trial, as detailed earlier. Ater our to response or stable disease ater our cycles o cisplatin
six cycles o the triplet therapy, patients continue both and pemetrexed therapy were randomized to peme-
pemetrexed and pembrolizumab as maintenance. trexed or placebo. Maintenance pemetrexed resulted
Whether both pemetrexed and pembrolizumab need in improved PFS (median, 4.1 vs 2.8 months; HR, 0.62;
to be continued as maintenance therapy remains 95% CI, 0.49–0.79), OS (median, 13.9 vs 11.0 months),
unknown, and clinical trials are planned to answer and 1-year survival rate (58% vs 45%).123 Maintenance
this question. For patients with SCC, pembrolizumab with bevacizumab versus pemetrexed versus the com-
alone is continued as maintenance. Optimal dura- bination pemetrexed plus bevacizumab ater therapy
tion o therapy with ICI has not been established. In with pemetrexed, carboplatin, and bevacizumab was
the CheckMate 153 trial, patients who discontinued studied in the ECOG 5508 study. Although there was a
nivolumab within 1 year with those who continued statistically signicant improvement in PFS (HR, 0.67;
treatment until disease progression or severe adverse P <.001) with combined maintenance, there was no
events were compared as an exploratory endpoint. improvement in OS (HR, 0.90; P = .28)124 compared with
In preliminary results available rom 163 patients, monotherapy with either pemetrexed or bevacizumab.
TABLE 24-16 Summary o Maintenance Cemoterapy Trials in Patients wit NonSmall Cell Lung
Cancer
Response PFS OS
Trial Histology Drug Rate (%) (months) (months) Trial Interpretation
Fidias et al All NSCLC Maintenance docetaxel 75 mg/ 41.4 5.7 12.3 Better PFS
(2009)117 m2 every 3 weeks × 6 ater with switch
ChAPTER 24
4 cycles o carboplatin + maintenance; no

gemcitabine OS benet
No maintenance; docetaxel at NA 2.7 9.7
time o progression
Ciuleanu et a, Nonsquamous Maintenance pemetrexed 58 4.4 15.5 Benet o switch
(2009)118 500 mg/m2 every 3 weeks maintenance with
ater our cycles o platinum pemetrexed
doublet
(Continued)
Cancer (Cont.)
Response PFS OS
No maintenance NA 1.8 10.3
119
SATURN (2010) EGFR mutant Erlotinib 150 mg/day NA 11 NA Benet o switch
maintenance ater our maintenance with
cycles o platinum-based erlotinib in EGFR-
chemotherapy mutant patients
NSCLC No maintenance NA 3 NA
EGFR WT Erlotinib 150 mg/day 11.9 3.07 12
maintenance ater our
cycles o platinum-based
chemotherapy
NSCLC No maintenance 5.4 2.7 11
IFCT-GFPC 0502 All NSCLC Erlotinib 150 mg/day NA 2.9 11.4 No benet o switch
(2012)120 (mostly EGFR maintenance ater maintenance
WT) cisplatin–gemcitabine with erlotinib or
maintenance with
gemcitabine in
EGFR WT patients
Gemcitabine 1250 mg/m2 day NA 3.8 12.1
1, day 8 maintenance
PARAMOUNT Nonsquamous Maintenance pemetrexed 500 NA 4.4 13.9 Benet o
(2013)121 mg/m2 every 3 weeks ater continuation
our cycles o cisplatin + maintenance with
pemetrexed pemetrexed
No maintenance NA 2.8 11
122
AVAPERL (2012) Nonsquamous Carboplatin AUC 6 + NA 7.4 Not PFS benet
pemetrexed 500 mg/m2 reached o adding
+ bevacizumab 15 mg/ pemetrexed to
kg every 3 weeks × 4; then maintenance
maintenance pemetrexed bevacizumab
500 mg/m2 +bevacizumab 15 ater cisplatin-
mg/kg every 3 weeks pemetrexed
induction
Carboplatin AUC 6 + NA 3.7 12.8
pemetrexed 500 mg/m2
+ bevacizumab 15 mg/
kg every 3 weeks × 4; then
bevacizumab 15 mg/kg
every 3 weeks
PointBreak, Nonsquamous Carboplatin AUC 6 + 34 6 12.6 No dierence
(2013)115 pemetrexed 500 mg/m2 between the
+ bevacizumab 15 mg/ two treatment
kg every 3 weeks × 4; then strategies
ChAPTER 24
maintenance pemetrexed
500 mg/m2 + bevacizumab
15 mg/kg every 3 weeks
Carboplatin AUC 6 + paclitaxel 33 5.6 13.4
200 mg/m2 + bevacizumab
15 mg/kg every 3 weeks
× 4; then maintenance
every 3 weeks
(Continued)
Cancer (Cont.)
Response PFS OS
Fidias et al All NSCLC Maintenance docetaxel 41.4 5.7 12.3 Better PFS with switch
(2009)117 75 mg/m2 every 3 maintenance; no OS
weeks × 6 ater our benet
cycles o carboplatin +
gemcitabine
No maintenance; docetaxel NA 2.7 9.7
at time o progression
Ciuleanu et a, Nonsquamous Maintenance pemetrexed 58 4.4 15.5 Benet o switch
(2009)118 500 mg/m2 every 3 maintenance with
weeks ater our cycles pemetrexed
o platinum doublet
119
SATURN (2010) EGFR mutant Erlotinib 150 mg/day NA 11 NA Benet o switch
maintenance ater our maintenance with
cycles o platinum-based erlotinib in EGFR-
chemotherapy mutant patients
NSCLC No maintenance NA 3 NA
EGFR WT Erlotinib 150 mg/day 11.9 3.07 12
maintenance ater our
cycles o platinum-based
chemotherapy
NSCLC No maintenance 5.4 2.7 11
IFCT-GFPC 0502 All NSCLC Erlotinib 150 mg/day NA 2.9 11.4 No benet o switch
(2012)120 (mostly maintenance ater maintenance
EGFR WT) cisplatin–gemcitabine with erlotinib or
maintenance with
gemcitabine in EGFR
WT patients
Gemcitabine 1250 NA 3.8 12.1
mg/m2 day 1, day 8
maintenance
PARAMOUNT Nonsquamous Maintenance pemetrexed NA 4.4 13.9 Benet o continuation
(2013)121 500 mg/m2 every 3 maintenance with
weeks ater our cycles o pemetrexed
cisplatin + pemetrexed
No maintenance NA 2.8 11
AVAPERL (2012)122 Nonsquamous Carboplatin AUC 6 + NA 7.4 Not PFS benet o adding
pemetrexed 500 mg/ reached pemetrexed to
m2 + bevacizumab 15 maintenance
mg/kg every 3 weeks bevacizumab ater
× 4; then maintenance cisplatin-pemetrexed
pemetrexed 500 mg/m2 induction
ChAPTER 24
+bevacizumab 15 mg/kg
every 3 weeks
Carboplatin AUC 6 + NA 3.7 12.8
kg every 3 weeks × 4;
then bevacizumab 15
mg/kg every 3 weeks
(Continued)
Cancer (Cont.)
Response PFS OS
PointBreak, Nonsquamous Carboplatin AUC 6 + 34 6 12.6 No dierence between
(2013)115 pemetrexed 500 mg/ the two treatment
m2 + bevacizumab 15 strategies
mg/kg every 3 weeks
× 4; then maintenance
kg every 3 weeks
Carboplatin AUC 6 + 33 5.6 13.4
paclitaxel 200 mg/m2
kg every 3 weeks ×
4; then maintenance
every 3 weeks
ECOG 5508124 Nonsquamous Carboplatin (AUC = 6), NR 4.2 14.4 Even though there
paclitaxel (200 mg/m2) are statistically
and bevacizumab (15 signicant dierences
mg/kg) every 3 weeks or in progression
up to 4 cycles ollowed ree survival or
by maintenance therapy the combination
with bevacizumab (15 maintenance versus
mg/kg) bevacizumab, there
were no statistically
signicant dierences
in overall survival;
thus, maintenance
with either single-
agent bevacizumab
or single-agent
pemetrexed is
considered standard,
and maintenance with
the combination is
not necessary
Carboplatin (AUC = 6), 5.1 15.9
paclitaxel (200 mg/m2),
and bevacizumab (15
mg/kg) every 3 weeks or
up to 4 cycles ollowed
by maintenance therapy
with pemetrexed (500
mg/m2)
Carboplatin (AUC = 6), 7.5 16.4
paclitaxel (200 mg/m)
and bevacizumab (15
ChAPTER 24
mg/Kk) every 3 weeks or

up to 4 cycles ollowed
by maintenance therapy
with bevacizumab (15
mg/kg) and pemetrexed
(500 mg/m2)
AUC, area under the curve; ECOG, Eastern Cooperative Oncology Group; NA, not applicable; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-
ree survival; WT, wild type.
Thus maintenance therapy with either pemetrexed or in patients with long (>6 months) platinum-ree inter-
bevacizumab is reasonable or nonsquamous NSCLC vals,129 and is not requently used. Currently, there are
ater bevacizumab-based rst-line therapy. no data to support the use o a dierent PD-(L)1 inhibi-
At MDACC, i ICI therapy is contraindicated, we tor ater ailing immunotherapy when used either sin-
recommend pemetrexed maintenance as monotherapy gly or in combination or rst-line treatment (eg, the
or patients with nonsquamous NSCLC use o atezolizumab as second-line therapy ater ail-
ing a pembrolizumab-containing combination as rst-
Chemotherapy or Patients with Platinum- line therapy). The only combination therapy approved
Reractory Disease by the FDA in the second-line setting is docetaxel with
the anti-VEGF receptor 2 (anti-VEGFR2) monoclo-
Patients with disease progression on or ater rst-line nal antibody ramucirumab.125 In the pivotal Ramuci-
therapy who maintain good perormance status are rumab plus docetaxel versus placebo plus docetaxel or
candidates or urther palliative systemic therapy. The second-line treatment o stage IV non-small-cell lung
agents that have proven ecacy ater progression on a cancer ater disease progression on platinum-based
platinum-based doublet include single-agent docetaxel, therapy (REVEL) trial comparing docetaxel alone with
paclitaxel, nab-paclitaxel, gemcitabine, pemetrexed docetaxel plus ramucirumab in patients with NSCLC
(in nonsquamous NSCLC only), and ramucirumab in o any histology, the combination arm had better PFS
combination with docetaxel125 (see Table 24–16). I (4.5 vs 3 months; P <.0001) and OS (10.5 vs 9.1 months;
ICIs have not been given in the rst line, then pembro- P =.023) with no increased risk o severe bleeding. It
lizumab, nivolumab, or atezolizumab can be given as a is important to highlight that only 14% o patients
second-line therapy (Table 24–17).78,93–95,97,125–133 enrolled in the REVEL study had received prior beva-
Reexposure to platinum in subsequent lines o ther- cizumab, making it dicult to draw conclusions about
apy increases response rates but not PFS or OS, even this group. Also, unlike the phase III bevacizumab trials
TABLE 2417 Summary o Second- and Tird-Line Cemoterapy and Targeted Terapy Trials in
Patients wit NonSmall Cell Lung Cancer
Response PFS OS
Second Line
TAX 317 (2000)126 All NSCLC Docetaxel 75 mg/m2 7.1 2.65 7 Benet o second-line
every 3 weeks docetaxel
Best supportive care 0 1.67 4.6
127 2
TAX 320 (2000) All NSCLC Docetaxel 75 mg/m 6.7 2.1 5.7 Benet o docetaxel
every 3 weeks over vinorelbine
(less toxicity, same
PFS and OS)
Vinorelbine 30 mg/ 0.8 1.9 5.6
m2 weekly or
iosamide 2 mg/
m2/day, days 1–3
every 3 weeks
Hanna et al Nonsquamous Pemetrexed 500 mg/ 12.8 3.5 9 Benet o
(2004)128,129 m2 every 3 weeks pemetrexed
over docetaxel
in nonsquamous
histologies
ChAPTER 24
Docetaxel 75 mg/m2 9.9 3.5 9.2

every 3 weeks
Squamous Pemetrexed 500 mg/ 2.8 2.3 6.2 Benet o docetaxel
m2 every 3 weeks over pemetrexed in
squamous NSCLC
Docetaxel 75 mg/m2 8.1 2.7 7.4
every 3 weeks
(Continued)
TABLE 2417 Summary o Second- and Tird-Line Cemoterapy and Targeted Terapy Trials in
Patients wit NonSmall Cell Lung Cancer (Cont.)
Response PFS OS
GOIRC 02 (2006)/ All NSCLC Carboplatin AUC 5 + 15 3.6 8.7 No benet o
NVALT-7 pemetrexed 500 platinum doublets
(2012)129 mg/m2 every 3 over nonplatinum
weeks single-agent
second-line
therapy
Pemetrexed 500 mg/ 9 3.5 8.2
m2 every 3 weeks
REVEL (2014)125 All NSCLC Docetaxel 75 mg/ 23 4.5 10.5 Benet o
m2+ ramucirumab ramucirumab
10 mg/kg every 3 when added
weeks to docetaxel in
second line
Docetaxel 75 mg/m2 14 3.0 9.1
every 3 weeks
TAILOR (2013)130 EGFR wild-type Erlotinib 150 mg/day 3 2.4 5.4 No benet o second-
NSCLC line erlotinib in
EGFR wild-type
NSCLC
every 3 weeks
Third Line
BR.21 (2005)131 All NSCLC Erlotinib 150 mg/day 8.9 2.2 6.7 Third-line erlotinib
(EGFR status can prolong
unknown) survival in patients
with NSCLC and
unknown EGFR
status
Placebo <1 1.8 4.7
DELTA (2014)132 EGFR wild-type Erlotinib 150 mg/day 17 1.3 9 Docetaxel is superior
NSCLC to erlotinib as
second- or third-
line therapy in
patients with no
activating EGFR
mutations
every 3 weeks
AUC, area under the curve; AVAPERL, A Study o Avastin (Bevacizumab) With or Without Pemetrexed as Maintenance Therapy Ater Avastin in First Line in Patients
With Non-Squamous Non-Small Cell Lung Cancer; DELTA, Docetaxel and Erlotinib Lung Cancer Trial; GOIRC, Italian Oncology Group or Clinical Research; IFCT-GFPC,
Intergroupe Francophone de Cancérologie Thoracique-Groupe Francaus de Pneumo-Carcerologie; NSCLC, non–small cell lung cancer; NVALT, Dutch society o
pulmonologists; OS, overall survival; PARAMOUNT, A Phase 3, Double-Blind, Placebo-Controlled Study o Maintenance Pemetrexed plus Best Supportive Care versus
Best Supportive Care Immediately Following Induction Treatment with Pemetrexed + Cisplatin or Advanced Non-Squamous Non-Small Cell Lung Cancer; PFS,
progression-ree survival; REVEL, Ramucirumab plus docetaxel versus placebo plus docetaxel or second-line treatment o stage IV non-small-cell lung cancer ater
ChAPTER 24
disease progression on platinum-based therapy; SATURN, Sequential Tarceva in Unresectable NSCLC, a phase 3 placebo controlled study; TAILOR, Erlotinib versus
docetaxel as second-line treatment o patients with advanced non-small-cell lung cancer and wild-type EGFR tumours.
that excluded patients with SCC, 25% o patients on can be considered i not used in prior lines o therapy,
this trial had squamous cell histology, and there was no all o which signicantly improve PFS ater rst-line
increased risk o bleeding seen in this group. As subse- chemotherapy. Notably, there have been no random-
quent lines o therapy, pemetrexed (or nonsquamous ized clinical trials to compare these three agents nor is
NSCLC), docetaxel, and gemcitabine monotherapy there evidence o OS benet in this reractory setting.
TABLE 2418 Summary o Immunoterapy Trials in te Second-line Treatment o Patients wit Non
Small Cell Lung Cancer
Patient Treatment Control Overall PFS

Trial Patients (n) population Arm(s) Arm RR OS (months) (months)
CheckMate 272 Previously Nivolumab (N)a Docetaxel 20% (N) vs 9.2 (N) vs 6 (D) 3.5 (N) vs 2.8
01794 treated (D) 9% (D) (HR, 0.59; (D) (HR,
squamous 95% CI, 0.62; 95% CI,
NSCLC 0.44–0.79; 0.47–0.81;
P <.001) P <.001)
CheckMate 582 Previously Nivolumab (N)a Docetaxel 19% (N) 12.2 (N) vs 9.4 2.3 (N) vs 4.2
05793 treated (D) vs 12% (D) (D) (HR, 0.92;
nonsquamous (D) (HR, 0.73; (95% CI,
NSCLC 96% CI, 0.77–1.11;
0.59–0.89; P = .39)
P = .002)
KEYNOTE 345 Previously Pembrolizumab Docetaxel 18 (P) vs 10.4 (P) vs 8.5 3.9 (P) vs 4 (D)
01095 (pembrolizumab treated NSCLC 2 mg/kg (P) (D) 9.3 (D) (D)b (HR, (HR, 0.88;
2 mg/kg) 0.71 95% CI, 95% CI
346 0.58–0.88; 0.74–1.05;
(pembrolizumab P = ·.0008) P = .07)
10 mg/kg)
343 (docetaxel)
Pembrolizumab Docetaxel 18.5 (P) vs 12.7 (P) vs 4 (P) vs 4 (D)
10 mg/kg (P) (D) 9.3 (D) 8.5 (D)b (HR, 0.79;
(HR, 0.61; 95% CI,
95% CI, 0.66–0.94;
0.49–0·75; P = .004)
P = .0001)
OAK151 850 Previously Atezolizumab Docetaxel 14% (A) 13.8 (A) vs 2.8 (A) vs 4 (D)
treated NSCLC (A) (D) vs 13% 9.6 (D) (HR, 0.95;
(D) (HR, 0.73; 95% CI,
95% CI, 0·82–1.10;
0·62–0·87; P = .49
P =·.0003).
a
Nivolumab, at a dosage o 3 mg/kg every 2 weeks.
b
Among patients with programmed cell death ligand 1 tumor proportion scores ≥50%, overall survival (OS) was 14.9 months (pembrolizumab 2 mg/kg) versus 8.2
months (docetaxel); hazard ratio (HR), 0.54; 95% condence interval (CI), 0.38–0.77; P = .0002. OS was 17.3 months (pembrolizumab 10 mg/kg) versus 8·2 months
(docetaxel); HR, 0.50; CI, 0.36–0·70; P <.0001).
NSCLC, non–small cell lung cancer; OAK, A Study o Atezolizumab Compared With Docetaxel in Participants With Locally Advanced or Metastatic Non-Small Cell Lung
Cancer Who Have Failed Platinum-Containing Therapy (OAK); PFS, progression-ree survival; RR: response rate.
Toxicity prole, prior therapies, and patient preer- age-related decline in organ unction, so close monitor-
ences generally guide this therapy decision.126,127,134 ing or toxicities is required.
Treatment o Stage IV Non–Small Cell Lung Management o Oligometastatic Disease

Cancer in Older Adults The term “oligometastatic” was used initially by Hell-
Treatment o advanced NSCLC in the older adults man and Weichselbaum136 to describe a restricted
has been addressed in several prospective studies and locoregional tumor load. It has now become synony-
ChAPTER 24
retrospective analyses, and the International Society mous with a limited number (typically one to ve)
o Geriatric Oncology (SIOG) has issued clear guide- metastatic lesions. Several retrospective and small pro-
lines.135 The general consensus is that older adult spective trials in the setting o oligometastatic NSCLC
patients (dened as patients 70 years o age or older) demonstrated a potential clinical benet or patients
with good perormance status should receive standard receiving aggressive therapy.137–142 In patients with soli-
therapy. They derive the same level o clinical benet tary brain metastasis resection or stereotactic radiation
as their younger counterparts. However, they may o the brain lesion ollowed by denitive therapy to
experience a higher level or toxicities secondary to an the primary tumor (resection or radiation), compared
with no treatment or the primary tumor, was associ- patients, which limited subgroup analysis in this study.
ated with signicant improvement in median OS (26 Furthermore, because this trial preceded the integra-
months vs 13 months) and 5-year survival rates (34% tion o immunotherapy in NSCLC, it did not assess
vs 0%).143 the impact o LCT in this context. Local consolidative
In patients with solitary adrenal metastasis, adre- therapies may work through multiple mechanisms.
nalectomy and denitive therapy to the primary LCT may reduce the pool o systemic therapy-resis-
tumor result in good outcomes, with a median OS o tant cells.146 Additionally, ablative therapies such as
26 months and a 5-year survival rate o 30%, which radiation aord the benets o tumor antigen release,
has been consistent in multiple studies.144 Patients T-lymphocyte expansion, and T-lymphocyte receptor
who develop isolated adrenal metastasis more than 6 diversication that may maniest as enhanced immu-
months ater the resection o the primary tumor are nosurveillance and antitumor immunity.138–150
the ones with the most benet. At MDACC, we consider local consolidative ther-
Patients with oligometastatic disease (one to ve apy in patients with good systemic control, particularly
lesions) should undergo complete staging, including those with oligometastatic presentation. However,
PET-CT scan and brain MRI. They can then be clas- urther research is ongoing to help better dene the
sied into three subgroups,145 and aggressive consoli- patient population most likely to benet rom this
dative therapies can be considered on a case-by-case therapeutic approach, especially with integration o
basis ater a multidisciplinary evaluation. ICI therapy.
• Low risk: development o oligometastatic disease
more than 2 months ater resection o the primary
tumor (5-year OS, 47.8%).
FUTURE DIRECTIONS
• Intermediate risk: synchronous metastases (at
The treatment or patients with NSCLC, especially
presentation or within 2 months o the resection o
in the metastatic setting, has witnessed remarkably
the primary) and no lymph node involvement (N0)
rapid change over the past 10 years. This change has
disease (5-year OS, 36.2%)
been driven by the recognition o signicant molecular
• High risk: synchronous metastases and N1/N2 dis-
heterogeneity o disease, identication o targetable
ease (5-year OS, 13.8%)
genetic changes dening the many subgroups, the
The term local consolidative therapy (LCT) is used development o well-tolerated and eective tyrosine
when the primary tumor and isolated sites o metas- kinase inhibitors, and the addition o immunotherapy
tasis are ablated by local treatment modalities, such to the NSCLC therapeutic armamentarium. Both tar-
as resection or radiation, ater systemic therapy. A geted therapy and immunotherapy are being inves-
randomized phase II study comparing the ecacy o tigated in patients with early-stage NSCLC with the
LCT versus standard systemic therapy only in oligo- goal o increasing cure rates.
metastatic NSCLC showed statistically signicant Certainly, the incorporation o immunotherapy has
improvement in ecacy outcomes in the LCT arm. substantially altered the lives o patients with NSCLC,
Both the PFS and OS avored LCT, with PFS at 14.2 and its ull impact is surely not yet ully realized. How-
months (95% CI, 7.4–23.1 months) in LCT arm versus ever, several challenges remain. An optimal biomarker
4.4 months (95% CI, 2.2–8.3 months) with mainte- that acilitates rational selection o initial immunother-
nance therapy or observation (MT/O) (P = .022) and apy still eludes us as does the identication o second-
the OS at 37.6 months in LCT arm versus 9.4 months line immunotherapy eective in those who progress
in the MT/O arm.146,147 Its important to note that early on PD-(L)1 inhibitors with without anti–CTLA-4. Both
closure o this trial by the Data Saety and Monitor- o these topics are top priorities in ongoing and uture
ing Board resulted in random assignment o only 49 research.

J We consider surgical treatment in patients with J We recommend molecular proling with NGS or all
ChAPTER 24
stage IIIA disease with good perormance status and patients with metastatic or recurrent NSCLC
without multistation or bulky (>2 cm) mediastinal J We consider LCT in patients with good systemic dis-
adenopathy. These patients are treated with neoad- ease control, particularly in those with oligometa-
juvant chemotherapy ollowed by consideration o static presentation.
surgery. Adjuvant radiation therapy is given i there
is evidence o mediastinal node involvement based
on assessment o surgical pathology.
21. The eect o vitamin E and beta carotene on the incidence o

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ChAPTER 24
25 Targeted Therapies in Non–Small
Cell Lung Cancer
Yasir Y. Elamin
Don L. Gibbons
Marcelo V. Negrao
KEY CONCEPTS
 Non–small cell lung cancer (NSCLC) can be classied based proto-oncogene 1 (ROS1), rearrangements, B-Ra proto-
on recurrent genetic alterations in genes encoding proteins oncogene (BRAF), rearranged during transection (RET),
essential to cell prolieration and survival. These genetic neurotrophic receptor tyrosinekinase gene (NTRK1-3), and
alterations are transormative, meaning that they play a MET (mesenchymal-epithelial transition) as well as prom-
pivotal role in transorming a noncancerous cell into a can- ising agents or HER2 (human epidermal growth actor
cerous one. NSCLCs that harbor these alterations are called receptor 2) and NRG1 (neuregulin 1).
oncogene-addicted. These genetic alterations are typically  Targeted treatment based on clinical demographic
mutually exclusive and are characterized by impressive sen- characteristics alone is not recommended.
sitivity to small-molecule receptor tyrosine kinase.
 Emergence o resistance targeted therapy is inevitable.
 Identiying patients with targetable alterations has impor- Resistance mechanisms can be broadly divided into target
tant therapeutic and prognostic implications. Molecular dependent or independent. The latter means activation o
proling o advanced NSCLC using tumor tissue, cell- bypass pathways, leading to clinical resistance. Identiying
ree DNA (cDNA), or both is strongly recommended resistance mechanisms to targeted therapy can determine
irrespective o tobacco exposure history. treatment decisions and; thereore, obtaining a tissue
 Oncogene-addicted advanced NSCLC should be treated biopsy, cDNA, or both on progression is generally indicated.
with targeted agents specic to each genetic altera-  Treatment o patients with oncogene-addicted NSCLC
tion. This is based on impressive clinical activity and the upon progression on a targeted agent should be individu-
tolerability o targeted agents. There are Food and Drug alized. Treatment options include clinical trial enrollment,
Administration–approved targeted agents or NSCLC continuing the same targeted agent with local ablative
that harbor alterations in EGFR (epidermal growth ac- therapy o progressing lesions, and cytotoxic chemother-
tor receptor), ALK (anaplastic lymphoma kinase), ROS apy with or without immunotherapy.
The wide use o molecular proling techniques com- (epidermal growth actor receptor), ALK (anaplastic
bined with a better understanding o signaling path- lymphoma kinase), ROS proto-oncogene 1 (ROS1),
ways in lung cancer and other tumors has led to the rearrangements, B-Ra proto-oncogene (BRAF), rear-
identication o mutually exclusive, activating genetic ranged during transection (RET), neurotrophic
alterations in specic tyrosine kinases that can be tar- receptor tyrosinekinase gene (NTRK1-3), and MET
geted using tyrosine kinase inhibitors (TKIs). Matching (mesenchymal-epithelial transition), as well as promis-
a specic targeted TKI to the specic driver mutation ing agents or HER2 (human epidermal growth actor
identied has produced a paradigm shit in the treat- receptor 2) and NRG1 (neuregulin 1). Herein, we will
ment o non–small cell lung cancer (NSCLC), with discuss each o these genetic alterations.
targeted therapy considered the preerred initial treat- The National Comprehensive Cancer Network
ment or patients with NSCLC who have such genetic (NCCN) guidelines recommend testing NSCLC or
alterations. We now have approved targeted therapies EGRF, ALK, ROS1, BRAF and NTRK (https://www.
or NSCLC that harbor activating alterations in EGFR nccn.org/proessionals/physician_gls/pd/nscl.pd).
535
536 Scion IV Lung Cancer
This is largely consistent with recommendations rom downstream signaling, resulting in cell prolieration,
the College o American Pathologists, the International survival, and migration independent o extracellular
Association or the Study o Lung Cancer, and the stimuli.14–16 EGFR mutations are the most common
Association o Molecular Pathologists.1,2 There is not targetable alterations in NSCLC, occurring in approxi-
a single standard platorm or testing that is typically mately 15% o lung adenocarcinoma in the United
done on tissue biopsies rom the primary or metastatic States.17 These mutations occur more requently in
sites. More recently, there has been increase in the use nonsmokers, emales, and Asian populations. EGFR
o cell-ree DNA (cDNA) or genotyping because it mutations can be divided into classical mutations,
provides a less invasive source o tumor DNA. cDNA L858R, or exon 19 deletions, comprising most EGFR-
is particularly useul in patients with insucient tumor mutant NSCLC cases, or atypical mutations spanning
samples or molecular proling or when obtaining a exons 18 to 21, including in-rame insertions or point
biopsy is not easible. The currently available cDNA mutations within exon 20.18
proling platorms have generally shorter turnaround
time compared with tumor tissue sequencing; how-
ever, they are less broad in their coverage compared
Classical EGFR Mutations
with tumor tissue proling. The cDNA specicity The most requent EGFR mutations are in-rame dele-
ranges between 60% and 95%.3 A limitation o cDNA tions in exon 19 that represent approximately 45% o
is a alse-negative rate o approximately 30%.4,5 This all EGFR mutations ollowed by point mutations in
may refect limited tumor DNA shedding into blood exon 21 (L858R), seen in 40%.
as a result o limited tumor burden.6,7 A negative result In advanced NSCLC, the presence o a classical
rom cDNA should not exclude the potential existence EGFR mutation (exon 19 deletion or L858R) strongly
o a targetable alteration, especially when there is a predicts or sensitivity to EGFR TKIs such as erlo-
strong clinical suspicion. Clinical therapeutic decisions tinib, getinib, aatinib, dacomitinib, and osimertinib;
can be made based on positive cDNA results because thereore, EGFR TKIs are standard-o-care rst-line
clinical studies have shown comparable outcomes to treatment or metastatic NSCLC harboring a classical
those achieved based on tumor tissue sequencing.8–12 EGFR mutation. Several phase 3 clinical trials showed
Table 25–1 summarizes the key genetic alterations the superiority o rst-generation TKIs (erlotinib and
and their testing techniques. getinib) and a second-generation TKI (aatinib) over
platinum-based cytotoxic chemotherapy in terms o
clinical ecacy and tolerability.19–25 However, newer
EGFR MUTATIONS data suggest improved outcomes with the third-gener-
ation TKI osimertinib in the rontline setting.
EGFR is a transmembrane protein and a member o In the phase III FLAURA trial, in which patients with
the HER amily o tyrosine kinase receptors that treatment-naïve EGFR-mutant NSCLC were random-
transduces important intracellular signaling.13 Activat- ized to osimertinib or a standard o care EGFR TKI
ing mutations in the EGFR gene lead to activation o (getinib or erlotinib), osimertinib led to improved
TABLE 25-1 Key Genetic Alterations and Related Testing Techniques in Non–Small Cell Lung Cancer
Frequency in Lung
Genetic Alteration Adenocarcinoma (%) Testing Techniques
EGFR mutations (exon 19 deletions, L858R, exon 15 NGS, RT-PCR, Sanger sequencing
20 insertions, others)
ALK usions 3–5 FISH break-apart probe, IHC (ALK [D5F3] CDx
Assay is FDA-approved), NGS, RT-PCR
ROS1 usions 2 FISH break-apart probe, NGS, RT-PCR
BRAF mutations 4 NGS, RT-PCR, Sanger sequencing
Chapter 25
MET exon 14 skipping mutations 2–4 NGS, RT-PCR

HER2 mutations 1.5 NGS, RT-PCR, Sanger sequencing
RET usions 1–2 FISH break-apart probe, NGS, RT-PCR
NTRK usions 1 NGS
NRG1 usions 0.2–0.3 NGS, IHC
ALK, anaplastic lymphoma kinase; BRAF, rearrangements, B-Ra proto-oncogene; EGFR, epidermal growth actor receptor; FISH, fuorescence in situ; FDA, Food and
Drug Administration; HER2, human epidermal growth actor receptor 2; IHC, immunohistochemistry; MET, mesenchymal-epithelial transition; NGS, next-generation
sequencing; NRG1, neuregulin 1; NTRK1-3, neurotrophic receptor tyrosinekinase gene; RET, rearranged during transection; ROS1, ROS proto-oncogene 1; RT-PCR:
reverse-transcriptase polymerase chain reaction.
C 25 Targeted Therapies in Non–Small Cell Lung Cancer 537
overall survival (OS) compared with standard o care wild-type EGFR tyrosine kinase activity. Accordingly,
TKI (38.6 months vs 31.8 months).8 Progression-ree the commonest adverse events o EGFR TKIs include
survival (PFS) was also longer in patients treated with cutaneous reactions and diarrhea.36 Cutaneous reac-
osimertinib compared with those treated with erlotinib tions include acneiorm rash, xeroderma, pruritus and
or getinib (18.9 months vs 10.2 months). Objective paronychia.36,37 Given its selectivity or the mutant
response rates (ORRs) or osimertinib and standard- protein, osimertinib generally has a better saety pro-
o-care TKIs were comparable (80% and 76%, respec- le.38,39 Other notable rare adverse events, including
tively). Furthermore, osimertinib was better tolerated interstitial lung disease (ILD), electrocardiogram QT
than standard-o-care EGFR TKI. Importantly, the PFS prolongation, and cardiomyopathy, are seen in ewer
in the subset o patients with central nervous sys- than 1% to 3% o patients treated with EGFR TKIs.36,40
tem (CNS) metastases receiving osimertinib was 15.2 There are no approved targeted therapies or
months compared with 9.6 months in patients receiv- patients with disease progression on osimertinib.
ing a rst-generation EGFR TKI. Among patients with Thereore, such patients should preerably be treated
brain metastases evaluable or response, the intracra- in a clinical trial. Other treatment options include local
nial response rate was 91% with osimertinib compared ablative therapy with radiation or surgery with osimer-
with 68% with a rst-generation EGFR TKI. Based on tinib continuation or patients with oligoprogressive
these data, osimertinib is now approved by the U.S. disease and platinum-based chemotherapy. A subset
Food and Drug Administration (FDA) and the preerred o 111 patients with NSCLC with EGFR mutation or
EGFR TKI or the rst-line treatment o patients with ALK usion were included in the IMpower 150 trial,
NSCLC that exhibits a classical EGFR mutation. which investigated the addition o atezolizumab (anti–
Dacomitinib is a second-generation TKI that was programmed cell death ligand 1 [PD-L1 antibody]) to
approved by the FDA in 2018 or the rst-line treat- the combination o carboplatin, paclitaxel, and beva-
ment o patients with metastatic NSCLC with EGFR cizumab, all o whom had progressed on a prior TKI.
exon 19 deletion or L858R mutation. A phase III trial Patients with EGFR-/ALK-positive NSCLC who were
compared dacomitinib with getinib in patients with randomized to receive atezolizumab had longer PFS
treatment-naïve EGFR-mutant NSCLC.26 Dacomi- (9.7 months vs 6.1 months) and OS (median not reached
tinib demonstrated an improved OS (34 months vs vs 17.5 months) compared with the control group.41
27 months) as well as improved PFS (14.7 months vs As such, the combination o carboplatin, paclitaxel,
9.2 months). Treatment-related toxicities were sig- bevacizumab, and atezolizumab may be considered
nicantly higher in patients treated with dacomitinib, or patients who progress on an EGFR TKI. A similar
especially diarrhea and skin rash. regimen is being investigated in KEYNOTE-789, a ran-
Treatment with an EGFR TKI is generally continued domized phase 3 trial evaluating pemetrexed plus plat-
until there is disease progression. Upon progression, a inum chemotherapy (carboplatin or cisplatin) with or
biopsy o a progressive lesion is usually indicated to without pembrolizumab in patients with TKI-resistant
determine the mechanism(s) o EGFR TKI-acquired EGFR-mutant metastatic NSCLC (NCT03515837).
resistance. Resistance mechanisms that are observed in The trial outcomes are pending.
all TKIs may be broadly divided into EGFR dependent
(eg, secondary EGFR mutations or EGFR amplication)
and EGFR independent (eg, MET amplication and
Atypical EGFR Mutations
small cell transormation).27–31 Mechanisms o acquired Atypical EGFR mutations represent 10% to 15% o all
resistance to rst- and second-generation TKIs include EGFR mutations.42–44 The most common o these are
the acquisition o a secondary EGFR mutation. The in-rame insertions within exon 20 o EGFR, which
most common secondary EGFR mutation is T790M, are generally resistant to currently approved EGFR
which increases the anity o the mutant oncopro- TKIs.45,46 Historical data or patients with EGFR exon 20
tein or ATP to near wild-type levels leading to TKI insertion mutations have shown that overall response
resistance.29,32–34 In a phase III trial, osimertinib has rates are approximately 3% to 8% to rst-line therapy
shown superior outcomes compared with platinum- with erlotinib, getinib, or aatinib. In silico modeling
based chemotherapy in patients with acquired EGFR revealed that insertions in exon 20 o EGFR result in
Chapter 25
T790M-positive NSCLC who progressed on prior steric hindrance o the drug-binding pocket resulting in
TKI. Osimertinib demonstrated a PFS o 10.1 months TKI resistance.47 Currently, there are no targeted thera-
compared with 4.4 months observed with platinum- pies approved or the treatment o patients with EGFR
based chemotherapy.35 Osimertinib is FDA-approved exon 20 insertion mutations. Clinical trials investigat-
or EGFR T790M-positive NSCLC patients who pro- ing novel EGFR TKIs, such as TAK-788 (mobocertinib)
gressed on rst- or second-line EGFR TKIs. and poziotinib, are in progress.
EGFR TKIs are generally well tolerated. Their Aatinib is approved or the rst-line treatment o
side eects are primarily related to inhibition o the patients with NSCLC whose tumors contain EGFR
TABLE 25-2 Epidermal Growth Factor Receptor Other rare ALK usions have been described in NSCLC,
Mutations and Standard Therapies in Non–Small including kinesin amily member 5B (KIF5B)–ALK,
Cell Lung Cancer kinesin light chain 1 (KLC1)–ALK, and protein tyrosine
phosphatase nonreceptor type 3 (PTPN3)–ALK and
Frequency o All striatin (STRN)–ALK.54
EGFR Mutation EGFR Mutations ALK usions can be detected using fuorescence
Type (%) Approved TKIs in situ hybridization (FISH), immunohistochemistry
Exon 19 deletion 80–85 Osimertinib (IHC), or next-generation sequencing (NGS). All these
and L858R (preerred), tests are FDA-approved or detecting ALK usion in
erlotinib, patients with NSCLC.55
getinib, Metastatic NSCLC that harbors ALK usions are
aatinib, highly sensitive to ALK TKIs, which are the standard-
dacomitinib o-care rst-line therapy or such patients. A summary
Exon 20 5–10 None approved o clinically relevant ALK TKIs is provided next.
insertions
Atypical point 10–15 Aatinib Crizotinib
mutations
(S768I, L861Q, Crizotinib has demonstrated superiority over plati-
and G719X num-based chemotherapy in the rontline setting and
EGFR, epidermal growth actor receptor; TKI, tyrosine kinase inhibitor. was the rst ALK TKI to be approved by the FDA.56
However, crizotinib has now been replaced by next-
generation ALK TKIs that have improved activity and
mutations S768I, L861Q, and G719X. The approval is ecacy.
a based on post-hoc analysis o a single group phase
2 trial (LUX-Lung 2) and randomized phase 3 trials Ceritinib
(LUX-Lung 3 and LUX-Lung 6).48 The analysis included
Ceritinib is a second-generation ALK TKI that, like
38 patients with EGFR S768I, L861Q, and G719X
crizotinib, has demonstrated superior ecacy over
alone or in combination with each other. In this subset
platinum-based chemotherapy in the rst-line setting
o patients, aatinib demonstrated an ORR o 71.1%
in terms o PFS and response rate.57 It has also shown
with a duration o response o 11.1 months and PFS
superior ecacy over single-agent chemotherapy in
o 10.7 months. The KCSG-LU15-09 was a multi-
patients who have progressed on rst-line crizotinib.
center open-label phase II trial that tested osimertinib
in the same population o rare EGFR mutations. ORR
was 50% (18 o 36 patients; 95% condence interval Alectinib
[CI], 33%–67%).49 The median PFS was 8.2 months, Alectinib is one o the currently preerred ALK TKI or
and duration o response was 11.2 months (95% CI, the rst-line treatment o patients with ALK-positive
7.7–14.7 months). metastatic NSCLC.58 In the global phase III study
Table 25–2 summarizes the types o EGFR muta- (ALEX), patients were randomly assigned to alec-
tions and their standard therapy. tinib or crizotinib. The median PFS was 35 months
in the alectinib group versus 11 months in the crizo-
tinib group; OS results are not yet mature. The CNS
ALK FUSIONS response rates in the subset o patients with baseline
measurable CNS lesions in the alectinib and crizotinib
The ALK gene was discovered in 1994 when a chromo- groups were 81% and 50%, respectively.
somal rearrangement t(2;5), resulting in a nucleophos-
min (NPM1)–ALK usion, was described in anaplastic
large-cell lymphoma.50–53 Since then, ALK usions have
Brigatinib
been discovered in several malignancies, including Brigatinib was compared with crizotinib in the phase
Chapter 25
NSCLC. These usion oncoproteins are transorming III trial ALTA-1L that enrolled treatment-naïve ALK-
in vitro and in vivo, constitutively activating the ALK positive patients with advanced NSCLC.59 Preliminary
kinase. ALK usions occur in 3% to 5% o patients with data demonstrate a PFS o 24 months with brigatinib
NSCLC and are associated with a history o never or versus 11 months with crizotinib. Among those with
light smoking and younger age.50,51 CNS metastases at baseline, the intracranial response
Echinoderm microtubule-associated protein-like rate was signicantly higher with brigatinib (78% vs
4 (EML4) is the most common ALK usion partner in 26%). These data led to the recent FDA approval o
NSCLC resulting in the EML4-ALK usion oncogene. brigatinib.
Emerging data indicate that ALK usion variants ALK TKIs with a CNS response rate o 63%. In patients
may have biologic and clinical implications in ALK- who were previously treated with two or more ALK
positive lung cancer. Among EML4-ALK variants iden- TKIs, lorlatinib resulted in a response rate o 38.7%.
tied to date, the most common are variant 1 (v1; exon In an analysis o the subset o patients who previously
13 o EML4 used to exon 20 o ALK [E13;A20]) and received a second-generation ALK TKI, lorlatinib dem-
v3a/b (exon 6a/b o EML4 used to exon 20 o ALK onstrated a response rate o 69% in patients with ALK
[E6a/b;A20]).60–62 Preclinical data suggest dierential secondary mutation, whereas the response rate was
response to crizotinib based on EML4-ALK variant.63 27% in those without a secondary mutation.74 Lorla-
In an analysis o ALTA-1L phase III trial, patients with tinib has been granted FDA approval or the treatment
variant 3 had shorter PFS than patients with variant 1 o patients with ALK-positive NSCLC who have pro-
in both study arms (brigatinib and crizotinib arms).64 A gressed on crizotinib and at least one other ALK inhibi-
similar trend was reported in the ALEX trial.65 tor, as well as or those who have progressed on either
Even though most patients derive clinical benet alectinib or ceritinib as rontline ALK inhibitor therapy
rom ALK TKIs, acquired resistance universally devel- or metastatic disease.
ops, leading to clinical progression. Parallel to what Patients with disease reractory to ALK TKIs should
is seen in EGFR TKIs, resistance mechanisms to ALK be considered or chemotherapy with or without
TKIs include ALK-dependent and -independent mech- immunotherapy. The aorementioned study, IMpower
anisms.66–69 Acquired ALK resistance mutations are 150, showed that the combination o carboplatin, pacli-
detected in 53% o patients with progressive disease taxel, bevacizumab, and atezolizumab results in longer
ater treatment with alectinib.70 The most common median OS and PFS compared with the same regimen
ALK secondary mutations in patients treated with without atezolizumab in the subset o patients with
alectinib are G1202R ollowed by I1171 mutations TKI previously treated EGFR-/ALK-positive NSCLC.41
(I1171T/N/S). G1202R maps to the solvent-exposed Thereore, this combination may be considered or
region o ALK, where the bulkier, charged side chain is such patients. Alternatively, platinum-based chemo-
thought to lead to steric hindrance o most ALK inhibi- therapy without immunotherapy can be considered.
tors.70,71 Molecular simulation analysis indicated that NSCLCs harboring ALK usions are associated with
the I1171T mutation is predicted to disrupt a hydro- low ORRs to single-agent programmed cell death pro-
gen bond between E1167 and alectinib, thus impairing tein 1 (PD-1) and PD-L1 inhibitors.75,76 Thereore, PD-1
drug binding. ALK-independent resistance mecha- and PD-L1 inhibitors should not be oered as single
nisms include MET amplication, EGFR pathway acti- agent to patient with ALK usion–positive lung cancer
vation via an NRG1–ERBB3 (erb-b2 receptor tyrosine beore exhausting other therapeutic options.
kinase 3)–EGFR axis or a TGFα–EGFR autocrine loop,
and epithelial–mesenchymal transition.68,70–72
Alectinib and brigatinib are generally better toler- ROS1 FUSIONS
ated than crizotinib and ceritinib. Common side eects
o crizotinib and ceritinib include nausea, vomiting, ROS1 is a tyrosine kinase receptor that is part o the
and diarrhea. The majority o these gastrointestinal insulin receptor amily. This gene is located on the long
toxicities are mild.56–59 Visual disturbance is a requent arm o chromosome 6 (6q22) and encodes a transmem-
side eect o crizotinib, reported in 25% to 36% o brane protein with intracellular C-terminal tyrosine
patients treated with crizotinib in phase III trials.58,59 kinase domain.77,78 It shares marked sequence homology
All grades o pneumonitis and ILD are seen with crizo- and structural similarities to the ALK oncogene.78 ROS1
tinib, ceritinib, alectinib, and brigatinib in 3%, 4%, is susceptible to chromosomal rearrangements that can
0.4%, and 4% to 9%, respectively, o patients treated alter the protein unction and lead to constitutive activa-
with these TKIs (https://www.accessdata.da.gov). tion o downstream pathways such as mitogen-activated
Brigatinib-related pneumonitis is unique in its early protein kinase (MAPK) and phosphoinositide 3-kinase
onset (median time to onset, 2 days).73 Thereore, (PI3K)–Ak strain transorming (AKT)–mammalian target
current prescribing inormation recommends starting o rapamycin (mTOR)to promote carcinogenesis.78,79
brigatinib at a leading dose o 90 mg or 1 week ol- ROS1 usions account or approximately 2% o
Chapter 25
lowed by escalation to 180 mg. NSCLC cases.79 Clinical and histologic eatures that
Lorlatinib is a third-generation reversible, ATP- are commonly associated with ROS1-positive NSCLC
competitive, macrocyclic TKI o ALK and ROS1 that include adenocarcinoma histology, never smokers, and
has activity against the majority o the known ALK younger patients.79 CD74 and SLC34A2 are among
TKIs resistance mutations. In a phase II study that the most common ROS1 usion partners in NSCLC,
included previously treated patients with ALK-positive but others such as SDC4 and EZR have also been
NSCLC,74 lorlatinib yielded a response rate o 47% in described.77,78,80,81 Although important or detection o
patients who were previously treated by one or more ROS1 usions, usion partners have not been associated
with dierences in clinical outcome.80–82 ROS1 usion In 2019, entrectinib, a dual ROS1-NTRK inhibitor,
detection can be perormed by FISH or NGS.82,83 For was approved or treatment o patients with advanced
NGS, RNA-based methods are preerred because o NSCLC harboring ROS1 usion based on a pooled
higher sensitivity or detecting genomic rearrange- analysis o three trials (STARTRK-1, STARTRK-2, and
ments with multiple usion partners.84,85 ALKA-372-001).82 Patients with locally advanced or
Crizotinib was the rst approved ROS1 usion TKI. metastatic TKI-naïve ROS1 usion NSCLC treated with
Two phase II trials or advanced NSCLC harboring ROS1 entrectinib 600 mg/day were included in the ecacy
usions showed crizotinib 250 mg orally (PO) twice a analysis. The majority o patients had adenocarcinoma
day (bid) led to an ORR o 72%, median duration o histology, 43% had brain metastasis, and only 32% were
response (DoR) o 20 to 24.7 months, and median pro- treatment-naïve. At median ollow-up period o 15.5
gression ree survival (mPFS) o 16 to 19.3 months.80,81,86 months, ORR was 77%, intracranial ORR was 55%,
Long-term ollow-up o the PROFILE 1001 trial (median mPFS was 19 months, and duration o response was
ollow-up, 62.6 month) showed that Median overall 24.6 months. Median PFS or patients with IC disease
survival (mOS) was 51.4 months, and 12-, 24-, 36-, and was 13.6 months, and intracranial duration o response
48-month OS were 79%, 67%, 53%, and 51%, respec- was 12.9 months. Median OS was not reached with
tively.81 The most common side eects reported were 82% o patients alive at 18 months. Almost all patients
visual impairment (87%), nausea (51%), edema (47%), had tumor shrinkage, and response occurred early, usu-
diarrhea (45%), vomiting (38%), elevated liver unction ally on the rst scan. The most common on-target side
test (LFT) results (36%), constipation (34%), atigue eects were dizziness (32%), weight gain (26%), par-
(21%), dysgeusia (19%), and dizziness (19%). A total o esthesias (17%), and cognitive changes (6%), which
94% o events were G1 to G2. Most common G3 toxici- are a result o the potent anti– Tropomyosin receptor
ties were hypophosphatemia (15%), neutropenia (9%), kinases A-C (TRKA-C) activity o entrectinib.82 Because
vomiting (4%), and elevated LFT results (4%).81 o a better saety prole and higher intracranial activity,
Ceritinib was also tested or treatment o advanced we recommend entrectinib or rontline standard-o-
NSCLC harboring ROS1 usion in a Korean phase II trial care treatment o patients with ROS1 usion NSCLC.
(n = 32). Patients with stage IV ROS1 usion NSCLC Lorlatinib, a potent ROS1-ALK inhibitor, was speci-
(6% pretreated with crizotinib and 94% treatment- cally developed or higher intracranial penetration83 and
naïve) received ceritinib 750 mg/day until disease pro- is currently under clinical testing or treatment o patients
gression. With a median ollow-up period o 14 months, with ROS1 usion NSCLC. In a phase I/II trial, the e-
ORR was 62%, disease control rate (DCR) was 81%, cacy o lorlatinib 100 mg/day or treatment o patients
mPFS was 9.3 months (crizotinib-naïve patients, 19.3 with ROS1 usion advanced NSCLC was dependent on
months), median DoR was 21 months, and median OS prior TKI exposure. For TKI-naïve and crizotinib-pre-
was 24 months. Intracranial disease control and ORR treated patients, ORRs were 62% and 35%, intracranial
were 63% and 25%, respectively. Despite its ecacy, response rates were 64% and 50%, and median DoRs
ceritinib showed high rates o G1 to G2 adverse events, were 25.3 and 13.8 months, respectively. Intracranial
including diarrhea (78%), nausea (59%), anorexia DoR was not reached. O the six patients harboring
(56%), vomiting (53%), cough (47%), and muscle pain G2032R resistance SFM, none achieved partial response
(41%), and the rate o G3 atigue was 16%.87 (PR), one had progressive disease (PD), and ve had sta-
The incidence o brain metastases in patients with ble disease (SD) (range o SD duration, 2.9–9.6 months).83
newly diagnosed ROS1 usion stage IV NSCLC ranges Repotrectinib is a TKI targeting ROS1-NTRK-ALK
rom 19% to 36%.88,89 A retrospective analysis showed that exhibits potent activity or inhibiting ROS1 usion
that CNS progression can be the rst and sole site o dis- proteins harboring SFM.90 Repotrectinib also compares
ease progression in almost hal o patients treated with avorably with other ROS1 targeting TKIs, such as
crizotinib (47%).88 This demonstrates that the blood– entrectinib, lorlatinib, ceritinib, and crizotinib, or tar-
brain barrier can hamper crizotinib’s intracranial pen- geting ROS1 harboring SFM in cell line models.90 In a
etration and lead to intracranial disease progression. preliminary analysis o the dose-escalation part o the
Other than low intracranial concentration, emergence phase I/II TRIDENT-1 trial (NCT03093116), patients
o resistance solvent-ront mutations (SFMs) have been with TKI-naïve ROS1 usion treated with repotrec-
Chapter 25
shown to account or approximately 64% o cases o tinib (n = 10) had an ORR o 80% and an intracranial
extracranial disease progression to crizotinib,89 with ORR o 100%. TKI pretreated patients (n = 17; major-
G2032R, D2033N, and S1986F being the most com- ity pretreated with crizotinib) had an ORR o 18%
monly reported.89,90 These mutations impede drug and an intracranial ORR o 25%. O the our patients
binding and promote crizotinib resistance.89 Because o harboring ROS1 G2032R SFM, three had SD, and one
low intracranial penetration and poor activity o crizo- achieved PR.91 This trial is ongoing to determine the
tinib or resistance SFM, novel ROS1 usion inhibitors recommended phase II dose, which will allow a better
are under clinical development. understanding o the ecacy o this agent.
Non–ROS1-mediated resistance remains poorly Currently, only BRAF class 1 V600E mutations have
understood, and no directed therapies are available FDA-approved targeted therapies in NSCLC. Vemu-
in this setting. ROS1 usion NSCLC has low tumor raenib, an anti-BRAF targeting TKI, showed an ORR o
mutational burden,92 and although data are limited, 37% to 42%, mPFS o 6.5 to 7.3 months, and median OS
small benet rom treatment with single-agent PD-1 o 15.4 months or treatment o patients with NSCLC
and PD-L1 inhibitors has been seen (ORR, 17%; PD harboring BRAF V600E mutations.105,106 The combina-
within 2 months o starting treatment, 43%).76 Even in tion o MAPK/ERK Kinase (MEK) inhibitor trametinib
the presence o positive (≥1%) or high-positive (≥50%) and BRAF inhibitor dabraenib has shown an ORR o
PD-L1 expression, we do not recommend treatment 63% to 64%, mPFS o 9.7 to 10.9 months, and median
with single-agent PD-1/PD-L1 inhibitors. Thereore, duration o response (mDoR) o 9.0 to 10.4 months in the
ater exhaustion o targeted therapies, we recommend rontline and salvage settings or BRAF V600E mutant
combination treatment with a platinum doublet plus a NSCLC.107,108 Noteworthy, G1and G2 side eects rom
PD-1/PD-L1 inhibitor (triple therapy)93 with or with- this combination include pyrexia (44%–53%), nausea
out bevacizumab (quadruple therapy).41 (40%–56%), diarrhea (32%–33%), peripheral edema
(23%–36%), and skin rash (19%).107,108 Other side eects
o interest include skin squamous cell carcinoma (4%),
BRAF MUTATIONS decreased let ventricle ejection raction (G3, 6%) and
ocular toxicity, which includes conjunctivitis (2.8%–
BRAF is a proto-oncogene located on the long arm 8.9%), uveitis (4%), retinal vein occlusion (0.2%), and
o chromosome 7. The BRAF gene encodes a serine/ serous retinopathy (3%–26%).107–112
threonine protein kinase named BRAF, which is a part Mechanisms o resistance to single-agent BRAF
o the MAPK pathway and a key driver o cell proli- inhibitor are better understood than or BRAF-MEK
eration and growth.94 Despite being enriched in mela- inhibitor combinations. Resistance to BRAF inhibi-
noma,95 BRAF mutations occur in approximately 4% tors can develop through reactivation o downstream
o NSCLC cases and are usually ound in ever smok- signaling o the MAPK pathway by acquired BRAF
ers.96–100 BRAF mutations have been previously classi- V600E splice site alterations,113 C-RAF mutations,114
ed as V600 and non-V600, but in recent years, a better and NRAS/MEK mutations.115 Because o this, novel
understanding o the non-V600 mutations has allowed treatment strategies or overcoming resistance include
urther classication o the BRAF mutations into three additional downstream inhibition o the MAPK path-
classes: 1, 2, and 3.94 Class 1 mutations correspond to way, such as with ERK inhibitors (eg, ulixertinib,
V600 mutations, o which V600E is the most common. LTT462). Another approach is novel BRAF inhibitors
Class 1 mutations promote RAS-independent constitu- that have dimer inhibition activity (eg, LXH254, li-
tive activity o BRAF in the orm o a monomer.101–104 raenib). These compounds are currently undergoing
Class 2 BRAF mutations are also RAS-independent clinical investigation. Clinical trial enrollment is rec-
constitutively active kinases, but contrary to class 1 ommended and warranted or this population.
mutations, they promote downstream signaling in the There are currently no approved targeted therapies
orm o BRAF homodimers.94,101 BRAF class 2 muta- or lung cancers harboring BRAF class 2 and 3 muta-
tions are urther subcategorized into three groups: a, b, tions. Similar to investigational approaches or target-
and c.101 Class 2a reers to mutations located in the acti- ing resistance in BRAF V600E mutant tumors, BRAF
vation segment o BRAF and include the K601, L597, dimer inhibitors, MEK inhibitors, ERK inhibitors, and
and E586 loci.101 Class 2b reers to mutations located SHP2 inhibitors are undergoing clinical development
in the glycine-rich P-loop and generally includes the either as single agents or as combination regimens.
G464 and G469 loci.101 Class 2c includes BRAF usions, This is based on preclinical or early clinical data sug-
where coupling o the C-terminal kinase domain with gesting that non-V600 mutations may be sensitive to
the N-terminal dimerization domain leads to consti- these agents.116–120 Thereore, clinical trial enrollment
tutive dimerization and activation o BRAF.94 It also is encouraged and recommended or this population.
includes in-rame deletions that remove about ve Recent retrospective data rom our group and oth-
amino acids near the β3–αC region o the BRAF kinase ers have shown that advanced NSCLC harboring BRAF
Chapter 25
and switch the α-C helix to an activated conorma- mutations may be more susceptible to PD-1/PD-L1
tional state to promote dimerization and downstream checkpoint blockade compared with other oncogene-
signaling.94 BRAF class 3 mutations are RAS-dependent driven NSCLC, yielding better ORR and mPFS.121,122
kinase impaired mutations that promote downstream In addition, high ORR and prolonged PFS have been
signaling in the orm o heterodimers with wild-type reported or phase I/II trials combining BRAF and MEK
RAF (eg, C-RAF). This commonly co-occurs because o inhibitors with PD-1/PD-L1 blockade in metastatic
additional RAS signaling either through activating RAS melanomas harboring BRAF V600 mutations. These
mutations or NF1 loss-o-unction alterations.102,103 ndings are based on preclinical data suggesting that
BRAF and MEK inhibition can enhance antitumor caution is warranted because RNA-based assays rely
immunity and have synergistic eect with immune on the quality o the RNA extracted rom tumor tis-
checkpoint inhibitors by promoting immunogenic cell sue.131 NGS blood-based assays or circulating tumor
death123 and increased T-cell inltration and activation DNA (ctDNA) detection can also be used and repre-
in the tumor microenvironment.124,125 Phase III trials sent an important tool or detecting MET exon 14 skip-
testing TKI plus immune checkpoint blockade combi- ping mutations both or clinical trial enrollment and
nations in metastatic melanoma are expected to read or standard clinical practice.10
out soon. I positive results emerge, it is likely that a The TKI crizotinib has shown activity or treatment
similar approach will be studied in NSCLC as well. o patients with advanced NSCLC harboring MET
For patients with advanced NSCLC whose tumors exon 14 skipping mutations in an expansion cohort
harbor a BRAF V600E mutation, we recommend ront- o the PROFILE 1001 trial (n = 69 patients). Treatment
line treatment with dabraenib and trametinib as stan- with crizotinib led to an ORR o 32%, median DoR
dard o care. Upon progression, our approach is to o 9.1 months, and mPFS o 7.3 months.129 Although
recommend treatment with a chemotherapy-immu- crizotinib is not approved by the FDA, it is sup-
notherapy backbone, such as carboplatin, pemetrexed, ported by the NCCN guidelines, which recommend
and pembrolizumab, or an immunotherapy combina- treatment with crizotinib or patients with advanced
tion with nivolumab and ipilimumab. For other BRAF NSCLC harboring a MET exon 14 skipping mutation
mutations, we recommend rontline chemoimmu- (NCCN.org). This is urther supported by retrospec-
notherapy or nivolumab–ipilimumab combinations tive data suggesting that patients with NSCLC har-
because o a lack o prospective clinical data showing boring MET exon 14 skipping mutation treated with
ecacy o MEK+/-BRAF inhibitor in this population. a targeted agent have longer mOS (24.6 months)
Clinical trial enrollment is encouraged or all patients compared with patients who never received a MET
with NSCLC harboring class 1, 2, and 3 BRAF muta- TKI (8.1 months; hazard ratio, 0.1; 95% C,I 0.0–0.9;
tions and or patients with NSCLC harboring BRAF P = .04).133
class 1 V600E mutations that have become resistant to Currently, three novel MET TKIs are in clinical devel-
BRAF+/-MEK inhibitors. opment: capmatinib, tepotinib, and savolitinib. These
three compounds have shown more potent activity in
preclinical models compared with crizotinib (hal max-
MET ALTERATIONS imal inhibitory concentration (IC50) 0.6–3.0nM vs 22.5
nM).134 In addition, capmatinib, tepotinib, and savoli-
MET is a proto-oncogene that codes or the tyrosine tinib have shown activity in NSCLC harboring MET
kinase hepatocyte growth actor receptor. It is located exon 14 skipping mutations in treatment-naïve and
in the long arm o chromosome 7 at position 31.2. previously treated patients.10,126,134–136 Table 25–3 sum-
Two types o genetic alterations are described or marizes the current ndings or TKIs targeting MET
MET oncogenesis: exon 14 skipping mutations and exon 14 skipping mutations. Capmatinib 400 mg PO
amplication. bid recently received FDA Accelerated Approval and
MET exon 14 skipping mutations are oncogenic is now standard o care or advanced NSCLC harbor-
drivers in 3% to 4% o NSCLCs and 8% to 32% o ing MET exon 14 skipping mutations. Tepotinib 500
sarcomatoid lung carcinomas.126 These alterations are mg PO daily has also received U.S. FDA Breakthrough
typically enriched in patients with older age.127 Exon Therapy Designation or this same indication and is
14 encodes a juxtamembrane region o the MET pro- currently under evaluation.
tein receptor that harbors a CBL E3 ubiquitin ligase The two most common side eects o MET TKIs
binding site, Y1003, and loss o this site impairs ubiq- are peripheral edema (36.6%–63.0%) and nausea
uitin-mediated degradation o the MET receptor. This (26%–48.8%), but grade 3 to 4 events o these toxici-
leads to decreased turnover o MET and increases ties were reported in 1% to 7.5% o patients. Other
MET signaling through the MAPK and PI3K path- common side eects include increased LFT results
ways to drive oncogenesis.10,128 Diverse mutational (7%–31.7%), diarrhea (11.4%–22%), vomiting (6%–
mechanisms such as point mutations, insertion and 31.7%), increased creatinine (18%–19.5%), hypoal-
Chapter 25
deletions, and large deletions are involved. They can buminemia (16%–19.5%), pyrexia (24.4%), anemia
disrupt distinct splicing sites fanking exon 14 and lead (17.1%), and decreased appetite (8%–17.1%). Upper
to exclusion o this exonic region at the RNA level128,129 abdominal pain and atigue can also occur in approxi-
or promote deleterious alterations in the Y1003 locus mately 5% and 7% to 13.8% o patients, respectively.
within exon 14.130 Tissue RNA-based NGS assays are Pneumonitis was an uncommon event (1.5%).10,134,135
preerred or detecting MET exon 14 skipping muta- Mechanisms o acquired resistance to MET TKIs
tions because o previous reports showing a 36% alse- remain poorly understood. Preliminary data suggest
negative rate or DNA-based assays.131,132 However, both on-target (eg, secondary MET mutations, MET
TABLE 25-3 Efcacy Results or Tyrosine Kinase Inhibitors Targeting MET Exon 14 Alterations in Patients
with Non–Small Cell Lung Cancer
Capmatinib Tepotinib Savolitinib Crizotinib

Treatment- Previously
Naïve (n = 28) Treated (n = 69) (n = 99) (n = 70) (n = 69)
ORR (%) 67.9 40.6 46.5 42.9 32
DCR (%) 96.4 78.3 65.7 82.9 78
mDoR (mo) 11.1 9.7 11.1 9.6 9.1
mPFS (mo) 9.7 5.4 8.5 6.9 7.3
Intracranial disease (n) 13 11 NA NA
Intracranial ORR (%) 54 55 NA NA
DCR, disease control rate; mDoR, median duration o response; MET, mesenchymal-epithelial transition; mPFS, median progression ree survival; NA, not available; ORR,
objective response rate.
amplication) and o-target bypass-pathway medi- benet rom targeted therapies. Real-time quantitative
ated resistance (eg, RAS and PI3K pathway activation, polymerase chain reaction (RT-qPCR) is also currently
EGFR amplication), but in up to 50% o the cases, the used to select patients or clinical trial enrollment.141
mechanism(s) o resistance are unknown.10,130,137,138 Treatment strategies under investigation or
Upon progression with MET TKIs, treatment patients with MET-amplied or -overexpressing
options include chemotherapy, immunotherapy, or tumors include TKIs, monoclonal antibodies, and
both. Clinical benet rom single-agent or combina- antibody–drug conjugates. In part 2 o the A8081001
tion immune checkpoint inhibition is modest or trial, 14 patients with MET amplication, dened as
treatment o patients with NSCLC harboring MET a MET-to-CEP7 ratio o 1.8 or greater, were treated
exon 14 skipping mutations. In a small retrospective with crizotinib (TKI). Conrmed ORR with crizotinib
cohort, ORR was 17%, and mPFS 1.9 was months.139 was dependent on the level o MET amplication: low
Thereore, we recommend combination treatment (MET-to-CEP7 ratio, 1.8–2.2; ORR, 0%), intermediate
with PD-1/PD-L1 inhibitor plus platinum doublet (MET-to-CEP7 ratio, 2.3-4.9; ORR, 17%), and high
chemotherapy with or without bevacizumab (tri- (MET-to-CEP7 ratio, ≥5.0; ORR, 67%).144 In addition,
ple or quadruple therapy)41,93 as standard o care or the GEOMETRY-1 study evaluated capmatinib (TKI)
patients with NSCLC harboring MET exon 14 skip- in previously treated (cohort 1a: n = 69) and treat-
ping mutations that progress on MET TKI as long as ment-naïve (cohort 5a: n = 15) MET-amplied (dened
perormance status and clinical condition allow or it. as gene copy number ≥10) advanced NSCLC. ORRs
Clinical trial enrollment, i easible, is warranted or were 40% and 29%, and DCRs were 66.7% and 71%
urther drug development in this space. One example or treatment-naïve and previously treated cohorts,
is Sym015, which consists o an antibody mixture respectively. Median DoR was 7.5 to 8.3 months,
targeting two nonoverlapping sites in the MET extra- and mPFS was 4.1 to 4.2 months.145 Other MET TKIs
cellular domain.140 Sym015 has shown early signs o are currently under investigation. In a phase I trial,
activity in NSCLC previously treated with MET tar- the antibody drug–conjugate telisotuzumab vedotin
geting agents (n = 9), including DCR o 56%, PFS o (ABBV-399) showed an ORR o 18.8%, mDoR o 4.8
5.4 months, and DoR o 6.5 months. 141 months, and mPFS o 5.7 months or treatment o
MET amplication occurs in 1% to 4% o patients with NSCLC with MET overexpression (n =
NSCLCs142,143 and is a poor prognosis biomarker.143 It 16) as dened by an IHC H-score o 150 or greater.146
is important to dierentiate amplication (true gene In a dose-escalation phase I trial, the monoclonal anti-
ocal copy number gain) rom high polysomy. For body Sym015 also showed activity in MET-amplied
Chapter 25
MET amplication, this has been dened through FISH (dened as ISH MET-to-CEP7 ratio ≥2.2 or NGS/qPCR
as an increase in the ratio o MET gene copy number >5 copies) treatment-naïve NSCLC (n = 7) with an
gain relative to centromere 7 (CEP7).144 Commercially ORR o 40%, DCR o 100%, mPFS o 5.5 months, and
available NGS assays use copy number callers to dis- mDOR o 18.4 months.141 Because o these promis-
tinguish high polysomy rom true copy number gain ing novel compounds, clinical trial enrollment, i ea-
amplication. However, it remains unclear what is the sible, is encouraged or patients with MET-amplied
optimal denition o NGS copy number gain to predict NSCLC.
HER2 MUTATIONS (AST; 24.5%, increased alanine aminotranserase (ALT;

23.8%), hypertension (23.2%), diarrhea (19.7%), and
Human epidermal growth actor receptor 2 (HER2/ atigue (16.8%). Only 2% (14 o 702) o patients dis-
ERBB2) is an HER/ERBB amily receptor tyrosine continued selpercatinib because o TRAEs.161
kinase. HER2 mutations occur in approximately 1.5% Pralsetinib (BLU-667) is a highly potent and selec-
o lung adenocarcinomas.147 The most requent HER2 tive RET inhibitor targeting oncogenic RET alterations,
mutations in lung cancer occur in exon 20 with the including those that coner resistance to multikinase
Y772dupYVMA mutation involving 34% o all HER2 inhibitors.11 The Arrow study is a phase 1/2 trial eval-
mutations.147 Point mutations, such as L755X and uating pralsetinib in RET usion–positive advanced
V777L, have also been detected in NSCLC. Target- tumors. The ORRs in previously untreated and plati-
ing HER2 mutations remain an unmet clinical need in num-pretreated patients with NSCLC were 61% and
which TKIs and HER2 monoclonal antibodies are cur- 73%, respectively.162
rently being tested. Emerging data suggest that both selpercatinib and
Trastuzumab deruxtecan (t-DxD) is a novel anti- pralsetinib have potent intracranial activity. In patients
body–drug conjugate that was tested in a phase 2 trial with baseline measurable CNS disease (selpercatinib,
that enrolled 42 patients with HER2-mutant NSCLC. 22 patients; pralsetinib, nine patients), the intracranial
The ORR was 61.9% with a PFS o 14 months.148 In a ORRs were 81.8% and 56%, respectively.162,163
smaller study o 18 patients, ado-trastuzumab emtan-
sine (also known as T-DM1), another antibody–drug
conjugate, resulted in an ORR o 44%.149 The combina- NTRK FUSIONS
tion o trastuzumab and pertuzumab yielded an ORR
o 21% when tested in a cohort o 36 patients.150 The tropomyosin receptor kinase (TRK) amily
Numerous TKIs are under development in this set- includes three transmembrane receptor proteins:
ting. Pyrotinib resulted in an ORR o 32% with a dura- TRKA, encoded by NTRK1, which is located in the
tion o response o 7 months in patients with HER2 long arm o chromosome 1; TRKB, encoded by NTRK2,
exon 20 mutant NSCLC.151 Aatinib, dacomitinib, which is located in the long arm o chromosome 9;
and neratinib have limited clinical activity in this set- and TRKC, which is located in the long arm o chro-
ting.152–154 Other TKIs in clinical testing include pozio- mosome 15.164,165 TRK receptors have tyrosine kinase
tinib147 and mobocertinib (TAK-788). activity and are activated by binding with the neu-
rotrophins nerve growth actor, brain-derived neuro-
trophic actor, and NT-3/4/5.164 Ater activation, these
RET FUSIONS receptors promote downstream signaling through the
MAPK and PI3K-AKT pathways to promote increased
The RET receptor tyrosine kinase is oncogenically prolieration, cellular growth, and survival.164 These
activated by chromosomal rearrangements produc- receptors are expressed in neuronal tissue and are par-
ing RET gene usions in 1% to 2% o patients with ticularly important or nervous system development
NSCLC.155 Several multikinase inhibitors with some during embryogenesis.165 Ater birth, these receptors
degree o anti-RET activity demonstrated modest continue to be primarily expressed in neuronal tissue
activity in RET usion–positive lung cancer in phase and modulate sensory perception (eg, pain, proprio-
2 studies.156–158 In a retrospective registry study o 165 ception), body weight, and memory.165
patients with RET-positive NSCLC, the response rates TRK can become an oncogenic driver by intra- or
to cabozantinib, vandetanib, and sunitinib were 37%, interchromosomal rearrangements. This occurs when
18%, and 22%, respectively.159 the TRK tyrosine kinase domain 3¢ terminal is joined
Selpercatinib is a highly potent and specic small- by a 5¢ sequence partner to generate a usion protein
molecule inhibitor o the RET kinase, with minimal that is constitutively activated or overexpressed164 and
inhibition o other kinase and nonkinase targets. In promotes continues downstream signaling. Currently,
a phase II study that enrolled 105 patients with RET- several usion partners have been detected or NTRK,
positive NSCLC with prior treatment with plati- such as CD74, TPM3, and ETV6.164,166 Although NTRK
Chapter 25
num-based chemotherapy, selpercatinib resulted in a usions can occur in all three NTRK genes, NTRK1
response rate o 68%. Median DoR was 18 months, and NTRK3 are the most commonly aected.167,168 In
and median PFS was 17 months.160,161 Selpercatinib NSCLC, NTRK usions are rare oncogenic drivers and
has received approval rom the U.S. FDA or patients occur in approximately 0.2% o adenocarcinomas.169
with RET usion–positive advanced NSCLC. Selper- The test o choice or detecting NTRK usion is NGS
catinib is generally well tolerated. The most common with an RNA-based method.169 Because o the diver-
treatment-related adverse events (TRAEs) were dry sity o usion partners and the need to cover all three
mouth (33.3%), increased aspartate aminotranserase NTRK genes, FISH requires large amounts o tissue to
test all necessary probes. IHC has shown lower sensi- and hamper drug binding. Examples include NTRK1
tivity compared with RNA NGS or detecting NTRK G595R and G667C, NTRK2 G639R, and NTRK3
usions169 likely because o limitations related to stain- G623R and G623E mutations.90,171,172 Currently, two
ing intensity and location and the tumors site o origin. novel TRK inhibitors are undergoing clinical testing to
Because NTRK are rare drivers, NGS allows or test- overcome resistance in the presence o these on-target
ing o several gene usions, simultaneously decreasing mutations: LOXO-195 and repotrectinib. Both agents
the need or specic NTRK testing, contrary to IHC have shown high activity in preclinical models harbor-
and FISH. NGS RNA-based methods are also preerred ing NTRK resistance mutations, and both have shown
compared with DNA NGS-based methods because o early signs o clinical activity by inducing responses
higher sensitivity169 due to diversity o usion partners in patients with tumors harboring NTRK1 G595R,
and inaccuracy or detecting truly activating usions, NTRK3 G623E, and NTRK3 G623R mutations.90,173
which are those that include the entire TRK tyrosine Preliminary results o a phase I trial evaluating LOXO-
kinase domain. 195 (NCT03215511) or treatment o patients whose
Currently, two TKIs are approved or treatment o tumors had progressed or had become intolerant to
patients with solid tumors, including NSCLC, harbor- TRK TKIs showed impressive activity o this com-
ing TRK usions: larotrectinib and entrectinib. In a pound with ORR ranging rom 25% to 50% depend-
pooled analysis o three phase 1/2 trials including 159 ing on the location o the acquired NTRK resistance
patients with solid tumors harboring a NTRK usion, mutation.174
larotrectinib showed an ORR o 79%, mDOR o 35.2 Integrated preclinical and clinical work with patient-
months, and mPFS o 28.3 months.170 For patients with derived cell lines, mouse xenograt models, and paired
NSCLC (n = 12), ORR was 75%, and mDOR was not blood molecular proling suggests that activation o
reached.170 Three patients had measurable intracra- bypass pathways, such as MAPK through BRAF and
nial disease with two achieving intracranial response. KRAS mutations and MET amplication and overex-
Most common G1 to G2 toxicities were atigue (30%), pression, can drive o-target resistance to TRK TKIs.175
ALT or AST increase (24%–25%), cough (27%), con- In addition, targeting these pathways with BRAF/MEK
stipation (27%), diarrhea (23%), nausea or vomiting inhibitors or MET inhibitors showed activity or over-
(24%), and dizziness (25%).170 Most common G3 to coming resistance in these cases.175
G4 toxicities were anemia (10%) and decreased neu- In the setting o disease progression on entrectinib
trophil count (5%), and no treatment-related deaths or larotrectinib, we recommend repeat molecular pro-
were reported.170 Similarly, the ecacy o entrectinib ling through either blood or tissue-based assays and
or treatment o patients with solid tumors harboring enrollment or reerral or enrollment in clinical trials
NTRK usions was also evaluated in a pooled analy- designed or NTRK usion tumors that have developed
sis o three phase 1 or 2 trials.168 For the 54 patients resistance to TRK targeting TKIs.
evaluated, ORR was 57%, mDoR was 10 months, and
mPFS was 11 months.168 For the NSCLC population (n
= 10), ORR was 70%.168 Twelve patients had baseline NRG1 FUSIONS
intracranial disease, and o them, intracranial ORR was
50%, and intracranial DCR was 83%. Median time to Neuregulins (NRGs) are signaling proteins that medi-
CNS progression was 17 months.168 Most common G1 ate cell–cell interactions in the nervous system, heart,
to G2 adverse events included dysgeusia (47%), con- and breast.176 NRG-producing cells bind to the extra-
stipation (28%), atigue (28%), diarrhea (27%), periph- cellular domain o the receptor tyrosine kinases ERBB3
eral edema (24%), and dizziness (24%). Most common and ERBB4 o the NRG-responsive cells to promote
G3 and G4 adverse events included anemia (12%), ERBB homo- and heterodimerization.176–178 This acti-
weight increase (10%), and atigue (7%).168 O note, vates intracellular pathways, such as PI3K-AKT and
additional reported on-target adverse events included MAPK, which regulate prolieration, apoptosis, migra-
peripheral sensory neuropathy (8%), disturbance in tion, dierentiation, and adhesion.176,178
attention (4%), hyperesthesia (3%), ataxia (3%), and The NRG1 gene is located on the short arm o
diplopia (4%). Congestive heart ailure was reported chromosome 8.176 NRG1 proteins and isoorms have
Chapter 25
in 2% o patients.168 In light o these results, we rec- an extracellular EGF-like domain that induces activa-
ommend rontline treatment with larotrectinib or tion o ERBB tyrosine kinase receptors.178 Most NRG1
entrectinib or patients with NSCLC harboring NTRK isoorms undergo proteolytic cleavage and release o
usions. the EGF-like domain, with the exception o type III,
Resistance to NTRK inhibitors can be on target which has a membrane-tethered EGF-like domain that
through NTRK mutations or o target by activation restricts signaling to cell–cell interactions.177,178
o bypass or downstream pathways. On-target NTRK NRG1 usions promote expression o NRG1 III-
mutations typically occur in the TRK kinase domain β3 on the cancer cell surace. This leads to ERBB3
binding and activation, which in turn dimerizes with ERBB3, both TKI and monoclonal antibodies, are
other ERBB tyrosine kinase receptors. This promotes under investigation or treatment o patients with
autocrine, paracrine, and juxtacrine activation o NRG1 usion–positive NSCLC (seribantumab [MM-
PI3K-AKT and MAPK pathways and ultimately leads 121]; zenocutuzumab [MCLA-128] [NCT04100694;
to cell growth and oncogenesis.85,177,178 NRG1 usions NCT02912949]; GSK2849330). Thereore, enrollment
are present in 0.2% o cancers and 0.3% o NSCLCs, in clinical trials is recommended or these patients.
making NSCLC the most common histology or these
alterations (61%).84,179 Currently, 17 usion partners
have been identied or NRG1, but CD74 (47%), CONCLUSION
SLC3A2 (16%), and SDC4 (7%) are the three most
common in NSCLC.84 NRG1 usions are enriched in The past decade has seen remarkable progress in the
invasive mucinous adenocarcinomas (27%–31% o lung cancer eld with novel actionable mutations and
cases) and are oten mutually exclusive rom KRAS, development o increasingly more eective targeted
another driver known to be enriched in this histologic therapies. However, the universal development o
subtype.84,85,180 Because the DNA rearrangements that resistance ocuses research eorts in this arena.
generate NRG1 usions typically occur in two large There is also excitement in the eld or targeting
intronic regions and because the usion partners are driver oncogenes that were previously untargetable,
diverse and incomplete characterized, RNA sequenc- and we look orward to novel compounds in this
ing is avored compared with DNA sequencing or regard. One example o this is KRAS with several
detecting these alterations.84,85 FISH or NRG1 and G12C inhibitors under clinical development. Eorts
IHC or p-ERBB3 are alternatives or NRG1 usion are also being made toward targeting tumor suppres-
detection.84,177,180 sor genes. Despite a current lack o approved therapies
There are currently no approved therapies or in this setting, novel treatment strategies are under
patients with NSCLC harboring NRG1 usions. investigation. Examples include STK11, KEAP1, and
Responses have been reported with the pan-HER am- TP53. Although not as straightorward as targeting
ily inhibitor aatinib (DoR, 6–12 months) and with the oncogene driver alterations, we believe the eld is
anti-ERBB3 monoclonal antibody GSK2849330 (DoR, making important progress, and we look orward to
19 months).84,85,181 Several agents capable o inhibiting results o upcoming clinical trials in this setting.
MD ANDERSON CANCER CENTER PRACTICE TIPS

J Use broad genomic proling or all NSCLC using J Always consider clinical trial enrollment i easible
tumor tissue and cDNA irrespective o tobacco and sae or the patient.
exposure history. NSCLC should be tested at least J In patients with oligometastatic disease, consider
or EGFR, ALK, ROS1, RET, MET, BRAF, and NTRK. local consolidation therapy (LCT) with surgery or
J I a patient requires start o systemic therapy beore radiation at the time o best response. LCT should
genomic proling results become available, con- also be considered or patients with oligopro-
sider starting cytotoxic chemotherapy only or the gressive disease along with continuing targeted
rst cycle. I the patient’s tumor is ound to harbor therapy.
a targetable oncogene alteration, this will prevent J Tumor biopsy and cDNA testing should be obtained
overlapping toxicities rom targeted therapy and to identiy acquired resistance mechanisms. Clinical
immune checkpoint inhibition, such as pneumoni- trials o novel targeted agents and rationale combi-
tis and hepatitis, when changing treatment to tar- nations should be considered based on molecular
geted therapy in the subsequent 2 to 3 weeks. proling results.
Chapter 25
18. Leduc C, Merlio JP, Besse B, et al. Clinical and molecular

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Chapter 25
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Chapter 25
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Chapter 25
Section V Head and Neck
Cancer
26 Head and Neck Cancer

26 Head and Neck Cance
Ruth Sacks
David Boyce-Fappiano
Amy Moreno
Frank Mott
KEY CONCEPTS
 Head and neck cancers are diverse. In this chapter, we  For early-stage HNSCC, surgery or denitive radiation pro-
ocus on the management o squamous cell carcinomas o vides excellent local control.
the head and neck (HNSCC).  Most patients present with locally advanced disease
 Tobacco and alcohol use are major risk actors, and the requiring a multimodality approach ocusing on organ
human papillomavirus (HPV) is a risk actor or oropharyn- preservation, managing metastatic risk, and minimizing
geal cancer (OPC). acute and chronic toxicities.
 All patients should undergo a multidisciplinary evaluation  Immune checkpoint inhibitors are now standard in
that includes surgical, medical, and radiation oncology recurrent and/or metastatic HNSCC.
specialists.
EPIDEMIOLOGY carcinogens and/or oncogenic viruses and genetic sus-

ceptibility. Certain genetic actors, such as metabolic
In the United States, head and neck cancer is estimated polymorphisms, DNA repair gene polymorphisms,
to represent approximately 3.6% (65,630) o new can- and variations in other pathways may contribute to
cer cases and 2% (14,500) o cancer deaths as o 2020.1 carcinogenesis.5–7 Impaired apoptosis (programmed
However, the disease is more common in many devel- cell death) may increase the risk o malignancy.8,9 In
oping countries, with a worldwide annual incidence o HPV-related HNSCC, only a small proportion o HPV-
more than 800,000 cases.2 In more than 90% o these inected individuals have cancer, likely because o
tumors, the histology is squamous cell carcinoma (SCC). genetic susceptibility.8,10–12 Rare germline mutations
Squamous cell carcinoma o the head and neck (HNSCC) have been associated with amilial atypical multiple-
primarily aects men, and the median age at diagnosis is mole melanoma and Fanconi anemia and coner a risk
60 years old. Established risk actors include tobacco and or the development o HNSCC.13–15
alcohol use. Although public health eorts have led to a
decrease in tobacco use and thus a reduction in smok-
ing-related malignancies, the incidence o oropharyngeal rIsK AssEssMENT
cancer (OPC) has been steadily rising as a result o the
impact o human papillomavirus (HPV) inection.3,4 The risk o developing HNSCC increases with age;
most patients are older than age 50 years. Moreover,
there is a clear association with HNSCC development
GENETIC PrEDIsPOsITION and the use o tobacco and alcohol. Smokeless tobacco
and betel quid (combination o betel lea, lime, and
The majority o head and neck cancers are multiac- areca nut), commonly used in India and areas o Asia,
torial diseases inuenced by the interaction between are associated with the development o oral cavity
555
556 Scion V Head and Neck Cancer
cancers. Molecular studies provide evidence that car- The molecular pathogenesis o HPV-positive
cinogens ound in these substances have a causal role. tumors diers rom that o HPV-negative tumors.
Mutations in the tumor suppressor gene p53 are prom- The HPV virus contains a double-stranded genome
inent in cancers o patients with a history o tobacco that encodes proteins E1–E7, associated with viral
Chapter 26
and alcohol use.16 Cancers o the oral cavity, larynx, gene regulation and cell transormation, and L1–L2,
and hypopharynx are uncommon in individuals with associated with the ormation o structural capsid
no smoking history. Patients with HNSCC with heavy proteins or the virus. The E6 and E7 proteins pro-
tobacco and alcohol exposures are at high risk o mul- mote carcinogenesis through their respective interac-
tiple cancers developing, with “feld cancerization” tions with tumor suppressor p53 and pRb.29 The E6
throughout the upper aerodigestive tract and bladder.17 oncoprotein leads to ubiquitination and degradation
In the United States, greater than 70% o cancers o p53, causing loss o cell-cycle arrest and apoptosis.
arising in the oropharynx, particularly in the palatine In addition, E6 can activate cellular telomerase, allow-
tonsils and tongue base, are HPV- related.18–20 The ing the inected cell to maintain telomere length,
incidence o OPC in the United States is increasing, which plays an essential role in cellular immortaliza-
primarily because o HPV-associated cases in men.21 tion and transormation. The E7 oncoprotein inacti-
HPV-positive OPC represents a distinct clinical and vates Rb proteins, resulting in overactivation o E2F
pathologic subgroup o HNSCC, with poorly dier- transcription actor with upregulation o cell-cycle
entiated basaloid histopathology and marked tumor genes, which leads to increased DNA synthesis and
responsiveness to radiation and chemotherapy.22 HPV cell prolieration. Inactivation o Rb proteins pro-
16 is the most common viral genotype, with other duces increased levels o p16, an inhibitor o cyclin
high-risk HPV genotypes such as HPV 18, 31, or 33 dependent kinase–4/cyclin D, via a eedback con-
being less common.20 trol mechanism, which is the reason p16 expression
Oncogenic oral HPV prevalence is higher in men serves as a surrogate biomarker or HPV inection.30
compared with women and increases with the number Smoking-related HNSCCs have a mutation rate
o lietime oral sexual partners and tobacco use.23 In approximately twice that o HPV-positive HNSCCs.
a study investigating patients with HPV-positive OPC Mutations include TP53, CDKN2A, PTEN, PIK3CA,
and their long-term sexual partners, the prevalence and HRAS. Additional mutations in genes that regu-
o oral HPV inection in the partners was comparable late squamous dierentiation, such as NOTCH1, IRF6,
with that o the general population, suggesting that the and TP63 have been described as well as mutations in
majority o long-term partners had cleared any expo- genes regulating apoptosis.31
sure to active oral HPV inection. However, several
patients had a previous or current sexual partner with
cervical dysplasia or cervical cancer.24 A retrospective DIAGNOsIs AND sTAGING
study rom the Swedish Family Cancer Database rom
1958 to 1996 ound that husbands o women with cer- Optimal treatment outcomes depend on the precise
vical cancer have a twoold increased risk o tonsillar identifcation o the primary tumor (Fig. 26–1) as well
cancer, supporting HPV transmission via oral sex rom as the local, regional, and distant extent o disease.
a partner with an oncogenic genital HPV inection.25 Patients with early-stage disease may present
with vague symptoms and minimal physical fnd-
ings. Patients with locally advanced disease may
MOLECULAr PATHOGENEsIs present with signs and symptoms according to
the subsite in the head and neck. Sinusitis, unilat-
The progression o HNSCC is thought to involve mul- eral nasal airway obstruction, and epistaxis may be
tiple stepwise alterations o molecular pathways in the early signs o cancers o the nasal cavity or parana-
squamous epithelium.26 Aberrations in the p53 and sal sinuses. Recurrent otitis media may be associated
Rb tumor suppressor pathways are the most common with nasopharyngeal cancer (NPC). Chronic otalgia,
molecular events. The epidermal growth actor recep- dysphagia, odynophagia, and throat soreness lasting
tor (EGFR) is also overexpressed in invasive HNSCC weeks may be symptoms o OPC or hypopharyn-
in a majority o sample tumors.27 Binding to EGFR geal cancers. Many patients with HPV-associated
by its natural ligands, mainly epidermal growth ac- OPC present with an otherwise asymptomatic neck
tor or transorming growth actor–α (TGF-α), prompts mass and may have limited or no smoking history.
dimerization o the receptor, resulting in autoactiva- Persistent hoarseness demands visualization o the
tion o tyrosine kinase rom the intracellular domain o larynx. In supraglottic laryngeal neoplasms a neck
the receptor, intracellular signaling, inhibition o apop- mass may be the presenting sign. Careul examina-
tosis, activation o cell prolieration and angiogenesis, tion o acial, cervical, and supraclavicular lymph
and increased metastatic potential.28 nodes is important because the anatomic patterns o
C 26 Head and Neck Cancer 557
Frontal
Frontal sinus sinus
Nasal cavity Orbit
Chapter 26
Ethmoid
Oral cavity sinus
Including anterior
2/3 of tongue Maxillary
sinus
Sphenoid
sinus
Parotid
Nasopharynx
Pharynx
Oropharynx
including base
of tongue
Hypopharynx
Vocal
Larynx cords
Cricoid Arytenoid Thyroid
cartilage cartilage cartilage Esophagus
FIGUrE 26–1 Head and neck anatomy.
lymphatic drainage may reect the specifc subsite o diagnosis o cancer. Detection o HPV or Epstein-Barr
the primary tumor (Fig. 26–2). 32 virus (EBV) DNA in a lymph node suggests a tumor o
Physical examination should include careul inspec- oropharyngeal or nasopharyngeal origin, respectively.
tion o the skin and oral/oropharyngeal mucosal sur- Direct laryngoscopic examination under anesthesia
aces; palpation o the tongue, oor o the mouth, and may detect a primary tumor. Suspicious lesions are
oropharynx; systematic palpation o the neck; and an biopsied, and consideration may be given to tonsillec-
indirect mirror examination o the oropharynx, hypo- tomy and/or biopsies o the nasopharynx, base o the
pharynx, and larynx, complemented by fberoptic tongue, and hypopharynx, depending on the pattern o
endoscopy.33,34 Leukoplakia (white mucosal patches lymphadenopathy. Open biopsy o the neck mass may
that cannot be removed by scraping) and higher-risk be perormed i FNA and panendoscopy have ailed to
erythroplakia (red or mixed red-white patches) are the yield a diagnosis, or in patients suspected o having
most common premalignant lesions in the head and an alternative process (ie, lymphoma). An experienced
neck. Any suspicious surace in the oral mucosa should head and neck surgeon may be prepared to proceed
undergo biopsy. with selective neck dissection i SCC o unknown
Patients who present with a suspicious neck mass head and neck primary origin is determined.
should undergo a systematic examination o the head Three-dimensional imaging with computed
and neck. I no obvious primary site is ound, fne- tomography (CT) rom the vertex to clavicles is
needle aspiration (FNA) o the mass may establish a the preerred local imaging modality or HNSCC.
A Preauricular nodes: B
skin of upper face
and scalp, parotid
Chapter 26
IB IIA IIB
Submental nodes: Subdigastric nodes:
anterior floor of lateral tongue,
mouth, lip posterior tongue,
Submaxillary nodes:
IA
and tonsils
skin of lateral face, Posterior
anterior tongue, cervical nodes:
floor of mouth nasopharynx III
Midjugular nodes: VA
larynx, pharynx,
hypopharynx
Low posterior
cervical nodes:
Low jugular nasopharynx IV VB
nodes: VI
thyroid, cervical
esophagus
Anterior scalene nodes:
intra-thoracic,
intra-abdominal
VII
FIGUrE 26–2 A. Nodal drainage. B. Nodal levels in the head and neck. (Reproduced with permission rom Hong WK, Bast RB
Jr, Hait WN, et al: Cancer Medicine. 8th ed. Shelton, CT: BC Decker—People’s Medical Publishing House-USA; 2010: 959-998.)
Magnetic resonance imaging (MRI) is warranted NATUrAL HIsTOrY AND

in specifc disease sites such as NPC and skull-base IMPLICATIONs FOr THErAPY
tumors. Because the lungs are the most common site
o distant metastases, a chest radiograph or CT or For patients with T1/2 disease (stage I/II), surgery or
symptomatic or high-risk patients (ie, patients with radiotherapy as a single modality is most oten appli-
multiple nodal sites, low neck [level 4] nodes, or cable and eective. Depending on the primary site and
supraclavicular metastases) should also be perormed. stage, a curative outcome will be achieved in 70% to
An 18-uorodeoxyglucose positron emission tomog- 95% o cases. Two-thirds o patients with HNSCC will
raphy (FDG-PET) scan is indicated when the primary present with stage III or IV disease.37 In these cases,
site is unknown or in the setting o indeterminate combined treatment strategies are the standard o care,
fndings on cross-sectional imaging. FDG-PET does designed to balance competing goals o tumor eradica-
not replace dedicated imaging with CT and/or MRI tion and organ preservation.26,38,39 Despite optimal local
o the primary site and neck. therapy, 25% to 50% o patients may develop local or
All patients should undergo a thorough multidis- regional recurrence, and nearly 20% to 30% are at risk
ciplinary evaluation that includes specialists rom or development o distant metastases depending on
surgery, medical oncology, and radiation oncology. the primary site and staging.40–42
Dental, nutrition, and speech/swallow evaluations as
well as smoking cessation are recommended. Modifed
barium swallow tests and baseline audiology examina-
Nasopharynx
tions should be considered depending on the disease More than 95% o endemic NPCs are associated with
site and expected treatment paradigm. EBV. NPC tends to occur in younger persons and is
The American Joint Committee on Cancer (AJCC) not associated with tobacco use. NPC is aggressive,
TNM staging system classifes tumors according to ana- with cervical lymph node metastases present in 60%
tomic site and extent o disease.35 Head and neck primary to 90% o patients at diagnosis. Radiotherapy alone
tumor (T) staging is complex and varies with the primary to the nasopharynx and bilateral neck is standard o
subsite. Classifcations or lymph nodes (N) are uniorm care or clinical T1N0M0 NPC and is associated with
or all sites, with the exception o HPV-positive OPC and high locoregional tumor control rates o more than
NPC.36 The eighth edition o the AJCC has divided OPC 90%.43
staging based on HPV positivity because o signifcant For locally advanced disease, including stage II
dierences in prognosis (Table 26–1A, B, C). (T2N0), chemoradiation is preerred.44 For years, the
tbl 26–1a Clinicl tNM Sging fo Ooynx (16–)
Pimay Tumo (T)

TX Primary tumor cannot be assessed
Chapter 26
Tis Carcinoma in situ
T1 Tumor ≤2 cm in greatest dimension
T2 Tumor >2 cm but not >4 cm in greatest dimension
T3 Tumor >4 cm in greatest dimension or extension to lingual surace o epiglottis
T4 Moderately advanced or very advanced local disease
T4a Moderately advanced local disease
Tumor invades the larynx, extrinsic muscle o tongue, medial pterygoid, hard palate, or
mandiblea
T4b Very advanced local disease
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or
encases carotid artery
regional Lymph Node (N)
NX Regional lymph nodes cannot be assessed
N0 No regional node metastases
N1 Metastasis to a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE(–)
N2 Metastasis to a single ipsilateral lymph node >3 cm but not >6 cm in greatest dimension and
ENE(–); or metastases in multiple ipsilateral lymph nodes none >6 cm in greatest dimension
and ENE(–); or in bilateral or contralateral lymph nodes none >6 cm in greatest dimension
and ENE(–)
N2a Metastasis in a single ipsilateral lymph node >3 cm but not >6 cm in greatest dimension and
ENE(–)
N2b Metastasis in multiple ipsilateral lymph nodes but not >6 cm in greatest dimension and ENE(–)
N2c Metastases in bilateral or contralateral lymph nodes none >6 cm in greatest dimension and
ENE(–)
N3 Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in any
node(s) and clinically overt ENE(+)
N3a Metastasis in a lymph node >6 cm in greatest dimension and ENE(–)
N3b Metastasis in any node(s) and clinically overt ENE(+)
Ditant Metatai (M)
MX Presence o distant metastasis cannot be assessed
M0 No evidence o distant metastasis
a
Mucosal extension to the lingual surace o the epiglottis rom primary tumors o the base o the tongue and vallecula does not constitute invasion o the larynx.
ENE, extranodal extension.
Used with permission o the American College o Surgeons, Chicago, Illinois. The original source or this inormation is the AJCC Cancer Staging System (2020).
standard o care was concurrent chemoradiotherapy The GORTEC 2006-02 trial compared induction
ollowed by adjuvant chemotherapy based on the docetaxel-cisplatin-5-uorouracil (TPF) ollowed by
Head and Neck Intergroup 0099 trial.45 As o this concomitant cisplatin-radiation (RT) versus concomi-
writing, induction chemotherapy ollowed by con- tant therapy alone and showed 3-year progression-
current chemoradiotherapy is standard or node-pos- ree survival (PFS) and overall survival (OS) o 73.9%
itive patients.46–49 For patients with T1 node-positive and 86.3% versus 57.2% and 68.9%, respectively,
tumors, sequential induction ollowed by radiation statistically avoring induction (P = .042 or PFS and
can be considered to avoid the toxicity o concurrent P = .05 or OS).47 In 2019, a phase 3 trial evaluating
chemoradiation. For node-negative patients (T2-4N0) induction chemotherapy with gemcitabine and cispla-
chemoradiation alone is standard.50,51 Because o the tin ollowed by concurrent chemoradiotherapy versus
rarity o NPC, patients should be treated at tertiary concurrent chemoradiotherapy alone demonstrated
reerral centers when easible. improved 3-year recurrence-ree survival (85.3% vs
tbl 26–1B Clinicl tNM Sging fo Ooynx (16+)
Pimay Tumo (T)

T0 No primary identied
Chapter 26
T1 Tumor ≤2 cm in greatest dimension

T2 Tumor >2 cm but not >4 cm in greatest dimension
T3 Tumor >4 cm in greatest dimension or extension to lingual surace o epiglottis
T4 Moderately advanced local disease
Tumor invades the larynx, extrinsic muscle o tongue, medial pterygoid, hard palate, or
mandible or beyonda
regional Lymph Node (N)
N0 No regional node metastases
N1 One or more ipsilateral lymph nodes, <6 cm
N2 Contralateral or bilateral lymph nodes, <6 cm
N3 Lymph node(s) >6 cm
Ditant Metatai (M)
MX Presence o distant metastasis cannot be assessed
M0 No evidence o distant metastasis
a
Mucosal extension to the lingual surace o the epiglottis rom primary tumors o the base o the tongue and vallecula does not constitute invasion o the larynx.
Used with permission o the American College o Surgeons, Chicago, Illinois. The original source or this inormation is the AJCC Cancer Staging System (2020).
76.5%; hazard ratio [HR] 0.51, 95% CI 0.34–0.77) and treating NPC given its proximity to critical organs
OS (94.6% vs 90.3%; HR 0.43, 95% CI 0.24–0.77) in such as the temporal lobes, brainstem, and optic
the induction group.48 structures. 55 Two-year locoregional control (LRC) and
Intensity-modulated radiation therapy (IMRT) OS rates o 100% and 89%, respectively, have been
improves tumor coverage, quality o lie, and reduces demonstrated or proton therapy in NPC.56 Moreover,
xerostomia compared with 3-D conormal tech- reductions in eeding tube placement with intensity-
niques.52–54 Because o protons’ unique physical char- modulated proton therapy (IMPT) versus IMRT is
acteristics (Bragg peak, ie, region o maximal dose thought to correspond with signifcant reductions in
deposition within tissue ollowed by a sharp dose mean oral cavity doses.57
allo and no exit dose) may be advantageous in
tbl 26–1C Clinicl Sg Gouing fo all Ooynx
P16 statu P16– P16+

Stage I T1 N0 M0 T0–T2 N0, N1 M0
Stage II T2 N0 M0 T0–T2 N2 M0
T3 N0–N2 M0
Stage III T3 N0 M0 T0–T3 N3 M0
T1–T3 N1 M0 T4 N0–N3 M0
Stage IV Any T Any N M1
Stage IVA T1–T3 N2 M0
T4a N0-N2 M0
Stage IVB Any T N3 M0
T4b Any N M0
Stage IVC Any T Any N M1
Oral Cavity are HPV-positive and are associated with a better

prognosis than HPV-negative disease.42,61–64 This led to
The majority o oral cavity neoplasms occur in the the recent development o separate staging systems
anterior two-thirds o the tongue (oral tongue) and or OPC based on HPV status (Table 26–1A, B, C);
the oor o the mouth (Fig. 26–3). Additional subsites
Chapter 26
thus, all patients should undergo tumor HPV DNA
include the buccal mucosa, lips, hard palate, gingiva, testing by in situ hybridization and p16 testing by
and retromolar trigone. Forty percent o patients pres- immunohistochemistry to determine the appropriate
ent with clinically evident lymph nodes, and bilateral prognosis and staging.61 Ideally, both tests should be
nodal involvement is not uncommon. perormed, but i only one is easible then p16 is pre-
Surgical resection is a common and eective local erred because it reects HPV-driven carcinogenesis,
treatment approach.26,39 Local tumor control rates ater whereas some tumors may have the HPV virus as a
surgery or patients with stage I and II tumors can passenger. Despite dierences in prognoses, manage-
approach 80% to 90% and 50% to 80%, respectively.58 ment or HPV-positive and HPV-negative malignan-
For deeply invasive T1/2 disease, we avor surgical resec- cies is similar.65
tion o the primary tumor with simultaneous selective Radiation therapy is used as a single modality or
neck dissection. T1 and many T2 tumors, with local control rates o
Ater surgery, postoperative radiotherapy should greater than 90%.66 In most cases, bilateral neck
be recommended or patients with high-risk actors regional lymph nodes are targeted with radiation ther-
including pT3 or pT4 disease, pN2 or pN3 disease, apy; however, unilateral neck radiation can be con-
low neck (level IV–V) disease, perineural invasion, and sidered or select well-lateralized tonsillar primaries.
lymphovascular invasion, whereas concurrent chemo- At MDACC, patients considered ideal candidates or
radiation should be pursued in the presence o positive unilateral neck radiotherapy include those with T1–2,
margins or extranodal extension.59,60 Reer to “Com- N0–N1 tonsillar primary tumors restricted to the ton-
bined-Modality Therapy” or urther details. sillar ossa or anterior pillar, with less than 1 cm o sot
palate involvement, and no base o tongue involve-
ment. Five-year OS and disease-ree survival rates o
Oropharynx
95% and 96% have been reported, with a contralateral
The most common cancers o the oropharynx are o nodal recurrence rate o 2%.67 Unilateral neck radio-
the base o tongue and tonsils, and greater than 80% therapy or such tonsillar cases is avored because it
FIGUrE 26–3 Right alveolar ridge cancer with bony destruction and masticator space invasion and bilateral cervical adenopa-
thy, cT4bN2bM0.
also greatly reduces the radiation doses to the contra- preservation to maintain unctional status and quality
lateral parotid gland and key swallowing structures. o lie has been the ocus o laryngeal cancer treatment
Surgery with minimally invasive transoral robotic since the 1970s. The most widely used treatment o
surgery (TORS) approaches is an option or some T1 and T2 tumors is radiotherapy, with control rates
Chapter 26
patients with OPC. The phase 2 ORATOR study com- greater than 90% or T1 disease and 70% to 80% or
pared TORS with defnitive radiotherapy. In this study, T2 tumors.69 For patients with potentially resectable,
71% o patients in the TORS group received postop- locally advanced disease, organ-preserving approaches
erative radiotherapy, and 68% o the radiotherapy arm using chemotherapy and radiation have proven eec-
received concurrent chemotherapy or node-positive tive and have replaced upront surgery or many
disease. Survival outcomes were excellent in both patients.
groups with data regarding quality-o-lie measures The Veterans Aairs laryngeal study established
seeming to avor defnitive radiotherapy.68 induction chemotherapy ollowed by radiation and
For locally advanced disease, concomitant chemo- surgical salvage, i needed, as an organ-preserving
radiotherapy is the current standard o care. Because alternative to primary surgery ollowed by postop-
HPV-associated OPC has an improved prognosis, erative radiation.70 The RTOG 91-11 trial established
several treatment de-intensifcation eorts have been concurrent chemoradiation as an acceptable standard
studied including systemic therapy de-intensifcation, o care.40 These treatment strategies are discussed in
radiation dose reduction, and potential toxicity reduc- urther detail in the “Organ Preservation” section.
tion using proton therapy. Proton therapy may be a
promising de-intensifcation option compared with
IMRT (Fig. 26–4). MDACC is leading a national multi-
Hypopharynx
institutional phase 2/3 study comparing IMPT versus With 65% to 85% o lesions occurring in the pyriorm
IMRT or stage III/IV OPC (NCT01893307). sinus, carcinoma o the hypopharynx is relatively
uncommon but virulent (Fig. 26–5). Treatment is similar
to that or the larynx. Small-volume disease may be
Larynx treated with surgery or radiation, but later-stage dis-
Given the critical role o the larynx in communication, ease requires multimodal therapy. At presentation,
swallowing, respiration, and airway protection, organ more than 75% o patients have advanced disease
FIGUrE 26–4 Comparative radiation therapy plans or an oropharyngeal case. A. IMPT plan. B. VMAT. C. Dose diference plans.
IMPT, intensity-modulated proton therapy; VMAT, volumetric-modulated arc therapy.
an unanswered question given the lack o defni-

tive randomized trials comparing this approach with
upront chemoradiation.
Three phase 3 studies compared induction chemo-
Chapter 26
therapy ollowed by chemoradiation versus chemora-
diation alone.75–77 The Spanish Head and Neck Cancer
Group cooperative trial randomly assigned patients
with locally advanced SCC o the oral cavity, orophar-
ynx, hypopharynx, and larynx to (1) induction TPF ol-
lowed by concurrent chemoradiation, (2) induction PF
ollowed by concurrent chemoradiation, or (3) concur-
FIGUrE 26–5 Axial computed tomography o advanced
rent chemoradiation alone. There were no statistically
squamous carcinoma o the pyriorm sinus, cT3N3M0.
signifcant dierences between PFS, time-to-treatment
ailure, and OS in the three groups; however, approxi-
mately hal o the patients did not complete concur-
(T3 or T4). The 5-year OS rate is lower than 30%. rent chemoradiation.77
For many patients, surgical treatment also requires The PARADIGM trial randomly assigned patients
removal o the larynx. The European Organization with locally advanced SCC o the oral cavity, oro-
or Research and Treatment o Cancer (EORTC), in a pharynx, hypopharynx, or larynx between induction
phase 3 trial, demonstrated that laryngeal preservation TPF ollowed by chemoradiation that was adapted
with sequential chemoradiotherapy is a easible alter- based on induction chemotherapy response versus
native to radical surgery.71 Reer to the “Organ Preser- chemoradiation alone using an accelerated raction-
vation” section or urther discussion. ation. Because o slow accrual, the trial closed with
145 patients enrolled, less than hal o the planned
enrollment. Overall 3-year survival was 73% (95% CI
COMBINED-MODALITY THErAPY 60%–82%) in the induction TPF ollowed by chemora-
diation group versus 78% in the chemoradiation alone
group.75
Induction Chemotherapy
The DeCIDE trial randomized patients with N2/3
Induction (neoadjuvant) chemotherapy is given beore M0 disease (based on the AJCC 7th edition staging)
surgery or radiation. It has been investigated as an between induction TPF ollowed by chemoradiation
approach to improve outcomes in terms o OS and or chemoradiation alone.76 This trial also ailed to
tumor control in patients with stage III/IV disease accrue well, enrolling 280 patients versus the planned
undergoing defnitive local therapy. Theoretical advan- 400 patients. There were no statistically signifcant di-
tages to this approach include reducing the risk o erences in OS (HR 0.91; 95% CI 0.59–1.41) or relapse-
distant disease recurrence, enhancing organ preserva- ree survival. In competing risk analysis, there was
tion, improving response to defnitive radiotherapy by a statistically signifcant reduction in risk o distant
reducing tumor bulk, and modifcation o subsequent relapse without locoregional recurrence in the induc-
local therapy to response. In a 2009 meta-analysis, tion arm (P = .043).
although concomitant chemoradiation was superior Thus, induction chemotherapy remains investiga-
to induction chemotherapy ollowed by radiation or tional, but it is appropriate (1) as a “bridge” to control
local control and survival, induction chemotherapy disease beore logistical delays in surgery or radiation,
was more eective at decreasing distant ailure.72 This (2) to acilitate locoregional therapy o very advanced
conclusion lent credence to contemporaneous trials disease, and (3) in patients deemed high risk or dis-
investigating induction chemotherapy ollowed by tant recurrence, such as those with N3 and/or low
chemoradiation. neck disease. In laryngeal and hypopharyngeal cancer,
In 2007, two multicenter phase 3 trials, the Euro- the induction chemotherapy approach is an eective
pean TAX 323 and the North American TAX 324, organ preservation strategy and is urther discussed in
demonstrated the superiority o induction TPF over the “Organ Preservation” section.
PF (cisplatin, 5-uorouracil) (Table 26–2).73,74 However, Induction chemotherapy is also being studied as a
these trials did not directly compare induction chemo- method to select chemosensitive patients to reduce
therapy with defnitive chemoradiotherapy. Neverthe- the intensity o subsequent treatment. In a phase 2
less, these trials led to FDA approval o induction TPF ECOG-ACRIN Cancer Research Group trial, response
or patients with locally advanced HNSCC in 2007. to induction chemotherapy was used to select patients
Despite the results o TAX 324, the value o adding with stage III/IV HPV-associated OPC or reduced radi-
induction chemotherapy to chemoradiation remained ation dose. Patients who did not achieve a complete
Chapter 26
564
Scion V
Head and Neck Cancer
tbl 26–2 Inducion Cmoy tils
Tial Phae Patient Incluion Citeia Teatment PogeionFee suvival Oveall suvival
European TAX 323 III 358 Stage III/IV, nonmetastatic, untreated TPF ollowed by RT vs Median PFS: 11 vs 8.2 mo (P Median OS: 18.8 vs 14.5 mo
SCCHN PF ollowed by RT = .007) (P = .02)
3-y PFS: 17% vs 14% 3-y OS: 37% vs 26%
North American III 501 Stage III/IV, nonmetastatic, TPF ollowed by CRT Median PFS: 38.1 vs 13.2 mo Median OS: 70.6 vs 34.8 mo
TAX 324 unresectable or low surgical (carboplatin) vs PF (P = .0114) (P = .014)
curability, untreated, SCC o oral ollowed by CRT 5-y OS: 52 vs 42%
cavity, larynx, oropharynx, or (carboplatin)
hypopharynx
Spanish Head and III 439 Stage III/IV, nonmetastatic, TPF ollowed by CRT Median PFS: 20.4 vs 18.1 vs Median OS: 35.6 vs 37.1 vs
Neck Cancer unresectable, untreated SCC o oral (cisplatin) vs PF 13.3 mo (P = .083) 29.4 mo
Cooperative cavity, oropharynx, hypopharynx, ollowed by CRT
Group or larynx (cisplatin) vs CRT
alone (cisplatin)
PARADIGM III 145 Stage III/IV, nonmetastatic, TPF ollowed by 3-y PFS: 67 vs 69% (P = .82) 3-y OS: 73% vs 78% (P = .77)
unresectable or low surgical CRT (docetaxel or
curability, untreated SCC o oral carboplatin) vs CRT
cavity, oropharynx, hypopharynx, alone (cisplatin)
or larynx
DeCIDE III 280 Nonmetastatic, untreated SCCHN, N2 TPF ollowed by Not assessed OS at 3.5 y: 28% vs 31% (P =
or N3 CRT (docetaxel, .69)
fuorouracil,
hydroxyurea) vs
CRT (docetaxel,
fuorouracil,
hydroxyurea)
GSTCC Italian Study II-III 414 Stage III/IV, nonmetastatic, untreated TPF ollowed by CRT Median PFS: 30.5 vs 18.5 mo Median OS: 54.7 vs 37.1 mo
Group SCC o oral cavity, oropharynx, (cetuximab or PF) (P = .013) (P = .031)
hypopharynx vs CRT (cetuximab 3-y PFS: 47% vs 38.5% 3-y OS: 57.5% vs 46.5%
or PF) alone
CRT, concurrent chemoradiation; OS, overall survival; PF, cisplatin/fuorouracil; PFS, progression-ree survival; RT, radiation; SCC, squamous cell carcinoma; SCCHN, squamous cell carcinoma o the head and neck; TPF, docetaxel,
cisplatin, fuorouracil.
response ater induction therapy were given a higher randomly assigned to cetuximab plus radiotherapy
dose o radiation (69.3 Gy in 33 ractions) compared versus cisplatin plus radiotherapy. The trial demon-
with those who achieved a complete response (54 Gy strated decreased OS or cetuximab with radiotherapy
in 27 ractions). Seventy percent o the total patients with a 2-year rate o 89% versus 98% and increased
Chapter 26
achieved a complete clinical response. In patients who disease recurrence with a 2-year rate o 16% versus
received lower-dose radiation with 54 Gy, the 2-year 6%.86 Given the results o these trials, platinum-based
PFS was 80% and OS was 94%, with approximately chemoradiation remains standard o care or HPV-
3-year median ollow-up. There were ewer radiation positive OPC, with cetuximab-radiotherapy being rec-
complications in the lower-dose radiation group such ommended or patients who are ineligible or cisplatin
as dysphagia (40% vs 89%; P = .011) and nutritional or patient preerence because o concern or cisplatin-
impairment (10% vs 44%; P = .025).78 related side eects.
The MARCH meta-analysis reported an absolute OS
beneft using hyperractionation over standard raction-
Concomitant Radiotherapy and ation, but survival signifcantly worsened when add-
Chemotherapy ing concomitant chemotherapy.87 Equivalent outcomes
Meta-analysis o prospective clinical trials demon- were observed with accelerated radiotherapy and two
strates enhanced local tumor control and improved doses o bolus cisplatin compared with standard rac-
survival with combined therapy over radiation alone, tionation and three doses o bolus cisplatin in the RTOG
establishing chemoradiation as the standard o care 0129 trial or patients with stage III/IV HNSCC.88 Both
in locally advanced nonsurgical disease. The eect approaches were easible and there was less cisplatin-
o chemotherapy was higher with single-agent plati- associated toxicity in the accelerated arm.
num than any other types o monotherapies (HR 0.74,
95% CI 0.67–0.82; P = .006).72 Single-agent cisplatin is Adjuvant Chemoradiotherapy
preerred in this setting.79–82 For patients with contra-
indications to cisplatin, cetuximab, an EGFR-targeted Adjuvant chemoradiotherapy is indicated in patients at
monoclonal antibody, is an acceptable alternative. high risk o recurrence ater surgical resection, gener-
Based on retrospective data, carboplatin was less eec- ally defned as having positive margins or extracapsu-
tive than cisplatin in one randomized trial,83 although lar spread.59,60,89 Two large phase 3 studies, RTOG 9501
the use o carboplatin in responders, subsequent to and EORTC 22931, tested cisplatin-based concomitant
induction chemotherapy, is acceptable based on the chemoradiotherapy in the adjuvant setting.59,60
TAX 324 and PARADIGM trials, especially or cispl- In RTOG 9501 ater a median ollow-up o 9.4
atin-ineligible patients.63,75 Taxanes, potent radiosensi- years, concomitant chemoradiotherapy signifcantly
tizers, are easible and eective in weekly low-dose improved LRC and disease-ree survival with a trend
schedules ater induction chemotherapy.63,75,84 toward improved OS in patients with extracapsular
Cetuximab is approved or use in combination with extension and/or positive margins.90 The incidence o
radiation in previously untreated patients. In a land- acute grade 3 or greater adverse eects was 34% in the
mark study, patients with locoregionally advanced radiotherapy group and 77% in the combined-therapy
HNSCC were randomly assigned to receive high-dose group (P < .001), with no dierences in late toxicity.
radiotherapy alone or high-dose radiotherapy plus In the EORTC 22931 trial, both the PFS and OS rates
weekly cetuximab.85 Locoregional control and OS were signifcantly higher in the combined-therapy
avored the combination. However, the rates o dis- group than in the radiotherapy group. Severe acute
tant metastases at 1 and 2 years were similar in both adverse eects were more requent ater combined
groups. Retrospective analysis demonstrated that the therapy than in the radiotherapy group. A combined
main beneft was in patients with OPC. analysis o both adjuvant therapy trials showed sig-
Cetuximab plus radiotherapy was directly com- nifcant risk reduction o 48% in locoregional relapse,
pared with cisplatin plus radiotherapy in 849 patients 30% in disease-ree survival, and 28% in OS when
with locally advanced HPV-associated OPC in a multi- using chemoradiation or patients with extracapsular
center, nonineriority phase 2 randomized trial (RTOG extension and/or positive margins.91
1016). In the cetuximab arm, there was inerior PFS (67 RTOG 0234 explored the incorporation o cetux-
vs 78%, HR 1.72, 95% CI 1.29–2.29), decreased OS imab into adjuvant chemoradiation.92,93 This phase 2
(78 vs 85%, HR 1.45), and greater locoregional ailure trial demonstrated that two biochemoradiotherapy
(17 vs 10%, HR 2.05, 95% CI 1.35–3.10) at 5 years.42 In regimens, docetaxel/radiation/cetuximab and cispla-
the international trial De-ESCALaTE HPV, 334 patients tin/radiation/cetuximab, outperormed the historical
with locally advanced, low-risk (nonsmoker or <10 control o high-dose cisplatin-based chemoradiother-
pack-year smoking history) HPV-positive OPC were apy rom RTOG 9501. Although these results are
promising, comparison with historical controls is prob- larynx and hypopharynx cancers. The 5-year larynx
lematic, and adding cetuximab to adjuvant chemora- preservation rate was 60% in the docetaxel arm (vs
diation is not currently standard. 39%), at least in part because o the higher response
rate with that combination. Survival was the same in
Chapter 26
both arms. Thus, the TPF regimen, i easible, is pre-

OrGAN PrEsErVATION erred in this setting.96
These trials indicate that, or patients with interme-
Many HNSCCs are diagnosed at a late stage. Stages diate-stage SCC o the larynx, a combined treatment
III and IV tumors oten necessitate extensive or radi- program with the objectives o tumor eradication and
cal surgery, which may alter organ unction. Prob- laryngeal preservation is appropriate. It is also impor-
lems with radical surgery include loss o speech, loss tant to recognize that patients with locally advanced,
o swallowing unction, or disfgurement without a destructive primary laryngeal cancers (ie, T4 tumors)
concomitant improvement in survival time. Thereore, were not included in the RTOG 91-11. These patients
preservation o unction is a major challenge. require total laryngectomy or optimal tumor control.
The Veterans Aairs laryngeal study randomly It should be noted that nonsurgical treatment also
assigned patients with stage III/IV SCC o the larynx carries a risk o morbidity and unctional impact.
to induction platinum-5FU (PF) ollowed by defnitive Radiation produces tissue changes that can result in
radiotherapy or surgery with postoperative radiother- immediate and long-term alterations in speech and
apy.70 In the chemotherapy group, patients who had swallowing. The adverse impact o radiation may equal
no tumor response ater two cycles underwent salvage or exceed that associated with surgery, depending on
laryngectomy, whereas those with a complete clinical the treatment dose and volume, and the sequelae o
or partial response received a third cycle o chemother- treatment may maniest or increase in severity years
apy ollowed by radiotherapy. Two-year OS was 68% ater the completion o treatment. Fibrosis may reduce
or both arms, and larynx preservation was achieved the range o motion o the tongue and jaw and dimin-
or 64% o patients treated with chemotherapy. How- ish pharyngeal wall motion.
ever, salvage laryngectomy was required or 56% o Historically, 20% to 40% o patients receiving
patients with T4 tumors. Patterns o ailure diered chemoradiotherapy or SCC o the oropharynx and
with decreased local ailures avoring surgery (2% vs hypopharynx may require long-term gastrostomy
12%; P < .01) but decreased distant metastasis avoring tube eedings. However, the long-term gastrostomy
sequential therapy (11% vs 17%; P < .001). Leebvre rate or patients with OPC treated with modern radia-
et al later reported that sequential chemotherapy and tion therapy is less than 10%.97 Radiation to the larynx
radiation could also be eective in selected patients oten results in swallowing problems related to pha-
with cancers o the hypopharynx.71 ryngeal transport. To counteract the deleterious eects
The RTOG 99-11 study randomly assigned patients o radiation and chemoradiotherapy, there are rehabili-
with larynx cancer to induction chemotherapy PF ol- tative options that are best administered by a qualifed
lowed by radiotherapy versus concomitant cisplatin- speech pathologist.
radiotherapy versus radiotherapy alone.94 Surgical
salvage was reserved or patients with persistent or
locally recurrent disease. Both chemotherapy groups rECUrrENT Or METAsTATIC
demonstrated improved laryngectomy-ree survival, the DIsEAsE
primary end point o the trial, compared with radiother-
apy alone. Crude larynx preservation rates, at 10 years, Prognosis or recurrent or metastatic HNSCC is gener-
regardless o survival, were higher with concurrent ally poor, with median survival ranging rom 6 to 15
treatment: 82% compared with 68% and 64% in the months. Locoregional recurrence remains the most
sequential chemotherapy/radiation and radiation alone common pattern o ailure, occurring in approximately
arms. Locoregional control was signifcantly improved 20% to 30% o patients.98 As a result, local therapy is
with concomitant chemoradiotherapy (HR 0.58; 95% oten clinically indicated and most commonly involves
CI 0.37–0.89; P = .005), whereas the induction chemoradiation therapy with or without surgical resection
therapy group showed a nonsignifcant trend toward whenever easible. Considering that a majority o
improved OS (HR 1.25; 95% CI, 0.98–1.61; P = .08).95 these patients have received prior radiation therapy or
There were late increased noncancer-related deaths their initial disease, there are concerns regarding the
observed with chemoradiation (Table 26–3).40 increased risks o toxicities with reirradiation.
The GORTEC 2000-01 trial compared induction Earlier reirradiation studies report 2-year LRC rates
cisplatin/5FU with and without docetaxel ollowed o 30% to 50% using 3-D conormal radiotherapy
by radiation therapy in partial responders with both or IMRT but with signifcant costs in grade 4 and 5
tbl 26–3 Lyngl/hyoyngl—Ogn psvion tils
Laynx
Tial Phae Patient Incluion Citeia Teatment Peevation Os
Chapter 26
VA study 3 332 Untreated stage III/IV SCC a) TL ollowed by RT 2 y: 66% 2 y, 3 y, 5 y:
o larynx b) PF × 3 ollowed 3 y: 62% a) 68%, 56%, 45%
by RT b) 68%, 53%, 42%
RTOG 3 Untreated stage III/IV a) PF × 3 ollowed 5 y, 10 y: 5 y, 10 y:
91-11 SCC o supraglottic or by RT a) 71%, 68% a) 58%, 39%
glottic larynx b) RT + P b) 84%, 82% b) 55%, 28%
c) RT c) 66%, 64% c) 54%, 32%
EORTC 3 450 Stage III/IV SCC o the a) PF × 4 ollowed 3 y: 3 y:
24954- larynx or hypopharynx by RT a) 40% a) 62.2%
22950 b) PF alternating + RT b) 45% b) 64.8%
GORTEC 3 213 Untreated stage III/IV a) PF × 3 ollowed 3 y: 3 y:
2000-01 SCC o the larynx or by RT a) 57.5% a) 60%
hypopharynx b) TPF × 3 ollowed b) 70.3% b) 60%
by RT
EORTC 3 202 SCC o the pyriorm sinus a) TLP ollowed by RT 3 y: 3 y:
24981 or the hypopharyngeal b) PF × 3 ollowed a) NA a) 43%
aspect o the by RT b) 42% b) 57%
aryepiglottic old 10 y: 10 y:
a) NA a) 14%
b) 27% b) 13%
EORTC, European Organization or Research and Treatment o Cancer; GORTEC, Groupe Oncologie Radiotherapies de la Tête et du Cou; P, cisplatin; PF, cisplatin/
fuorouracil; RT, radiation; RTOG: Radiation Therapy Oncology Group; SCC: squamous cell carcinoma; TL, total laryngectomy; TLP, total laryngectomy with partial
pharyngectomy; TPF, docetaxel, cisplatin, fuorouracil.
toxicity (Table 26–4).99–111 Proper patient selection and >6 months ater the completion o chemotherapy as
the use o newer radiation techniques such as ste- part o curative-intent treatment) metastatic or recur-
reotactic body radiation therapy (SBRT) are showing rent HNSCC.112 Eight-hundred fty-our patients were
promising results. SBRT is a highly conormal therapy stratifed based on PD-L1 CPS, p16 status, and ECOG
that uses advanced image guidance and noncoplanar PS and randomly assigned to receive pembrolizumab
beam arrangement to deliver highly ablative doses alone, pembrolizumab plus platinum/5-FU, or cetux-
o radiation with millimeter precision in three to fve imab plus platinum/5-FU.
treatments. Preliminary fndings o a prospective reg- Pembrolizumab plus chemotherapy compared
istry study conducted at MDACC comparing SBRT, with cetuximab plus chemotherapy improved OS in
proton therapy, and IMRT reported equivalent OS and the total population (HR 0.65, 95% CI 0.63–0.93; P <
LRC between modalities, with a signifcantly lower .0001) along with CPS greater than or equal to 1 and
rate o acute grade 3 and 4 toxicities using SBRT.99 greater than or equal to 20 populations.112 Single-agent
Systemic therapy options are determined based on pembrolizumab improved OS compared with cetux-
prior therapies, patient comorbidities, perormance imab plus chemotherapy in patients with CPS greater
status, distribution o disease, and programmed death than or equal to 1 (HR 0.78, 95% CI 0.64–0.96; P =
ligand 1 (PD-L1) expression status. It is essential or .0086) and CPS greater than or equal to 20 (HR 0.61,
providers to obtain adequate core biopsies rather than 95% CI 0.45–0.83; P = .0007). Notably, in the total
FNAs to perorm a PD-L1 combined positive score population, pembrolizumab alone was not inerior to
(CPS), a test mandated by the FDA, on tumor speci- platinum/5-FU and cetuximab (Table 26–5).
mens in the setting o frst-line metastatic disease. CPS Based on the fndings rom this trial, patients with
is the number o PD-L1 staining cells (tumor cells and PD-L1–positive disease qualiy or treatment with
immune cells) divided by the total number o viable pembrolizumab alone; however, we recommend using
tumor cells multiplied by 100. the CPS as a guide to determine the optimal treatment
The randomized phase 3 study KEYNOTE-048 approach. For patients with CPS 20 or higher, con-
established pembrolizumab (PD-1 monoclonal anti- sider pembrolizumab alone. For patients with CPS 1
body) with chemotherapy as a frst-line regimen in or higher and lower than 20, consider pembrolizumab
patients with cisplatin-sensitive (no prior cisplatin or with or without chemotherapy depending on ECOG
tbl 26–4 ridiion tils nd Sudis
Cohot
study Patient Detail rT Technique Outcome Toxicity
Chapter 26
Lee et al 2007 105 86% SCC IMRT (70%) and 2-y LRC: 42% G3–4: 15%
MSK101 (34% surgery, 3DRT 2-y OS: 37% Brain necrosis: 4%
71% CRT)
Langer et al 105 >77% SCC IMRT and 2-y LRC: 30% G4–5: 28% (8 deaths)
2007 3DRT, with 2-y OS: 26% ORN: 18%
RTOG 99-11100 chemotherapy Carotid rupture: 5%
Heron et al 70 100% SCC SBRT 2-y LC: 34% (SBRT), Acute G3–5: 57% (SBRT), 63%
2011110 (SBRT vs. 49% (SBRT+cetux) (SBRT+cextux)
SBRT+ 2-y OS: 21% (SBRT), Late G3–5: 23% (SBRT), 23%
cetuximab) 53% (SBRT+cetux) (SBRT+cetux)
Phan et al 2015 60 67% SCC (58% Proton 2-y LRC: 73% G3: 20%
MDA104 surgery, (62% SCC) G5: 3%
73% CRT) 2-y OS: 70% Feeding tube: 10%
(60% SCC) Higher toxicity with
CTV1 ≥50 cm3
Takiar et al 207 84% SCC (51% IMRT 2-y LRC: 65% G3–5 at:
2015 surgery, (59% SCC) 2-y: 32%
MDA102 67% CRT) 2-y OS: 57% 5-y: 48%
(51% SCC) Higher toxicity with
CTV1 >50 cm3
Ward et al 412 96% SCC IMRT 2-y LRC: 40% G3: 19%
2016 (100% (surgery), 66% G4: 4.4%
MIRI RT, 45% (denitive RT) G5: 1.2%
Collaborative103 surgery, 2-y OS: 40% Feeding tube: 11%
44% CRT)
Yamazaki et al 107 43% surgery SBRT 2-y LRC: 64% Late G3–5: 21%
2016111 2-y OS: 35% Carotid rupture: 10%
(9 deaths; ulceration
predictive o
carotid rupture)
Romesser et al 92 57% SCC (39% Proton 1-y LRC: 75% Acute G3: 31%
2016 surgery, 1-y OS: 65% Late G3–5: 19%
MSK105 39% CRT) -Skin: 9%
-Carotid rupture: 3%
McDonald et al 61 53% SCC (48% Proton 2-y LRC: 80% Acute G3–5: 15%
2016106 surgery, 2-y OS: 33% Late G3–5: 25%
28% CRT) -Necrosis: 15%
Vargo et al 414 99% SCC (70% IMRT (52%) and 2-y LRF: 57% Acute G3–5: 17% (IMRT),
2018108 CRT) SBRT (48%) (IMRT), 45% 12% (SBRT)
(SBRT) Acute G4–5: 5% (IMRT),
2-y OS: 35% (IMRT), 0.5% (SBRT)
16% (SBRT) Late G3–5: 12.4% (IMRT),
11.6% (SBRT)
Gogineni et al 60 74% SCC (53% SBRT 2-y LC: 79% Late G3: 3% (aerodigestive
2019109 surgery, 2-y RC: 70% tract), 1% (skull base)
57% CRT) 2-y OS: 45% Late G4–5: None
3DRT, 3D conormal radiation therapy; CRT, chemoradiation; CTV1, clinical target volume 1; ECE, extracapsular extension; G, grade; IMRT, intensity-modulated radiation
therapy; LC, local control: LRC, locoregional control; LRF, locoregional ailure; ORN, osteoradionecrosis; RC, regional control; RT, radiation; SABR, stereotactic ablative
radiotherapy; SBRT, stereotactic body radiation therapy; SCC, squamous cell carcinoma.
tbl 26–5 Immunoy tils fo Msic nd rcun hd nd Nck Cnc
Tial Phae Patient Incluion Citeia Teatment Outcome
Chapter 26
KEYNOTE-048 3 882 Treatment naïve, Pembrolizumab + Median Os:
metastatic or platinum + 5-FU vs Total study population:
recurrent SCC o cetuximab + platinum 13 vs 10.7 mo
the oropharynx, + 5-FU PD-L1 CPS ≥20: 14.7 vs 11 mo
oral PD-L1 CPS ≥1: 13.6 vs 10.4 mo
cavity, 2 y Os:
hypopharynx, or PD-L1 CPS ≥20: 35 vs 19%
larynx Pembrolizumab vs PD-L1 CPS ≥1: 31 vs 17%
cetuximab + platinum Median Os:
+ 5- FU Total study population:
29 vs 19%
PD-L1 CPS ≥20: 14.9 vs 10.7 mo
PD-L1 CPS ≥1: 12.3 vs 10.3 mo
2 y Os:
PD-L1 CPS ≥20: 38 vs 22%
PD-L1 CPS ≥1: 30 vs 18%
KEYNOTE-040 3 495 Recurrent or Pembrolizumab vs Median Os:
metastatic SCCHN investigator choice Total population: 8.4 vs 6.9 mo
o oral cavity, therapy PD-L1 CPS ≥ 50%: 11.6 vs 6.6 mo
oropharynx, PD-L1 CPS <50%: 6.5 vs. 7.1 mo
hypopharynx, PD-L1 CPS ≥ 1%: 8.7 vs 7.1 mo
larynx; ailed PD-L1 CPS < 1%: 6.3 vs 7 mo
platinum therapy 12 mo Os:
Total population: 37 vs 26.5%
PD-L1 CPS ≥ 50%: 47 vs 25%
PD-L1 CPS ≥ 1%: 40% vs 26%
KEYNOTE-012 1b 192 Recurrent or Initial cohort: Median Os:
metastatic SCCHN Pembrolizumab 10 Total population: 8 mo
mg/kg q2wk PD-L1 CPS ≥ 1%: 10 mo
Expansion cohort: PD-L1 CPS < 1%: 5 mo
Pembrolizumab 200 Os 12 mo:
mg q3wk Total population: 38%
KEYNOTE-055 2 171 Recurrent or Pembrolizumab 200 Median Os: 8 mo
metastatic SCCHN mg Os 6 mo:
o oral cavity, q3wk Total population: 59%
oropharynx, HPV(+): 72%,
hypopharynx, or HPV(–): 55%
larynx resistant to PD-L1 CPS >1%: 59%
both platinum and PDL-1 CPS <1%: 56%
cetuximab
Checkmate-141 3 361 Recurrent or Nivolumab 3 mg/kg Median Os:
metastatic SCCHN q2wk vs single-agent Total population: 7.5 vs 5.1 mo
o oral cavity, investigator’s choice PD-L1 CPS ≥1%: 8.7 vs 4.6 mo
pharynx, or larynx; therapy PD-L1 CPS <1%: 5.7 vs 5.8 mo
platinum reractory Os 1 y:
Total population: 36 vs 16.6%
NCT02369874 3 736 Recurrent or Durvalumab alone Completed accrual, results
metastatic SCCHN; vs Durvalumab + pending
platinum reractory tremelimumab
5-FU, 5-fuorouracil; CPS, combined positive score; HPV, human papillomavirus; ORR, overall response rate; PD-L1, programmed death-ligand 1; SCC, squamous cell
carcinoma; SCCHN, squamous cell carcinoma o the head and neck.
PS. For patients with CPS o 0 or score unavailable, con- Second-line therapy is primarily dictated by treat-
sider chemotherapy with or without pembrolizumab. ment eligibility and prior exposure to platinum and
In the setting o aggressive disease, to avoid early pro- immunotherapy agents. Subsequent therapy or plati-
gression, the combination o pembrolizumab with che- num-reractory disease (<6 months rom prior platinum
Chapter 26
motherapy should be considered independent o CPS. therapy) in immunotherapy-eligible patients includes

The KEYNOTE 048 trial led to the FDA approval in pembrolizumab or nivolumab, monoclonal antibodies
June 2019 o PF as the designated chemotherapy regi- directed against programmed death-1 protein (PD-1).
men in combination with pembrolizumab. Although Two large nonrandomized studies, KEYNOTE-012 and
the trial utilized PF as the chemotherapy regimen, our KEYNOTE-055, and one phase 3 trial KEYNOTE-040
preerence at MDACC is a taxane (docetaxel or pacli- demonstrated the clinical beneft o pembrolizumab
taxel) in place o inusional 5-FU. This is supported in this setting.120–122 KEYNOTE-040 randomly assigned
by trials comparing platinum-taxane doublets with 495 patients that ailed platinum therapy to pembro-
PF showing no dierence in survival.113,114 Inusional lizumab versus the investigator’s choice o therapy
5-FU requires a central line and administration via an (methotrexate, docetaxel, or cetuximab).123 Although
ambulatory pump over 96 hours with a required sec- the dierences in response rates were not statistically
ond return to the treatment center or pump removal signifcant (15% vs 10%), the duration o response
and line ush. It is requently complicated by diar- was longer in the pembrolizumab arm (18 months vs
rhea, mucositis, hand-oot syndrome, and a rare but 5 months). Overall survival in the total population was
lie-threatening potential or coronary vasospasm and 37% versus 27% at 12 months, and median OS was 8.4
arrhythmias. Hospital admissions to manage these versus 6.9 months (HR 0.8 95% CI 0.65–0.98). Explor-
toxicities are not uncommon, and thus the cost o atory analysis demonstrated that patients with PD-L1
this regimen both in physical toxicity and in mon- expression o 50% or higher demonstrated a statisti-
etary resources is high. Docetaxel, on the other hand, cally signifcant survival beneft compared with those
is easily administered through a peripheral vein over with PD-L1 expression lower than 50%.
an hour. It is generally well tolerated, with cosmetic Nivolumab has shown clinical activity and beneft
alopecia and neutropenia as its most common side in the phase 3 trial CHECKMATE-141.124,125 Three-
eects. Prophylactic granulocyte–colony-stimulating hundred sixty-one patients were randomly assigned
actor is requently given to prevent ebrile neutrope- to receive nivolumab versus single-agent physician’s
nia. Cumulative neuropathy may occur ater several choice (methotrexate, docetaxel, or cetuximab). The
cycles, but therapy is typically limited to 4 to 6 cycles. study demonstrated superior OS (median 7.5 months
For immunotherapy-ineligible patients, rontline vs 5.1 months; 97.73% CI 0.51–0.96, HR 0.70; P = .01)
platinum doublets and cetuximab are recommended. and response rates (13.3% vs 5.8%) in the nivolumab
The phase 3 EXTREME trial demonstrated that the arm regardless o PD-L1 expression and p16 status
addition o cetuximab to cisplatin/5-FU signifcantly (Table 26–5). A more signifcant survival beneft was
increased OS, PFS, and response rates compared with seen in patients with HPV-positive disease (HR 0.56;
cisplatin/5-FU alone.92 The phase 2 GORTEC 2008- 95% CI 0.3–0.99) and patients with PD-L1 expression
03 trial o the TPEx regimen (docetaxel, platinum, 1% or greater (HR 0.55; 95% CI 0.36–0.83).
cetuximab) showed a avorable median survival o 14 For patients with progression o disease ater plat-
months.115 This regimen was subsequently compared inum-based therapy and who are immunotherapy
against the EXTREME trial regimen (5-FU, platinum, ineligible or reractory, subsequent lines o treatment
cetuximab), thus substituting docetaxel or 5-FU. include cetuximab or single-agent chemotherapy.
Patients with metastatic HNSCC were randomly Phase 2 trials have demonstrated the beneft o cetux-
assigned between EXTREME and TPEx as frst-line imab in the platinum-reractory setting and objective
treatment. Ater a median ollow-up o 30 months, the response rates are approximately 10%.126,127
median OS was 14.5 months or TPEx and 13.4 months
or EXTREME (HR 0.87; P = .15). More signifcantly,
the grade 4/5 adverse events were only 34% in the rIsK rEDUCTION AND PrEVENTION
TPEx regimen versus 50% in the EXTREME regimen.
Thus, substituting a taxane (specifcally docetaxel) Tobacco and alcohol use are major risk actors or the
or 5-FU results in similar efcacy and reduced toxic- development o head and neck cancer; thus, tobacco
ity.116 For patients not considered to be candidates or and alcohol counseling are essential components o
immunotherapy and/or combination chemotherapy, prevention and risk reduction. It is important or cli-
single agents can be given depending on predicted nicians to stress the importance o tobacco cessation
tolerance and previous exposure. Active single agents because o the risk o development o secondary malig-
include platinums, 5-FU, taxanes, methotrexate, and nancies and the impact on clinical outcomes in patients
cetuximab.117–119 who continue to smoke during active treatment.
As the incidence o HPV-related head and neck can- the incidence o HNSCC is yet to be determined.128 As
cer continues to rise, preventive strategies targeting this o this writing, there are no chemoprevention strate-
inectious agent are being explored. HPV vaccination gies that have been shown to decrease the incidence
is being used to prevent cervical and HNSCC cancer. o HNSCC, despite multiple trials with a variety o
Chapter 26
Although the HPV vaccine has been shown to reduce agents including vitamin A, vitamin E, beta carotene,
the prevalence o oral HPV inections, its impact on and retinoid.129–135
MD ANDErsON PrACTICE TIPs

J Multidisciplinary discussion and management are J Chemoradiation with cisplatin is the standard o
necessary to determine the optimal treatment care or locally advanced disease. However, cetux-
course and to address cancer as well as therapy- imab and other agents along with alternative
related symptoms. approaches such as induction therapy, ollowed by
J Early-stage disease is typically treated with curative carboplatin with radiation, are used in patients with
intent and single-modality treatment, either sur- contraindications to cisplatin.
gery or radiation. J PD-L1 CPS, perormance status, and prior thera-
J Higher-volume stage III (T3N0–1) and stage IV pies should play an integral role in determining
disease without distant metastases should be the appropriate treatment in the recurrent or
approached with curative intent, multimodality metastatic setting to balance potential therapy
therapy such as surgery and radiation, or concur- beneit with toxicity, especially in the palliative
rent chemoradiation. setting. Anti–PD-1 antibodies should be given to
all patients with recurrent disease, unless contra-
J There are no denitive data that the incorpora-
indications exist.
tion o induction therapy beore chemoradiation
leads to improved survival except in the setting o J It is likely that immunotherapy will become a stan-
node-positive nasopharyngeal cancer. Its use with dard o care in curative-intent treatment in the near
sequential radiation as a larynx preservation strat- uture.
egy is a standard treatment option.
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85. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetux- 102. Takiar V, Garden AS, Ma D, et al. Reirradiation o head and neck
imab or squamous-cell carcinoma o the head and neck. N Engl cancers with intensity modulated radiation therapy: outcomes
J Med. 2006;354:567-578. and analyses. Int J Radiat Oncol Biol Phys. 2016;95:1117-1131.
86. Mehanna H, Robinson M, Hartley A, et al. Radiotherapy plus 103. Ward MC, Riaz N, Caudell JJ, et al. Refning patient selection
cisplatin or cetuximab in low-risk human papillomavirus-pos- or reirradiation o head and neck squamous carcinoma in the
itive oropharyngeal cancer (De-ESCALaTE HPV): an open- IMRT era: a multi-institution cohort study by the MIRI Col-
label randomised controlled phase 3 trial. Lancet. 2019;393: laborative. Int J Radiat Oncol Biol Phys. 2018;100:586-594.
51-60. 104. Phan J, Sio TT, Nguyen TP, et al. Reirradiation o head and
87. Lacas B, Bourhis J, Overgaard J, et al. Role o radiotherapy neck cancers with proton therapy: outcomes and analyses. Int J
ractionation in head and neck cancers (MARCH): an updated Radiat Oncol Biol Phys. 2016;96:30-41.
meta-analysis. Lancet Oncol. 2017;18:1221-1237. 105. Romesser PB, Cahlon O, Scher ED, et al. Proton beam reirra-
88. Nguyen-Tan PF, Zhang Q, Ang KK, et al. Randomized phase III diation or recurrent head and neck cancer: multi-institutional
trial to test accelerated versus standard ractionation in combi- report on easibility and early outcomes. Int J Radiat Oncol Biol
nation with concurrent cisplatin or head and neck carcinomas Phys. 2016;95:386-395.
in the Radiation Therapy Oncology Group 0129 trial: long-term 106. McDonald MW, Zolali-Meybodi O, Lehnert SJ, et al. Reirradia-
report o efcacy and toxicity. J Clin Oncol. 2014;32:3858-3866. tion o recurrent and second primary head and neck cancer with
89. Bachaud JM, Cohen-Jonathan E, Alzieu C, et al. Combined proton therapy. Int J Radiat Oncol Biol Phys. 2016;96:808-819.
postoperative radiotherapy and weekly cisplatin inusion 107. Gao J, Hu J, Guan X, et al. Salvage carbon-ion radiation therapy
or locally advanced head and neck carcinoma: fnal report or locoregionally recurrent head and neck malignancies. Sci
o a randomized trial. Int J Radiat Oncol Biol Phys. 1996;36: Rep. 2019;9:4259.
999-1004. 108. Vargo JA, Ward MC, Caudell JJ, et al. A multi-institutional
90. Cooper JS, Zhang Q, Pajak TF, et al. Long-term ollow-up o comparison o SBRT and IMRT or defnitive reirradiation o
the RTOG 9501/intergroup phase III trial: postoperative con- recurrent or second primary head and neck cancer. Int J Radiat
current radiation therapy and chemotherapy in high-risk squa- Oncol Biol Phys. 2018;100:595-605.
mous cell carcinoma o the head and neck. Int J Radiat Oncol Biol 109. Gogineni E, Zhang I, Rana Z, et al. Quality o lie outcomes ol-
Phys. 2012;84:1198-1205. lowing organ-sparing SBRT in previously irradiated recurrent
91. Bernier J, Cooper JS, Pajak TF, et al. Defning risk levels in head and neck cancer. Front Oncol. 2019;9:836.
locally advanced head and neck cancers: a comparative analy- 110. Heron DE, Rwigema J-CM, Gibson MK, et al. Concurrent cetux-
sis o concurrent postoperative radiation plus chemotherapy imab with stereotactic body radiotherapy or recurrent squa-
trials o the EORTC (#22931) and RTOG (# 9501). Head Neck. mous cell carcinoma o the head and neck: a single institution
2005;27:843-850. matched case-control study. Am J Clin Oncol. 2011;34:165-172.
111. Yamazaki H, Ogita M, Himei K, et al. Reirradiation using 123. Cohen EEW, Soulieres D, Le Tourneau C, et al. Pembrolizumab
robotic image-guided stereotactic radiotherapy o recurrent versus methotrexate, docetaxel, or cetuximab or recurrent or
head and neck cancer. J Radiat Res. 2016;57:288-293. metastatic head-and-neck squamous cell carcinoma (KEY-
112. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone NOTE-040): a randomised, open-label, phase 3 study. Lancet.
or with chemotherapy versus cetuximab with chemotherapy 2019;393:156-167.
Chapter 26
or recurrent or metastatic squamous cell carcinoma o the 124. Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab or
head and neck (KEYNOTE-048): a randomised, open-label, recurrent squamous-cell carcinoma o the head and neck. N
phase 3 study. Lancet. 2019;394:1915-1928. Engl J Med. 2016;375:1856-1867.
113. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evalu- 125. Gillison ML, Blumenschein G Jr, Fayette J, et al. CheckMate
ation o cisplatin plus uorouracil versus cisplatin plus pacli- 141: 1-year update and subgroup analysis o nivolumab as frst-
taxel in advanced head and neck cancer (E1395): an intergroup line therapy in patients with recurrent/metastatic head and
trial o the Eastern Cooperative Oncology Group. J Clin Oncol. neck cancer. Oncologist. 2018;23:1079-1082.
2005;23:3562-3567. 126. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled,
114. Peyrade F, Cupissol D, Georois L, et al. Systemic treatment multicenter phase II study to evaluate the efcacy and toxicity
and medical management o metastatic squamous cell carci- o cetuximab as a single agent in patients with recurrent and/
noma o the head and neck: review o the literature and pro- or metastatic squamous cell carcinoma o the head and neck
posal or management changes. Oral Oncol. 2013;49:482-491. who ailed to respond to platinum-based therapy. J Clin Oncol.
115. Guigay J, Fayette J, Dillies AF, et al. Cetuximab, docetaxel, and 2007;25:2171-2177.
cisplatin as frst-line treatment in patients with recurrent or 127. Fury MG, Sherman E, Lisa D, et al. A randomized phase II
metastatic head and neck squamous cell carcinoma: a multi- study o cetuximab every 2 weeks at either 500 or 750 mg/m2
center, phase II GORTEC study. Ann Oncol. 2015;26:1941-1947. or patients with recurrent or metastatic head and neck squa-
116. Guigay J, Fayette J, Mesia R, et al. TPExtreme randomized trial: mous cell cancer. J Natl Compr Canc Netw. 2012;10:1391-1398.
TPEx versus Extreme regimen in 1st line recurrent/metastatic 128. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence
head and neck squamous cell carcinoma (R/M HNSCC). J Clin o oral human papillomavirus (HPV) 4 years ater bivalent HPV
Oncol. 2019;37:6002-6002. vaccination in a randomized clinical trial in Costa Rica. PLoS
117. Forastiere AA, Metch B, Schuller DE, et al. Randomized com- One. 2013;8:e68329.
parison o cisplatin plus uorouracil and carboplatin plus 129. Bolla M, Leur R, Ton Van J, et al. Prevention o second primary
uorouracil versus methotrexate in advanced squamous-cell tumours with etretinate in squamous cell carcinoma o the oral
carcinoma o the head and neck: a Southwest Oncology Group cavity and oropharynx. Results o a multicentric double-blind
study. J Clin Oncol. 1992;10:1245-1251. randomised study. Eur J Cancer. 1994;30a:767-772.
118. Jacobs C, Lyman G, Velez-García E, et al. A phase III random- 130. van Zandwijk N, Dalesio O, Pastorino U, et al. EUROSCAN, a
ized study comparing cisplatin and uorouracil as single agents randomized trial o vitamin A and N-acetylcysteine in patients
and in combination or advanced squamous cell carcinoma o with head and neck cancer or lung cancer. For the EUropean
the head and neck. J Clin Oncol. 1992;10:257-263. Organization or Research and Treatment o Cancer Head and
119. Clavel M, Vermorken JB, Cognetti F, et al. Randomized com- Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst.
parison o cisplatin, methotrexate, bleomycin and vincristine 2000;92:977-986.
(CABO) versus cisplatin and 5-uorouracil (CF) versus cisplatin 131. Mayne ST, Cartmel B, Baum M, et al. Randomized trial o
(C) in recurrent or metastatic squamous cell carcinoma o the supplemental beta-carotene to prevent second head and neck
head and neck. A phase III study o the EORTC Head and Neck cancer. Cancer Res. 2001;61:1457-1463.
Cancer Cooperative Group. Ann Oncol. 1994;5:521-526. 132. Bairati I, Meyer F, Gelinas M, et al. A randomized trial o
120. Mehra R, Seiwert TY, Gupta S, et al. Efcacy and saety o antioxidant vitamins to prevent second primary cancers in
pembrolizumab in recurrent/metastatic head and neck squa- head and neck cancer patients. J Natl Cancer Inst. 2005;97:
mous cell carcinoma: pooled analyses ater long-term ollow- 481-488.
up in KEYNOTE-012. Br J Cancer. 2018;119:153-159. 133. Benner SE, Pajak TF, Lippman SM, et al. Prevention o second
121. Seiwert TY, Burtness B, Mehra R, et al. Saety and clinical primary tumors with isotretinoin in patients with squamous
activity o pembrolizumab or treatment o recurrent or meta- cell carcinoma o the head and neck: long-term ollow-up.
static squamous cell carcinoma o the head and neck (KEY- J Natl Cancer Inst. 1994;86:140-141.
NOTE-012): an open-label, multicentre, phase 1b trial. Lancet 134. Hong WK, Lippman SM, Itri LM, et al. Prevention o second
Oncol. 2016;17:956-965. primary tumors with isotretinoin in squamous-cell carcinoma
122. Bauml J, Seiwert TY, Pfster DG, et al. Pembrolizumab or o the head and neck. N Engl J Med. 1990;323:795-801.
platinum- and cetuximab-reractory head and neck can- 135. Dannenberg AJ, Lippman SM, Mann JR, et al. Cyclooxygen-
cer: results rom a single-arm, phase II study. J Clin Oncol. ase-2 and epidermal growth actor receptor: pharmacologic
2017;35:1542-1549. targets or chemoprevention. J Clin Oncol. 2005;23:254-266.
Section VI Gastrointestinal
Cancer
Section Editor: Robert A. Wolf
27 Gastric, Gastroesophageal Junction, and Esophageal Cancers
28 Pancreatic Cancer
29 Biliary Tract Cancer
30 Hepatocellular Carcinoma
31 Small Bowel Cancer and Appendiceal Tumors
32 Colorectal Cancer
33 Anal Cancer
34 Neuroendocrine Tumors
27 Gastric, Gastroesophageal
Junction, and Esophageal Cancers
Mariela Blum Murphy
Elena Elimova
Ahmed Abdelhakeem
Jaer Ajani
KEY CONCEPTS
 Gastric cancer remains the third most common cause o  Results o the CROSS trial also emphasized the benecial
cancer-related death worldwide. role o chemoradiotherapy beore surgery, which led to a
 Two dierent pathogeneses o gastric cancer have been signicant increase in overall survival (OS) irrespective o
proposed, correlating to two histologic types: intestinal tumor histology.
and diuse.  More than 60% o patients who present with newly diag-
 Gastrectomy is the recommended treatment in rela- nosed gastric, GEJ, and esophageal cancers will have
tively early localized gastric cancer (T1b); however, in advanced unresectable or metastatic disease. Although a
more advanced gastric cancers (T2N0, T1aN+, or T1b- cure is not possible, systemic therapy can prolong survival
T3N+), adjunctive therapy in addition to gastrectomy is compared with best supportive care.
recommended.  As o this writing, patients in the United States are likely to
 The results o INT-0116 study (adjuvant chemoradiation) undergo rontline therapy with platinum-, uoropyrimidine-,
and Medical Research Council ST02/MAGIC and the FLOT or taxane-based chemotherapy regimens, with the addition
study (perioperative chemotherapy) have shaped the o trastuzumab in patients with HER2-positive disease.
current practice o resectable gastric cancer treatment in  Based on positive results rom the RAINBOW trial, pacli-
Western countries. taxel and ramucirumab (vascular endothelial growth actor
 In Asia, postoperative chemotherapy has been considered receptor–2 targeted drug) is considered to be a standard or
standard ater gastrectomy with D2 dissection. In addition second-line treatment. Ramucirumab monotherapy is also
to the ACTS-GC trial and CLASSIC trial (S-1 or 1 year and considered a second-line option in advanced gastric cancer.
CAPOX or 6 months, respectively), two new regimens (DS  Pembrolizumab is currently approved or the treatment o
and SOX or 6 months) are established standards o care metastatic squamous cell carcinoma (SCC) o the esopha-
or stage II and/r LN-positive gastric cancer. gus as second-line treatment or tumors with combined
 Only 30% to 40% o patients with esophageal cancer positive score (CPS) more than 10 and programmed cell
have potentially resectable disease at presentation, and death protein 1 (PD-L1)–positive advanced gastric can-
in many series, only 5% to 20% o those undergoing sur- cer as third-line treatment in the US. Nivolumab is also
gery alone or clinically localized disease are alive at 3 to approved in the US or metastatic SCC o the esophagus
5 years. regardless o PD-L1 expression, and in Japan, South Korea,
and Taiwan or the treatment o gastric cancer.
 Endoscopic therapy is most eective when used to treat
small (<2 cm diameter), solitary, at lesions that are con-  The Cancer Genome Atlas analysis has uncovered our geno-
ned to mucosa (T1a). types o gastric cancer; however, it is not sufcient to change
our treatment strategies, and additional work is needed.
 Surgery remains the best chance or durable survival or
patients with locally advanced esophageal and gastro-  A multimodality approach to therapy will be the corner-
esophageal junction (GEJ) cancers. stone to screening, diagnosing, staging, treating, and sup-
porting patients with upper gastrointestinal cancers.
579
580 Section VI Gastrointestinal Cancer
GASTRIC CANCER carcinomas, whereas the Lauren classication divides

GACs into intestinal, diuse, and mixed types.7 Intes-
tinal-type GAC likely begins with an H pylori inec-
Epidemiologic Characteristics
tion that leads to multistep progression (chronic active
The incidence o gastric cancer varies widely world- nonatrophic gastritis, multiocal atrophic gastritis,
wide. The highest incidence (>20 per 100,000 in men) is intestinal metaplasia, dysplasia, and invasive adeno-
seen in Japan, China, Eastern Europe, and South Amer- carcinoma).8 More than 40% to 50% o distal GACs
ica, whereas the lowest incidence (<10 per 100,000 in are associated with H pylori inection.6 Other environ-
men) is seen in Northern America, parts o Arica, and mental risk actors and infammatory cytokines may
Northern Europe.1 In the United States, 27,600 new infuence and contribute to this multistep progression.
cases o gastric cancer were estimated in 2020, with Population studies have identied certain environ-
11,010 deaths.2 Gastric cancers occur at a median age mental risk actors associated with gastric cancer. Low
o 69 years or men and 73 years or women.3 Arican consumption o ruits and vegetables, high intake o
Americans, Hispanic Americans, and Native Ameri- N-nitroso compounds in salted and preserved oods,
cans are 1.5 to 2.5 times more likely to develop gastric and occupational exposure in coal mining and nickel,
cancer than are Whites.3 In the United States, there are rubber, and timber processing are commonly described
changing epidemiologic patterns regarding the ana- risk actors. Additional notable risk actors include
tomic location o esophagogastric cancers, with a trend meat consumption,9 smoking,10 gastric surgery,11 and
o decreased occurrence o distal or noncardia gastric reproductive hormones.12
ChApTER 27
cancers.4 The reason or the decline is not known but Overall, the pathogenesis o intestinal-type GACs
may be related to change in dietary habits and ood involves a series o events. This sequence o events—
preservation. However, an increase in the incidence increased cell prolieration caused by the promotional
o gastric cardia cancers has been observed, rom 2.4 eects o hypergastrinemia or bile refux, increased
cases per 100,000 individuals (1977–1981) to 2.9 cases luminal levels o mutagens (eg, N-nitroso compounds
per 100,000 individuals (2001–2006) in the White and ree radicals), and decreased luminal levels o
population.4 Similarly, the Surveillance, Epidemiology, protective actors (eg, vitamin C)—provides an ideal
and End Results (SEER) cancer registry program in the milieu or carcinogenesis in susceptible hosts.8
United States shows an approximate 2.5-old increase In contrast to intestinal-type gastric cancer, diuse-
in the incidence o gastroesophageal junction (GEJ) type GAC results rom deective intracellular adhe-
adenocarcinomas rom 1973 to 1992, rom 1.22 cases sion molecules, which is the consequence o loss o
per 100,000 individuals (1973–1978) to 2.00 cases per E-cadherin protein expression, which is encoded by
100,000 individuals (1985–1990), with rates stabilizing the cadherin 1 (CDH1) gene. This can occur through
in the last two decades, with an incidence o 1.94 cases germline or somatic mutation, loss o heterozygosity,
per 100,000 individuals (2003–2008).3,5 or epigenetic silencing o gene transcription through
Population studies suggest that proximal cancers aberrant methylation o the CDH1 promoter. A study
have a dierent pathogenesis than distal cancers.6 Poten- by Zheng et al showed a positive rate o E-cadherin
tial causes o distal gastric cancers include Helicobacter promoter methylation in dysplasia, early cancer, and
pylori inection or E-cadherin expression loss, whereas advanced cancer.13 Furthermore, 30% o amilies with
proximal gastric cancers may behave similarly to distal hereditary diuse gastric cancer show CDH1 germline
esophageal and GEJ cancers, which progress rom Bar- mutations, whereas the rest remain genetically unex-
rett metaplasia to dysplasia to invasive adenocarcinoma. plained.14 Currently, many amilies with hereditary
Only 26% o newly diagnosed gastric cancers are local- diuse gastric cancer have CDH1 germline mutations.
ized. The 5-year overall survival (OS) rate is 28.3%, Inheritance is dominant. The lietime cumulative risk
which has not changed signicantly over the past 30 to or advanced gastric cancer has been estimated to be
40 years.1 Surgery is still the only chance or cure, and 40% to 67% in men and 60% to 83% in women.15
survival can be improved with multimodality therapy. Women in aected amilies are also at high risk or
The 5-year OS rate o patients with advanced disease developing lobular breast cancer, with a cumulative
remains dismal, at less than 5%. Thus, despite decreas- risk o 52%.15 A germline mutation in TP53 is asso-
ing incidence, gastric cancer remains a public health con- ciated with amilial gastric cancer,14 which includes
cern in the United States because o its high atality rate. Li-Fraumeni syndrome. Another amilial cancer syn-
drome associated with gastric cancer is hereditary
nonpolyposis colorectal cancer, resulting rom deects
Histologic Classifcation and Risk Factors o DNA mismatch repair genes (hMLH1 and hMSH2,
The most requent type o gastric cancer is gastric more requently) (Table 27–1).16
adenocarcinoma (GAC). The WHO classies GAC Epstein-Barr virus–associated gastric cancers have
into tubular, papillary, mixed, and poorly cohesive distinct clinicopathologic characteristics, including
Cater 27 Gastric, Gastroesophageal Junction, and Esophageal Cancers 581
Table 271 Summary of Selected Recurrent Cytogenetic Abnormalities and Frequent Molecular
Canges Associated wit Gastric Cancer
Conventional Cytogenetics Simple Karyotypes Complex Karyotypes

+X, +8, +9, +19, del(7q), i(8q) 1, 3, 6, 7, 8, 11, 13, 17, 19
Molecular Cytogenetics Gains Loss
3q, 7p, 7q, 8q, 13q, 17q, 20p, 20q 4q, 9p, 17p, 18q
Genes Abnormalities Clinical Association
c-met Amplication Tumor invasion, lymph node metastasis, poor prognosis
K-sam Amplication Advanced tumor stage/poor prognosis
c-erbB2 Amplication Advanced tumor stage, lymph node and liver
metastases, poor prognosis
c-myc Amplication Poor clinical course/predictor o aggressiveness
TP53 Loss o heterozygosity Prolierative rate/lymph node metastasis/shortened
survival
Mutation
Hypermethylation
ChApTER 27
BCL-2 Loss o heterozygosity Depth o invasion, lymph node metastasis and survival
RUNX3 Deletion Metastasis
Hypermethylation
Loss o expression
PTEN Loss o heterozygosity Advanced tumor stage/metastasis
Mutation
E-cadherin (CDH1) Loss o heterozygosity Tumor metastatic ability and poor prognosis
Mutation
Hypermethylation
Reduced expression
Cyclin E Amplication Disease aggressiveness/lymph node metastasis
p27 Reduced expression Advanced tumor stage/depth o invasion/lymph node
metastasis
p16 Reduced expression Tumor invasion/metastasis
DNA repair genes/ Mutation Age/low prevalence o lymph node metastasis/
microsatellite instability prolonged survival
Hypermethylation
Reduced expression
Syndecan-1 Reduce expression Tumor dierentiation
β-catenin Amplication Lymph node metastasis
CD44s and CD44v6 Amplication Lymph node metastasis
Sp1 Amplication Cancer angiogenic potential, poor prognosis
male predominance, preerential location in the gastric Prevention

cardia or postsurgical gastric stump, lymphocytic inl-
Results rom a number o population studies have
tration, and a more avorable prognosis.17,18
demonstrated an increased likelihood o H pylori
Despite recent progress, the precise etiologic charac-
inection in patients with gastric cancer, particularly
teristics o gastric cancer and the relationship between
cancer o the distal stomach. 19,20 However, gastric can-
the environment and host are unknown. Ongoing
cer does not occur in most patients inected with H
research promises to better elucidate the tumorigen-
pylori. Although the role o H pylori in gastric cancer
esis o gastric cancer.
pathogenesis is well dened, currently there is no nearly 80% harboring a protein-changing alteration
denitive evidence showing that mass eradication in PIK3CA.
could reduce the incidence o gastric cancer.21 A large 2. Tumors showing microsatellite instability, in
Chinese study o 1630 patients showed no benet which malunctioning DNA repair mechanisms
in the prevention o gastric cancer with the eradica- cause a high rate o mutations, including muta-
tion o H pylori.22 However, in a subgroup o patients tions o genes encoding targetable oncogenic sig-
with no precancerous lesions on presentation, gastric naling proteins. About 20% o tumors ell into this
cancer did not develop in any patient during a ollow- subtype.
up o 7.5 years ater H pylori eradication treatment 3. The largest category o tumors, making up about
compared with six patients who received placebo hal o the cancer specimens, was termed chromo-
(P = .02).22 In another large study, short-term treatment somally unstable. These contained a jumble o extra
with amoxicillin and omeprazole statistically signi- or missing pieces o genes and chromosomes (aneu-
cantly reduced gastric cancer incidence by 39% during ploidy) and have a striking number o genomic
the period extending 14.7 years ater H pylori treat- amplications o key receptor tyrosine kinases. This
ment.23 A meta-analysis suggested that eradication subtype o tumor is requently ound in the junction
could reduce the risk o gastric cancer; however, this between the stomach and the esophagus, a type o
meta-analysis was criticized or methodologic issues.24 gastric cancer that has been increasing dramatically
As o this writing, the treatment o this inection is in the United States.
strongly recommended or patients with peptic ulcer 4. The ourth group was termed genomically stable
ChApTER 27
disease, patients with mucosa-associated lymphoid because they lacked the molecular eatures o the
tissue lymphoma, and ater endoscopic resection or other three types. These tumors, making up 20%
esophagogastric cancer; a role or a broad prevention o the specimens, were largely those o a specic
strategy has yet to be dened. class o gastric cancer enriched or the diuse-type
histologic variant, with approximately 30% o
Clinical Presentation these tumors having genomic alterations in the Ras
homolog gene amily, member A (RHOA) signaling
At presentation, the majority o patients with symp- pathway. These tumors were characterized by the
toms will have advanced disease. Symptoms can be lack o high levels o aneuploidy and high meta-
constitutional, such as night sweats and unintentional static potential.
weight loss, or they can be vague, such as early sati-
ety, abdominal pain, and nausea. Dysphagia is more This classication may serve as a valuable adjunct
common in patients with cancer originating in the to histopathology and provides patient stratication as
gastric cardia or GEJ. Occult gastrointestinal (GI) a guide to targeted agents.
bleeding is also common, whereas overt bleeding is
observed in only 20% o cases. Staging and Prognosis
Upper GI series with barium swallow and upper
Pathologic and Molecular Characteristics esophagogastroduodenoscopy (EGD) are mainstays
or diagnosing gastric cancer and provide comple-
More than 95% o gastric cancers are adenocarcinoma. mentary diagnostic inormation. EGD is more sensi-
The remaining 5% include neuroendocrine tumor, tive and specic to obtain tissue diagnosis. A single
lymphoma, SCC, and sarcoma. biopsy has 70% sensitivity or diagnosing gastric
The Cancer Genome Atlas Research Network has cancer; perorming seven biopsies rom the ulcer
classied gastric cancer into our subtypes based on the margin and base increases the sensitivity to more
molecular characterization o 295 primary adenocarci- than 98%.26 In contrast, barium swallow with upper
nomas in a way that can ultimately guide patient ther- GI series can identiy both malignant gastric ulcers
apy.25 They clearly converged on our major genomic and inltrating lesions, including some early gastric
subtypes o gastric cancer with distinct eatures and cancers. However, the alse-negative rate with bar-
classes o molecular alterations: ium swallow can be as high as 50% 27 and may be
1. Tumors containing Epstein-Barr virus, along with even higher or early gastric cancer, and sensitivity
recurrent mutations in the PIK3CA gene pathway, can be as low as 14%.27
extreme DNA hypermethylation, amplication Cancer staging is critical prior treatment, the stag-
o Janus kinase 2 (JAK2), and extra copies o pro- ing system by the American Joint Committee on Can-
grammed death ligand 1 (PD-L1) and PD-L2 genes, cer (AJCC) 8th edition (2017) is the most current used
which are suppressors o immune response. This (Table 27–2)28 and includes gastric carcinoma, gastric
group made up about 10% o the cancers, with neuroendocrine carcinoma, GEJ carcinoma with an
epicenter more than 2 cm into the stomach, and cardia tumor invasion depth and local and regional lymph
carcinoma. node involvement. Contrast-enhanced CT scans o
In this newest version, three staging guidelines by the the chest, abdomen, and pelvis can assess the locale(s)
TNM (tumor, node, metastasis) classication o malig- o distant extension o GAC. Currently, CT is used in
nant tumors are available: clinical stage (c stage) based conjunction with endoscopic ultrasonography (EUS)
on databases rom United States and Japan; pathologic o the primary site, which provides the most accu-
stage (p stage) determined ater primary surgery o rate data or depth o tumor invasion and locoregional
localized GAC; and post-neoadjuvant therapy pathol- lymph node involvement. Endoscopic ultrasonogra-
ogy classication (yp stage), ater the use o neoadju- phy has an accuracy o 77% (vs 40%–50% with CT)
vant therapy beore surgery. According to the AJCC 8th or staging depth and 69% or staging nodes.29 The
edition, Siewert-Stein type II tumors are staged accord- availability o EUS-guided biopsy o suspicious local
ing to the esophageal cancer system, and type III tumors and regional lymph nodes has circumvented its limi-
are staged according to the gastric system. tations (Figs. 27–1 and 27–2). Laparoscopy with peri-
Because o its noninvasive nature, computed tomog- toneal washings is more invasive than CT or EUS,
raphy (CT) has become the cornerstone o gastric can- but it has the advantage o directly visualizing the
cer staging, although it is not sensitive at detecting the liver surace, peritoneum, and local lymph nodes. It is
ChApTER 27
Table 272 A. American Joint Cancer Committee TNM Staging System for Gastric Cancer
Primary Tumor (T)

Tx Primary tumor cannot be assessed
T0 No evidence o primary tumor
Tis Carcinoma in situ: intraepithelial tumor with invasion o the lamina propria, high-grade dysplasia
T1 Tumor invades the lamina propria, muscularis propria, or submucosa
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosa
T2 Tumor invades muscularis propriaa
T3 Tumor penetrates the subserosal connective tissue without invasion o visceral peritoneum or adjacent structuresb,c
T4 Tumor invades serosa (visceral peritoneum) or adjacent structuresb,c
T4a Tumor invades serosa (visceral peritoneum)
T4b Tumor invades adjacent structures/organs
Regional Lymph Nodes (N)

Nx Regional lymph node(s) cannot be assessed
N1 Metastasis in 1–2 regional lymph nodes
N3 Metastasis in ≥7 regional lymph nodes
N3a Metastasis in 7–15 regional lymph nodes
N3b Metastasis in ≥16 regional lymph nodes
Distant Metastases (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastases
M1 Distant metastases, microscopically conrmed
a
A tumor may penetrate the muscularis propria with extension into the gastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without
peroration o the visceral peritoneum covering these structures. In this case, the tumor is classied as T3. I there is peroration o the visceral peritoneum covering the
gastric ligaments or the omentum, the tumor should be classied as T4.
b
The adjacent structures o the stomach include the spleen, transverse colon, liver, diaphragm, pancreas, abdominal wall, adrenal gland, kidney, small intestine, and
retroperitoneum.
c
Intramural extension to the duodenum or esophagus is not considered invasion o an adjacent structure but is classied using the depth o the greatest invasion in any
o these sites.
AJCC prognostic Stage Grous: B. Clinical (cTNM) 27-2B
When T is ... And N is ... And M is ... Then the stage group is ...
Tis N0 M0 0
T1 N0 M0 I
T2 N0 M0 I
T1 N1, N2, or N3 M0 IIA
T2 N1, N2, or N3 M0 IIA
T3 N0 M0 IIB
T4a N0 M0 IIB
T3 N1, N2, or N3 M0 III
T4a N1, N2, or N3 M0 III
T4b Any N M0 IVA
Any T Any N M1 IVB
C. patological (TNM)
ChApTER 27
Tis N0 M0 0
T1 N0 M0 IA
T1 N1 M0 IB
T2 N0 M0 IB
T1 N2 M0 IIA
T2 N1 M0 IIA
T1 N3a M0 IIB
T2 N2 M0 IIB
T3 N1 M0 IIB
T4a N0 M0 IIB
T2 N3a M0 IIIA
T3 N2 M0 IIIA
T4a N1 M0 IIIA
T4a N2 M0 IIIA
T4b N0 M0 IIIA
T1 N3b M0 IIIB
T2 N3b M0 IIIB
T3 N3a M0 IIIB
T4a N3a M0 IIIB
T4b N1 M0 IIIB
T4b N2 M0 IIIB
T3 N3b M0 IIIC
T4a N3b M0 IIIC
T4b N3a M0 IIIC
T4b N3b M0 IIIC
Any T Any N M1 IV
D. post-Neoadjuvant Teray (yTNM) 27-2D
T1 N0 N0 I
T2 N0 M0 I
T1 N1 M0 I
T3 N0 M0 II
T2 N1 M0 II
T1 N2 M0 II
T4a N0 M0 II
T3 N1 M0 II
T2 N2 M0 III
T1 N3 M0 II
T4a N1 M0 III
T3 N2 M0 III
T2 N3 M0 III
ChApTER 27
T4b N0 M0 III
T4b N1 M0 III
T4a N2 M0 III
T3 N3 M0 III
T4b N2 M0 III
T4b N3 M0 III
T4a N3 M0 III
Any T Any N M1 IV
Used with permission o the American College o Surgeons, Chicago, Illinois. The original source or this inormation is the AJCC Cancer Staging System (2020).
sensitive at diagnosing liver metastases and peritoneal addition o FDG-PET to CT increases diagnostic accu-
carcinomatosis in up to 23% o patients in whom no racy or recurrent gastric cancer because PET/CT is as
such involvement was seen on CT30 and up to 13% o sensitive and specic as contrast CT at detecting recur-
patients with positive cytology only.31 Diagnostic lap- rent disease, except peritoneal seeding.38
aroscopy is usually perormed when all noninvasive Among patients with gastric cancer who had sur-
studies (CT and EUS) demonstrate localized or poten- gery, actors aecting gastric cancer prognosis include
tially resectable disease in patients with higher than nodal involvement, tumor location, histologic grade,
T1b disease on EUS. Positive peritoneal cytology rep- and lymphovascular invasion.39 Patients with proximal
resents stage IV disease according to the AJCC system. gastric cancer have a poorer prognosis than those with
The eectiveness o fuorodeoxyglucose (FDG) distal gastric cancer, at 28.5 versus 58.6 months (P <
positron emission tomography (PET) at diagnosing .02).40 Although associations have been ound between
gastric cancer is uncertain because as many as 50% o molecular genetic changes and pathologic eatures
primary tumors are FDG negative, particularly early and biologic behavior and prognosis, the clinical sig-
gastric cancers.32 Insucient FDG uptake is mostly nicance o these genetic changes has not yet been
associated with diuse-type gastric cancer with signet established. In other words, these genetic parameters
ring cells and mucinous content.33 Currently, FDG-PET have been unable to translate into meaningul clini-
has no role in the primary detection o gastric cancer cal diagnostic, predictive, or prognostic biomarkers.
because o its low sensitivity. On the other hand, FDG- Thereore, the putative biomarker screening method
PET shows better results in the evaluation o lymph or gastric cancer also remains elusive. However, with
node metastases in gastric cancer compared with CT better appreciation o the complex interplay between
and could thus have a role in preoperative staging. For environment and host actors leading to gastric tumor-
patients with FDG-positive disease, FDG-PET can be igenesis, researchers hope to produce more eective
used to predict histologic response and survival out- screening methods or high-risk patients, better prog-
comes,34–36 similar to results seen among patients with nostic and predictive biomarkers, and superior thera-
distal esophageal and GEJ adenocarcinoma.37 The peutic indices o cancer drugs.
ChApTER 27
FIGURE 27–1 Gastric cancer: T1 lesion. A. Endoscopic view. B. Endoscopic ultrasound view. (Reproduced with permission rom
http://www.massgeneral.org/gastro/endo_homepage.htm)\
FIGURE 27–2 Gastric cancer: T2N1 lesion. A. Endoscopic view. B. Endoscopic ultrasound view. (Reproduced with permission
rom http://www.massgeneral. org/gastro/endo_homepage.htm)
Treatment hoped) eradication o gastric cancer and (2) attainment

o accurate pathologic staging. Considerations or sur-
Gastric cancer is treated according to the cancer stage gical management o gastric cancer are the (1) extent o
at presentation. Refecting the newest changes in the luminal resection (total vs partial gastrectomy) and (2)
AJCC staging system, treatment or GEJ and proxi- extent o lymph node dissection. Total gastrectomy is
mal gastric adenocarcinoma smaller than 5 cm rom mainly reserved or proximal gastric cancer and large
the GEJ is discussed in the esophageal cancer section. midgastric tumors or linitis plastica (wherein a large
Treatment or patients with locally advanced gas- region o the stomach is extensively inltrated by can-
tric cancer is dichotomized into resectable and unre- cer, resulting in a rigid, thickened old), whereas par-
sectable disease. Surgery remains the best chance or tial gastrectomy may be used in distal gastric tumors.
long-term survival, but 5-year survival rates ater sur- Two randomized controlled trials have demonstrated
gery alone are 20% to 50%, and adjunctive therapy, similar survival outcomes or total and partial gastrec-
such as chemotherapy or chemoradiotherapy, must tomy or distal gastric cancer.47,48 OS rates improved
be oered. Localized gastric cancer can be classied as rom 5% or R2 (surgical resection with gross residual
clinical T1 disease or higher with or without involved disease) to 50% or R0.47
regional lymph nodes. A minimum o 15 examined Japanese surgeons routinely perorm extended
lymph nodes is recommended or adequate surgical lymphadenectomy, whereas in the United States,
staging.41 The adjunctive therapy used or the treat- 54% o patients who underwent primary gastrec-
ment o localized gastric cancer in addition to surgery tomy undergo less than a D1 lymphadenectomy.42 A
depends on geographic location in the world. In North
ChApTER 27
D1 lymphadenectomy reers to a limited dissection o
America and Europe, results rom the Intergroup INT- the perigastric lymph nodes, whereas D2 reers to the
011642 (the adjuvant chemoradiotherapy approach) and removal o nodes along the hepatic, let gastric, celiac,
Medical Research Council Adjuvant Inusional Chemo- and splenic arteries, as well as those in the splenic
therapy (MAGIC)43 (the perioperative chemotherapy hilum. A D3 lymph node dissection includes lymph
approach) trials established the standard o care in the nodes located within the porta hepatis and periaortic
early 2000s. Most recent trials like FLOT (continuous regions.
inusion 5-FU, leucovorin, oxaliplatin, and docetaxel) Proponents o extended lymphadenectomy argue
given perioperatively have also become standard o that only with extended dissection can accurate stag-
care. In Asia, however, adjuvant chemotherapy ater a ing be guaranteed, which also implies accurate pre-
D2 nodal dissection is considered the gold standard.44,45 diction o stage-specic survival. Furthermore, with
Unortunately, the main therapeutic goal in patients extensive nodal dissection, locoregional relapse rates
with unresectable locally advanced disease remains are lower. Using SEER Project data rom 1973 to 2000,
symptom palliation. The treatment o unresectable Schwarz and Smith49 evaluated 1377 patients with
locally advanced and metastatic gastric cancers is locally advanced gastric cancer (stages IIIA, IIIB, and
discussed in two separate subsections: Unresectable IV, M0). The total lymph node (LN) count (or number
Locally Advanced Gastric, Gastroesophageal Junction, o negative LNs examined; P < .0001) and number o
and Esophageal Cancers; and Advanced and Meta- positive LNs (P < .0001) were independent prognos-
static Gastric, Gastroesophageal Junction, and Esopha- tic survival predictors. Furthermore, the stage-based
geal Cancers. survival prediction depended on the total LN number
and number o negative LNs. In their earlier analysis o
SEER data rom 1973 to 1999, these same investigators
Resectable Disease
demonstrated that or every 10 extra LNs dissected,
Surgery survival improved by 7.6% (T1/2N0), 5.7% (T1/2N1),
Surgical resection oers the best chance or long-term 11% (T3N0), or 7% (T3N1).50 The results o this analy-
survival in patients with localized disease, particularly sis demonstrated that or all T stages, extensive nodal
in combination with postoperative (adjuvant) chemo- dissection aects survival outcomes. Similarly, a 5-year
radiotherapy42 or perioperative chemotherapy.43 Even survival benet was reported or patients with D2 and
with newer staging modalities, the major barrier to D3 dissections compared with D1 lymphadenectomy
accurately identiy patients with potentially resectable (60% vs 54%, P = .041) in a Taiwanese study involving
disease is the ability to accurately stage disease. In the 221 patients with resectable gastric cancer.51
United States, 67% o patients present with stage III or Despite this evidence, prospective studies per-
IV disease, and only 10% present with stage I disease.46 ormed in non-Asian countries were unable to conrm
By denition, curative resection (also reerred to these ndings.41,52–54 The Medical Research Council
as R0 resection) involves removal o the primary can- (MRC) randomly assigned 400 patients with resectable
cer and regional lymph nodes with ree margins. The gastric cancer to D1 or D2 nodal dissection. Postopera-
goals o surgery are twoold: local control and (it is tive morbidity and mortality rates were higher or D2
(46% and 13%) than or D1 (28% and 6%) dissection.54 A second, French study supports the ndings o the
Both the initial and long-term ollow-up results in the MAGIC trial. The Fédération Nationale des Centres
Dutch Gastric Cancer Group study demonstrated a sig- de Lutte Contre le Cancer (FNCLCC) and the Fédéra-
nicant increase in morbidity and mortality, with no tion Francophone de Cancérologie Digestive (FFCD)
survival dierence between D1 and D2 dissections.41,53 multicenter phase 3 trial was terminated prematurely
Although these large prospective studies perormed in or poor accrual and is thereore not adequately pow-
non-Asian countries could not conrm the initial nd- ered.60 Overall, 224 patients with resectable adenocar-
ings, they went on to suggest that extended lymph- cinoma o the lower esophagus, GEJ, or stomach (only
adenectomy carries increased rates o morbidity and 25%) were randomly assigned to either perioperative
mortality, with a negligible change in survival. chemotherapy (with cisplatin and 5-FU) and surgery
Despite some disagreement about the benets o ollowed by three to our cycles o cisplatin and 5-FU
D2 dissection, most experts agree that localized gastric or surgery alone. Only approximately 50% o patients
cancer with clinical stage higher than T1b is best treated received any postoperative chemotherapy. Despite
with multidisciplinary approaches and at high-volume these issues, the chemotherapy and surgery group
centers, particularly by high-volume surgeons.55,56 We had a signicantly higher OS (HR or death, 0.69; 95%
acknowledge that the literature lacks convincing results CI 0.50–0.95; P = .02) and disease-ree survival (DFS;
in avor o D2 dissection in randomized studies to date HR or recurrence or death, 0.65; 95% CI 0.48–0.89;
that have compared D1 versus D2 dissections; however, P = .003). Five-year survival rates were 38% (95% CI
the pendulum is swinging in avor o a more thorough 29%–47%) in the chemotherapy and surgery group
ChApTER 27
nodal dissection by experienced surgeons. A nodal dis- compared with 24% (95% CI 17%–33%) in the sur-
section approaching D2 can have the ollowing advan- gery group. These results are quite similar to those o
tages: accurate nodal staging and removal o more the MAGIC trial and bring into question the useul-
uninvolved nodes, which is associated with prolonged ness o the addition o epirubicin to cisplatin and 5-FU.
survival.53,57 A 15-year update o the Dutch trial showed In contrast, a study by the European Organiza-
benet in the D2 group in terms o the hazard ratio (HR) tion or Research and Treatment o Cancer (EORTC
or gastric cancer–related death (0.74; 95% CI, 0.59–0.93; 40954) did not demonstrate a benet rom the addition
P = .01); however, only a ew patients were at risk.58 o perioperative chemotherapy.61 This trial showed a
signicantly increased R0 resection rate but ailed to
Perioperative Chemotherapy demonstrate a survival benet with the addition o
This approach is based on the assumption that neoad- chemotherapy; however, it was not suciently pow-
juvant systemic therapy can lead to tumor downstag- ered to demonstrate a dierence, given its premature
ing, leading to an improved R0 resection rate. This is termination because o poor accrual.
particularly signicant in Western patients in whom the The Arbeitsgemeinschat Internistische Onkologie
tumors are usually bulky at diagnosis.59 The MAGIC (AIO) German group conducted a multicenter, open-
trial established level 1 evidence or this approach.43 label, randomized phase 2/3 trial (FLOT4) comparing
The study enrolled 503 patients with gastric, GEJ, and our pre- and our postoperative cycles o conven-
esophageal adenocarcinoma.43 These patients were tional ECF versus FLOT in 716 patients with resect-
randomly assigned to receive three cycles o periop- able gastric or GEJ adenocarcinoma. Most patients
erative chemotherapy consisting o epirubicin, cispla- had T3–4 disease (79%–83%) and were node-positive
tin, and inusional 5-fuorouracil (5-FU) (ECF) ollowed (78%–81%), and a minority had diuse histology
by surgery, ollowed by three more cycles o ECF, or primaries (27%). The OS was signicantly improved
surgery ollowed by observation. In this trial, post- with FLOT versus ECF (50 vs 35 months; HR 0.77; P
operative chemotherapy proved hard to deliver, with = .012), with a projected improvement in 5-year OS
only 34% o patients receiving this treatment, and (45% vs 36%). PFS was also improved with FLOT (30
only 68% o patients underwent a curative resection. vs 18 months; HR 0.75; P = .0036), as were rates o
Despite this, both progression-ree survival (PFS) and R0 resection (85% vs 78%), tumor stage T1 or higher
OS were improved in the group receiving ECF (HR or (25% vs 15%), and nodal status N0 (49% vs 41%).
progression, 0.66; 95% CI 0.53–0.81; P < .001; HR or Rates o adverse events were comparable or the two
death, 0.75; 95% CI 0.60–0.93; P = .009). Five-year sur- regimens. The FLOT4 study has established FLOT as
vival rates were 36.3% (95% CI 29.5%–43.0%) among the new standard o care or perioperative chemother-
patients in the perioperative chemotherapy group and apy in patients with resectable gastric cancer who can
23.0% (95% CI 16.6%–29.4%) among those in the tolerate a triplet chemotherapy regimen.62
surgery group.43 Taken together, these data suggest The Japanese Clinical Oncology Group (JCOG
that the majority o the benet may in act come rom 0501) published results rom their randomized phase
the preoperative portion o the chemotherapy. 3 trial o gastrectomy with or without neoadjuvant
S-1 plus cisplatin or type 4 (linitis plastica) or large and ater 5-FU plus concurrent radiation in 546 patients
type 3 (>8 cm ulcerative) gastric cancer. Patients were with gastric or GEJ tumors ater curative resection.64 In
randomly assigned to surgery ollowed by adjuvant a preliminary report presented at the 2011 American
chemotherapy (S-1, days 1–28, q42d or 1 year) (Arm Society o Clinical Oncology annual meeting, patients
A) or neoadjuvant chemotherapy (NAC) (S-1, 80–120 receiving ECF had lower rates o diarrhea, mucositis,
mg/body, days 1–21 and cisplatin, 60 mg/m2, day 8, and grade 4 or worse neutropenia. Overall survival, the
q28d, 2 courses) ollowed by gastrectomy plus the primary end point, was not signicantly better with ECF
same adjuvant chemotherapy (Arm B). The primary (3-year OS, 52% vs 50% or ECF and 5-FU/LV, respec-
end point was OS. S-1 adjuvant chemotherapy or one tively), regardless o the location o the primary tumor.
year showed remarkable survival results or type 4 or The Adjuvant Chemoradiation Therapy in Stom-
large type 3 gastric cancer, and additional NAC with ach Cancer (ARTIST) trial compared adjuvant chemo-
S-1 plus CDDP was not recommended.63 radiotherapy with adjuvant chemotherapy ater an
R0 resection with D2 dissection in 458 patients.66
Postoperative Chemoradiotherapy The ARTIST trial was a negative study because its
The indication o adjuvant chemoradiotherapy primary end point, 3-year DFS rate, was not statisti-
comes rom level 1 evidence o its benet rom the cally dierent between the two groups. In subgroup
Intergroup INT-0116 trial that showed a signicant analyses, patients with node-positive disease in the
improvement in OS in the group o patients treated adjuvant chemoradiotherapy group had a signi-
with adjuvant chemoradiotherapy.42,64 In this trial, 559 cantly improved 3-year DFS rate than those in the
ChApTER 27
patients with stage IB to IV disease were randomly adjuvant chemotherapy group. The improved DFS
assigned to chemoradiotherapy ater surgery or sur- among patients with node-positive disease was later
gery alone. The chemoradiotherapy group received conrmed in the recently published update; however,
chemotherapy consisting o one 5-day cycle o 5-FU there was no improved OS despite the prolonged
and leucovorin (LV) starting on day 1, ollowed by ollow-up interval.67 This improved DFS nding may
chemoradiotherapy beginning 28 days ater the start suggest that compared with adjuvant chemother-
o the initial cycle o chemotherapy. Chemoradio- apy, adjuvant chemoradiotherapy may be benecial
therapy consisted o 45 Gy o radiation at 1.8 Gy/ among patients with node-positive resectable gastric
day 5 days per week or 5 weeks, with 5-FU (400 mg/ cancer, a theory that was tested in the ARTIST-2 trial
m2/d) and LV (20 mg/m2/d) on the rst our and the (see below). Dierent rom INT0116, all patients in
last three days o radiotherapy. One month ater the the ARTIST-2 trial were required to have a D2 nodal
completion o radiotherapy, two 5-day cycles o 5-FU dissection, and the chemotherapy administered to all
(425 mg/m2/d) plus LV (20 mg/m2/d) were given one patients consisted o S-1 versus S-1 and oxaliplatin
month apart. The 3-year survival rates were 50% in with or without radiotherapy. Hence, ARTIST-2 was
the chemoradiotherapy group and 41% in the sur- designed to evaluate the benet o chemoradiother-
gery-only group. The HR or death in the surgery-only apy ater a D2 nodal dissection.68,69
group, compared with the chemoradiotherapy group, The Dutch phase 3 (CRITICS) trial evaluated the
was 1.35 (95% CI 1.09–1.66; P = .005). The HR or strategy to integrate postoperative chemoradiotherapy
relapse in the surgery-only group, compared with the with conventional perioperative strategy.70 Postopera-
chemoradiotherapy group, was 1.52 (95% CI 1.23– tive chemoradiotherapy in addition to preoperative
1.86; P < .001).42 Recently updated results o this study chemotherapy did not improve OS compared with
continue to demonstrate a benet in terms o both OS perioperative chemotherapy in patients with resect-
and recurrence-ree survival (RFS).65 The major issue able gastric cancer treated with adequate preopera-
o this study was that the majority o patients did tive chemotherapy and surgery. In this study, only
not receive an adequate LN dissection. Although a D1 60% o all randomly assigned patients could receive
resection was mandated per protocol, more than 50% the planned postoperative treatment, which was
o patients underwent a D0 resection, and only 10% consistent with the MAGIC approach. Optimizing
o patients underwent a D2 nodal dissection. There- preoperative strategies is the ocus o the CRITICS II
ore, it is questioned whether the survival dierence (NCT02931890) study.71
occurred because o inadequate surgery rather than The TOPGEAR trial, which is underway in Aus-
rom a true benet o chemoradiotherapy.42 tralia, Europe, and Canada, directly compares periop-
Cancer and Leukemia Group B (CALGB) 80101, a erative chemotherapy alone (ECF/ECX/EOX or FLOT)
US intergroup study, was designed to evaluate postop- versus preoperative chemoradiotherapy in patients
erative bolus 5-FU and LV with 5-FU plus concurrent with resectable adenocarcinoma o the stomach and
radiation (an INT0116 trial treatment regimen) versus GEJ (NCT01924819).72 Ajani et al73 reported the results
postoperative ECF (the MAGIC trial regimen) beore o several phase 2 studies that demonstrated the
easibility and eectiveness o a three-step strategy. The Lancet Oncology.67 By the clinical cuto date, 103
Thirty-seven patients with locally advanced resectable patients (20%) had died in the adjuvant capecitabine
gastric cancer were treated with trimodality therapy and oxaliplatin group versus 141 patients (27%) in the
in a phase 2 clinical trial. Chemotherapy consisted o observation group (stratied HR 0.66; 95% CI 0.51–
inusional 5-FU, cisplatin, and paclitaxel (FPT); 45 Gy 0.85, P = .0015). Estimated 5-year OS was 78% (95%
o radiotherapy was administered concurrently with CI 74%–82%) in the adjuvant capecitabine and oxali-
FPT. R0 and pathologic complete response (pathCR) platin group versus 69% (95% CI 64%–73%) in the
rates were 95% and 30%, respectively. Fourteen per- observation group. Based on these results, CAPOX has
cent o patients had only microscopic residual disease. been established as another standard postoperative
Patients who achieved pathCR or pathologic partial treatment or patients with stage II/III gastric cancer
response ater preoperative chemoradiotherapy had in Asia.
signicantly longer median survival durations than Recently, Japan Clinical Cancer Research Organiza-
those who did not (63.9 vs 12.6 months; P = .03). tion (JACCRO) demonstrated the superiority o RFS
As a result o the MDACC’s single-institution suc- (HR 0.632) o docetaxel plus S1 (DS) versus S1 alone
cess with preoperative trimodality therapy, the Radia- or stage III GC patients. In the DS group, one 3-week
tion Therapy Oncology Group (RTOG) sponsored cycle o S1 was given on days 1 to 14, ollowed by six
a multi-institution cooperative study, RTOG 9904. cycles o S1 (days 1–14) and 40 mg/m2 o docetaxel on
The primary end point was pathCR rate. Forty-nine day 1 every 3 weeks. This was ollowed by S1 on days
patients with localized resectable gastric cancer rom 1 to 28 every 6 weeks or up to one year. Postoperative
ChApTER 27
20 institutions received 5-FU, LV, and cisplatin (FLP) DS has become the new standard or the curatively
as induction chemotherapy, ollowed by concurrent resected stage III GC in Japan.76,77
chemoradiotherapy with 5-FU and weekly paclitaxel. The Korean phase 3 trial (ARTIST-II) randomly
The pathCR and R0 resection rates were 26% and assigned, in a 1:1:1 ratio, patients with pathologically
77%, respectively. At one year, more patients who had staged II or III, node-positive, D2-resected gastric can-
achieved pathCR (82%) were alive than those who did cer, to receive adjuvant S-1 (40–60 mg twice daily 4
not (69%).74 A D2 dissection was perormed in 50% o weeks on/2 weeks o) or one year, S-1 (2 weeks on
patients. The heterogeneity o dierent treating insti- and 1 week o) plus oxaliplatin 130 mg/m2 (SOX)
tutions minimized the selection bias typical o single- or 6 months, or SOX plus chemoradiotherapy 45 Gy
institution results. Outcomes in RTOG 9904 were no (SOXRT). A total o 538 patients were included or
better or worse than those o more recent studies, par- this interim ecacy analysis.78 The DFS at 3 years
ticularly the pathCR and D2 lymphadenectomy rates. was ound to be 65%, 78%, and 73% in the S-1, SOX,
and SOXRT arms, respectively. No dierence in DFS
Postoperative Chemotherapy between SOX and SOXRT was ound (HR 0.910; P =
The benets o adjuvant chemotherapy ater a D2 .667). The independent monitoring committee ended
nodal dissection were initially demonstrated in Japan, the trial early, concluding that in patients with cura-
and the chemotherapy used was S-1.44 The Adju- tively D2-resected, stage II/III, node-positive GC,
vant Chemotherapy Trial o S-1 or Gastric Cancer adjuvant SOX was eective in prolonging DFS, when
(ACTS-GC) trial randomly assigned 1059 patients to compared with S-1 monotherapy.
one year o S-1 or observation. The updated analysis Positive results were also reported in another
ater 5 years o ollow-up has demonstrated consistent Korean trial, the PRODIGY study.79 In this trial, 530
results.75 The OS rate at 5 years was 71.7% in the S-1 patients with newly diagnosed locally advanced gastric
group and 61.1% in the surgery-only group (HR 0.669; or GEJ adenocarcinoma (cT2,3/N[+]M0 or cT4/N[any]
95% CI 0.540–0.828). The RFS rate at 5 years was M0, per AJCC 7th ed), ECOG PS 0-1, were random-
65.4% in the S-1 group and 53.1% in the surgery-alone ized 1:1 to NAC docetaxel, oxaliplatin, and S-1 (DOS)
group (HR 0.653; 95% CI 0.537–0.793). then surgery and adjuvant S-1 (n = 266), or surgery and
Another Asian study, the Capecitabine and Oxali- adjuvant S-1 (n = 264). NAC was docetaxel 50 mg/m2
platin Adjuvant Study in Stomach Cancer (CLASSIC) intravenous and oxaliplatin 100 mg/m2 intravenous on
trial, randomly assigned 1035 patients who had under- day 1, S-1 40 mg/m2 twice by mouth on days 1 to 14
gone D2 gastrectomy to capecitabine plus oxaliplatin every 3 weeks or 3 cycles. Standard surgery was D2
or 6 months or observation.45 The study demonstrated gastrectomy. DOS and postoperative S-1 showed lon-
a benet in patients treated with capecitabine and ger PFS (primary end point) over postoperative S1 in
oxaliplatin or the primary end point o DFS (at 3 years; cT2/3-LN positive or cT4 resectable GC.
HR 0.56; 95% CI 0.44–0.72; P < .0001) at the prespeci- All major phase 3 trials in localized gastric cancer
ed interim analysis. Ater this analysis, the trial was and the most important ongoing studies in this setting
stopped ater a recommendation by the data monitor- are summarized in Tables 27–3 and 27–4. Given the
ing committee. The mature OS data were published in variability in outcomes in many phase 3 trials, several
Table 273 Major Phase 3 Trials for Gastric Cancer in the Localized Setting
Primary End Point

No. o Comparison in Months
Trial Patients Treatment Arms HR or OS (P value) (Survival Rates in %)
Perioperative Chemotherapy
Cunningham et al 503 ECF → surgery → ECF vs surgery 0.75 (.009) 5-y OS: 36.3% vs 23%
(MAGIC)43
Ychou et al (FNLCC/ 224 CF → surgery → CF vs surgery 0.69 (.02) 5-y OS: 38% vs 24%
FFCP)60
Schuhmacher et al 144 CFL → surgery vs surgery (only 0.16 Underpowered to
(EORTC 40954)61 preoperative CT) demonstrate a survival end
point because o limited
accrual (144/360 patients)
Al-Batran et al 716 ECF → surgery → ECF 0.77 (.012) OS: 25 months vs 50 months
(FLOT4)62 vs FLOT → surgery → FLOT 5-y OS: 36% vs 45%
Terashima et al 300 Surgery → S1 0.74 3-y OS: 17.5% vs 27.5%
(JCOG0501)63 vs S-1+cisplatin → surgery → S1
ChApTER 27
Cunningham et al 1063 ECX+bevacizumab → surgery 1.08 (.36) 3-y OS: 48.1% vs 50.3%
(MAGIC B/ST03)80 → ECX+bevacizumab →
maintenance bevacizumab
vs ECX → Surgery → ECX
Park et al 538 Surgery → S-1 vs 0.617 (.016) S-1 vs 3-y DFS: 65% vs 78% vs 73%
(ARTIST-2)78 Surgery → S-1+oxaliplatin (SOX) SOX
vs 0.686 (.057) S-1 vs
Surgery → SOX+CTRT (SOXRT) SOXRT
Postoperative Chemoradiotherapy
Macdonald et al 556 Surgery → FL/CTRT (45 Gy+FL)/FL 1.32 (.004) OS: 36 vs 27
(INT-0116)42 vs surgery
Fuchs et al (CALGB 546 Surgery → ECF/CTRT+FL/ECF vs 1.03 (.80) OS: 38 vs 37
80101)64 surgery → FL/CTRT+FL/FL
Lee et al (ARTIST)66 458 Surgery → XP/XRT/XP vs surgery 1.130 (.5272); N+ 5-y OS: 75% vs 73%; N+
→ XP patients: HR or patients: 3-y DFS: 76% vs
DFS, 0.70 (.04) 72%
Cats et al (CRITICS)70 788 CT → surgery → CT 1.01 (.09) OS: 43 vs 37
vs CT→ surgery → CTRT
Postoperative chemotherapy
Sasabo et al 1059 Surgery → S-1 vs surgery 0.68 (.003); HR at 5 3-y OS: 80.1% vs 70.1%; 3-y
(ACTS- GC)75 years: 0.669 RFS: 72.2% vs 59.6%
Bang et al 1035 Surgery → CapeOx vs surgery 0.56 (< .0001) 3-y DFS: 74% vs 59%
(CLASSIC)45
Tsuburaya et al 1495 Surgery → UFT vs surgery → S-1 HR or DFS 0.81 3-y DFS: 53% vs 58.2%
(SAMIT), 2× 2 vs surgery → paclitaxel+UFT vs (.0048) or (UFT vs S-1), 54% vs
actorial design81 surgery → paclitaxel+S-1 monotherapy 57.2% (monotherapy vs
(0.151 or sequential)
nonineriority o
UFT), 0.92 (.273)
or monotherapy
vs sequential
Yoshida et al 915 Surgery →S-1+docetaxel vs 0.632 (<.001) 3-y RFS: 66% vs 58%
(JACCRO GC-07)77 surgery →S-1
CapeOx, capecitabine and oxaliplatin; CF, cisplatin and 5-uorouracil; CFL, cisplatin, 5-uorouracil, and leucovorin; CT, chemotherapy; CTRT, chemoradiotherapy; DFS,
disease-ree survival; ECF, epirubicin, cisplatin, and 5-uorouracil; FL, 5-uorouracil and leucovorin; HR, hazard ratio; OS, overall survival; RFS, recurrence-ree survival;
SOX, S-1 + oxaliplatin UFT, tegaur and uracil; XP, capecitabine and cisplatin; XRT, capecitabine and radiotherapy.
Table 274 List of Ongoing pase 3 Trials in Localized Gastric Cancer
Trials No. o Patients Treatment Arms Control Arm Status

Perioperative Chemotherapy
Ychou et al (FNLCC 250 CF → surgery (only neoadjuvant CT) Surgery Active, not
94012-FFCD recruiting
9703)60
Postoperative + Preoperative Chemoradiotherapy
Leong et al 752 ECF → CTRT + 5-FU–based CT → Surgery ECF → Surgery → ECF Recruiting
(TOPGEAR)72 → ECF
Kang et al 530 CT→ Surgery→ S-1 Surgery → S-1 Active, not
(PRODIGY)79 recruiting
CF, cisplatin and 5-uorouracil; CT, chemotherapy; CTRT, chemoradiotherapy; CX, cisplatin and capecitabine; ECF, epirubicin, cisplatin, and 5-uorouracil; ECX,
epirubicin, cisplatin, and capecitabine; 5-FU, 5-uorouracil; S-1 Ox, S-1 and oxaliplatin.
Table 275 perioerative or postoerative Teray for Localized Gastric Cancer: Results of
ChApTER 27
Meta-Analyses
Reerence No. o Studies No. o Patients HR or OS Treatment

82
Diaz-Nieto et al 34 7,824 0.85 Postoperative chemotherapy
83
Ronellentsch et al 14 2,422 0.81 Perioperative chemo(radio)therapy
Oba et al84 14 3,288 DFS: 0.92 Postoperative chemotherapy
Earle et al84 13 NR (non-Asian 0.80 Postoperative chemotherapy
patients)
DFS, disease-ree survival; HR, hazard ratio; NR, not reported yet; OS, overall survival.
meta-analyses have been undertaken (Table 27–5), all was reduced by 15% (HR or death, 0.85; 95% CI
o which support a signicant survival benet or peri- 0.80–0.90).
operative or adjuvant chemotherapy with somewhat Based on the previously mentioned trials and meta-
better prognosis shown in Asian compared with West- analyses, postoperative chemoradiotherapy (United
ern populations,82–84, including one that was limited States), perioperative chemotherapy (Europe), and
to trials rom Western (non-Asian) countries.85 One adjuvant chemotherapy ater a D2 nodal dissection
o the most recent o these analyses evaluated data (Asia) can all be regarded as standards o care in the
rom 34 randomized trials comparing adjuvant sys- management o localized gastric cancer.
temic chemotherapy versus surgery alone, conducted Figure 27-3A summarizes MDACC’s approach to
in both Asian and Western populations.82 The risk o localized gastroesophageal cancer.
death in patients receiving adjuvant chemotherapy

RESECTABLE GASTRIC CANCER
J All patients with newly diagnosed gastric cancer or all patients, but it is especially useul or those
undergo a CT imaging and upper endoscopy. with resectable disease. Preoperative trimodality
J Patients with resectable gastric cancer also undergo therapy consisting o induction chemotherapy ol-
EUS and diagnostic laparoscopy with peritoneal lowed by chemoradiotherapy and then surgical
washings. resection has been tested and evolved at MDACC
over many years.
J MDACC has been developing the practice o multi-
modality management in a multidisciplinary setting
Unresectable/
Definitive
Cervical/
Chemo-
Esophagus/
radiotherapy
SCC
Endoscopic
T1aN0
Management
Resectable
Localized Multidisciplinary
Mid-
Esophageal, Evaluation,
Esophageal, T2N0 Esophagectomy
GEJ and PET, CT,
Esophagus,
gastric cancer EUS
GEJ
Concurrent
>T1N+ Esophagectomy
chemoradiation
ChApTER 27
Endoscopic
T1aN0
Management
Gastric Surgical
T1bN0
Cancer management
Chemotherapy+
T2N0 or Laparoscopy
Chemo-
T1aN+ or for all patients
radiotherapy +
T1b-T3N+ >T1b
A D2 dissection
Ramucirumab
MSS
±Paclitaxel*
Platinum-based
HER 2+ Chemotherapy + PD-L1 = 0 TAS-102
Metastatic Trastuzumab
Esophageal, Second-line Third-line
GEJ and treatment treatment
Gastric Cancer Platinum-based
HER 2– PD-L1 ≥ 1% Pembrolizumab
Chemotherapy
MSI Pembrolizumab
*consider FOLFIRI in second or third-line treatment.
B
FIGURE 27–3 The University o Texas MD Anderson Cancer Center Treatment algorithms or (A) localized gastroesophageal
cancer and (B) metastatic gastroesophageal cancer. CT, computed tomography; EUS, endoscopic ultrasound; GEJ, gastro-
esophageal junction; HER2, human epidermal growth actor receptor 2; PET, positron emission tomography; PS, perormance
status; SCC, squamous cell carcinoma.
ESOphAGEAL AND cancer death worldwide.86 In 2020, the estimated num-

GASTROESOphAGEAL JUNCTION bers o new cases and deaths rom esophageal cancer
CANCERS in the United States are 18,440 and 16,170, respec-
tively.2 Esophageal cancer is three to our times more
Esophageal cancer is estimated to be the eighth most common in men than in women,87 with a mean age o
common cause o cancer death among men in the 67 years.88 The lietime risk o developing esophageal
United States and the th most common cause o cancer is 1 in 125 or men and 1 in 435 or women.87 For
classication purposes (AJCC staging, 8th ed), primary can also increase the risk. Some data have suggested
tumors o the GEJ and proximal gastric cancer with that interactions between risk actors may be more
epicenters extending no more than 2 cm into the stom- important than individual risk actors. A study was
ach are included with esophageal cancers. The inci- perormed on 305 patients with esophageal adenocar-
dence o GEJ cancer has continued to increase over the cinoma and 339 age- and sex-matched controls; the
last several decades. In recent years, this trend reached strongest individual risk actor identied was refux.101
a new plateau, coinciding with the increased incidence Barrett esophagus (BE) is generally believed to be a
o distal esophageal adenocarcinoma since the mid- consequence o severe and chronic gastroesophageal
1990s, a phenomenon conned to North America and refux disease. The presence o BE is associated with
other non-Asian countries. Overall, the prognosis o an increased risk o esophageal adenocarcinoma. The
patients with esophageal/GEJ cancer remains poor. median age o BE diagnosis is 40 to 55 years, and it is
Histologic type makes a dierence, because SCC has a most common in men.102
poorer prognosis than adenocarcinoma. Surgery is still
the only chance or cure, and survival can be improved
with multimodality therapy.
The presenting symptoms o esophageal cancer usu-
Epidemiologic Characteristics ally include dysphagia, weight loss, bleeding, throat
pain, and hoarseness. Early symptoms are usually
Although SCC is the most common histologic type in nonspecic, and the patient may present with subtle
ChApTER 27
many parts o the world, it is relatively uncommon out- symptoms, or example, ood “sticking” transiently
side o Asian and Middle Eastern countries. Squamous and refux/regurgitation o ood or saliva. This may
cell cancer is 20 times more common in China than in precede rank dysphagia, which by all accounts is the
the United States.89 Esophageal cancer has a poor sur- most common complaint and becomes apparent when
vival rate; only 19.9% o patients in the United States3 the esophageal lumen is narrowed to one-third o its
and 10% o patients in Europe90 survive at 5 years. normal diameter. For proximal esophageal tumors,
increasing cough may be a sign o tracheoesophageal
stula. Chronic GI blood loss resulting rom esopha-
Etiologic Characteristics and Risk Factors geal cancer may result in iron deciency anemia.
The most signicant risk actors associated with almost
90% o esophageal SCCs (ESCCs) are tobacco use,
alcohol use, and a diet low in ruits and vegetables.10,91
Pathologic Characteristics
Smoking and alcohol can synergistically increase the Esophageal cancer includes adenocarcinoma, SCC,
risk o ESCC. Dietary associations with ESCC, such as mucoepidermoid carcinoma, small cell cancer, sar-
oods containing N-nitroso compounds, have long been coma, adenoid cystic carcinoma, and primary lym-
implicated.92 Betel nut chewing, widespread in certain phoma. Adenocarcinoma is now more prevalent than
regions o Asia,93 and the ingestion o hot oods and SCC in non-Asian countries and primarily develops in
beverages (such as tea)94 in other endemic regions, such the distal esophagus.103 In general, SCC is ound in the
as Iran, Russia, and South Arica, have been associated upper hal o the esophagus, whereas adenocarcinoma
with ESCC. Long-standing achalasia increases the risk predominates closer to the GEJ. This chapter ocuses
o SCC by 16 times.95 On average, SCC develops 41 on carcinomas o the esophagus/GEJ, whereas other
years ater ingestion o lye. Tylosis, a rare disease associ- chapters in this book are dedicated to other types o
ated with hyperkeratosis o the palms o the hands and malignancy o the esophagus/GEJ.
soles o the eet, is associated with a high rate o ESCC.96
Unlike SCC, the risk actors or esophageal adeno-
carcinoma remain elusive. The strongest and most
Staging and Prognosis
consistent risk actors include gastroesophageal refux Esophageal cancer is a treatable disease but is rarely
disease, smoking, obesity,97 and dietary exposure curable. Since the mid-1990s, the histologic type and
to nitrosamines; these are ound in almost 80% o location o cancer o the upper GI tract have changed.
cases in the United States.98 According to a Denmark The incidences o proximal gastric, GEJ, and distal
study, more than 50% o esophageal adenocarcinoma esophageal adenocarcinomas have steadily increased
cases were ound to have no history o symptomatic up until the last several years, where it now appears to
refux disease.99 However, a large study conducted in have reached a steady state. The most current version
Sweden demonstrated an association between refux o the AJCC TNM staging (8th edition, Tables 27–6,
symptoms and esophageal adenocarcinoma (odds A–G) now includes primary tumors o the GEJ or prox-
ratio, 7.7) and adenocarcinoma o gastric cardia (odds imal gastric cancer extending 2 cm into the stomach as
ratio, 2.0).100 A high-at, low-protein, high-calorie diet part o esophageal cancer staging.39
Table 276A American Joint Cancer Committee TNM Staging System for Gastroesoageal Junction
and Esoageal Cancers
Primary Tumor (T)

T0 No evidence o primary tumor
Tis High-grade dysplasia, dened as malignant cells conned to the epithelium by the basement membrane
T1 Tumor invades lamina propria, muscularis mucosae, or submucosa
T1a Tumor invades lamina propria or muscularis mucosae
T2 Tumor invades muscularis propria
T3 Tumor invades adventitia
T4 Tumor invades adjacent structures
T4a Tumor invades the pleura, pericardium, azygos vein, diaphragm, or peritoneum
T4b Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc.
ChApTER 27
Nx Regional nodes cannot be assessed
N0 No regional nodal metastasis
N3 Metastasis in ≥7 regional lymph nodes
Distant Metastases (M)
M1 Distant metastases
Grade (G)
GX Grade cannot be assessed—stage grouping as G1
G1 Well dierentiated
G2 Moderately dierentiated
G3 Poorly dierentiated
G4 Undierentiated—stage group as G3 squamous
Location
Upper 15 to <20 cm
Middle 25 to <30 cm
Lower 30–45 cm
AJCC prognostic Stage Grous for Esoageal Squamous Cell Carcinoma B. Clinical (cTNM)
When cT is ... And cN is ... And M is ... Then the stage group is ...
Tis N0 M0 0
T1 N0–1 M0 I
T2 N0–1 M0 II
T3 N0 M0 II
T3 N1 M0 III
T13 N2 M0 III
T4 N0–2 M0 IVA
Any T N3 M0 IVA
Any T Any N M1 IVB
C. Pathological (pTNM)
When pT is ... And pN is ... And M is ... And G is ... And Location is ... Then the stage group is ...
Tis N0 M0 N/A Any 0
T1a N0 M0 G1 Any IA
T1a N0 M0 G2–3 Any IB
T1a N0 M0 GX Any IA
T1b N0 M0 G1–3 Any IB
T1b N0 M0 GX Any IB
T2 N0 M0 G1 Any IB
T2 N0 M0 G2–3 Any IIA
T2 N0 M0 GX Any IIA
T3 N0 M0 G1–3 Lower IIA
T3 N0 M0 G1 Upper/Middle IIA
T3 N0 M0 G2–3 Upper/Middle IIB
T3 N0 M0 GX Lower/Upper/Middle IIB
T3 N0 M0 Any Location X IIB
ChApTER 27
T1 N1 M0 Any Any IIB

T1 N2 M0 Any Any IIIA
T2 N1 M0 Any Any IIIA
T2 N2 M0 Any Any IIIB
T3 N1–2 M0 Any Any IIIB
T4a N0–1 M0 Any Any IIIB
T4a N2 M0 Any Any IVA
T4b N0–2 M0 Any Any IVA
Any T N3 M0 Any Any IVA
Any T Any N M1 Any Any IVB
D. post-neoadjuvant Teray (yTNM)
When ypT is ... And ypN is ... And M is ... Then the stage group is ...
T0-2 No M0 I
T3 N0 M0 II
T02 N1 M0 IIIA
T3 N1 M0 IIIB
T03 N2 M0 IIIB
T4a N0 M0 IIIB
T4a N1–2 M0 IVA
T4a NX M0 IVA
T4b N0–2 M0 IVA
Any T N3 M0 IVA
Any T Any N M1 IVB
AJCC prognostic Stage Grous for Esoageal Adenocarcinoma E. Clinical (cTNM)
When cT is … And cN is ... And M is ... Then the stage group is ...
Tis N0 M0 0
T1 N0 M0 I
T1 N1 M0 IIA
T2 N0 M0 IIB
When cT is … And cN is ... And M is ... Then the stage group is ...
T2 N1 M0 III
T3 N0–1 M0 III
T4a N0–1 M0 III
T14a N2 M0 IVA
T4b N0–2 M0 IVA
Any T N3 M0 IVA
Any T Any N M1 IVB
F. patological (TNM)
Then the stage group

When pT is ... And pN is ... And M is ... And G is ... is …
Tis N0 M0 N/A 0
T1a N0 M0 G1 IA
T1a N0 M0 GX IA
ChApTER 27
T1a N0 M0 G2 IB
T1b N0 M0 G1–2 IB
T1b N0 M0 GX IB
T1 N0 M0 G3 IC
T2 N0 M0 G1–2 IC
T2 N0 M0 G3 IIA
T1 N1 M0 Any IIB
T3 N0 M0 Any IIB
T1 N2 M0 Any IIIA
T2 N1 M0 Any IIIA
T2 N2 M0 Any IIIB
T3 N1–2 M0 Any IIIB
T4a N0–1 M0 Any IIIB
T4a N2 M0 Any IVA
T4b N0–2 M0 Any IVA
Any T N3 M0 Any IVA
Any T Any N M1 Any IVB
G. post-neoadjuvant Teray (yTNM)
When ypT is … And yp N is … And M is ... Then the stage group is ...
T0-2 N0 M0 I
T3 N0 M0 II
T02 N1 M0 IIIA
T3 N1 M0 IIIB
T03 N2 M0 IIIB
T4a N0 M0 IIIB
T4a N1–2 M0 IVA
T4a NX M0 IVA
T4b N0–2 M0 IVA
Any T N3 M0 IVA
Any T Any N M1 IVB
Used with permission o the American College o Surgeons, Chicago, Illinois. The original source or this inormation is the AJCC Cancer Staging System (2020)
Clinical staging uses EGD with EUS, CT, and FDG- been perormed in patients with esophageal cancer
PET. In patients with proximal esophageal cancer, ater preoperative treatment, with PET being exam-
additional bronchoscopy is recommended to evaluate ined or predicting prognosis.104,106 and treatment
potential tracheal invasion or document and palliate response.107 Fluorodeoxyglucose-PET can better reveal
tracheoesophageal stula. Among patients with dis- bone metastasis than bone scans108 and commonly
ease extending into the stomach, most experts agree refects images o multiple oci o intense uptake. Stud-
that laparoscopic peritoneal staging is also necessary to ies have shown signicant correlations between FDG
evaluate occult peritoneal seeding that is not well visu- uptake and tumor invasion depth and LN metastasis
alized with noninvasive modalities (Figs. 27–4 to 27–9). and survival rates, with a high degree o accuracy in
In various studies, FDG-PET has been consistently the neck and upper thoracic and abdominal regions.109
shown to have better specicity than CT at diagnosing Unlike with gastric cancer, FDG-PET results have been
metastatic disease and LN status. PET serves the pri- ound to be important predictors o response and
mary purpose o detecting occult metastases that are prognosis. In a retrospective analysis, Swisher et al
present in 15% to 20% o patients newly diagnosed reported the results o FDG-PET use in 103 consecutive
with esophageal cancer.104,106 Multiple studies have patients with locally advanced esophageal cancer who
ChApTER 27
FIGURE 27–5 Esophageal mass, endoscopic view. (Used

with permission rom Klaus Monkemuller, MD, University o
FIGURE 27–4 Barrett esophagus, endoscopic view. (Used Alabama at Birmingham, Birmingham, Ala.)
with permission rom Klaus Monkemuller, MD, University o
Alabama at Birmingham, Birmingham, Ala.)
FIGURE 27–6 A. Schematic representation o esophagus layers showing depth

o tumor invasion. B. Endoscopic ultrasound image o T1 esophageal cancer.
(Reproduced with permission rom http://www.massgeneral.org/gastro/endo_
homepage.htm)
FIGURE 27–7 A. Schematic representation o esophagus layers showing depth o tumor invasion. B. Endoscopic ultrasound
image o T2 esophageal cancer. (Reproduced with permission rom http://www.massgeneral.org/gastro/endo_ homepage.
htm)
ChApTER 27
FIGURE 27–8 A. Schematic representation o esophagus layers showing depth o tumor invasion. B. Endoscopic ultrasound
image o T3 esophageal cancer. (Reproduced with permission rom http://www.massgeneral.org/gastro/endo_ homepage.
htm)
underwent preoperative chemoradiotherapy.110 At sur- o Neoadjuvant Chemotherapy in Esophageal and

gery, 58 patients (56%) had experienced a pathologic Esophagogastric Adenocarcinoma (MUNICON-1)
response to chemoradiotherapy (surgical pathologic trial. Lordick et al36 evaluated the easibility and
results ≤10% viable residual cancer cells). Pathologic applicability o FDG-PET in clinical practice in 110
response was associated with FDG-PET standardized evaluable patients with locally advanced esophageal
uptake value (SUV) (3.1 vs 5.8, P = .01). A post-chemo- adenocarcinoma. Patients with adenocarcinoma o the
radiotherapy FDG-PET SUV o 4 or higher had the esophagogastric junction types I and II (tumors extend-
highest accuracy and was an independent predictor o ing to the esophagus 5 cm above and 2 cm below the
survival (HR 3.5; P = .04) on multivariate analysis.110 GEJ) underwent 2 weeks o induction chemotherapy
Perhaps the strongest endorsement or using with platinum and 5-FU (FLP). Fluorodeoxyglucose-
FDG-PET as a predictor o response came rom the PET scans were obtained or all patients at baseline
Metabolic Response Evaluation or Individualization and ater induction chemotherapy. Metabolic response
chemotherapy or 3 months beore surgery. This

prospective study showed the easibility o a PET-
guided treatment algorithm. However, by comparing
the groups o nonresponding patients in the current
trial and the previous published MUNICON I trial,
increased histopathologic response was observed ater
salvage radiochemotherapy, but the primary end point
o the study to increase the R0 resection rate was not
met.111
Treatment
The gold standard or treating high-grade dysplasia
and early or supercial esophageal cancer is esophagec-
tomy. However, endoscopic mucosal resection (EMR)/
endoscopic submucosal dissection, with or without
photodynamic therapy, has become a popular alter-
native to surgery or early esophageal disease. Endo-
scopic mucosal resection has been reported in several
ChApTER 27
small prospective case series to be eective, with an

initial complete remission rate o 59% to 99%.112,113
The ideal clinical characteristics or EMR are small (<2
FIGURE 27–9 A. Endoscopic image o T4 esophageal cancer. cm diameter), solitary, fat lesions that are conned
B. Endoscopic ultrasound image o the same tumor. (Repro- to the mucosa (T1a). Because EMR has a relatively
duced with permission rom http://www.massgeneral.org/ high recurrence rate, it is recommended that BE and
gastro/endo_homepage.htm) high-grade dysplasia or patients with early esophageal
cancer be ollowed up endoscopically every 3 months
during the rst year and annually thereater. Compli-
was dened as an SUV decrease by 35% or more. cations associated with EMR are bleeding (4%–46%),
Responders underwent more chemotherapy with FLP peroration (1%), and stricture (20%).114
or olinic acid and fuorouracil plus cisplatin and pacli- Despite the recognized epidemiologic and clinical
taxel, or olinic acid, 5-FU, and oxaliplatin (FOLFOX) dierences between ESCCs and adenocarcinomas,
or 12 weeks ollowed by surgery. Nonresponders there is still inadequate evidence that treatment or
discontinued urther chemotherapy ater the 2 weeks esophageal cancer should be based on histologic type.
o initial induction chemotherapy and underwent sur- Locally advanced cervical esophageal cancer is preer-
gery. In this study, there were 54 responders (meta- ably managed with denitive chemoradiotherapy. For
bolic response rate, 49%). One-hundred our patients all other esophageal cancers, current evidence sup-
(54 responders and 50 nonresponders) underwent sur- ports the use o preoperative chemoradiotherapy to
gery. At 2.3 years o ollow-up, the median OS was not enhance surgical survival outcome in patients with
reached or responders and was 25.8 months (HR 2.13; locally advanced resectable disease.115 Surgery remains
P = .015) or nonresponders. The median event-ree the best chance or long-term survival. Ongoing inter-
survival durations or responders and nonresponders national clinical research with novel cytotoxic and
were 29.7 months and 14.1 months, respectively (HR targeted agents will continue to urther dene and
2.18; P = .002). Major pathologic remissions (<10% improve survival outcomes o patients with locally
residual tumor) were noted in 58% o responders and advanced curable esophageal and GEJ cancers. Unor-
0% o nonresponders.36 In the MUNICON-1 study, tunately, the main therapeutic goal is symptom pal-
the response to induction therapy was valuable or liation in patients with locally advanced, unresectable
stratiying patients to appropriate therapy, urther disease.
establishing the clinical utility o FDG-PET in limit-
ing exposure to unnecessary toxicity and maximizing
Resectable Disease
therapeutic benets. The MUNICON-2 prospective
trial was carried out to improve the clinical outcome o Surgery
metabolic nonresponders using a salvage neoadjuvant Only 23% o patients with esophageal cancer pres-
radiochemotherapy. In this study, PET nonresponders ent with clinically resectable localized disease.116
received salvage neoadjuvant radiochemotherapy, Surgical resection is the mainstay o treatment or
whereas metabolic responders received neoadjuvant these patients117 and should only be recommended as
upront treatment in T1b/T2 tumors without nodal Cisplatin plus 5-FU (CF) was administered in both
involvement by EUS. Recent data indicate that the studies. The two studies had completely divergent
overall 5-year survival rate o patients with esophageal ndings. INT0113 ound no clinical/pathologic benet
cancer ater curative surgery is about 25%.42,43,118 or survival improvement with preoperative chemo-
Thereore, preoperative chemotherapy or preopera- therapy ollowed by surgery compared with surgery
tive chemoradiotherapy have become the mainstay alone.121 The median survival was 14.9 months or
strategies or treatment to improve surgical outcome, patients who received preoperative chemotherapy
whereas denitive chemoradiotherapy has been rec- and 16.1 months or those who underwent immedi-
ommended or patients with cervical tumors or unre- ate surgery (P = .53). The recent updated analysis o
sectable disease. INT0113 conrmed the lack o benet o preoperative
Cancers o the middle or lower third o the esopha- chemotherapy.123 The MRC-OEO-2 trial, however,
gus (SCC or esophageal adenocarcinoma, except GEJ reported a statistically signicant improved R0 resec-
cancers) generally require total esophagectomy, which tion rate (78% vs 70%) and median OS time (17.2 vs
is a challenging procedure with a high complication 13.3 months) in patients who underwent preoperative
rate. No uniorm surgical approaches to curative resec- chemotherapy.122 Results o both INT0113 and OEO-2
tion exist, but the most common procedures in North studies did not help determine the role o preoperative
America include transhiatal, transthoracic (Ivor-Lewis), chemotherapy in patients with resectable esophageal
and tri-incisional esophagectomy. For patients with cancer. In the United Kingdom and other countries in
potentially resectable disease, R0 resection is generally Europe, preoperative chemotherapy has become the
ChApTER 27
believed to be necessary to achieve durable survival.119 acceptable standard o care.
R0 resection is dened as resection o the primary The three most recent randomized studies o pre-
tumor with negative proximal, distal, and circumeren- operative and perioperative chemotherapy, FNCLCC,60
tial margins. Despite a lack o prospective randomized UK MAGIC,43 and UK FLOT trials124–126 are the strongest
studies, there is a growing consensus that more exten- validations o the benets o preoperative and perioper-
sive nodal dissection is needed; including the removal ative chemotherapy. These three studies are described
o all cancerous tissue rom the mediastinum improves in detail in the “Gastric Cancer” section o this chapter.
DFS and OS durations through better control o locore- In addition to the FLOT, MAGIC, and French trials, a
gional recurrence. Also, aggressive lymphadenectomy third Japanese trial on patients with SCC (JCOG 9907)
is generally recommended to increase the accuracy o deserves mention because it rendered positive results.
pathologic staging. In the United States, en bloc resec- Patients were given two cycles o cisplatin and 5-FU
tion o the mediastinal and upper abdominal LNs is (CF) preoperatively. Postoperatively, CF was adminis-
considered standard or transthoracic esophagectomy, tered to node-positive patients only. O the above men-
and three-eld lymphadenectomy is not considered tioned three trials, this one showed the highest 5-year
a standard treatment or patients with esophageal survival rate in both arms.127
cancer. MRC-OEO-5 evaluated the use o preoperative che-
motherapy, comparing two preoperative chemother-
Preoperative Chemotherapy apy regimens, CF versus ECX (epirubicin, cisplatin,
Preoperative chemotherapy theoretically increases the and capecitabine) in resectable esophageal adenocar-
curative resection rates by downsizing and downstag- cinoma.128 In this study, 879 patients were random-
ing the primary tumor and LN metastases, reducing ized to receive two cycles o CF or our cycles o ECX
the local and distant relapse rates through suppres- beore surgery. The median survival was 23.4 months
sion and elimination o micro-metastases, improving in the CF group and 26.1 months in the ECX group (HR
tumor-related symptoms with early initiation o anti- 0.90, P = .19). This trial showed that adding epirubicin
neoplastic therapy, and appraising in vivo the chemo- to platinum-based therapy and more cycles o chemo-
sensitivity o the primary tumor that will infuence the therapy did not improve survival. The addition o tar-
choice o chemotherapy in the adjuvant setting. Pre- geted therapy to perioperative chemotherapy was also
operative therapy is hypothesized to result in tumor not helpul. The MRC ST03 trial80 demonstrated that
downstaging, which allows or higher R0 resection the addition o bevacizumab ECX chemotherapy did
and pathCR rates.120 not prolong OS over chemotherapy alone. Table 27–7
The two largest studies evaluating the role o pre- lists the ongoing studies o locally advanced resectable
operative chemotherapy were the US Intergroup gastric, GEJ, and distal esophageal adenocarcinomas.
trial (INT0113)121 and UK Marsden Royal College
(MRC)-OEO-2 randomized controlled trials.122 Both Preoperative Radiation
studies determined the survival benet o preopera- Preoperative radiotherapy was studied in the early
tive chemotherapy compared with surgery alone in 1980s. However, in several phase 3 studies, a benet
patients with resectable ESCC and adenocarcinoma. similar to that o surgery alone was not shown. In a
Table 277 Key Esoageal Cancer Trials
Treatment Arm Control HR or OS (P

Study No. o Patients Arm value) OS (%)
Pre- and Perioperative Chemotherapy
Kelsen et al (INT-113)121 467 3 × CF → S 0.75 (NR) 5-y OS: 36% vs 23%
S
Allum et al (MRC-OEO-2)122 802 2 × CF → S 0.84 (.03) 5-y OS: 23% vs 17.1%
S
Ychou et al (ACCORD 7)60 169 2/3 × CF → S 0.69 (.02) 5-y OS: 38% vs 24%
S
Alderson et al 897 2 × CF → S 0.9 (0.19) 3-y OS: 39% vs 42%
(MRC-OEO-5)128 4 × ECX → S
Cunningham et al (MRC 1100 3 × ECX → S 1.09 (.36) 3-y OS: 50.3% vs 48.1%
ST-03)80 ECX, B → S
Ando et al (JCOG 9907)127 380 S → 2× CF 0.73 (.04) 5-y OS: 43% vs 55%
2 × CF → S
ChApTER 27
Preoperative Chemoradiotherapy
Tepper et al (CALGB 9781)129 56 2 × CF; 50.4 Gy → S 1.46-5.69 (NR) 5-y OS: 39% vs 16%
S
Shapiro et al (CROSS)115 366 5 × carboplatin/paclitaxel; 0.657 (.003) 5-y OS: 47% vs 34%
41.4 Gy → S
S
Preoperative CT vs Preoperative CRT
Stahl et al (POET)130 119 2.5 × CF, Leu → S 0.67 (.07) 3-y OS: 27.7% vs 47.4%
2 × CF, Leu → CE 30 Gy → S
Postoperative CT
Ando et al (JCOG 9204)131 242 S (.13) 5-y OS: 52% vs 61%
S → 2 CF
B, bevacizumab; CE, cisplatin and etoposide; CF, cisplatin and 5-uorouracil; CRT, chemoradiotherapy; CT, chemotherapy; ECX, epirubicin, cisplatin, and capecitabine;
HR, hazard ratio; Leu, leucovorin; NR, not reported; OS, overall survival, S; surgery.
recent quantitative meta-analysis comprising ve ran- OS duration o 4.5 versus 1.8 years (P = .002) in avor
domized trials and 1147 patients, it was again demon- o trimodality therapy. The 5-year OS rates were 39%
strated that there is no improvement in survival with (95% CI 21%–57%) versus 16% (95% CI 5%–33%) in
preoperative radiotherapy alone in potentially resect- avor o trimodality therapy.129 Gebski et al134 reported
able esophageal cancer.132,133 improved survival with preoperative chemotherapy
and chemoradiotherapy. The HR or all-cause mor-
Preoperative Chemoradiotherapy tality with preoperative chemoradiotherapy versus
In the United States, pre- or perioperative chemo- surgery alone was 0.81 (95% CI 0.70–0.93; P = .002),
therapy is not as common as preoperative chemora- corresponding to a 13% absolute dierence in survival
diotherapy or locally advanced esophageal and GEJ at two years, with similar results or dierent histo-
cancers. Preoperative chemoradiotherapy has the goal logic tumor types (SCC: HR 0.84, P = .04; adenocar-
to improve the pathCR rate, locoregional control, and cinomas: HR 0.75, P = .02). The HR or preoperative
survival. chemotherapy was 0.90 (95% CI 0.81–1.00; P = .05),
The CALGB 9781 trial provided additional sup- which indicates a 2-year absolute survival benet o
port or preoperative chemoradiotherapy, although it 7%. There was no signicant eect on all-cause mor-
was stopped early because o a slow patient accrual tality or preoperative chemotherapy in SCC (HR 0.88;
rate. Fity-six patients were randomly assigned to sur- P = .12), but there was a benet in adenocarcinoma
gery alone (n = 26) or CF chemotherapy and concur- (HR 0.78; P = .014).134 With chemoradiotherapy, evi-
rent radiotherapy (n = 30). At a median ollow-up o dence seems to suggest that treating physicians can
6 years, an intent-to-treat analysis showed a median expect a pathCR rate o 20% to 30%, a median OS
duration o 16 to 24 months, and a therapy-related resulted rom the combination o surgery and preop-
mortality rate o 5% to 10%. erative chemoradiotherapy and, to a lesser extent, pre-
The Chemoradiotherapy or Oesophageal Can- operative chemotherapy.
cer Followed by Surgery Study (CROSS) trial was a Since these studies, results rom the Preoperative
well-executed study that established level 1 evidence Chemotherapy or Radiochemotherapy in Esophago-
or preoperative chemoradiotherapy. Three-hundred gastric Adenocarcinoma (POET) trial, presented by
sixty-eight patients with localized esophageal can- Stahl et al,130 have provided urther support or three-
cer (adenocarcinoma or squamous) were randomly step preoperative therapy, although the study was
assigned to receive either preoperative paclitaxel and closed prematurely because o slow patient accrual.
carboplatin with concurrent radiation 41.4 Gy (n = The POET trial was designed to evaluate the sur-
178) or surgery alone (n = 188). With a median ollow- vival outcomes o patients treated with preoperative
up time o 45.4 months, the median OS or preopera- chemotherapy compared with preoperative chemo-
tive chemoradiotherapy group was 49.4 months versus radiotherapy. One-hundred nineteen patients were
24.0 months or the surgery-alone group (HR 0.657, randomly assigned to chemotherapy ollowed by
95% CI 0.495–0.871; P = .003). Five-year OS was again chemoradiotherapy and surgery (n = 59) or chemo-
in avor o the chemoradiotherapy group (47%) ver- therapy ollowed by surgery (n = 60); the R0 resec-
sus the surgery-alone group (34%).135 The complete tion rates were 72% and 70% (P = not signicant), the
resection rate was higher in the chemoradiotherapy pathCR rates were 16% and 2% (P < .001), and the
group (92%) versus the surgery-alone group (69%), N0 rates were 64% and 38% (P < .001), respectively.
ChApTER 27
and 29% o patients in the chemoradiotherapy group The 3-year OS rate trended toward improvement with
had pathCR. In a subgroup analysis, the patients with induction chemotherapy, chemoradiotherapy, and sur-
SCC demonstrated the best outcomes (HR 0.453 or gery (47% vs 28% with chemotherapy and surgery; P
squamous cancer vs 0.732 or adenocarcinoma).135,136 = .07).130 Patients in the chemoradiotherapy arm had
The recently published RTOG 1010 study was a signicantly higher probability o a pathCR (15.6%
designed to determine whether trastuzumab increases vs 2.0%). Postoperative mortality rates did not dier
DFS when combined with trimodality treatment or between the chemoradiotherapy and chemotherapy
patients with HER2-overexpressing esophageal adeno- arms (10% vs 4%; P = .26). These results suggest that
carcinoma.137 This randomized phase 3 trial included preoperative chemoradiotherapy coners a survival
patients with newly diagnosed stage T1N1–2, advantage over preoperative chemotherapy in distal
T2–3N0–2 adenocarcinoma o the esophagus involv- esophageal and GEJ adenocarcinoma.
ing the mid, distal, or esophagogastric junction and up The use o induction chemotherapy beore chemo-
to 5 cm o the stomach. All patients received chemoradiotherapy and surgery has been evaluated in several
therapy o paclitaxel 50 mg/m2 and carboplatin (area phase 2 studies.73 Trimodality-eligible patients were
under the curve = 2) weekly or 6 weeks, with radiation randomized to receive no induction chemotherapy (Arm
(50.4 Gy in 28 ractions) ollowed by surgery. Patients A) or induction chemotherapy (oxaliplatin/FU; Arm B)
were randomly assigned 1:1 to receive weekly trastu- beore oxaliplatin/FU/radiation. Surgery was attempted
zumab 4 mg/kg or week 1 and then 2 mg/kg weekly × about 5 to 6 weeks ater chemoradiation. The pathCR,
5 during CXRT then 6 mg/kg or one dose beore sur- postsurgery 30-day mortality, OS, and toxic eects
gery and 6 mg/kg every 3 weeks or 13 treatments ater rates were assessed. Results rom this study showed
surgery. The median DFS time was no dierent at 19.6 that induction chemotherapy produces a nonsignicant
months (13.5–26.2) or the CXRT+trastuzumab arm increase in the pathCR rate and does not prolong OS.
compared with 14.2 months (HR 0.97). The median In Europe and the United Kingdom, the treatment
OS time was 38.5 months or the CXRT+trastuzumab approach varies accordingly to tumor histology. For
arm compared with 38.9 months or the CXRT arm resectable SCC, patients are commonly treated with
(HR1.01). This study demonstrated that adding trastu- preoperative chemoradiotherapy,140 whereas or
zumab to standard chemotherapy was not better than resectable adenocarcinomas, either preoperative CRT
standard chemotherapy alone in treating localized or perioperative chemotherapy is administered. In the
esophageal adenocarcinoma in patients with trimodal- United States, preoperative chemoradiotherapy is the
ity therapy.137 standard o care irrespective o histology.
Preoperative Chemotherapy Versus Preoperative Postoperative Therapy

Chemoradiotherapy Few studies have been perormed to evaluate postop-
Meta-analyses have been perormed to urther support erative chemotherapy versus surgery alone. Refecting
the available evidence or preoperative therapy.134,138,139 the incidence o esophageal cancer during the 1980s
Cumulatively, these three meta-analyses determined and 1990s, these studies included more patients with
that the most consistent signicant survival benet squamous cell cancer than with adenocarcinoma; this
is a shortcoming o these early studies. In a study by in a benet. However, ew randomized comparisons
Pouliquen et al, no survival improvement was ound have been perormed with surgery alone versus sur-
in the patients who were administered postoperative gery and postoperative treatment. Extrapolation o the
chemotherapy (CF).141 INT-0116 study42 (described in the gastric section) as
The second study, a randomized trial, JCOG 9204, supporting evidence or postoperative chemoradio-
compared the outcomes o patients who underwent therapy in esophageal cancer should be perormed
surgery alone versus patients who underwent surgery with caution.
ollowed by adjuvant CF. The 5-year DFS rates avored On the basis o the available evidence, patients with
the postoperative chemotherapy group (55% vs 45%; esophageal cancer gain limited survival benet with
P = .037). However, the dierence in the 5-year OS rate postoperative chemotherapy and chemoradiotherapy
was not statistically signicant (61% vs 52%; P = .13). ater R0 resection. The limited contribution o post-
The duration o adjuvant therapy was suboptimal, and operative therapy is probably caused by the moderate
approximately 25% o patients assigned to the postop- toxicity, which leads to treatment-related complica-
erative chemotherapy group ailed to receive the ull tions or an inability to complete therapy.
course o therapy.131 The limited ability to deliver therapy ater sur-
Another retrospective case-control study was gery, as demonstrated by results rom the INT-0116,
designed to evaluate the eect o postoperative che- MAGIC, and FLOT studies,42,43 suggests that all eec-
motherapy in 211 patients who underwent R0 esoph- tive therapy should be administered beore surgery.
agectomy with radical lymphadenectomy. O 211 The utility o adjuvant checkpoint inhibitor ater
ChApTER 27
patients, 94 received postoperative chemotherapy, trimodality therapy in both adenocarcinoma and squa-
whereas the other 117 patients received surgery alone. mous cell carcinoma patients with esophageal or GEJ
The OS was compared between the two groups ater cancers is being evaluated in the CHECKMATE 577
they were stratied by the numbers o metastasis- study. Results are eagerly awaited.146
positive LNs. In the subgroup o patients with more
than eight positive LNs, postoperative chemotherapy Defnitive Chemoradiotherapy
signicantly improved OS compared with surgery The potential activity o chemotherapy against
alone. Thereore, the authors suggested that postop- micro-metastases and its ability to act as a radiother-
erative chemotherapy was benecial only in patients apy-sensitizing agent ormed the basis or combin-
with more than eight metastatic LNs,142 reducing the ing chemotherapy and radiotherapy to treat locally
risk o relapse. However, postoperative chemotherapy advanced cancer. In the RTOG 85-01 study, patients
did not improve OS compared with surgery alone. with locally advanced esophageal adenocarcinoma or
Many studies have been perormed to evaluate SCC were randomly assigned to chemoradiotherapy
the role o postoperative radiotherapy versus surgery with CF or radiotherapy alone. The 5-year OS rates
alone. In two studies conducted by Teniere et al,143 were 0% and 26% or radiotherapy and chemoradio-
postoperative radiotherapy did not improve survival. therapy, respectively.147
Results rom two other randomized studies revealed A comprehensive review o the pattern o care or
conficting ndings. Xiao et al144 demonstrated that esophageal cancer in the United States rom 1992 to
postoperative radiotherapy improved the 5-year OS in 1994 surveyed 400 patients with locally advanced
patients with esophageal cancer with stage III disease. esophageal cancer treated at 63 institutions.148 The
In contrast, Fok et al ound shorter survival durations study conrmed that using combined concurrent
in patients who underwent postoperative radiother- chemoradiotherapy as a nonoperative strategy to
apy as a direct result o irradiation-related death and achieve superior survival and local tumor control was
the early appearance o metastatic disease.145 Thus, the better than radiotherapy alone.148 The report also sug-
utility o postoperative radiotherapy may be limited. gested a trend toward survival improvement with
O these studies, only the one by Zieren et al evalu- chemoradiotherapy beore surgery compared with
ated quality o lie, which was ound to be better in the chemoradiotherapy or surgery alone.
surgery-alone group. In the INT-0123 (RTOG 94-05) study, patients
Malthaner et al139 perormed a meta-analysis o 34 (n = 236) were administered concurrent CF (similar to
randomized controlled trials and six meta-analyses in RTOG 85-01) but were assigned randomly to dierent
which patients with locally advanced esophageal can- radiation doses, either 50.4 or 64.8 Gy. No association
cer underwent pre- or postoperative chemotherapy, was ound between higher radiation doses and higher
radiotherapy, or chemoradiotherapy. No signicant median survival (13 vs 18 months or 50.4 vs 64.8 Gy,
dierence in survival was observed in the postopera- respectively) or 2-year survival (31% vs 40%, respec-
tive radiotherapy group. tively). Higher radiation dose was also more toxic.149
The available evidence suggests that postopera- The reason or the ailure o the higher radiation dose
tive chemotherapy or radiotherapy does not result to improve survival is unclear.
The multi-institutional RTOG 0113 trial evalu- et al.150 Patients with resectable ESCC were treated
ated induction chemotherapy ollowed by denitive with two cycles o CF along with concurrent radio-
chemoradiotherapy in patients with localized unre- therapy (conventional/split course). Patients who
sectable esophageal cancer. The primary goal was experienced a response (n = 259) were then randomly
to determine whether any approach would result in assigned to surgery or more chemoradiotherapy. The
more than 78% 1-year OS, surpassing the historical 2-year OS rates were 34% and 40% (HR 0.90; P = .44),
66% rate rom RTOG 94-05. Seventy-two evaluable the median OS durations were 18 and 19 months (P
patients were randomly assigned to receive either = not signicant), the 2-year local control rates were
induction with fuorouracil, cisplatin, and paclitaxel 66% and 57% (P < .01), and the 3-month mortality
and then fuorouracil plus paclitaxel with 50.4 Gy o rates were 9.3% and 0.8% (P = .002), respectively. The
radiation (Arm A) or induction with paclitaxel plus cis- authors concluded that in patients who experience a
platin and then the same chemotherapy with 50.4 Gy response to chemoradiotherapy, surgery ater chemo-
o radiation (Arm B). Both arms o RTOG 0113 were radiotherapy resulted in no added benet over contin-
associated with high morbidity, and the study did not ued chemoradiotherapy.150
meet its 1-year survival end point.149 In a phase 3 study by the Chinese University
Research Group or Esophageal Cancer (CURE), inves-
Defnitive Chemoradiotherapy Versus tigators rom China are comparing the survival benets
Chemoradiotherapy Plus Surgery o esophagectomy versus chemoradiotherapy. From
Stahl et al130 perormed a randomized comparison o 2000 to 2004, 80 patients were randomly assigned to
ChApTER 27
chemotherapy ollowed by chemoradiotherapy and esophagectomy (n = 44) or chemoradiotherapy (n =
then surgery (surgical arm, n = 86) and chemotherapy 36). A two- or three-stage esophagectomy with two-
ollowed by chemoradiotherapy and no surgery (non- eld lymphadenectomy was perormed. Chemoradio-
operative arm, n = 86) in 172 patients with locally therapy consisted o CF and concurrent 50 to 60 Gy o
advanced ESCC. The median ollow-up duration was radiation. Tumor response was assessed by EGD, EUS,
6 years. The OS rates were similar or the surgical and and CT. Salvage esophagectomies were perormed or
nonsurgical arms (P < .05). The 2-year local PFS rate incomplete response or recurrence. The median ollow-
was higher in the surgical arm than the nonsurgical up time was 1.4 years. No dierence in the early cumu-
arm (64% vs 41%; HR 2.1; 95% CI 1.3–3.5; P = .003). lative survival rate was ound between the two groups
The treatment-related mortality rate was signicantly (RR 0.89; 95% CI 0.37–2.17; P = .45), nor was there a
higher in the surgical arm (12.8% vs 3.5%; P = .03). dierence in DFS. Patients treated with surgery only
The clinical tumor response to induction chemother- had a slightly higher recurrence rate in the mediasti-
apy was the only independent prognostic actor or OS num, whereas those treated with chemoradiotherapy
(HR 0.30; 95% CI 0.19–0.47; P < .0001). The results o had a higher rate in the cervical or abdominal region.151
this study suggested that adding surgery to chemora- Surgery is the oundation o treatment or locally
diotherapy improves local tumor control but not sur- advanced resectable esophageal cancer. Early results
vival in patients with locally advanced ESCC. Tumor rom European studies suggested that patients with
response to induction chemotherapy is associated ESCC will not benet rom surgery ater chemora-
with a avorable prognostic group in these high-risk diotherapy.152 The caveat o the nonsurgical approach
patients, regardless o treatment. O course, the di- to solid tumors is detecting minimal residual disease.
culty o incorporating these results into clinical practice Thereore, until more conrmatory evidence and clini-
is detecting residual disease or response ater preopera- cal tools become available or detecting minimal resid-
tive therapy. ual disease or molecular or imaging predictive markers
Another randomized comparison in only respond- in patients who require surgery ater preoperative
ers to chemoradiotherapy (45 Gy conventional or 60 therapy, the treatments or squamous cell cancer and
Gy split-course radiation) was conducted by Bedenne adenocarcinoma will remain similar.

RESECTABLE GASTRIC CANCER
J All patients with newly diagnosed invasive cancer bronchoscopy as part o a recommended staging
undergo staging, which includes endoscopic assess- workup.
ment o the location and size o the primary tumor J Staging laparoscopy is perormed in some patients
and EUS staging, CT, and/or PET/CT. Patients with with cardia cancer, but the decision is made on a
cervical or proximal esophageal cancer also undergo case-by-case basis.
J Patients with localized disease are discussed at the include chemoradiotherapy and then surgery. For
weekly Esophageal Multidisciplinary Tumor Board. GEJ adenocarcinoma, postoperative chemoradio-
J Patients with locally advanced cervical esophageal therapy and perioperative chemotherapy are addi-
cancer are treated with primary denitive chemo- tional options available to patients. With the results
radiotherapy, even those with resectable disease. o the CROSS trial, we now recognize that a mini-
Salvage surgery is considered only in patients with mum dose o 41.4 Gy may be sufcient in the pre-
persistent or locally recurrent disease. operative setting, although our preerence is to use
a higher dose (50.4 Gy).
J Currently at MDACC, treatment modalities or
locally advanced resectable esophageal cancer
Figure 27–3A summarizes the MDACC approach to addition o docetaxel was superior in terms o response
resectable gastroesophageal cancer. rate (37% vs 25%; P = .01), time to tumor progres-
sion (5.6 vs 3.7 months; P < .001), and OS (9.2 vs 8.6
months; P = .02).154 One could question the clinical sig-
ADVANCED AND METASTATIC nicance o a less than 1 month absolute improvement
ChApTER 27
GASTRIC, GASTROESOphAGEAL in OS, particularly in the context o signicant toxici-

JUNCTION, AND ESOphAGEAL ties, most notably a high rate o ebrile neutropenia
CANCERS (30%). Importantly, this regimen should not be used in
patients who have a reduced perormance status.
The prognosis o patients with advanced or metastatic The third randomized phase 3 trial enrolled 305
gastric, GEJ, and esophageal cancers is poor; thus, clini- patients in Japan to either S-1 alone or S-1 and cispla-
cians should be cognizant o the patient’s quality o lie tin. Median OS was signicantly longer in patients
and weigh the risks and benets o therapy. The overall assigned to S-1 plus cisplatin (13.0 months) than in
5-year survival rate o metastatic gastric and esophageal those assigned to S-1 alone (11.0 months; HR or death,
cancer patients is less than 5%. The standard o care 0.77; 95% CI 0.61–0.98; P = .04). Progression-ree sur-
or advanced disease is systemic chemotherapy. Dier- vival was signicantly longer in patients assigned to
ent rontline combination chemotherapy regimens are S-1 plus cisplatin than in those assigned to S-1 alone
available, but no head-to-head comparison has been (median PFS, 6.0 vs 4.0 months; P < .0001).157 This trial
perormed or most o these; thus, the optimal choice is provided evidence or the superiority o the addition
not obvious, and treatment remains regionally variable. o cisplatin when compared with a fuoropyrimidine
The medical treatment o metastatic gastric and alone and established the use o a fuoropyrimidine
esophageal cancer is primarily palliative and coners in addition to a platinum as a reasonable treatment
a modest eect on OS. Multiple agents are active in option.
the treatment o gastric cancer, including fuoropyrimi- Trastuzumab was the rst targeted agent with
dines (5-FU, capecitabine, and S-1), anthracyclines, documented clinical activity in the advanced gastric
platinum agents, taxanes, irinotecan, and some tar- and gastroesophageal cancer setting. This treatment
geted therapies such as trastuzumab or human epider- is useul in the HER2-enriched population; however,
mal growth actor receptor 2 (HER2)-overexpressing only approximately 20% o gastric cancers and 30%
gastric cancers. Combination regimens are associated o gastroesophageal cancers overexpress HER2, so that
with higher response rates and, according to one meta- a relatively small proportion o patients benet rom
analysis, are also associated with increased survival the treatment. The ToGA trial randomly assigned
when compared with single-agent chemotherapies.153 584 patients whose tumors overexpressed HER2 by
immunohistochemistry (IHC) or fuorescence in situ
hybridization to receive a fuoropyrimidine (5-FU or
First-Line Therapy capecitabine) plus cisplatin with or without trastu-
Only a minor amount o level 1 evidence exists or zumab. The chemotherapy was administered every 3
the treatment o gastric cancer in the rst-line setting. weeks or six cycles, and trastuzumab was adminis-
In act, only docetaxel,154 cisplatin/oxaliplatin,155 and tered every 3 weeks until disease progression.156 The
trastuzumab156 are supported by high-level evidence. investigators ound that the addition o trastuzumab to
A phase 3 trial involving 445 patients with meta- chemotherapy increased OS rom 11.1 to 13.8 months
static cancer randomly assigned patients to receive CF (HR 0.74, 95% CI 0.60–0.91; P = .0046). The secondary
or CF plus docetaxel. The investigators ound that the end points o PFS (6.7 vs 5.5 months; P = .0002) and
response rate (47.3% vs 34.5%; P = .0017) were also The role o lapatinib, a dual EGFR and HER2 tyro-
improved. On extended ollow-up, the HR o OS or sine kinase inhibitor (TKI), was investigated in com-
the addition o trastuzumab has decreased to 0.80,158 bination with capecitabine plus oxaliplatin (CapeOx)
indicating that although real, the response to trastu- in 545 patients with HER2-positive advanced/meta-
zumab may be short lived. The dierence in median static gastroesophageal adenocarcinomas in the
OS was reduced rom 2.7 months to merely 1.4 TRIO-013/LOGiC trial. The addition o lapatinib
months, representing an approximate 50% decrease in to CapeOx did not improve ecacy (OS and PFS)
the eect o trastuzumab, which suggests that only a among untreated patients with HER2-positive meta-
ew patients benet. Based on this trial, the combina- static gastric cancer.165 Similarly, the concept o dual
tion o trastuzumab and chemotherapy has become HER2 inhibition was studied in the JACOB trial.
the standard o care in patients whose tumors overex- The JACOB trial was a double-blinded, placebo-con-
press HER2. trolled, randomized, multicenter, international phase
In contrast to the positive results with trastuzumab 3 trial evaluating the ecacy and saety o adding
in HER2-overexpressing gastroesophageal cancers, pertuzumab to trastuzumab and chemotherapy in
bevacizumab ailed to demonstrate an OS benet rst-line treatment o HER2-positive metastatic gas-
when it was added to a combination o cisplatin and tric cancer/GEJ cancer. Unortunately, adding pertu-
fuoropyrimidine in patients with advanced gastric zumab to trastuzumab and chemotherapy did not
and GEJ adenocarcinoma.159 A total o 774 patients signicantly improve OS in patients with HER2-pos-
were randomly assigned, and the median OS was 12.1 itive metastatic gastric or GEJ cancer compared with
ChApTER 27
months with bevacizumab plus fuoropyrimidine-cis- placebo. 166
platin and 10.1 months with placebo plus fuoropyrim- The KEYNOTE 062 study assessed whether in a
idine-cisplatin (HR 0.87, 95% CI 0.73–1.03; P = .1002). PD-L1–positive (dened as CPS ≥1), HER2-negative
Both median PFS (6.7 vs 5.3 months; HR 0.80, 95% CI advanced gastric or GEJ adenocarcinoma patient
0.68–0.93; P = .0037) and overall response rate (46.0% population pembrolizumab was noninerior to cis-
vs 37.4%; P = .0315) were signicantly improved with platin-based chemotherapy and whether the addi-
bevacizumab versus placebo.159 In a preplanned sub- tion o pembrolizumab to chemotherapy aected
group analysis, the investigators were able to show that outcomes.167 The investigators ound that in patients
a benet in terms o OS existed or “Pan-American” with a CPS o 1 or higher, pembrolizumab was non-
patients but not or European and Asian patients. This inerior to chemotherapy, with a median survival o
might point to dierences in tumor biology but is also 10.6 versus 11.1 months (HR 0.91). For patients with a
dependent on other actors. A subsequent retrospec- PD-L1 CPS o 10 or more, the survival with pembroli-
tive biomarker analysis o the AVAGAST trial showed zumab was superior to chemotherapy (HR = 0.69); the
that patients with high baseline plasma VEGF-A levels median OS was 17.4 months or those receiving pem-
and low baseline expression o neuropilin-1 seemed to brolizumab compared with 10.8 months or those
have an improved OS. For both biomarkers, subgroup receiving chemotherapy. In the combination-therapy
analyses demonstrated signicance only in patients arm, the addition o pembrolizumab to chemother-
rom non-Asian regions.160 It is important to note apy added nothing in terms o OS or PFS when com-
that neither o these biomarkers has been validated. pared with chemotherapy alone regardless o patient
Unlike the ToGA trial, the AVAGAST trial did not use CPS status. As o this writing, the CHECKMATE-649
a biomarker-enriched patient population, underscor- (NCT02872116) study addressing the question o
ing the importance o appropriate patient selection in whether the addition o nivolumab to standard o care
randomized controlled trials and the use o predictive FOLFOX chemotherapy increases OS is ongoing and
biomarkers to direct care. Similarly, the AVATAR trial, will soon be reported. The nivolumab/ipilumimab
which included an all Asian patient population, did not arm o this study was stopped early ater an item
show any survival benet o adding bevacizumab to analysis. Recently, the JAVELIN Gastric 100 study168
the cisplatin-capecitabine combination.161 addressed whether maintenance avelumab prolonged
Equally disappointing results were also reported OS in patients with metastatic HER2-negative gas-
rom two EGFR-targeting trials: the Erbitux (cetuximab) tric or GEJ cancer in patients who received rst-line
in Combination with Xeloda (capecitabine) and Cis- oxaliplatin-based chemotherapy and did not progress.
platin in Advanced Esophagogastric Cancer (EXPAND) Reported study results ound no dierence in OS o
and Revised European American Lymphoma (REAL-3) patients with PD-L1 1 or higher with a median OS
trials.162,163 A biomarker analysis o the REAL-3 trial o 16.2 months in avelumab versus 17.2 months in
did not identiy any biomarkers whose presence pre- the chemotherapy arm (HR 1.13; P = .635). This dem-
dicted resistance to modied epirubicin, oxaliplatin, onstrates that there is no role or maintenance ave-
and capecitabine (EOC) and panitumumab; however, lumab in patients who do not progress on standard
only a ew biomarkers were evaluated in this study.164 chemotherapy.
In summary, the standard o care in the rst-line average patient in the study treated with ramuci-
setting remains a combination o fuoropyrimidine rumab received treatments or 2 weeks longer than
and platinum-containing chemotherapy, with the the average patient treated with placebo. In the pub-
addition o trastuzumab in the HER2-enriched popula- lished Ramucirumab in Metastatic Gastric Adenocar-
tion. The results o targeted therapy trials have mostly cinoma (RAINBOW) trial, ramucirumab was added
been disappointing, but none o these trials looked at to weekly paclitaxel as a second-line therapy in 665
an appropriately biomarker-enriched population. For patients with advanced or metastatic gastric cancer,
immunotherapy, CPS appears to be a better biomarker demonstrating a signicant improvement in both
than PD-L1 score; however, testing methodology and PFS and OS over paclitaxel alone. 172 A statistically
optimal cutos need to be better established in gastro- signicant prolongation o OS was demonstrated
esophageal cancers. (HR 0.81, 95% CI 0.68–0.96; P = .017). Median OS
times were 9.6 and 7.4 months in the ramucirumab-
plus-paclitaxel arm and placebo-plus-paclitaxel arm,
Second-Line Therapy respectively. The PFS was also signicantly longer or
The validity o the use o second-line chemotherapy patients receiving ramucirumab plus paclitaxel (HR
and its benet in gastric cancer has long been ques- 0.64, 95% CI 0.54–0.75; P < .001) with an overall
tioned; however, all recently published trials demon- good saety prole, urther supporting its role in com-
strated an OS prolongation, albeit very modest, when bination with chemotherapy.
chemotherapy was compared with best supportive In the second-line setting, targeted HER2 therapy
ChApTER 27
care (BSC).169–172 A small German phase 3 study com- with TKIs has been a ailure.174,175 Lapatinib has been
pared the ecacy o irinotecan plus BSC to BSC alone investigated in a large 420-patient study (TyTAN trial),
in patients with advanced gastric or GEJ adenocarci- which randomly assigned HER2-positive patients to
noma.170 Only 40 patients were randomly assigned lapatinib plus paclitaxel (L+P) versus paclitaxel alone.
to treatments, and the study closed early due to poor Median OS was 11.0 months or L+P and 8.9 months
accrual. The HR or death was 0.48, with a 95% CI or paclitaxel alone in the intent-to-treat population
o 0.25 to 0.92, avoring the active treatment with iri- (HR 0.84; P = .2088). In a preplanned subgroup analy-
notecan (P = .023). The median survival time was 4.0 sis, median OS in the HER2 IHC 3+ subgroup was 14.0
months (95% CI 3.6–7.5) in the irinotecan arm and months or the combination therapy and 7.6 months
2.4 months (95% CI 1.7–4.9) in the BSC arm.170 There or paclitaxel alone (HR 0.59; P = .0176).175 Interestingly,
were no documented responses to irinotecan in this it has recently been demonstrated that although the
trial. study mandated IHC HER2 positivity, 35% o patients
The second trial, COUGAR-02, randomized 186 in the TyTAN trial had tumors classied as IHC 0/1. 175
patients to docetaxel plus BSC versus BSC alone. Antibody-drug conjugates represent a promising class
Docetaxel signicantly improved OS compared with o drugs because o their ecient drug delivery to anti-
BSC alone, with a median OS o 5.2 months (95% CI gen-expressing tumor cells. Trastuzumab emtansine
4.1–5.9) or docetaxel and 3.6 months (95% CI 3.3– (T-DM1) is an antibody-drug conjugate comprised o
4.4) or BSC (HR 0.67, 95% CI 0.49–0.92; P = .01).171 trastuzumab linked to the tubulin inhibitor emtansine
Another study that demonstrated an OS benet or by a stable linker. In the GATSBY trial, second-line
patients treated with chemotherapy (either docetaxel T-DM1 ailed to prolong OS compared with taxane in
or irinotecan) versus BSC was published by Kang et previously treated HER2-positive gastric cancer.176
al.173 Median OS was 5.3 months among 133 patients Equally disappointing, the UK Getinib or Oesoph-
in the chemotherapy arm and 3.8 months among 69 ageal Cancer Progressing Ater Chemotherapy (COG)
patients in the BSC arm (HR 0.657, 95% CI 0.485– trial in patients with adenocarcinoma o the esopha-
0.891; one-sided P = .007). There was no median OS gogastric junction types I/II (tumors extending to the
dierence between docetaxel and irinotecan (5.2 vs 6.5 esophagus 5 cm above and 2 cm below the GEJ) in the
months; P = .116).79 second-line setting randomized 449 patients to receive
The role o angiogenesis inhibition as a target in getinib or placebo.177
gastric cancer was investigated in the Ramucirumab Multiple studies highlight the importance o iden-
Monotherapy or Previously Treated Advanced tication and targeting o driver mutations and their
Gastric or Gastro-Oesophageal Junction Adenocar- useulness in the creation o appropriate biomarkers to
cinoma (REGARD) trial, which randomly assigned direct care.178,179 MET amplication and/or overexpres-
355 patients to receive ramucirumab or placebo. 169 sion o its protein product has long been implicated
This study demonstrated a marginal improvement in in the pathogenesis o gastric cancer, supporting its
median OS (5.2 months in the ramucirumab group role as a poor prognostic actor.45 Hepatocyte growth
and 3.8 months in the placebo group; HR 0.776, actor/MET-targeted treatments were evaluated in
95% CI 0.603–0.998; P = .047). Interestingly, the patient-selected phase 3 trials (RILOMET-1 and MET
Gastric).180,181 Both antibodies (rilotumumab and onar- Third-Line Therapy

tuzumab) ailed to improve survival in gastric cancer
that was IHC-positive or MET expression. Apatinib is a small-molecule multitargeted TKI with
The role o poly (adenosine diphosphate–ribose) activity against VEGFR. Ater showing improved PFS
polymerase (PARP) inhibitors in gastric cancer and OS in heavily pretreated patients with metastatic
was investigated in a phase 2 study in which 124 gastric cancer in a phase 2 trial,188 apatinib was evalu-
patients who progressed on luoropyrimidines (sec- ated in a phase 3 trial in 271 patients with advanced
ond-line metastatic setting) were randomly assigned gastric cancer.189 Patients had prior ailure to second-
to receive olaparib plus paclitaxel versus paclitaxel line chemotherapy and were stratied according to the
alone. 182 There was no improvement in PFS, but number o metastatic sites (≤ or >2 sites). This trial met
the addition o olaparib signiicantly improved OS its primary end point, showing signicant improve-
(HR 0.56, 95% CI 0.35–0.87; P = .010). The subse- ment in OS and PFS. The median OS time was 6.5
quently perormed phase 3 trial yielded negative months or apatinib and 4.7 months or placebo (HR
results, unortunately. 183 Overall survival did not di- 0.71, 95% CI 0.54–0.94; P = .015), and the median PFS
er between treatment groups in the overall patient was 2.6 months or apatinib and 1.8 months or pla-
population (median OS 8.8 months in the olaparib cebo (HR 0.44; 95% CI 0.33–0.61; P < .0001). This trial
group vs 6.9 months in the placebo group; HR 0.79; urther supports the angiogenesis inhibition as a target
P = ·026) or in the ataxia telangiectasia-mutated in this disease.
protein-negative population (12.0 months vs 10.0 In addition to treatment with standard cytotoxic che-
motherapy and targeted therapy, immune checkpoint
ChApTER 27
months; HR 0.73; P = .25).183
The role o immunotherapy has also been assessed inhibitors with antiprogrammed cell death protein 1
in second-line therapy or gastroesophageal cancers. monoclonal antibodies (PD-1 inhibitors) have emerged
The KEYNOTE-061 trial also ailed to show a survival as a therapeutic option in the metastatic setting. As
benet or pembrolizumab over paclitaxel in the sec- o this writing, the PD-1 inhibitor, pembrolizumab,
ond-line setting in patients with a PD-L1 CPS (a pro- is approved or all patients with mismatch repair–
portional assessment o PD-L1 staining on tumor and decient tumors ater ailure o rst-line cytotoxic
immune cells) expression >1.184 O note, in a post hoc chemotherapy. In KEYNOTE-059 Cohort 1, a multi-
analysis, patients with CPS scores o 5 or more and center, open-label, single-arm phase 2 trial conducted
10 or more did appear to see benet. These disap- at 67 sites in 17 countries, 259 patients (ater ailing
pointing results add weight to the hypothesis that two or more lines o chemotherapy including cisplatin
only a minority o patients benet rom single-agent and 5-FU; patients with HER2-positive tumors must
immunotherapy. The phase 3 KEYNOTE-181 185 study have received treatment with trastuzumab) received
evaluating pembrolizumab versus physician’s choice a xed dose o 200 mg pembrolizumab in a 3-weekly
chemotherapy in patients with advanced esophageal/ cycle. Pembrolizumab showed an objective response
GEJ adenocarcinoma and SCC who had progressed rate o 11.6% (95% CI 8.0%–16.1%), with complete
ater rst-line therapy ailed to meet its primary end response o 2.3% (95% CI 0.9%–5.0%). The response
point o OS in the intention-to-treat population o rate was higher in the patients with PD-L1–positive
patients with a CPS o 1 or more, with median OS tumors (PD-L1–positive vs PD-L1–negative: 15.5% vs
o 7.1 months in both arms (HR 0.89; P = .056). They 6.4%). A total o seven (4%) tumors were microsatel-
ound that in the subgroup o patients with a CPS o lite instable–high and the response rates were higher,
10 or higher, the median survival was 9.3 versus 6.7 with an overall response rate o 57.1%. Median PFS
months (HR 0.69; P = .0074). In a press release, the was 2.0 months and median OS was 5.6 months. Based
FDA granted approval or nivolumab in unresectable on these results, the FDA has approved pembroli-
advanced, recurrent, or metastatic ESCC ater prior zumab as the third-line treatment or PD-L1–positive
fuoropyrimidine- and platinum-based chemotherapy. gastric adenocarcinoma.190
The approval is based on the phase 3 ATTRACTION-3 Nivolumab, an immune checkpoint inhibitor, was
trial in which patients treated with nivolumab (n = evaluated in the phase 3 ATTRACTION-2 study191 in
210) demonstrated superior OS versus those treated patients with gastric or GEJ cancer treated with two
with taxane chemotherapy (n = 209) (investigator’s or more prior chemotherapy regimens. Patients were
choice o docetaxel or paclitaxel) (HR 0.77, 95% randomly assigned (2:1) to receive 3 mg/kg nivolumab
CI 0.62–0.96; P = .0189). The median OS was 10.9 or placebo intravenously every 2 weeks. Nivolumab
months (95% CI 9.2–13.3) or nivolumab compared was associated with a signicant OS benet versus pla-
with 8.4 months (95% CI 7.2–9.9) or docetaxel or cebo (OS 5.32 vs 4.14 months; P < .0001; 12-month OS
paclitaxel.186 Nivolumab is the rst approved immu- 26.6% vs 10.9%). Nivolumab reduced mortality risk
notherapy in this setting regardless o tumor PD-L1 by 37% compared with placebo. The survival advan-
expression level.187 tage was persistent over time with nivolumab and
irrespective o PD-1/PD-L1 expression. Nivolumab is involving targeted agents in the rst-, second-, and
currently not approved in the United States or meta- third-line settings.
static GEJ or gastric cancer.191
TAS-102 (trifuridine/tipiracil) is an oral combi-
nation drug o two active compounds: trifuridine,
Supportive Measures or Advanced
a thymidine analog (nucleoside antitumor agent), Gastric, Gastroesophageal Junction, and
and tipiracil hydrochloride, a thymidine phosphory- Esophageal Cancers
lase inhibitor, in a ratio o 1:0.5. In the international The goal o symptom palliation is to optimize qual-
phase 3 randomized control trial, the TAGS study, ity o lie. Current or potential signs or symptoms that
507 patients with advanced/metastatic gastric adeno- aect quality o lie should be assessed during the initial
carcinomas (including adenocarcinoma o the GEJ) evaluation o patients with unresectable disease. Avail-
were randomly assigned to TAS-102 or placebo in a able treatment options include palliative radiotherapy
2:1 ratio. In patients with prior gastrectomy, OS (6.0 without concurrent chemotherapy197; chemotherapy;
months vs 3.4 months, HR 0.57, 95% CI 0.41–0.79) endoscopic palliation with luminal dilation, stents, or
and PFS (2.2 months vs 1.8 months, HR 0.65, 95% CI laser or chemical ablation; and palliative surgery. Pal-
0.49–0.85) were more avorable among the TAS-102 liative surgery is rarely perormed because it is rare
group versus those receiving placebo. Moreover, the that the potential benets clearly outweigh the risks o
patients who did not have gastrectomy also showed surgery. Several special issues to consider in this group
OS (HR 0.80, 95% CI 0.60–1.06) and PFS (HR 0.65, o patients include (1) problems specically associated
ChApTER 27
95% CI 0.49–0.85) benet to treatment with TAS- with primary disease, (2) nutrition, (3) diagnosis and
102.192 More patients in the TAS-102 arm achieved dis- treatment o tracheoesophageal stulas, and (4) man-
ease control compared with the placebo group (44% agement o oral secretions.
vs 14%; P < .0001).192 All patients, especially those who present with
Table 27–8 lists major phase 3 trials or advanced/ more than 15% weight loss rom their normal base-
metastatic esophageal, GEJ, and gastric cancer involv- line, should undergo ormal nutritional evaluation,
ing chemotherapy agents, and Table 27–9 lists trials and alternative nutritional support methods should
Table 278 Major pase 3 Gastric Cancer Trials Involving Cemoteray Agents in te Advanced/
Metastatic Setting
No. o Primary End Point

Trials Patients Treatment Arms HR or OS (P value) Comparison in Months
Advanced Gastric Cancer: First Line
Van Cutsem et al (V325 445 DCF vs CF TTP: 1.47 (< .001) OS: 1.29 TTP: 5.6 vs 3.7
study group)154 (.02) OS: 9.2 vs 8.6
Cunningham et al155 1002 ECF vs ECX vs EOF vs 0.80 (.02) OS: 9.9 vs 9.9 vs 9.3 vs 11.2
EOX
Koizumi et al (SPIRITS)157 305 S-1 + cisplatin vs S-1 0.77 (.04) OS: 13.0 vs 11.0
193
Ajani et al (FLAGS) 1053 Cisplatin + S-1 vs 0.92 (.20) OS: 8.6 vs 7.9
cisplatin + 5-FU
Advanced Gastric Cancer: Second Line
Thuss-Patience et al 40 Irinotecan + BSC vs BSC 0.48 (.012) OS: 4.0 vs 2.4
(AIO)170
Cook et al 168 Docetaxel + ASC vs ASC 0.67 (.01) OS: 5.2 vs 3.6
(COUGAR-02)171
Kang et al173 202 Docetaxel or irinotecan 0.657 (.007) OS: 5.3 vs 3.8
vs BSC
Higuchi et al (TCOG 130 Biweekly irinotecan + 1.00 (.9823) PFS: 3.8 vs 2.8
GI–0801/BIRIP)194 cisplatin vs irinotecan OS: 10.7 vs 10.1
ASC, active symptom control; BSC, best supportive care; CF, cisplatin and 5-uorouracil; DCF, docetaxel, cisplatin, and 5-uorouracil; ECF, epirubicin, cisplatin, and
5-uorouracil; ECX, epirubicin, cisplatin, and capecitabine; EOF, epirubicin, oxaliplatin, and 5-uorouracil; EOX, epirubicin, oxaliplatin, and capecitabine; 5-FU,
5-uorouracil; HR, hazard ratio; OS, overall survival; PFS, progression-ree survival; TTP, time to progression.
Table 279 Major pase 3 Gastric Cancer Trials Involving Targeted Agents in te Advanced/Metastatic
Setting
No. o Primary End Point

Trials Patients Treatment Arms HR or OS (P value) Comparison in Months
Advanced Gastric Cancer: First Line
Bang et al (ToGA)a156 584 CX/CF + trastuzumab vs CX/CF 0.74 (.0046) OS: 13.8 vs 11.1
159
Ohtsu et al (AVAGAST) 774 CF + bevacizumab vs CF 0.87 (.1002) OS: 12.1 vs 10.1
PFS: 6.7 vs 5.3
Lordick et al (EXPAND)162 904 CX + cetuximab vs CX 1.004 (.9547) OS: 9.4 vs 10.7
163
Waddell et al (REAL-3) 553 mEOC + panitumumab vs EOC 1.37 (.013) OS: 8.8 vs 11.3
Hecht et al (LOGiC)195 545 CapeOx + lapatinib vs CapeOx + 0.91 (.35) OS: 12.2 vs 10.5
placebo
Tabernero et al (JACOB)166 780 Pertuzumab + Trastuzumab + CT 0.84 (.057) OS: 24.4 vs 25
vs Placebo + Trastuzumab + CT
Advanced Gastric Cancer: Second Line
Fuchs et al (REGARD)169 355 Ramucirumab + BSC vs BSC 0.776 (.0473) OS: 5.2 vs 3.8
ChApTER 27
172
Wilke et al (RAINBOW) 665 Paclitaxel + ramucirumab vs 0.81 (.017) OS: 9.6 vs 7.4
paclitaxel
Ohtsu et al (GRANITE-1)174 656 Everolimus + BSC vs placebo + 0.90 (.1244) OS: 5.4 vs 4.3
BSC
Satoh et al (TyTAN)175 261 Lapatinib + paclitaxel vs 0.84 (.2088) OS: 11.0 vs 8.9
paclitaxel
Dutton et al (COG)177 449 Getinib vs placebo 0.90 (.29) OS: 3.73 vs 3.63
Thuss-Patience et al 415 Standard taxane vs Trastuzumab 1.15 (.86) OS: 8.6 vs 7.9
(GATSBY)176
Catenacci et al 609 Rilotumumab + epirubicin + 1.34 (.003) OS: 8.8 vs 10.7
(RILOMET-1)180 cisplatin + capecitabine
vs placebo + epirubicin +
cisplatin + capecitabine.
Shah et al (MET Gastric)181 562 Onartuzumab + mFOLFOX6 vs 0.82 (.24) OS: 11 vs 11.3
placebo + mFOLFOX6
Bang et al (GOLD)183 643 Olaparib + paclitaxel vs placebo 0.79 (.026) OS: 8.8 vs 6.9
+ paclitaxel
Shitara et al 592 Pembrolizumab vs paclitaxel 0.82 (.0421) OS: 9.1 vs 8.3
(KEYNOTE-061)184
Kojima et al 751 Pembrolizumab vs CT 0.69 (.0074)(when OS: 9.3 vs 6.7(when CPS ≥10)
CPS ≥10)
(KEYNOTE-181)185
Advanced Gastric Cancer: Third Line
Qin et al (apatinib)189 271 Apatinib + BSC vs BSC 0.71 (.015) OS: 6.5 vs 4.7
PFS: 2.6 vs 1.8
Ohtsu et al (GRANITE-1)174 656 Everolimus + BSC vs placebo + 0.90 (.1244) OS: 5.4 vs 4.3
BSC
Fuchs et al (KEYNOTE-059 259 Pembrolizumab monotherapy OS: 5.8 vs 4.9
– Cohort 1)190 in PD-L1–positive vs OR: 15.5 vs 6.4
PD-L1–negative
Kang et al 493 Nivolumab vs placebo 0.63 (.0001) OS: 5.26 vs 4.14
(ATTRACTION-2)196
Shitara et al (TAGS)192 507 TAS-102 vs placebo 0.69 (.00029) OS: 5.7 vs 3.6
a
HR reduced to 0.8 on ollow-up analysis.
BSC, best supportive care; CapeOx, capecitabine and oxaliplatin; CF, cisplatin and 5-uorouracil; CX, cisplatin and capecitabine; EOC, epirubicin, oxaliplatin, and
capecitabine; HR, hazard ratio; mEOC, modied epirubicin, oxaliplatin, and capecitabine; OR, objective response (CR+PR); OS, overall survival; PFS, progression-ree
survival; TAS-102, triuridine/tipiracil.
be considered. Adequate nutrition and hydration are should be addressed, whenever easible, with gastros-
crucial to ensure that patients complete the ull course tomy or a jejunostomy tube. Upper GI bleeding and
o therapy. Jejunostomy eeding tubes (J-tubes), which pain can be palliated with radiotherapy, alone or with
are inserted primarily via a surgical procedure, can be endoscopic cauterization. Finally, eective chemother-
considered in patients with gastric and GEJ cancer; apy can directly improve symptoms such as dysphagia
they can be placed during the initial laparoscopic evalu- and pain, as well as indirectly improve nutrition and
ation. Percutaneous gastrostomy eeding tubes, placed minimize bleeding risk and aspiration.
by endoscopic (percutaneous endoscopic gastrostomy) Although genetic proling o tumors (next-gen-
or radiologic (G-tube) guidance, can be considered or eration sequencing) has become a more widely used
esophageal cancer. The continued use o jejunostomy, tool in the treatment o gastric, GEJ, and esophageal
gastrostomy, or nasogastric eeding tubes is considered cancers, patients are oten ound to have multiple and
the rst choice i nutrition cannot be supported orally. nontargetable mutations. Even when a potentially tar-
Patients with advanced gastric, GEJ, and esophageal getable mutation is ound and the patient is treated
cancers might be candidates or denitive chemoradio- with a given drug, we have ound that responses are
therapy. Chemotherapy agents used in combination rare, likely because o our poor knowledge o driver
with radiotherapy include cisplatin, paclitaxel, carbopl- mutations. However, with the advent o more tar-
atin, oxaliplatin, or 5-FU. Patients with borderline per- geted treatments in combination with cytotoxic agents
ormance status may not be candidates or denitive or immunotherapy, we emphasize the enrollment o
chemoradiotherapy, even with consistent nutritional patients into available clinical trials.
ChApTER 27
support via eeding tubes. Therapy should be based on Figure 27–3A and B summarize the MDACC
the patient’s most pressing symptoms. Malnutrition approach to advanced gastric, GEJ, and esophageal
cancer.

ADVANCED GASTRIC, GASTROESOPHAGEAL JUNCTION, AND ESOPHAGEAL CANCERS
J Our approach in the metastatic setting is to provide J In the second line, we use ramucirumab combined
palliation o symptoms and prolongation o lie. with paclitaxel; however, in patients with severe
J In HER2-positive gastric cancer, there is an OS ben- neuropathy, irinotecan-based chemotherapy is also
et with the addition o anti-HER2 therapy to rst- an alternative.
line chemotherapy. J Since the approval o pembrolizumab in PD-L1–
J A reasonable option in the rst-line setting is a plat- positive gastric cancer, our approach is to use
inum-based doublet with the addition o docetaxel immunotherapy in patients with PD-L1–positive
depending on the perormance status o the tumors (CPS >1) that have progressed on two lines
patient. o chemotherapy.
J Additional options or treatment include TAS102.
21. Parsonnet J, Forman D. Helicobacter pylori inection and gastric

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identies a small and aggressive subgroup o esophagogastric pembrolizumab monotherapy in patients with previously
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in combination with epirubicin, cisplatin, and capecitabine 191. Chen L-T, Satoh T, Ryu M-H, et al. A phase 3 study o
as rst-line treatment or gastric or oesophagogastric junction nivolumab in previously treated advanced gastric or gastro-
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180. Catenacci DVT, Tebbutt NC, Davidenko I, et al. Rilotumumab sus placebo in patients with heavily pretreated metastatic
plus epirubicin, cisplatin, and capecitabine as rst-line therapy gastric cancer (TAGS): a randomised, double-blind, placebo-
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181. Shah MA, Bang YJ, Lordick F, et al. Eect o fuorouracil, cil in advanced gastric or gastroesophageal adenocarcinoma
leucovorin, and oxaliplatin with or without onartuzumab in study: the FLAGS trial. J Clin Oncol. 2010;28:1547-1553.
HER2-negative, MET-positive gastroesophageal adenocarci- 194. Higuchi K, Tanabe S, Shimada K, et al. Biweekly irinotecan plus
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2019;37:2-2. Clin Oncol. 2015;33(suppl 3):6.
28 Pancreatic Cancer
Jonathan D. Mizrahi
Anirban Maitra
Robert A. Wol
KEY CONCEPTS
 Pancreatic cancer has a ve-year survival o 10%, and it is because it can classiy pancreatic cancers as resectable,
expected to become the second leading cause o cancer borderline resectable, locally advanced, or metastatic.
death in the United States by 2030.  The only potentially curative treatment or pancreatic can-
 Modiable risk actors or pancreatic cancer include cer is surgical resection, which is an option or only 15% to
tobacco use, obesity, diabetes mellitus (particularly new- 20% o patients, because most patients are diagnosed at
onset diabetes), and chronic pancreatitis. Age and amily an advanced stage.
history are well-established, nonmodiable risk actors.  Recent advances in combination chemotherapy, particu-
 KRAS mutations and p16 inactivation are near universal larly FOLFIRINOX and gemcitabine plus nab-paclitaxel,
genomic events identied in pancreatic cancers, and his- have increased survival or patients with advanced pan-
tologically, pancreatic adenocarcinomas are characterized creatic cancer; FOLFIRINOX also improves survival in the
by a dense, collagenous stroma. adjuvant setting.
 High-quality multidetector computed tomography imag-  Precision medicine is slowly emerging in pancreatic
ing is the gold-standard diagnostic and staging modality, cancer
When clinicians use the term pancreatic cancer, they reer atal malignancy. In the United States, it represents 3%
to adenocarcinoma o the pancreas, one o the most chal- o all cancer cases but accounts or 7.5% o all can-
lenging malignancies acing oncologists, patients, and cer deaths.1 As o this writing, it is the third leading
caregivers today. This disease is characterized by signi- cause o cancer-related deaths, ranking behind lung
cant morbidity and a poor prognosis. At the MDACC, and colorectal cancers. The 5-year survival rate has
we manage pancreatic cancer using a multidisciplinary marginally improved over the past ew decades (2%
approach. For patients with localized disease, we gen- in 1974–1976, 6% in 2014) and has recently reached
erally employ a stepwise multimodality approach. For 10% or the rst time.2,3 Over the next decade, deaths
most patients with locally advanced disease and all caused by pancreatic cancer are projected to increase
patients with metastatic disease, palliation is a high pri- dramatically, overtaking colorectal cancer as the sec-
ority. This chapter summarizes our current knowledge ond leading cause o cancer-related death.
about pancreatic cancer, including its epidemiology, risk
actors, molecular biology, diagnosis and staging, and
clinical strategies or therapy. EPIDEMIOLOGY
There are approximately 56,000 new cases o pan-
HARD FACTS ABOUT PANCREATIC creatic cancer each year in the United States and
CANCER 459,000 cases worldwide.4 Incidence rates are high-
est in industrialized societies and Western countries.
Pancreatic adenocarcinoma, the most common pan- O note, the risk o pancreatic cancer among Blacks,
creatic neoplasm, is an aggressive and oten rapidly in whom pancreatic cancer mortality rates are higher
619
620 Sction VI Gastrointestinal Cancer
than most other ethnic groups in the United States, is Diabetes Mellitus
considerably higher than the rates or Arican Blacks.5
The risk o developing pancreatic cancer is low in the Diabetes has been implicated both as an early maniesta-
rst three to our decades o lie but increases sharply tion o pancreatic cancer and as a predisposing actor. As
ater the age o 50 years. The average age at the time many as hal o pancreatic cancer patients report a his-
o diagnosis is 72 years; it is uncommon in persons tory o new-onset diabetes (NOD) or worsening hyper-
younger than 40 years. However, there has been an glycemia, and an additional one quarter report impaired
increasing interest in early-onset pancreatic cancer glucose tolerance.8 In these cases, the occult pancreatic
(usually dened as age o onset beore 50 years). cancer is responsible or inducing hyperglycemia, likely
Our group has recently reported that patients with through altering peripheral insulin resistance. Changes
early-onset pancreatic cancer are more apt to have in glycemic control can occur as early as 36 months
germline mutations in DNA damage repair pathway beore clinical diagnosis, providing an opportunity or
genes compared with patients considered to have earlier detection. However, because only around 1% o
later onset.6 NOD is caused by an underlying pancreatic cancer, ur-
ther enrichment o this high-risk population is needed to
conduct meaningul surveillance. Our team is currently
leading a multicenter prospective NOD cohort that will
RISK FACTORS FOR PANCREATIC accrue 10,000 patients with NOD or hyperglycemia and
CANCER ollow them or the development o incidental pancre-
ChapTer 28
atic cancer. Longitudinal collection o biospecimens or

Both genetic and environmental actors have been biomarker studies aims to better dene and enrich this
implicated in the risk o pancreatic cancer develop- population or pancreatic cancer risk.9
ment. Table 28–1 summarizes these risk actors.
Body Mass Index
Tobacco
Epidemiologic studies have also implicated a high
Cigarette smoking is one o the better-established body mass index as increasing the risk or pancreatic
liestyle risk actors or pancreatic cancer, albeit the cancer.10 Numerous molecular mechanisms—both
odds ratio is lower than that o lung cancer. Overall, local (infammatory mediators produced by abdominal
cigarette smoking is estimated to account or roughly adipocytes within the peri-pancreatic milieu) and sys-
25% to 30% o pancreatic cancer cases.7 temic (secreted adipokines and hyperinsulinemia)—are
Tbl 28–1 Acquired and Genetic Risks Factors Associated with Pancreatic Cancer
Acquired Risk Factors Relative Risk Comments

Tobacco smoking 2–5 Risk increases with increasing exposure
Diabetes mellitus 2 Not all authorities concur; many
patients have altered glucose
metabolism on presentation
High body mass index 2
Chronic pancreatitis 13–18 Not all authorities concur with this
degree o increased risk
Inherited Disorders Relative Risk Known Deects
Hereditary pancreatitis 10–53 PRSS1
FAMMM syndrome 22 p16INK/CDKN2
HNPCC 8 MLH1, MSH2, MSH6
Peutz-Jeghers syndrome 13–30 LBK1/STK11
Familial adenomatous polyposis 4–5 APC
Li-Fraumeni syndrome ? p53
Familial breast and ovarian cancer 3–5 DNA repair pathways, BRCA2
FAMMM, amilial atypical mole and melanoma; HNPCC, hereditary nonpolyposis colon cancer.
Ct 28 Pancreatic Cancer 621
postulated to contribute toward the increased risk o therapy approved or pancreatic cancer based on its
pancreatic cancer in obesity.11,12 For example, studies clinical benet in the maintenance setting in germ-
in preclinical models rom MDACC have shown the line BRCA–mutated patients with disease control on
infuence o obesity-associated lipocalin-2 levels in initial platinum-based chemotherapy. 20,21
accelerating pancreatic carcinogenesis.13
Diet MOLECULAR EVENTS IN HUMAN

PANCREATIC CARCINOGENESIS
Positive associations have been discovered between
pancreatic cancer and meat and carbohydrate intake.14 With the advent o next-generation sequencing plat-
However, there is no consensus on the contribution o orms, several publicly unded initiatives such as the
dietary at. Epidemiologic studies o pancreatic cancer International Cancer Genome Consortium and The
have shown a protective role or high ruit and veg- Cancer Genome Atlas have comprehensively mapped
etable intake. the genomic landscape o pancreatic cancer across
hundreds o tumors.22–24 These large-scale eorts
Chronic Pancreatitis have not only identied the major recurrent altera-
tions in pancreatic cancer, but also less requently
Early clinical studies have suggested an association altered mutations, many o which are “actionable.”25
between chronic pancreatitis and pancreatic cancer. As much as one quarter o patient tumors may harbor
ChapTer 28
Studies have suggested that hereditary pancreatitis, potentially actionable mutations and this inorma-
in particular, may aect the risk. Mutations o several tion can be returned to the oncologist in a easible
genes can be associated with hereditary pancreatitis, timerame.26,27
o which PRSS1, encoding or cationic trypsinogen, is
the most common.15
Oncogenes in Pancreatic Cancer
Familial Pancreatic Cancer and Other Oncogenic mutations o KRAS are the dening
Genetic Syndromes genetic eature o pancreatic cancer, occurring in
about 90% o cases. 24 KRAS mutations most com-
Approximately 10% o patients with pancreatic monly involve codon 12 and are usually either a
cancer harbor a germline mutation that predisposes glutamine-to-valine (KRASG12V) or glutamine-to-
them to pancreatic cancer. 16,17 Notably, only about aspartic-acid (KRASG12D) alteration. The uncommon
hal o these patients report a amily history o pan- KRASG12C mutations are observed in only about 1.5%
creatic cancer, and thereore, the National Compre- o pancreatic cancer. 28
hensive Cancer Network (NCCN) and the American O note, around 10% o cases are wild-type KRAS.
Society or Clinical Oncology (ASCO) both recom- In these cases, it is not uncommon to nd alternative
mend universal germline testing or all patients. 18,19 drivers, including NRG1, ALK, or NTRK usions that
Known cancer predisposition syndromes that are drive cancer progression,29 and or which targeted
associated with increased risk o pancreatic cancer agents are readily available.30–32 Thereore, the absence
include hereditary nonpolyposis colorectal cancer, o a demonstrable KRAS mutation in conrmed pan-
ataxia-telangiectasia, Peutz-Jeghers syndrome, amil- creatic adenocarcinoma should prompt interrogation
ial breast and ovarian cancer, and amilial atypical or these alternative drivers.33,34
multiple-mole melanoma. The most common class
o genes associated with amilial predisposition to
pancreatic cancer are those whose protein products Tumor Suppressor Genes in Pancreatic
are involved in the cellular DNA repair response, Cancer
including BRCA2, BRCA1, ATM, and PALB2. O The most common recurrently altered tumor suppres-
these, BRCA1/2 and PALB2 proteins are key com- sor genes in pancreatic cancer are TP53, CDKN2A/
ponents o homologous recombination through the p16, and DPC4/SMAD4.24 TP53 is the most commonly
repair o DNA double-strand breaks. The poly(ADP- mutated gene in human cancer, and somatic altera-
ribose) polymerase (PARP) enzyme is integral or tions are present in about 75% o pancreatic cancers.
single-stranded DNA repair, and inhibition results Nearly all pancreatic cancers harbor anomalies o the
in DNA breaks that require intact BRCA proteins cyclin-dependent kinase inhibitor gene CDKN2A/p16.
or repair. Thereore, in the presence o mutant DPC4/SMAD4 alterations are observed in approxi-
BRCA1/2 or PALB2 proteins, PARP inhibition results mately 55% o pancreatic cancers. In solid tumors,
in synthetic lethality. As we discuss later, the PARP DPC4/SMAD4 aberrations are somewhat specic or
inhibitor, olaparib, became the rst biomarker-based advanced pancreatic cancer.35
Potentially Actionable Gene Mutations in broblast (CAF), and recent single-cell RNA sequenc-
Pancreatic Cancer ing studies have identied at least three distinct types
o CAFs,49,50 with potentially distinct tumor-promot-
As o this writing, the most clinically relevant are ing versus tumor-suppressive roles. This is important
genes encoding or proteins involved in DNA damage because generic strategies to target the pancreatic can-
response and repair, including BRCA2, BRCA1, PALB2, cer CAFs (eg, using small-molecule inhibitors targeting
CHEK2, ATM, RAD51, among others.22,24 Although the Hedgehog pathway) have been counterproduc-
germline mutations o these genes occur in the con- tive,51 underscoring the distinct roles played by vari-
text o amilial pancreatic cancer, approximately 15% ous CAF populations in constraining or promoting the
o cases harbor somatic loss o unction mutations and neoplastic process. Third, the pancreatic cancer TME
such cases could be targets or DNA repair targeted is characterized by high interstitial pressure, which has
therapies, such as PARP inhibitors. Approximately 1% been ascribed to the deposition o extracellular matrix
o pancreatic cancer cases harbor mutations in genes proteins like hyaluronic acid and other glycosaminol-
involved in a particular class o DNA repair known glycans,52 and is implicated in reducing the delivery o
as mismatch repair, including MLH1, MSH2, PMS2, systemic chemotherapy to the tumor milieu. Although
and MSH6, and the corresponding tumors have an preclinical studies supported the ecacy o reducing
exceptionally high tumor mutation burden (so-called interstitial pressure by targeting hyaluronic acid with
“hypermutators”).36 Hypermutator tumors are suscep- a pegylated hyaluronidase and acilitating the infux
tible to immune checkpoint inhibitor immunotherapy o therapeutic agents,53,54 the phase 3 clinical trial o
ChapTer 28
and can be oered this in the rst or second line based this agent (PEG-PH20), in combination with cytotoxic
on recent FDA directives.37 Finally, one needs to men- chemotherapy, ailed to improve survival in metastatic
tion the class o genes that encode or protein involved disease, again reinorcing the complexities o stromal
in chromatin regulation (such as ARID1A, PBRM1, biology in pancreatic cancer.
KDM6A, MLL3, among others) that are cumulatively
mutated in 15% to 25% o cases.38,39 In other solid
tumors, there are emerging data to suggest the poten- PATHOLOGY
tial or using immunotherapy combinations against
these tumors.40,41 Pancreatic acinar cells account or approximately 80%
o the cell number and volume o the gland; islet cells
Transcriptomic Subtypes of Pancreatic account or 1% to 2%. The ductal system is com-
Cancer posed o single-layer, cuboidal epithelial cells repre-
senting 10% to 15% o the gland’s structure, with a
Currently, the most widely accepted classication sparse interlacing network o blood vessels, lymphat-
scheme assigns pancreatic cancers into so-called “clas- ics, nerves, and collagenous stroma. In carcinoma, this
sical” and “basal-like” subtypes.24,42 The “classical” architecture is markedly altered. The predominant
phenotype is characterized by the expression o the histologic eature is a desmoplastic (brous) stroma
endodermal transcription actors GATA6 and HNF4A, with atrophic acini, usually preserved islet cell clus-
both o which are absent in the “basal-like” tumors.43,44 ters, and a haphazard growth o cancerous ducts
In contrast, basal-like, sometimes called “squamous (Fig. 28–1). The diagnosis o ductal adenocarcinoma
subtype,” is characterized by an aggressive natural rests on the identication o mitoses; nuclear and cellular
history, and emerging data suggest that the basal-like pleomorphism; and evidence o perineural, vascular, or
tumors are resistant to FOLFIRINOX.45 lymphatic invasion.55 Intraductal precursor lesions in
the surrounding pancreatic parenchyma are common
Pancreatic Cancer Stroma with two major subtypes. The rst and most com-
mon (~90% o cancers arise rom these precursors) are
No discussion o the molecular pathology o pan- the microscopic pancreatic intraepithelial neoplasia or
creatic cancer is complete without alluding to the PanIN lesions. Histologically, PanIN lesions are graded
stroma and immune cell types that comprise the as “low” and “high” grades. High-grade PanINs oten
complex tumor microenvironment (TME) in this dis- harbor many o the genetic alterations ound in rank
ease. A credible review o the pancreatic cancer TME carcinomas.56 The macroscopic precursors o ductal
is beyond the scope o this chapter, and the reader is adenocarcinomas are mucinous cysts o the pancreas,
pointed to several recent reviews on this topic.46–48 A presenting either as intraductal papillary mucinous
ew highlights are emphasized. First, the pancreatic neoplasms or mucinous cystic neoplasms.57 Analogous
cancer stroma is comprised o a multitude o cell types to PanINs, the cystic lesions also demonstrate low- and
and extracellular matrix proteins.46 Second, the most high-grade epithelial dysplasia, culminating in invasive
common nonimmune cell type is the cancer-associated neoplasia.
Tbl 28–2 Histologic Classifcation o Primary

Eocrine Pancreatic Tumors
Malignant
Ductal adenocarcinoma
Mucinous cystadenocarcinoma
Acinar carcinoma
Unclassied large cell carcinoma
Small cell carcinoma
Pancreatoblastoma
Benign
Serous cystadenoma
Variable Malignant Potential
Intraductal papillary mucinous tumor
Mucinous cystadenoma
Papillary cystic neoplasm
ChapTer 28
cause unremitting, severe back pain, and tumors in the
pancreatic tail may be associated with let upper quad-
rant pain.
Painless jaundice, another common presentation,
is generally associated with tumors in the pancreatic
head or uncinate process. When the tumor does not
FIGURE 28–1 Photomicrograph o ductal adenocarcinoma arise in proximity to the intrapancreatic portion o the
o the pancreas with well-preserved islet cells and pancreatic bile duct, diagnosis may be delayed and characterized
architecture above and infltrating tumor with poorly ormed by abdominal pain or back pain without jaundice.
glandular structures below.
Acute pancreatitis, although uncommon, can be
caused by a ductal adenocarcinoma in patients with no
other reason or acute pancreatitis (lack o gallstones,
Almost all malignant neoplasms o pancreatic origin no history o alcohol or precipitating drugs).59 Symp-
(95%) arise rom the exocrine portion o the gland, with toms o chronic pancreatitis are relatively common,
ductal adenocarcinomas being the most common.58 Pan- including diarrhea, bloating or constipation, abdominal
creatic neuroendocrine tumors arising rom the islets o distention, and weight loss. Patients with tail lesions
Langerhans are much more inrequent, and primary oten remain asymptomatic until the development o
nonepithelial tumors (eg, lymphomas or sarcomas) are signs or symptoms o metastatic disease.
extremely rare. The histologic classication o exocrine
pancreatic neoplasms is presented in Table 28–2.
DIAGNOSIS AND STAGING
CLINICAL PRESENTATION Pancreatic cancer can be dicult to diagnose, particu-
larly in patients with nonspecic complaints. Circu-
The clinical presentation o pancreatic cancer is pri- itous workups and interventions are not uncommon
marily dependent on the location o the tumor within and may include upper endoscopy, which may be
the pancreas. The majority (85%) develop within the misleading and demonstrate mild esophagitis, gastri-
pancreatic head. About 10% are located in the pancre- tis, or duodenitis, with or without evidence o Heli-
atic body, and 5% are located in the tail. Nonspecic, cobacter pylori. Patients complaining o right upper
poorly localized, epigastric or back pain is the most quadrant pain may undergo ultrasonography, poten-
common initial presentation. It is usually caused by tially revealing gallstones, prompting cholecystec-
invasion or compression o the celiac, splanchnic, or tomy. For patients presenting with complaints o back
mesenteric plexi. Tumors in the head or neck typically pain, a musculoskeletal evaluation is commonly done.
cause pain in the epigastric area or in the right upper Most patients ultimately undergo cross-sectional body
quadrant o the abdomen. Cancers o the body may imaging with the discovery o a pancreatic mass.
For patients who present with obstructive jaundice, are typically small to medium sized. Bulky lymph nodes
suspicion o pancreatic cancer is suciently high that are more oten seen in other pancreatic neoplasms such
the diagnostic workup usually proceeds in an orderly as acinar cell carcinomas or pancreatic neuroendocrine
ashion with directed imaging studies. These usually tumors. Tumors o the esophagus, stomach, duodenum,
include abdominal ultrasonography, computed tomog- and sometimes the colon can lead to bulky peripancre-
raphy (CT) scan o the abdomen, or both. atic lymph nodes. Lymphoma, non–small-cell lung can-
cer, and carcinomas o unknown primary origin may
also lead to bulky peripancreatic lymphadenopathy and
Tissue Acquisition be mistaken or a primary pancreatic neoplasm. Thin-
With rare exception, all patients seen at MDACC are cut, contrast-enhanced dynamic-phase CT will usually
advised to undergo biopsy to conrm the presence o rule out the presence o a primary mass in the pancreas
malignancy and type i it is not perormed beore reer- in this setting. Another helpul radiographic nding may
ral. Cross-sectional imaging, (our preerence is dual- be the presence or absence o atrophy o the pancreatic
phase multidetector CT), should always be perormed body and tail. Although commonly seen with adenocar-
beore interventional endoscopic or other invasive cinomas, this nding is usually absent in the setting o
procedures to prevent procedure-related infamma- neuroendocrine and acinar cell tumors.
tory changes, which may conound assessment o the
tumor’s potential or resection. In patients who present
with obstructive jaundice and radiographic evidence o
High-Quality Computed Tomography
ChapTer 28
a localized pancreatic mass, endoscopic retrograde chol- At MDACC, the single most important imaging
angiopancreatography and endoscopic ultrasound (EUS) modality is dynamic-phase CT. This technique is used
with biopsy are oten perormed concurrently. EUS- to objectively dene (anatomically) potentially resect-
guided biopsies are preerred over percutaneous biopsies able disease and allows or imaging o the pancreas and
in patients who may be candidates or surgical resection surrounding vascular structures in arterial and venous
to decrease the risk o peritoneal or needle-track seeding, phases o intravenous contrast. For optimal pretreat-
which has been reported among patients undergoing ment staging, a CT report in a patient with suspected
transcutaneous ultrasound– or CT-directed biopsies.60 pancreatic cancer should include the ollowing:
Alternatively, when CT or magnetic resonance imaging 1. The presence or absence o a primary tumor in
clearly demonstrates an unresectable, locally advanced the pancreas or periampullary region
cancer, CT- or ultrasound-guided transcutaneous biopsy 2. The presence or absence o peritoneal and hepatic
may substitute or EUS-guided aspiration. I a patient metastases
presents with obstructive jaundice and biliary stricture 3. Description o the patency o the superior mes-
without radiographic evidence o a pancreatic mass, EUS enteric vein (SMV) and portal vein (PV) and the
examination is also advised. EUS can also be useul in relationship o these veins to the tumor
the evaluation o regional lymph nodes and oers an 4. Description o the relationship o the tumor to
opportunity or biopsy i the primary tumor is techni- the superior mesenteric artery (SMA), celiac axis,
cally dicult to biopsy. and hepatic artery
When there is clear radiographic evidence o met- Objective radiographic criteria can be used to dene
astatic disease and an obvious pancreatic mass, we a potentially resectable primary tumor o the pancre-
preer biopsy o a metastatic site, such as the liver. atic head or uncinate process (Fig. 28–2). The MDACC
This conrms both the diagnosis and the presence o criteria include: (1) no extrapancreatic disease; (2) a
metastatic disease with one procedure. In addition, patent SMV and PV (assuming the technical ability
core-needle biopsies o metastatic sites can gener- to resect and reconstruct this venous confuence); and
ally be obtained saely and provide sucient tissue (3) a denable tissue plane between the tumor and
or molecular proling. Just as the NCCN and ASCO regional arterial structures, including the celiac axis
recommend germline testing or patients with pancre- and SMA. A recent meta-analysis has estimated the
atic cancer, the NCCN also encourages molecular and positive predictive value or resectability based on con-
genomic proling o tumor tissue whenever easible.61 trast-enhanced CT imaging is 81%.62 CT o the chest is
now routinely part o our staging workup. Bone scans
and brain imaging are rarely indicated and should not
Misdiagnosis of Pancreatic Cancer be part o routine staging.
It is not uncommon or patients to be misdiagnosed with
pancreatic cancer. The most common mistake we see is
in the setting o bulky peripancreatic adenopathy mim-
Positron Emission Tomography
icking a pancreatic mass. Adenocarcinomas o the pan- Positron emission tomographic (PET) scans are not a rou-
creas do metastasize to regional lymph nodes, but these tine part o our staging. However, they are sometimes
Tumor SMA 19-9 antigen, seen in patients who are Lewis antigen–
negative (5%–7% o general population).69
The TNM System Versus Clinically Oriented

Staging
The tumor, node, metastasis (TNM) staging system
or pancreatic cancer is outlined in Table 28–3. For
patients undergoing resection (who represent the small
minority o patients with pancreatic cancer), the TNM
system is somewhat useul in providing prognostic
inormation.
Stent
TREATMENT STRATEGIES FOR
PANCREATIC CANCER
FIGURE 28–2 Computed tomographic image o tumor At MDACC, patients are initially staged clinically as
within the pancreatic head. Note the stent in the bile duct having potentially resectable, borderline resectable,
ChapTer 28
and the subtle low-density mass within the head. The supe- locally advanced/unresectable, or metastatic disease
rior mesenteric artery (SMA) has a at plane completely sur- (Fig. 28–3). For patients with potentially resectable
rounding it. This defnes a potentially resectable tumor. disease and no contraindications to surgery based on
railty or comorbidities, surgery with curative intent
should be pursued. As discussed later, we avor neo-
obtained in the setting o equivocal radiographic nd- adjuvant therapy ollowed by surgery, over upront
ings, such as indeterminate lesions in the liver or lungs. surgery and adjuvant therapy. Patients with metastatic
Note that small lesions (<1 cm) may be 18F-fuorodeox- disease and adequate perormance status (PS) usually
yglucose (FDG)-PET–negative, even when metastatic receive systemic therapy. For patients presenting with
disease is present.63 We also nd 18FDG-PET useul to locally advanced disease, treatment should be individ-
evaluate or isolated local recurrence when a patient has ualized and usually initially involves systemic therapy.
undergone previous resection and subsequently exhibits
a rising CA19-9 with sot tissue changes in the surgical Resectable Pancreatic Cancer
bed indeterminate or brosis or recurrence.
It is widely known that surgery holds the only hope
o cure or patients with pancreatic cancer. Most cases
Serum CA19-9 Determinations o resectable pancreatic cancers are comprised o small
CA19-9 measures the specic carbohydrate moiety o tumors located in the head o the pancreas. These are
the mucin MUC-1.64 This is the most commonly ele- removed with a Whipple procedure,70 more appropri-
vated tumor marker in pancreatic cancer, but it is not ately described as a pancreaticoduodenectomy.
specic and may be elevated in other gastrointestinal There are two distinct approaches to the manage-
tumors. Most retrospective analyses generally suggest ment o a patient with potentially resectable pancre-
that a high preoperative CA19-9 level (>500–1000 IU/ atic cancer: (1) proceed with upront surgery and, i
mL) implies more advanced disease. Serial measure- possible, deliver adjuvant therapy or 6 months post-
ments o CA 19-9 during a course o neoadjuvant operatively; or (2) deliver neoadjuvant therapy and, i
therapy is increasingly used to predict who among appropriate, proceed with surgical resection thereater
those with resectable or borderline resectable disease (Fig. 28–4).
will derive the most benet rom surgical resection.65,66
Conversely, in patients undergoing surgery as initial Modern Adjuvant Therapy for Resected
therapy, when postoperative CA19-9 levels do not
Pancreatic Cancer
normalize within 8 to 12 weeks postoperatively, early
relapse with poor prognosis oten ensues.67 Decreas- Despite our preerence or neoadjuvant therapy over
ing CA19-9 levels o 50% or more during induction upront surgery and adjuvant therapy, the majority o
systemic chemotherapy has been correlated with patients with resectable pancreatic cancer undergo a
improved survival.68 A small subset o patients will surgery-rst approach. For those who recover well and
have undetectable CA 19-9 levels based on lack o the have no clinical evidence o early relapse, 6 months
enzyme ucosyltranserase needed to produce the CA o systemic adjuvant therapy remains the standard o
Tbl 28–3 TNM Criteria or Pancreatic Adenocarcinoma TNM Defnitions
No evidence o primary tumor T0 Complete pathologic response to neoadjuvant therapy may result in T0
tumor
Tumor <2 cm in greatest dimension T1 T1 tumors would generally be resectable based on high-quality imaging
Tumor >2 and <4 cm in greatest T2 T2 tumors may be resectable or borderline resectable (nonmetastatic)
dimension
Tumor >4 cm in greatest dimension T3 T3 oten with extrapancreatic extension and may be borderline
resectable
Tumor involves the CA, HA, or SMA T4 Encasement o these vessels dene locally advanced disease;
<180° = borderline resectable
No regional lymph node metastasis N0 Negative lymph node involvement in 60% o cases ater neoadjuvant
therapy
Metastasis in one to three regional N1 Positive lymph node involvement occurs in 57% cases with upront
LNs surgery
Metastases in our or more regional N2 Positive lymph node involvement occurs in 57% cases with upront
LNs surgery
ChapTer 28
No distant metastasis M0
Distant metastasis M1 Common metastatic sites would include the liver, lung, and peritoneum
Pathologic Staging Classifcation

IA IB IIA IIB III III IV
T1 T2 T3 T1-T3 T1-T3 T4 Any T
N0 N0 N0 N1 N2 Any N Any N
M0 M0 M0 M0 MO M0 M1
More avorable More avorable More avorable Intermediate Intermediate Locally Metastatic
prognosis: prognosis: prognosis: survival survival advanced disease
median median median (median (median disease median
survival 36 survival 36 survival 36 18–24 mo 18–24 mo expected survival
mo mo mo survival 9–12 mo
14–18 mo
Data rom Edge SB, Byrd DR, Byrd DR, et al: AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.
LN, lymph node.
care. Since the last edition o this text, results using o gemcitabine postoperatively (13 and 22.8 months,
adjuvant therapy or pancreatic cancer have improved. respectively) compared with surgery alone (6.9 and
However, as discussed urther below, not all o the 20.2 months).74 Subsequently, the European Society
improvement in survival observed over time is com- o Pancreatic Cancer (ESPAC) reported on their results
pletely attributable to the improvement o systemic in the ESPAC-4 trial, which randomly assigned surgi-
therapy in the adjuvant setting. cally resected patients to adjuvant gemcitabine with
A comprehensive history o adjuvant therapy or or without capecitabine.75 The chemotherapy dou-
pancreatic cancer is beyond the scope o this text and blet demonstrated an improvement in OS (28 vs 25.5
ocused on the delivery o 5-FU–based chemoradia- months; P = .032).
tion which, taken together, were inconclusive as to its More recently, the results o the PRODIGE-24/
survival benet.71–73 Gemcitabine monotherapy was CCTG study established another new standard o care
subsequently shown to improve disease-ree survival or the adjuvant setting.76 Patients were randomized to
(DFS) and overall survival (OS) over surgery alone in either 6 months o modied 5-FU, leucovorin, irinote-
a trial conducted by Charité Onkologie (CONKO). can, and oxaliplatin (mFOLFIRINOX) or gemcitabine.
CONKO 001 was a randomized phase 3 trial that com- The combination chemotherapy arm signicantly
pared 6 months o gemcitabine with observation alone improved DFS rom 12.8 to 21.6 months and median
ater curative intent surgery. Investigators showed a OS rom 35 to 54.4 months. Despite the impressive
signicant improvement in DFS and OS with the use survival data rom the PRODGE-24/CCTG study, it is
Suspicion of Pancreatic Cancer

(Mass seen on previous imaging or presentation with obstructive jaundice)
Dynamic phase, helical CT scan
Visible tumor No visible mass
Unresectable or metastatic disease

Resectable by CT-criteria EUS
by CT-criteria
Systemic therapy or chemoradiation EUS FNA No

Mass evident
mass visible
Biopsy Biopsy Consider

FNA
adenocarcinoma nondiagnostic surgery
ChapTer 28
Preoperative Inadequate
Surgery
chemo XRT recovery
Adequate recovery
Restaging No further
within 12 weeks
therapy
until evidence
relapse
Resectable with
Metastatic disease Restaging
no metastatic disease
No evidence of
Surgery Systemic therapy
residual disease
Adjuvant therapy to
include radiation
FIGURE 28–3 General algorithm or diagnostic workup and management o newly diagnosed pancreatic cancer.
important to recognize that the study patients repre- the combination over single-agent gemcitabine. O
sented a very select cohort. For example, patients with note, however, there was some improvement in OS
postoperative CA 19-9 levels greater than 180 U/mL or patients receiving gemcitabine and nab-paclitaxel
within 21 days o random assignment were excluded. compared with those receiving gemcitabine alone (40
Moreover, enrollment was limited to patients with a vs 36 months), but this did not meet statistical signi-
World Health Organization PS o 0–1. cance and was not the primary end point.
The most recent trial o adjuvant therapy or pan- Table 28–4 summarizes the results o the recently
creatic cancer was the Adjuvant Pancreatic Adenocar- completed adjuvant trials. Note that the survival o
cinoma Clinical Trial (APACT), which compared the patients randomly assigned to gemcitabine has steadily
combination o gemcitabine and nab-paclitaxel with increased rom 22.8 months in 2013 to 25 months in
gemcitabine or 6 months.77 The primary end point 2017 and up to about 35 months in 2018–2019. This
o the study was independently assessed DFS. The suggests that patient selection or trial enrollment has
results, presented at the ASCO annual meeting in 2019, become increasingly stringent rom the early 2000s
demonstrated no signicant improvement in DFS or to the present time. Moreover, treatment options
Resectable Pancreatic Cancer
High-riska Low-risk
Elevated CA 19-9 with other Up-front surgical Preoperative

Comorbidities
signs of metastatic disease resection clinical trials
Consider staging laparoscopy If adequate postoperative

recovery within 12 weeks,
restaging CT, then
gemcitabine-based systemic
therapy and consider radiation
Staging laparoscopy + for
metastatic disease
ChapTer 28
Evidence of
No Yes progression on
restaging
Systemic chemotherapy vs Treat for stage of Yes
gemcitabine or 5-FU–based disease
chemoradiation
Consider resection No
based on operative risk
FIGURE 28–4 Treatment algorithm or the management o resectable pancreatic cancer. aHigh-risk clinical eatures: suspicion
o metastatic disease; CA19-9 >1000 with normal bilirubin; comorbidities suggesting high operative risk.
available at the time o relapse have slowly expanded postoperative complications o 23%. For patients with
during this same time interval. no serious postoperative complications, the rate o adju-
vant therapy delivery was 62%; or those with at least
one postoperative complication, the delivery o adjuvant
Challenges Associated with Upfront therapy was only 44%.78 Pancreatic cancer surgery can
Surgery Followed by Adjuvant Therapy also result in death. Among roughly 15,000 patients who
In most centers, upront surgical resection is the main- underwent curative intent surgery or pancreatic cancer,
stay o treatment or potentially resectable pancreatic 30-day mortality was only 3.4%, whereas 90-day mor-
cancer. However, careul analysis o results rom a sur- tality was twice that, at 7.5%.79
gery-rst approach uncovers signicant potential faws 2. Positive surgical margins are associated with inerior
in sequencing therapy this way. prognosis and are quite requent with upront surgery.
1. Surgical morbidity and mortality remain quite high Pancreatic cancer is notorious or being locally invasive,
ater pancreaticoduodenectomy and impact the delivery and surgical margins at the time o surgical resection are
o adjuvant therapy. oten microscopically positive (R1 resection). In modern
Potentially resectable pancreatic cancer is oten diagnosed trials o adjuvant therapy, the requency o R1 resections
in patients in their 60s to 70s and, given the known risk among enrolled patients varies widely between 17%
actors or pancreatic cancer, many patients may have and 60% (Table 28–4). Prospective and retrospective
a prior history o tobacco use, diabetes, or obesity, or analyses have shown that R1 resections are associated
they may present in a deconditioned state. Any o these with worse survival compared with R0 resections.80–82
comorbidities can increase the risk o postoperative com- In ESPAC-4, survival was superior or patients under-
plications, hamper recovery, and reduce the chances o going R0 resection compared with those having an R1
receiving adjuvant therapy. An analysis perormed by the resection, irrespective o assigned therapy, as shown in
American College o Surgeons National Surgical Quality Table 28–4.75
Improvement Program evaluating data rom the National While some have advocated or postoperative radi-
Cancer Data Base (NCDB) has reported a rate o serious ation as a component o adjuvant therapy or patients
Tbl 28–4 Results o Upront surgery in modern adjuvant therapy trials.
Number o R1 Median Survival (Months)

Number o Patients Enrolled Resection
Study Year Patients Per Site Per Year Rate Control Arm Experimental Arm
CONKO 001 364 0.64 17 Observation Gemcitabine
2013 20.2 22.8
ESPAC 4 730 1.32 60 Gemcitabine Gemcitabine +
2017 Full Cohort capecitabine
25.5 Full Cohort
R0 27.9 28.0
R1 23.0 R0 39.5
R1 23.7
PRODIGE/ 493 1.90 43 Gemcitabine FOLFIRINOX
CCTG 35.0 54.4
2018
APACT 866b Not stated 24 Gemcitabine Gemcitabine + nab-
2019a 36.2 paclitaxel
40.5
ChapTer 28
a
1226 patients were screened or enrollment, 360 (29%) ailed screening; o these, 200 (17%) ailed based on presence o postoperative radiographic evidence o
persistent or metastatic disease, or postoperative CA 19-9 level >100 U/mL.
b
The primary end point was independently assessed disease-ree survival; overall survival was not the primary end point o this trial.
who undergo an upront R1 resection,83,84 our view is 1. Assessment o postoperative recovery

that neoadjuvant therapy is a more logical strategy to First and oremost, ensuring adequate recovery rom
reduce the risk o a positive resection margin.85 surgery is an important step in determining whether
3. Upront surgery results in persistent disease or metasta- the patient has recuperated adequately to consider
ses within the immediate postoperative period. adjuvant therapy. Patients should be ambulatory
The preliminary report o the APACT trial did report and capable o sel-care with minimal assistance. At
on screen ailures or enrollment. A total o 1266 MDACC, adjuvant therapy is generally initiated 8 to
patients were evaluated or enrollment in this random- 10 weeks postoperatively, although we accept a ull 12
ized phase 3 trial, but only 866 (71%) were enrolled. weeks o postoperative recovery as the outer bound
O the 366 screen ailures, 200 (17%) were ineligible or embarking on adjuvant therapy. This is based on
based on postoperative radiographic evidence o per- analysis o results rom patients treated on ESPAC tri-
sistent or metastatic disease, or a postoperative serum als o adjuvant therapy, which showed no dierence in
CA 19-9 level greater than 100.77 survival or those patients beginning adjuvant therapy
In summary, upront surgery is associated with sig- at 6 to 8 weeks compared with those starting treat-
nicant morbidity and mortality, it oten leaves micro- ment 12 weeks postoperatively.86 Moreover, or those
scopic residual disease, and it puts the patient at risk patients who did not receive a ull six cycles o adju-
or early relapse in the immediate postoperative period. vant therapy, improved survival was demonstrated
Thus, based on current estimates, o the patients who i treatment was initiated later (>8 weeks), implying
undergo upront surgery with curative intent, as much that premature initiation o adjuvant therapy may be
as 40% to 50% do not receive adjuvant therapy, proven detrimental.
to be a necessary component o treatment.78 2. Assessment o disease status
Beore initiating adjuvant therapy, patients undergo
MDACC Approach to Adjuvant Therapy restaging studies that include measurement o serum
As will be discussed in more detail, our institutional tumor markers and CT imaging o the abdomen and
bias is to deliver neoadjuvant therapy beore consider- pelvis. A specic cuto or CA 19-9 suggesting per-
ing surgery. Nevertheless, we have a subset o patients sistent disease has not been established, but a post-
who are advised to undergo surgery rst as part o operative level o 200 or higher should cause concern
their overall treatment plan. In addition, patients pres- or the presence o gross residual disease. We recom-
ent to MDACC in the postoperative period seeking mend postoperative imaging as the patient approaches
our opinion about a specic plan or adjuvant therapy. adequate recovery rom surgery, usually 8 to 10 weeks
In these circumstances, our approach has several postoperatively.
acets. A. A specic plan or adjuvant therapy
Assuming the patient has adequate recovery and no 3. The Role o Radiation in Resected Pancreatic Cancer
clinical, biochemical or radiographic evidence o dis- As a general rule, although nal surgical pathology
ease on postoperative assessment, the patient’s peror- is prognostic, it is not typically used as a major ac-
mance status is the primary actor in determining the tor in adjuvant treatment planning. The exception to
specic recommendations. this applies to patients who undergo an R1 resection.
A.Modied (m)FOLFIRINOX: In that setting, systemic therapy or at least 4 months
For patients with very good PS (ECOG 0–1) and no is advised. At that juncture, patients may be oered
contraindications to treatment with this combina- repeat imaging, and i there is no interval development
tion, such as baseline peripheral neuropathy, mFOL- o metastatic disease, chemoradiation may be consid-
FIRINOX delivered once every 2 weeks or six cycles ered to complete adjuvant therapy. Decisions about
(24 weeks) is the preerred regimen. Note that in the the role o postoperative chemoradiation are made by
original report o this regimen as adjuvant therapy, the consensus during our weekly multidisciplinary pancre-
dose o irinotecan was reduced rom 180 mg/m2 to atic cancer conerences.
150 mg/m2, which improved overall tolerance to the
treatment.76 In the case o progressive peripheral neu-
Neoadjuvant Therapy for Potentially
ropathy during treatment, we have a low threshold to
reduce the dose or omit oxaliplatin completely or the
Resectable Disease
remainder o the planned 6 months. At MDACC, our strong preerence is or neoadjuvant
b. Gemcitabine and Capecitabine therapy to be ollowed by surgery in the appropriate
ChapTer 28
For patients with ECOG PS 1–2, treatment with gem- setting. This preerence is based on the potential draw-
citabine and capecitabine delivered over 24 weeks is backs associated with upront surgery outlined previ-
generally recommended. In our experience, many ously. Neoadjuvant therapy ollowed by surgery oers
patients do not tolerate a 28-day cycle o this regimen some distinct theoretic advantages over immediate
(3 weeks on, 1 week o), and i patients have unac- surgery and adjuvant therapy.
ceptable toxicity or develop progressive intolerance, • Neoadjuvant therapy allows delivery o chemother-
we generally switch to treatment on a 21-day cycle. apy or chemoradiation to a relatively well-perused
Regardless o cycle length, adjuvant therapy is usually tumor bed and provides early treatment to micro-
given over 24 weeks. scopic metastases.
Tbl 28–5 Analyses o R0 Resection Rate and Lymph Node Involvement with Upront Surgery and
Adjuvant Therapy Versus Neoadjuvant Therapy and Surgery
R0 Resection Rate (%) Negative Lymph Node Rate (%)

Number
Author Study Details o Neoadjuvant Neoadjuvant
Year Patients Upront Surgery Therapy Upront Surgery Therapy
Roland
MDACC/Single Institution 307 85 92 26 50
2013
Youngwirth
NCDB 18,243 78 85 43 59
2017
Mokdad
NCDB/Propensity 15,237 76 83 23 52
Matching
2017
Versteijne
Meta-Analysis 3484 67 87 35 56
2018
Versteijne
PREOPANC Randomized 246 40 71 22 67
Trial
2020
• It can generate meaningul locoregional treatment those patients assigned to upront surgery (P = .096).
eect, increasing the chance o a margin-negative However, among the patients who underwent surgi-
resection and reducing the likelihood o positive cal resection, there was a clear survival advantage or
lymph nodes (Table 28–5). patients who had received preoperative treatment,
• It allows or observation o the tumor’s underlying 35.2 months versus 19.2 months (P = .029). The PREO-
biology over time and acilitates the identication PANC trial, although negative or improvement in OS
o patients with interval development o metastatic based on intent to treat, showed a survival advantage
disease, sparing them a major surgical procedure or those undergoing curative resection and has paved
which will not be o benet. the way or more robust eorts to assess the value o
• Neoadjuvant therapy also provides an opportunity neoadjuvant therapy compared with upront surgery
to observe the patient’s tolerance to nonsurgical in pancreatic cancer. Furthermore, investigation o the
treatment and allow or adjustments in its duration relative contributions o chemotherapy and chemora-
or intensity to maximize the patient’s chances or diation in neoadjuvant trials is ongoing.
recovery rom preoperative treatment beore surgi-
cal intervention.
• Neoadjuvant therapy allows or prehabilitation,
MDACC Approach to Neoadjuvant Therapy
which may involve gradual weight loss, improve- in Patients with Resectable Disease
ments in nutrition and glucose control, and exercise Patients who are identied beore reerral as having
to increase cardiovascular and physical tness.87 localized disease are initially seen by one o our sur-
ChapTer 28
We have been conducting neoadjuvant trials in poten- gical oncologists to assess PS and comorbidities and
tially resectable pancreatic cancer at MDACC since the conrm adenocarcinoma rom outside specimens or
early 1990s.88–92 Our data demonstrated that preopera- rom biopsies obtained here. Routine laboratory stud-
tive therapy is associated with high rates o R0 resec- ies are obtained to include complete blood counts and
tions and relatively low local ailure rates compared coagulation studies, a comprehensive metabolic panel,
with adjuvant therapy. Subsequent analysis o our sur- hemoglobin A1C, and serum tumor markers, speci-
vival results in patients undergoing surgery ater pre- cally carcinoembryonic antigen, CA 19-9, and CA 125.
operative therapy has demonstrated increases in OS High-quality dynamic-phase pancreatic protocol CT
over time rom 1990 to 2014 using our successive time imaging o the chest, abdomen, or pelvis is obtained
periods, with median OS improving rom 24.1 months and reported in a templated ormat described earlier in
rom 1990 to 1999 to 43 months in 2010 to 2014.93 the chapter. Patients clinically staged as having poten-
A growing number o comparisons between the tially resectable disease and considered to be surgical
use o neoadjuvant therapy ollowed by surgery and candidates are presented to multidisciplinary pancre-
upront surgery with or without adjuvant therapy atic cancer conerences to consider enrollment in a
have been conducted (Table 28–5).94–98 All o these clinical trial or to develop a preliminary plan or o-
analyses conclude that neoadjuvant therapy is more protocol therapy.
likely to result in an R0 resection compared with Outside o a clinical trial, i neoadjuvant therapy
upront surgery and increase the likelihood o negative is recommended, therapy is generally a well-dened
lymph nodes on nal pathology. These analyses have course o induction systemic therapy consisting or 3
been limited by a lack o randomized data compar- to 4 months o mFOLFIRINOX or gemcitabine/nab-
ing neoadjuvant therapy and subsequent surgery with paclitaxel. Restaging studies are perormed every 2
upront surgery and adjuvant therapy. The exception months during induction chemotherapy. I no interval
is the recently published PREOPANC trial conducted metastases are noted on restaging, long-, medium-, or
at 16 centers in the Netherlands, summarized in Table short-course capecitabine-based chemoradiation (50.4
28–5.98 This study allowed enrollment o patients with Gy over 28 ractions, 36 Gy over 12 ractions, or 30
resectable or borderline resectable disease (the latter to Gy over 10 ractions, respectively) is delivered. Deci-
be discussed below). The study enrolled 246 patients sions about the induction chemotherapy are let to the
between 2013 and 2017. Patients were randomly discretion o the treating oncologist and are generally
assigned to receive three courses o gemcitabine, based on comorbidities and PS. Patients with ECOG
with the second course given in conjunction with PS 0–1 are usually treated with mFOLIRINOX and
radiation to a dose o 36 Gy delivered over 15 rac- patients with ECOG PS 1–2, or with comorbidities,
tions, ollowed by surgery, ollowed by our courses more oten receive gemcitabine and nab-paclitaxel. In
o postoperative gemcitabine; or to upront surgery terms o the radiation dose and schedule, this is pri-
and six cycles o adjuvant gemcitabine. Based on the marily the purview o the treating radiation oncologist
intent-to-treat analysis, patients who were assigned with input rom the surgeon and medical oncologist.
to neoadjuvant therapy had a slightly better median Whenever possible, we advise our patients to receive
OS o 16.0 months compared with 14.3 months or neoadjuvant chemoradiation at MDACC. However,
we allow the delivery o o-protocol induction che- 3. The role o radiation in the neoadjuvant treatment o
motherapy in collaboration with the patient’s reerring borderline resectable disease is unclear.
oncologist. Radiation as a component o neoadjuvant therapy has
yet to be rmly established because there are no well-
designed randomized trials published to date. There are
Borderline Resectable Pancreatic Cancer
reports that neoadjuvant chemoradiation may improve
In the late 1990s and early 2000s, the negative prognostic R0 and pN0 resections compared with neoadjuvant
implications o an R1 resection were increasingly appre- chemotherapy alone, but no survival advantage has yet
ciated. This coupled with improvements in cross-sec- been demonstrated .104 PREOPANC2 is a randomized
tional imaging allowed or the identication o tumors clinical trial that will compare systemic gemcitabine and
abutting but not encasing critical arterial structures sur- gemcitabine-based chemoradiation with FOLFIRINOX
rounding the pancreas (celiac trunk and SMA). Such alone in patients with resectable and borderline resect-
tumors were recognized as putting patients at risk or able pancreatic cancer.98 In addition, the Alliance or
an R1 resection with upront surgery and, in many cen- Clinical Oncology Trial A021501 is comparing FOLFIRI-
ters, were considered locally advanced and unresectable. NOX × 7 doses ollowed by SBRT with FOLFIRINOX ×
However, as we and others developed experience with 8 doses ollowed by surgery.105 Results rom these and
neoadjuvant chemoradiation and observed signicant other trials may clariy the role o neoadjuvant radiation
treatment eect on nal pathology, it was noted that a in borderline resectable disease.
subset o patients having tumors with vessel abutment
ChapTer 28
could undergo R0 resection ater a period o neoadjuvant

MDACC Approach to Borderline Resectable
therapy. In that context, the concept o borderline resect-
able pancreatic cancer emerged.99
Disease
As o this writing, there is variability in denitions Whenever possible, patients with borderline resectable
o borderline resectable disease, but or the purposes pancreatic cancer are enrolled in clinical trials. Outside
o this text, a borderline resectable tumor is one that o a clinical trial, patients with borderline resectable
puts the patient at high risk or an R1 resection with pancreatic cancer are treated using a tailored approach,
upront surgery. A growing number o single-insti- taking into account PS, comorbidities, baseline CA
tution reports o neoadjuvant therapy or borderline 19-9 measurements, and presence o indeterminate
resectable tumors are being published. Multi-institu- liver, lung, or peritoneal lesions (Fig. 28–5).
tional and cooperative group trials specically designed In general, patients with PS 0–1 and no contraindi-
or patients with borderline resectable disease are cations to FOLFIRINOX are treated with this regimen.
now being conducted, with some results already pub- Induction chemotherapy is usually delivered over a
lished.100 Although there is no standard approach to longer interval (4+ months) compared with patients
neoadjuvant therapy or borderline resectable disease, with potentially resectable disease (3–4 months). For
some general observations are becoming evident. patients with PS 1, comorbidities, or contraindica-
1. Neoadjuvant therapy ollowed by surgery or borderline tions to FOLFIRINOX, we usually administer gem-
resectable disease appears to oer a survival advantage citabine and nab-paclitaxel or a similar time rame.
over upront surgery and adjuvant therapy. We have ound that normalization o CA 19-9 levels
Using the NCDB, investigators analyzed outcomes o ater completion o neoadjuvant therapy (which or us
patients with borderline resectable disease treated with usually involves chemoradiation ater induction che-
upront surgery and adjuvant therapy and compared motherapy), improves the likelihood o a major patho-
them with similar patients treated with neoadjuvant logic response at the time o surgery and increases the
and subsequent surgery.101 Median OS was superior chance o long-term survival.65,66 Thereore, serial CA
using a neoadjuvant approach compared with upront 19-9 measurements are obtained as patients receive
surgery (25.7 vs 19.6 months; P < .0001). Moreover, R0 induction chemotherapy. I a patient’s clinical or
resections were higher using neoadjuvant therapy and marker response to the rst two cycles (8 weeks) o
the rate o node-positive disease was lower. rontline neoadjuvant FOLFIRINOX is considered sub-
2. Induction gemcitabine/nab-paclitaxel or FOLFIRINOX optimal, we will consider a switch in chemotherapy
with or without subsequent chemoradiation are the most to gemcitabine and nab-paclitaxel. Based on a retro-
common neoadjuvant regimens being reported recently. spective analysis, this strategy ultimately allowed sur-
Two studies have reported on clinical outcomes ater gical resection in 40% to 50% o patients who did not
neoadjuvant therapy and subsequent surgery using respond to initial FOLFIRINOX.106 We do not currently
FOLFIRINOX compared with gemcitabine and nab- know whether a switch to FOLFIRINOX will also sal-
paclitaxel.102,103 Based on these results, there is no rm vage the patient’s candidacy or surgery i initial treat-
conclusion regarding the superiority o one regimen ment with gemcitabine and nab-paclitaxel treatment
over the other. is ineective.
Borderline Resectable
Pancreatic Cancer
ECOG PS 0-1 ECOG PS 1-2
FOLFIRINOX (2 months) Gemcitabine + nab-paclitaxel

(2 months)
Restaging CT Scan
Metastatic Disease No Metastatic Disease

Present Present
ChapTer 28
Second-line Continue same chemotherapy
chemotherapy (2 months)
No Metastatic
Disease Present Restaging CT Scan
Chemoradiation Surgical Resection
FIGURE 28–5 Treatment algorithm or the management o borderline resectable pancreatic cancer.
Neoadjuvant therapy in borderline resectable dis- SMV-PV confuence, or signicant involvement o the
ease serves to identiy the subset o patients with common hepatic artery originating rom the celiac
avorable response who should undergo an attempt at trunk. There should be no clinical or radiographic evi-
surgical resection. Thus, maintaining or improving t- dence o metastatic disease. Currently, roughly hal o
ness or surgery remains a priority during neoadjuvant all patients present with locally advanced disease. As
therapy. We take a two-pronged approach. First, we with resectable pancreatic cancer, an understanding o
have ound that modest de-escalation o FOLFIRINOX certain principles aid in decision making.
or gemcitabine and nab-paclitaxel intensity is well • Locally advanced pancreatic cancer poses unique challenges.
tolerated, generates anticancer eects, and minimizes Local tumor progression with worsening pain, new
toxicity that could compromise a patient’s surgical or recurrent biliary obstruction, PV thrombosis, or
candidacy.107 Second, we have increasingly used or- gastric outlet obstruction represent dicult treat-
malized prehabilitation as part o our neoadjuvant pro- ment problems.
gram to assist patients with nutritional modications, • Assessment o response to therapy can be difcult.
gradual intentional weight loss, and to provide specic These tumors may be composed o small nests o
recommendations or exercise to increase cardiovascu- adenocarcinoma surrounded by large areas o des-
lar tness and muscle strength. moplasia (Fig. 28–6). Even when cytotoxic ther-
apy is eective, the desmoplastic component o
Management o Patients with Locally Advanced the residual mass may not regress, and the overall
Disease tumor mass may appear unchanged.
• All surgical interventions should be considered care-
Patients are dened as having locally advanced pan- ully and based on patient PS and lie expectancy.
creatic cancer when there is radiographic evidence Palliative nonsurgical procedures may produce
o SMA or celiac artery encasement, occlusion o the results similar to those o aggressive surgery.
aggressive tumor biology negating any benet rom

local therapy, and thereore the initial use o systemic
therapy would serve to identiy patients with avor-
able biology, making them attractive candidates or
local control.
Systemic Therapy Alone for Locally

Advanced Disease
The strategy o systemic therapy ollowed by consoli-
dative chemoradiation was challenged by the results
o LAP 07.111 In this trial, patients were randomly
assigned to gemcitabine or gemcitabine plus erlotinib
(100 mg/d) or 4 months. Participants with controlled
disease ater induction chemotherapy were subse-
quently randomly assigned to urther chemotherapy
or 2 more months or to chemoradiation (54 Gy) with
capecitabine 1600 mg/m2/d). All treatment then ceased.
O the 442 patients initially randomly assigned, 269
ChapTer 28
patients (61%) entered the second-round randomiza-

tion phase, thus identiying the subset o patients with
unavorable tumor biology unlikely to benet rom
local control. Median OS in the chemotherapy arm
was 16.5 months compared with 15.2 months or the
chemoradiation group (hazard ratio [HR] 1.03, 95% CI
0.79–1.34; P = .83). It appeared neither radiation nor
erlotinib improved survival in this population. How-
FIGURE 28–6 Photomicrograph o ductal adenocarcinoma
ever, the administration o radiation delayed the reini-
o the pancreas with intense desmoplastic reaction. Even
tiation o anticancer therapy or progressive disease
i the tumor cells regress in response to therapy, a residual
fbrotic mass may remain. This conounds assessment o (3.7 months or the chemotherapy arm, 6.1 months
response to therapy using standard radiographic criteria. or chemoradiation; P = .02). This potential or a lon-
ger chemotherapy-ree interval ater consolidating
chemoradiation may be o value to patients and has
been used to justiy continued studies o consolidat-
The Evolution o Therapy or Locally Advanced ing chemoradiation ater a period o systemic therapy.
Disease As o this writing, or patients with good PS (ECOG
0–1), the NCCN Pancreatic Cancer Guidelines sub-
Concurrent chemoradiation had historically been the committee endorses induction chemotherapy (or 4–6
initial treatment approach or patients with locally months) or patients with locally advanced disease. I
advanced pancreatic cancer. Ater approval o gem- the patient remains with locally advanced, nonmeta-
citabine in 1997, a common practice or management static disease, chemoradiation or SBRT are accepted as
o locally advanced disease was to deliver 5-FU–based subsequent therapeutic options.
chemoradiation ollowed by systemic gemcitabine as
tolerated until disease progression.
MDACC Approach to Locally Advanced
Pancreatic Cancer
Induction Chemotherapy Followed by
Chemoradiation For patients with adequate PS (ECOG ≤2), outside
o a clinical trial, our general approach is to initiate
The old paradigm o chemoradiation ollowed by che- therapy with gemcitabine and nab-paclitaxel rather
motherapy was challenged by analyses suggesting that than FOLFIRINOX. This is based in part on our o-
induction chemotherapy ollowed by chemoradiation protocol approach to treatment with gemcitabine/nab-
might be a better strategy.108–110 Two o these stud- paclitaxel (given day 1 and 15 every 28 days) which we
ies showed that approximately 30% o patients with nd quite tolerable or the majority o our patients.107
locally advanced pancreatic cancer would develop This allows us to consider second-line FOLFIRINOX
metastatic disease within 2 to 4 months o starting or 5-FU with liposomal irinotecan i no benet is
systemic therapy. This implied that such patients had observed with rst-line gemcitabine and nab-paclitaxel
Locally Advanced Pancreatic Cancer
ECOG PS 0–1 ECOG PS ≥2
Gemcitabine-based
Gemcitabine or
chemotherapy
Supportive care
(≥3 months)
Restaging CT Scan Second-line

chemotherapy
Stable or Response Progression
Chemoradiation Restaging CT Scan
ChapTer 28
Stable or Response Progression
Surveillance
FIGURE 28–7 Treatment algorithm applied to the management o patients with locally advanced pancreatic cancer.
and provides another active regimen i interval meta- who demonstrate a clinical, biochemical, or radio-
static disease develops (Fig. 28–7). graphic response to systemic therapy, we avor con-
The exception to the use o gemcitabine and nab- solidating chemoradiation, particularly when surgical
paclitaxel as rontline therapy in locally advanced resection remains a possibility.
disease pertains to patients who are more likely to Outside o a clinical trial, we generally administer
be reconsidered or surgery ater a period o neoad- capecitabine as the radiosensitizer, based on results
juvant therapy. These patients usually have PS 0 and rom the SCALOP trial, a randomized phase 2 trial
limited comorbidities to allow or aggressive neoad- perormed in the United Kingdom. Patients with
juvant therapy and subsequent surgery. Support or locally advanced pancreatic cancer who did not have
this approach comes rom retrospective data reported disease progression ater 12 weeks o induction che-
rom the Johns Hopkins Hospital. A total o 415 LAPC motherapy with gemcitabine plus capecitabine were
patients were included in the study, and 84 patients randomly assigned to either gemcitabine (300 mg/m2/
ultimately underwent resection o the primary tumor week) or capecitabine (830 mg/m2 twice daily on days
(20%) ater neoadjuvant therapy. FOLFIRINOX-based o radiotherapy) concurrently with radiation (50.4 Gy
therapy and SBRT correlated with increased probabil- in 28 ractions).114 Median OS was 17.6 months in the
ity o resection (P = .006). Resected patients had better capecitabine arm compared with 14.6 months in the
PS, smaller median tumor size (P = .029), and lower gemcitabine arm (adjusted HR 0.68; P = .185).115 Fur-
median CA 19-9 values (P < .001. Patients who under- thermore, or patients who receive chemoradiation we
went surgical resection had signicant higher median consider maintenance therapy using capecitabine or
OS compared with those who did not (35.3 vs 16.3 at least 3 months ater completion.
months; P < .001).112 A more recent report also sup- Whenever possible, patients with stable disease
ports FOLFIRINOX (combined with losartan) ollowed or response ater a period o systemic therapy, are
by chemoradiation as a strategy to allow a subset o encouraged to enroll in clinical trials using novel radio-
patients with locally advanced disease to ultimately sensitizers or radioprotectants.
undergo surgery with curative intent.113 Our approach O note, i patients do not derive any signicant
is similar or these patients and we generally admin- clinical, biochemical, or radiographic response rom
ister FOLFIRINOX or at least 4 months. For patients rst- and/or second-line induction chemotherapy, we
generally do not pursue chemoradiation as an alterna- • Responses to therapy are rarely observed in patients
tive strategy. This is also true or patients who remain with poor PS or high tumor burden, and combina-
with relatively high CA 19-9 levels ater a trial o sys- tion therapy in these patients is associated with
temic therapy. It is our perception that patients with increased toxicity.
chemoresistant disease harbor tumors that are like- • When metastatic disease is conned to the lungs, its
wise radioresistant. course may be more indolent.
For patients with poor PS, supportive care is encour- • Although newer cytotoxic chemotherapy regimens
aged, and systemic therapy and radiation are usually have improved survival or patients with advanced
contraindicated. In the subgroup o patients with sig- disease, urther advances in the treatment or pan-
nicant pain related to the primary tumor, aggressive creatic cancer are desperately needed, and patients
use o opioids is initiated, with emphasis on slow- with good PS should be encouraged to participate
release, long-acting ormulations. When poor toler- in clinical trials.
ance to opioids or inadequate pain control occurs with
their administration, celiac or splanchnic nerve block Gemcitabine-Based Therapy for Advanced
is recommended. I adequate pain control is achieved, Pancreatic Cancer
patients with improving PS can be reconsidered or
anticancer therapy. Gemcitabine
Gemcitabine was the rst FDA-approved drug or
ChapTer 28
Localized and Locally Advanced Pancreatic advanced pancreatic cancer based on a randomized
Cancer Summary trial. The study compared weekly gemcitabine with
bolus weekly 5-FU in previously untreated patients.117
Clinical and autopsy data have repeatedly proven that Patients treated with gemcitabine achieved a higher
adenocarcinoma o the pancreas is both a locally inva- response rate (5.4% vs 0%) and improvement in median
sive disease and a systemic disease, and it is estimated OS compared with those treated with 5-FU (5.65 vs
that 20% o patients who die as a result o pancre- 4.41 months; P = .0025). The 1-year survival rate or
atic cancer succumb to progressive local disease. As a gemcitabine-treated patients was 18% compared with
general rule, in patients with localized disease (poten- 2% or those treated with 5-FU. Importantly, more
tially or borderline resectable, and locally advanced clinically meaningul eects on disease-related symp-
disease), systemic therapy remains the oundation o toms were recorded with gemcitabine therapy com-
anticancer therapy and in our view should be deliv- pared with 5-FU treatment (24% vs 5%).
ered beore surgery. When appropriate, an array o
local therapies should be considered in patients who
Gemcitabine Doublet Therapy
demonstrate disease response or prolonged local dis-
ease stabilization. This might involve ultimate surgi- Ater gemcitabine’s approval in 1997, a number o
cal resection, various radiation techniques, or other gemcitabine doublets were tested. These trials gen-
locally ablative techniques such as irreversible elec- erally combined gemcitabine with another cytotoxic
troporation (i applied properly by experienced clini- agent: 5-FU, cisplatin, irinotecan, oxaliplatin, and
cians). 116 Moreover, as our systemic therapy continues docetaxel.118–123 Most doublets showed some modest
to evolve and improve, durable local disease control improvement in objective response rate (15%–20%
will become increasingly relevant or better patient vs gemcitabine at 10%); alas, no meaningul improve-
outcomes. ment in survival was observed using cytotoxic doublet
therapy in unselected patients.
Management o Metastatic Disease Similar to cytotoxic doublets, no signicant progress
has been made combining gemcitabine with molecular
Compared with patients having other common malig- targeted agents.124–129 More recently, the ocus o inves-
nancies, such as cancer o the colon or breast, patients tigation has been aimed at the tumor microenviron-
with advanced pancreatic cancer oten have more ment. Early ventures into this arena have likewise been
tumor-related symptoms and unctional compro- disappointing. Only erlotinib, an oral EGF-R inhibitor,
mise. Thereore, palliation must be a primary goal o which led to a slightly longer median survival com-
therapy. Management o metastatic disease should be pared with gemcitabine alone (6.24 vs 5.91 months;
guided by the ollowing principles: P = .038),130 has demonstrated improved ecacy in
• The disease course may be quite dynamic, and combination with gemcitabine. This is likely explained
the clinical status o a patient can change quickly. by the lack o a predictive biomarker or any o the
Patients thereore require requent reassessment, drugs tested and the relative impotence o single-agent
regardless o whether they are undergoing cyto- gemcitabine as delivered in clinical trials (1000 mg/m2
toxic therapy. over 30 minutes).
Gemcitabine and Capecitabine receiving other therapies (P = .98).133 Based on pre-

In contrast to other cytotoxic drugs, capecitabine, the clinical data and such clinical observations, it has been
orally bioavailable fuorinated pyrimidine, has shown hypothesized that or patients with a strong amily his-
modest added benet compared with treatment with tory o breast, ovarian or pancreatic cancer, germline
gemcitabine alone. In a phase 3 trial, Cunningham and mutations o BRCA or other DNA damage repair path-
colleagues randomly assigned patients to receive gem- way genes would be more common and more likely
citabine versus gemcitabine plus capecitabine.131 The sensitive to gemcitabine and platinum therapy. This has
addition o capecitabine to gemcitabine signicantly been supported by a recent randomized phase 2 trial
improved overall response rate (19.1% vs 12.4%) and in which germline BRCA- or PALB2-mutated patients
progression-ree survival (HR = 0.78) (P < .03 and .004, received gemcitabine and cisplatin with or without
respectively). The combination also showed a trend velaparib.134 The addition o veliparib did improve
toward improved OS (P = .08). The NCCN Pancreatic the objective response rate rom 65% to 74% but this
Cancer Guidelines subcommittee continues to include did not reach statistical signicance. Nevertheless, the
this doublet as a reasonable regimen to deliver in median OS o patients enrolled in this trial was impres-
patients with advanced disease. sive, ranging rom 15.5 to 16.4 months. Thus, a strong
amily history o breast, ovarian, and/or pancreatic can-
Gemcitabine and Nab-Paclitael cer, or a documented germline mutation in BRCA1/2
In September 2013, the FDA rst approved a gem- or PALB2 may serve as a predictive biomarker to treat-
citabine-based combination chemotherapy regi- ment with gemcitabine and cisplatin. Over time, inves-
ChapTer 28
men with nab-paclitaxel as a standard treatment or tigation o platinum-containing regimens in the setting
advanced pancreatic cancer. This was based on a phase o other mutated DDR genes, such as PALB2, ATM, or
3 study showing an OS advantage o gemcitabine plus ATR, should expand the number o patients who may
nab-paclitaxel over gemcitabine alone (8.5 months benet rom this doublet.
vs 6.7 months; HR or death 0.72; 95% CI 0.62–0.83;
P < .001).132 The 1-year survival rates were 35% ver-
sus 22%, respectively. The response rate according to
Triplet Chemotherapy for Advanced
independent review was 23% versus 7% in the two Pancreatic Cancer
groups (P < .001). Patients in the combination arm did FOLFIRINOx
have increased neutropenia, atigue, and neuropathy.
Importantly, enrollment allowed patients with Kar- In 2011, investigators in France tested a three-drug
nosky Perormance Status score o at least 70% and chemotherapy regimen consisting o oxaliplatin, irino-
suggested that this combination could be used saely tecan, fuorouracil, and leucovorin (FOLFIRINOX) and
in patients with compromised unctional status. The compared it with gemcitabine in patients with meta-
gemcitabine and nab-paclitaxel combination there- static pancreatic cancer with ECOG PS 0–1.135 There
ore is an attractive drug regimen or patients with were 342 patients enrolled and randomly assigned to
advanced disease having some degree o railty or receive FOLFIRINOX (oxaliplatin, 85 mg/m2 body sur-
comorbidities, which make triplet drug therapy less ace area; irinotecan, 180 mg/m2; leucovorin, 400 mg/
attractive. m2; and fuorouracil, 400 mg/m2 given as a bolus ol-
lowed by 2400 mg/m2 given as a 46-hour continuous
Gemcitabine and Cisplatin: Good or DNA Damage inusion every 2 weeks) or gemcitabine. The median
Repair Defciency? OS was 11.1 months in the FOLFIRINOX group com-
As experience with gemcitabine was growing, we pared with 6.8 months in the gemcitabine group (HR
and others ound that some subsets o patients with or death 0.57, 95% CI 0.45–0.73; P < .001). The objec-
advanced disease appeared to have some dramatic tive response rate was also markedly improved in the
responses to gemcitabine and cisplatin. In a retrospec- FOLFIRINOX group, 31.6% versus 9.4% (P < .001).
tive review o clinical data sets rom MDACC and the FOLFIRINOX is approved or use as rontline therapy
Johns Hopkins group, patients with amily or pedigree in patients with advanced pancreatic cancer having
history o cancer had superior OS when treated with ECOG PS 0–1 and in that population is considered a
gemcitabine and a platinum analogue over gemcitabine standard o care.
monotherapy. This was especially true in patients with
three or more relatives with a history o breast, ovar- Gemcitabine, Nab-Paclitael, and Cisplatin
ian, or pancreatic cancers (HR 0.49, 95% CI 0.30–0.80;
Very recently, a gemcitabine triplet combination has
P = .003). As the number o relatives with these can-
been similarly reported as highly active, with overall
cers increased, the OS rate improved or individuals
acceptable toxicity in patients with metastatic disease.
receiving rst-line platinum therapy (HR 0.76, 95% CI
This regimen builds on gemcitabine and nab-paclitaxel
0.65–0.89; P = .0004), which was not the case or those
with the addition o cisplatin or treatment o patients
with advanced disease. In a multicenter phase 1b/2 damage repair (DDR) response.139–142 The most studied
trial, patients were treated with standard doses o nab- among these are germline BRCA1 and BRCA2 muta-
paclitaxel plus gemcitabine plus various doses o cispla- tions, which occur in as much as 7% o patients with
tin, 25–50 mg/m2, on days 1 and 8 o a 21-day cycle.136 pancreatic cancer.143,144
Among the 25 enrolled patients, there were two com- Patients whose tumors are decient in DDR proteins
plete responses (8%), 15 partial responses (62%), our sta- display heightened susceptibility to DNA-damaging
ble disease (17%), and three progressive disease (12%). agents, including platinum chemotherapy and radio-
Median progression-ree survival was 10.1 months, with therapy. Recent therapeutic ocus on inhibitors
a median OS o 16.4 months. Moreover, 16 patients o PARP, a crucial component o the homologous
(64%) were alive at 1 year, 10 (40%) at 2 years, 4 (16%) recombination pathway or single-strand DNA
at 3 years, and 1 (4%) at 4-plus years. On a cautionary breaks, has identied this class o drugs as being par-
note, atal events occurred in three patients (12%); two ticularly eective in patients with DDR mutations.
were thought to be treatment related. A larger phase 2 Early-phase studies evaluating the PARP inhibitors
trial o this regimen is now underway (NCT03915444). olaparib and rucaparib revealed promising activity in
pretreated patients with pancreatic cancer with germ-
line or somatic BRCA1 and BRCA2 mutations. 145,146
Second-Line Chemotherapy Most prominently, the phase 3 POLO trial randomly
Nanoliposomal irinotecan has gained approval in the sec- assigned 154 patients with metastatic pancreatic can-
ond-line setting or patients with metastatic pancreatic cer with germline BRCA1 or BRCA2 mutations whose
ChapTer 28
cancer who received prior gemcitabine-based therapy disease had not progressed on at least 16 weeks o
based on the results o the phase 3 NAPOLI-1 study.137 In rst-line platinum-based chemotherapy to mainte-
this trial, 417 patients whose disease had progressed on nance therapy with either placebo or olaparib. 20 The
gemcitabine-based chemotherapy were randomized to median PFS in the maintenance olaparib arm was sig-
one o three arms: (1) 5-FU + leucovorin, (2) nanoliposo- nicantly longer than in the placebo arm (7.4 vs 3.8
mal irinotecan, or (3) combination o 5-FU + leucovorin months, HR 0.53; P = .004). As o this writing, there
+ nanoliposomal irinotecan. Median OS in the triplet- has been no dierence in OS between the groups. In
therapy group with 5-FU + leucovorin + nanoliposomal December 2019, olaparib was granted FDA approval
irinotecan was 6.1 months, compared with 4.2 months as a maintenance therapy or this population.21
in the 5-FU + leucovorin group (HR 0.67; P = .012).
Second-line options or systemic chemotherapy are NTRK Fusions
based largely on a patient’s PS at the time o progres- Fusions in the NTRK gene are rare but clinically sig-
sion. Previously treated patients should be encour- nicant molecular events, occurring in up to 1% o
aged to participate in clinical trials where available. patients with pancreatic cancer. This aberration has
Outside o a clinical trial, or patients who are treated been demonstrated in case reports to be a potent target
with rst-line gemcitabine plus nab-paclitaxel, those with the TRK inhibitor, entrectinib.147 In 2019, the FDA
who retain a good PS are usually oered 5-FU + leu- approved entrectinib in a tumor-agnostic setting or the
covorin + nanoliposomal irinotecan. Rarely, patients treatment o patients with advanced solid tumors har-
with excellent PS may be considered or second-line boring NTRK usions.148 As tumor molecular proling
FOLFIRINOX, although data on the triplet regimen in becomes increasingly used, medical oncologists should
the pretreated setting are limited. For patients whose be aware o this population who have the potential to
disease progresses on rst-line FOLFIRINOX and who derive dramatic benets rom targeted therapy.
maintain an adequate PS, gemcitabine plus nab-pacli-
taxel is an appropriate second-line option.138 Stromal Re-engineering and Targeted Therapy
The traditional view o pancreatic cancer stroma has
Future Directions in Systemic Therapy for been as a hindrance to delivery o chemotherapy and
Pancreatic Cancer accounting or the adverse prognosis associated with
this cancer. Hedgehog inhibitors were particularly
Modern Targeted Therapy in Pancreatic Cancer eective in causing stromal depletion.149 This theory,
For years, targeted therapy in pancreatic cancer proved however, was disproven in the clinical setting, with
disappointing predominantly based on the lack o pre- randomized trials o two hedgehog inhibitors, IPI-
dictable biomarkers. More recent investigations o target 926 and vismodegib, ailing to improve survival when
therapy have yielded somewhat more positive results. added to gemcitabine compared with gemcitabine
alone. Kalluri et al, rom MDACC, recently showed
Targeting Mutations in DNA Repair Proteins that stromal depletion in genetically engineered mouse
Up to 25% o patients with pancreatic cancer may har- models resulted in accelerated tumor growth. In addi-
bor mutations in genes that play a role in the DNA tion, they showed that stromal-depleted pancreatic
cancers were sensitive to the CTLA-4 (cytotoxic T or pancreatic cancer have taken a variety o orms to
lymphocyte-associated antigen 4) antibody ipilim- include harvest o tumor-inltrating lymphocytes or
umab.150 Similar ndings were reported by Rhim et al, leukapheresis o circulating T-cells or ex vivo expan-
who demonstrated that stroma is protective in pancre- sion and reinusion with or without checkpoint inhibi-
atic cancer, and deletion o sonic hedgehog accelerated tors or other immune mediators. In addition, some
tumor growth; this eect was again reproduced by investigators have been evaluating the combination
treatment with smoothened inhibitor.151 Stroma as a o cytotoxic chemotherapy with checkpoint inhibi-
target or therapy continues to be investigated in the tion with or without a CD40 agonist. Other strategies
clinic. include integration o cytotoxic checkpoint inhibitors
A recently investigated stromal component is the and other immune mediators, pancreatic cancer vac-
extracellular matrix component hyaluronan. Enzy- cines, adoptive T-cell transer, monoclonal antibodies
matic depletion o hyaluronan by the pegylated hyal- acting at the immune checkpoint level, cytokines, and
uronidase (PEGPH20) resulted in inhibition o cancer regulatory T-cell depletion. None o these strategies has
growth and prolonged survival when combined with a proven benet thus ar and more rigorous preclini-
gemcitabine in preclinical studies.54 Despite early cal models will be required to accelerate progress with
provocative results, PEGPH20 combined with gem- immunotherapy in pancreatic cancer.
citabine and nab-paclitaxel ailed to demonstrate any
clinical benet over treatment with gemcitabine/nab-
paclitaxel alone.152 Even more troubling, in a phase
MD Anderson Approach to Metastatic
Disease
ChapTer 28
1b/2 trial conducted by SWOG, PEGPH20 combined
with FOLFIRINOX, led to signicantly inerior sur- Metastatic pancreatic cancer is characterized by
vival compared with FOLFIRINOX alone. The median anorexia, cachexia, and pain. Thereore, palliation
OS in the mFOLFIRINOX arm was 14.4 months (95% must always be a major ocus or this group o patients
CI 10.1–15.7) versus 7.7 months (95% CI 4.6–9.3) in and is acilitated by a multidisciplinary approach.
the experimental arm.153 Symptomatic relie o biliary obstruction and pain
should be addressed beore the consideration o sys-
temic therapy. I pain is not well controlled with oral
Immunotherapy for Pancreatic Cancer
or transdermal opioids, or i these agents are poorly
Immunotherapy has nally come o age, and immune tolerated, patients should undergo an evaluation with
targeting is rapidly changing the course o several an interventional pain specialist to consider celiac or
cancers. Both innate and adaptive immune systems splanchnic plexus neurolysis. In addition to aggressive
are involved in the immunosurveillance mechanisms, pain control eorts, other supportive measures should
which include cytotoxic CD8 T-cells, T helper 1 (Th1) be considered, including appetite enhancers, antide-
cells, dendritic cells, tissue macrophages (M1), and nat- pressants, and central nervous system stimulants.
ural killer cells. Cancers must escape these surveillance Biliary obstruction should be relieved by nonsur-
mechanisms to fourish and degrade health.154 Preclini- gical means whenever possible, and we advocate the
cal models o pancreatic cancer have inormed us that insertion o expandable metal stents rather than poly-
immunosuppressive tumor-associated macrophages, ethylene biliary stents. Occasionally, percutaneous
regulatory T-cells, along with scarce eector T-cells biliary drainage may be required in the setting o extra-
(CD8+) occur at even the earliest preinvasive stages hepatic biliary obstruction.
and persist through the development o invasive can- When a patient develops gastric outlet obstruction,
cer. High concentrations o CD8+ T-cells, when inre- we try to estimate the prognosis at that juncture. I lie
quently present in pancreas cancer, are associated with expectancy is greater than 12 weeks, surgical inter-
a good prognosis.155 vention or denitive gastric bypass is considered. For
Early eorts using modern immunotherapy, spe- patients with end-stage metastatic disease, the use
cically checkpoint inhibitors were disappointing. o duodenal stents is encouraged. For patients with
Ipilimumab was investigated in 27 cases o pancreatic intractable symptomatic ascites, it is important to real-
adenocarcinoma, and one delayed response occurred.156 ize that this may not be caused by carcinomatosis and
An anti–PD-L1 antibody was studied in an expansion requently results rom PV or SMV thrombosis. Mod-
cohort o pancreatic cases (n = 14) without any thera- erate ascites secondary to portal hypertension may
peutic responses.157 These data have highlighted the respond to diuretics, including spironolactone, whereas
act that predictive criteria or checkpoint inhibitors large volume ascites, malignant or otherwise requires
are needed. As o this writing, the only biomarker or repeated paracentesis or an indwelling peritoneal cath-
potential response to checkpoint inhibition is microsat- eter or symptomatic relie. Gastroparesis is another
ellite instability, a hallmark o hereditary nonpolyposis commonly occurring problem that requires promotil-
colon cancer.37 Current immunotherapy approaches ity agents and dietary and behavioral modication.
MDACC Approach to Systemic Therapy for our o-protocol approach is to deliver FDR gemcitabine
Advanced Pancreatic Cancer (600–750 mg/m2) at a rate o 10 mg/m2 per minute,
weekly. Adding erlotinib yields marginal benet and
Systemic therapy or metastatic disease should be is not as relevant with the availability o more modern
actively discouraged in patients with poor PS (ECOG therapy. Nevertheless, when gemcitabine monotherapy
>2) or signicant metastatic burden. End-o-lie discus- is advised, the addition o erlotinib is not unreasonable.
sions are appropriate at the time o diagnosis. For the When an objective response or stable disease is
majority o patients with newly diagnosed disease, observed, chemotherapy is usually continued until there
we recommend germline genetic testing and, i ea- is radiographic or clinical evidence o disease progression,
sible, molecular proling is obtained whenever su- with restaging studies generally perormed every 8 to 12
cient tissue is available. When possible, patients with weeks. However, when FOLFIRINOX is being delivered,
good PS should be treated with systemic therapy in a shiting to a period o maintenance therapy with FOLFIRI
clinical trial. O protocol, patients with ECOG PS 0–1 or capecitabine may avoid unctional impairment rom
and no contraindications to treatment with FOLFIRI- progressive peripheral neuropathy. Gemcitabine-plati-
NOX are generally advised to receive this regimen as num doublets are now generally oered only to patients
rst-line therapy. Ater progression on FOLFIRINOX, with BRCA-associated pancreatic cancer.
gemcitabine-based regimens like gemcitabine plus
nab-paclitaxel are considered. Ater gemcitabine and
nab-paclitaxel, FOLFOX or single-agent capecitabine Summary: Metastatic Disease
ChapTer 28
are preerred. For patients with ECOG PS 1–2, we Clinically meaningul advances in the treatment o
generally avor gemcitabine and nab-paclitaxel. At the metastatic pancreatic cancer have occurred in the past
time o disease progression, or those with preserved 5 years. These developments have changed the treat-
PS, treatment in a clinical trial is preerred. When this ment paradigm or patients with advanced disease,
is not available or easible, treatment with inusional and more patients are experiencing modest improve-
5-FU and liposomal irinotecan, FOLFIRI, or FOLFOX ments in survival and quality o lie. Continued eorts
are all reasonable. to enroll patients with advanced disease into well-
For patients who are not candidates or multiagent designed clinical trials should remain a high priority
chemotherapy, gemcitabine as rst-line therapy can be or oncologists. Finally, attention to palliation should
recommended with careul monitoring. At MDACC, always be a major ocus o clinical care.

J When there are no contraindications to intravenous tumor DNA assay (liquid biopsy) as an alternative to
contrast dye, we preer high-quality multidetector mutational proling.
CT imaging or diagnosis and staging o pancreatic J At MDACC, serum tumor markers (most commonly
cancer, because it can classiy pancreatic cancers as CA 19-9) are routinely ollowed every 2 to 4 weeks
resectable, borderline resectable, locally advanced, as surrogate markers o response or resistance to
or metastatic. Furthermore, our clinicians are com- therapy. In some patients in whom CA 19-9 levels
ortable reviewing CT imaging over magnetic reso- are undetectable or normal, we have ound serum
nance imaging and generally rely on CT imaging or carcinoembryonic antigen or CA 125 levels may
restaging purposes. occasionally serve as alternative markers.
J On presentation, we recommend germline genetic J Outside a clinical trial, we deliver FOLFIRINOX and
testing o patients diagnosed with pancreatic can- gemcitabine/nab-paclitaxel every 2 weeks.
cer, especially those with a amily history o breast,
J For patients with localized disease, presentation to
ovarian, pancreas, or colon cancer.
our multidisciplinary pancreatic cancer conerence
J When choosing a site to biopsy or tissue conrma- is encouraged or input rom specialists in medi-
tion, we preer to biopsy a metastatic site versus cal, surgical, and radiation oncology. Similarly, or
the tumor in the pancreas. This generally provides patients with limited metastatic disease, input rom
more tissue or molecular proling compared with specialists in radiation oncology, interventional
tissue obtained rom ne-needle aspiration o the radiology, and surgical oncology is obtained in con-
pancreatic primary. erence ormat.
J Whenever easible, i insufcient tumor tissue is
available or interrogation, we will obtain circulating
21. US Food and Drug Administration. FDA approves olaparib

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ChapTer 28
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ChapTer 28
29 Biliary Tract Cancer
Shalini Makawita
Sunyoung Lee
Yun Shin Chun
Millicent A. Roach
Eugene J. Koay
Milind Javle
KEY CONCEPTS
 Biliary tract cancers are rare tumors (prevalence <6/100,000  Neoadjuvant chemotherapy is considered or high-risk
persons/year) with signicant geographic variability. eatures.
 Risk actors include cholelithiasis, polyps, porcelain gallblad-  In clinical practice, combination chemotherapy (gem-
der, chronic inammatory states such as inammatory bowel citabine-cisplatin or gemcitabine-capecitabine) is used
disease, primary sclerosing cholangitis and nonalcoholic ste- adjuvantly, particularly in node-positive disease or R1
atohepatitis, genetic syndromes (Peutz-Jeghers or Gardner resection.
syndrome), and chronic inection (Salmonella typhi carriers,  Systemic therapy in metastatic disease is guided largely
Opisthorchis viverrine, and Clonorchis sinensis, particularly in by molecular proling and actionable targets. FGFR, IDH1,
Southeast Asia, hepatitis B and C). HER2, and BRAF alterations are among the most enriched,
 Five-year overall survival rates post R0 resection range and numerous clinical trial options are available or these
rom 40% to 50%. High-risk eatures include positive lymph patients.
nodes/margins, vascular invasion, and multiocal disease.  Cholangiocarcinoma has low rates o high microsatellite
 In localized disease, a multimodality approach is oten used: instability and programmed cell death ligand 1 positiv-
 In early-stage intrahepatic cholangiocarcinoma, surgical ity. It remains overall a “cold tumor,” though methods to
resection with nodal dissection is ollowed by adjuvant improve immune cell inltration and predict responders
capecitabine or gemcitabine-cisplatin; radiation therapy to immunotherapy are underway.
is given postoperatively or positive margins.
INTRODUCTION types varies—perihilar cholangiocarcinoma occurs most

requently, ollowed by the extrahepatic distal and
Biliary Tract Cancers intrahepatic types. Cholangiocarcinoma has been sub-
classied by the Liver Cancer Study Group o Japan
Biliary tract cancers include gallbladder carcinoma and according to the growth pattern and macroscopic
cholangiocarcinoma, both o which arise rom the appearance o the tumor into three types as mass-
ductal epithelium. Cholangiocarcinomas are urther orming, periductal-inltrating, and intraductal growth
classied based on their anatomic site as intrahepatic, types.1 The mass-orming type has an expansive pattern
perihilar, and distal types (Fig. 29–1). Intrahepatic chol- o growth, whereas the periductal-inltrating type o
angiocarcinoma (ICC) occurs in the bile ducts proximal tumor extends toward the portal pedicle. The intraductal
to the confuence o the right and let hepatic ducts. type spreads along the mucosal layer and is associated
Perihilar cholangiocarcinoma includes the ductal con- with abundant mucin production.
fuence up to the origin o the cystic duct rom the At a microscopic level, cholangiocarcinoma is
common bile duct, whereas distal cholangiocarcinoma adenocarcinoma consisting o tubules, acini, solid
includes the bile duct below the cystic duct origin to nests, or trabeculae embedded within a desmoplastic
the ampulla o Vater. The incidence o these anatomic stroma.2 Other types are exceedingly rare and include
647
648 Scion VI Gastrointestinal Cancer
• iCCA: bile ducts

proximal to confluence
of RHD and LHD
iCCA
RA RP
RHD LHD
• pCCA: ductal
pCCA confluence to origin of
CHD cystic duct from CBD
CD
GB
CBD • dCCA: bile ducts

dCCA
below cystic duct to
ampulla of Vater
Chapter 29
• RA, right anterior; RP, right posterior

• RHD, right hepatic duct; LHD, left hepatic duct
• CHD, common hepatic duct; CD, cystic duct
• CBD, common bile duct
• GB, gallbladder
• iCCA, intrahepatic cholangiocarcinoma; pCCA, perihilar
cholagniocaricnoma; dCCA, distal cholagniocarcinoma
Visual Art: © 2014 The University of Texas MD Anderson Cancer Center
FIGURE 29–1 An overview of cholangiocarcinoma subtypes based on anatomic location. (Reproduced with permission ©2020
The University of Texas MD Anderson Cancer Center.)
adenosquamous and squamous carcinomas that including papillary adenocarcinoma, mucinous ade-
arise in metaplastic epithelium and rom liver cysts. nocarcinoma, clear cell adenocarcinoma, and signet
Adenocarcinoma, particularly ICC, is radiologically cell carcinoma. Aggressive histologies o the gallblad-
indistinguishable rom metastatic tumors rom other der carcinoma include small cell/high grade neuroen-
sites, including those o the stomach, pancreas, lung, docrine carcinoma and squamous histology. These
or breast. A pattern o immunohistochemical staining are discussed in detail elsewhere.5,6
is used to distinguish cholangiocarcinoma rom other
tumor types. The tumor cells typically express cyto-
keratins AE1/AE3,7, and 19, and epithelial membrane
Epidemiology
antigen, and display a cytoplasmic positivity or carci- Biliary tract cancers are described as rare cancers (a
noembryonic antigen (CEA). The absence o a mem- prevalence o less than 6/100,000 persons per year).
brane staining or polyclonal CEA and hepatocyte There is signicant geographic heterogeneity in the
antigen (HepPar 1) aids in distinguishing ICC rom incidence and prevalence o these cancers worldwide,
hepatocellular carcinoma (HCC) with the pseudoglan- likely secondary to environmental exposures and
dular pattern. Other important immunohistochemis- genetic susceptibilities. The peak age at diagnosis o
try characteristics that distinguish cholangiocarcinoma cholangiocarcinoma is in the seventh decade o lie,
rom other common malignancies are depicted in and there is a slightly higher incidence in males com-
Table 29–1.3,4 Most cholangiocarcinomas, particularly pared with emales. The global incidence o cholangio-
the perihilar type have a high degree o desmoplasia, carcinoma is depicted in Table 29–2.7,8
leading to treatment resistance. Several recent studies indicate that the incidence o
Gallbladder malignancies are almost exclusively ICC is rising. Saha et al9 examined the Surveillance,
adenocarcinoma. Rare variants have been described, Epidemiology, and End Results data to assess 40-year
C 29 Biliary Tract Cancer 649
tbl 29–1 Pattern o Immunohistochemical Staining in Cholangiocarcinoma
Positive
AE1/AE3 (or other broad-spectrum Difuse, moderate to strong staining
keratins, eg, pankeratin)
CK7 Difuse, moderate to strong staining in most ICC (>90%).
CK17/CK19 Difuse, moderate to strong staining in most ICC (>80%).
Albumin in situ hybridization (ISH) Focal to difuse, moderate to strong staining in most ICC (>90%).
MOC31 Focal to difuse, moderate to strong staining in most cholangiocarcinoma.
Negative
CK20 Negative in most ICC. Focal or multiocal, moderate staining can be seen more (<50%)
in ICC that arises rom large bile ducts. This mirrors the expression in hilar and ECC.
CDX2 Negative in most ICC. Focal or multiocal, weak to moderate staining can be
seen (<30%).
TTF1 Negative in most ICC.
GATA3 Negative in most ICC. Focal or multiocal, weak expression can be seen (<10%).
I there is difuse, strong staining or GATA3, other carcinomas, eg, breast and
Chapter 29
bladder, would have to be excluded.
HepPar-1/arginase-1/glypican-3 Negative in most ICC. I there is robust staining, HCC or combined HCC and
cholangiocarcinoma would be a consideration.
SMAD4 (DPC4) Negative, ie, intact staining, in most ICC.
PAX8 Negative in most ICC.
ER/PR/BRST-2 (GCDFP15) Negative in most ICC.
NKX3.1/PSA Negative in ICC.
Table 292 Global Incidence Rates o o ECC increased modestly rom 0.95 to 1.02 per
Cholangiocarcinoma 100,000 persons during the 40-year period (APC,
0.14%). The incidence o cancer o unknown primary
Age- standardized Incidence origin with histologic eatures potentially consistent
Region Rate/100,000 Population with cholangiocarcinoma decreased by 51% between
Thailand — North 85 1973 and 2012 (APC, –1.87%). Gallbladder carcinoma
Thailand — South 5.7 on the other hand has a dierent geographic distribu-
tion, with high incidence rates reported in South Asia,
China 7.6
Latin America, East Asia, and Eastern Europe. The
South Korea 8.8 highest mortality rate o gallbladder carcinoma in the
Japan 3.5 world, 35 per 100,000 inhabitants, is ound in South-
Germany 3 ern Chile, which is inhabited by Mapuche Indians.10
United Kingdom 2.2 Countries with the top ve highest age-standardized
incidence rates per 100,000 or males are Bolivia
United States 1.6
(12.8%), Thailand (9.0%), Republic o Korea (8.4%),
Australia 0.4 Chile (6.6%), and Nepal (6.0%). In the US, an esti-
Canada 0.4 mated 5000 patients are diagnosed with gallbladder
carcinoma annually.11 There is a strong emale pre-
dominance with two-thirds o cases and deaths occur-
ring among women. Native American and Alaska
trends in the age-standardized incidence o ICC and Natives have the highest incidence and death rates
extrahepatic cholangiocarcinoma (ECC) between in the country (3.2 cases and 1.6 deaths per 100,000
1973 and 2012. They reported that the incidence o people). Gallbladder carcinoma incidence rates are
ICC increased rom 0.44 to 1.18 cases per 100,000 per- decreasing among all racial and ethnic groups except
sons, representing an annual percentage change (APC) non-Hispanic Blacks. The incidence rate increased
o 2.30%; this trend has accelerated during the past 2.2% per year among non-Hispanic Black men and
decade to an APC o 4.36%. In contrast, the incidence women in the last decade.12
Gallbladder Carcinoma: Risk Factors there are inconsistent data regarding cirrhosis as a risk
actor in this setting. Given the high risk, most guide-
The principal risk actor or gallbladder carcinoma lines recommend surveillance with annual or biennial
is gallstone disease/cholelithiasis. The association imaging (ultrasound, magnetic resonance imaging, or
between gallstones and cancer has been proven by magnetic resonance cholangiopancreatography) and
case-control studies, autopsy studies, and screening laboratory workup including CA 19-9 levels.18
surveys. However, the risk o cancer in cholelithiasis
is very low at 1%, although 90% o gallbladder carci-
noma cases are associated with gallstones. It has been Genetic Epidemiology o Biliary Cancers
postulated that the chronic infammation resulting rom As discussed above, biliary cancers have unique epide-
gallstones leads to epithelial dysplasia and adenocarci- miologic trends, and considerable research has ensued
noma. Gallstone size has been correlated with cancer to identiy a genetic basis o these cancers. The largest
risk, especially with stone size smaller than 3 cm, and experience in this eld is a genome wide association
the vast majority are composed o cholesterol.13 These study rom Tata Memorial Hospital, in Mumbai, India.19
stones are positively correlated with age, emale gen- The study included 1042 patients with gallbladder car-
der, multiparity, genetic actors, high body mass index, cinoma and 1709 control patients and demonstrated
and amily history o gallstones. Gallbladder diseases signicant single-nucleotide polymorphisms (SNPs) in
like adenomyomatosis, polyps, and porcelain gallblad- the chromosomal region containing the hepatobiliary
der are associated with a high risk o cancer. phospholipid transporter genes, ABCB1 and ABCB4.
Chapter 29
Other conditions associated with gallbladder car- A smaller Japanese genome wide association study
cinoma include infammatory bowel disease, includ- noted that the SNP rs7504990 in the deleted in colon
ing Crohn disease and ulcerative colitis, Peutz-Jeghers cancer (DCC) gene is associated with an increased risk
syndrome, multiple amilial polyposis (Gardner syn- o gallbladder carcinoma.20 Other genomic variations
drome), and anomalous pancreatobiliary junction, noted in gallbladder carcinoma include variations in
particularly in East Asia. Chronic inections, including cytochrome P450 enzymes, some o which play a key
Salmonella typhi carrier state has also been linked with role in estrogen metabolism, which may explain the
gallbladder carcinoma, independent o the presence o emale predominance.21 Bile acids are important or
gallstones.14 cholesterol homeostasis and the polymorphisms o
CYP7A1, which encodes or a rate-limiting step in the
Cholangiocarcinoma: Risk Factors bile acid synthesis pathway and may lead to gallblad-
der carcinogenesis.22
Cholangiocarcinoma is rare in the Western world, It is believed that cholangiocarcinoma may be
but more common in Asia. In most cases in the West, related to dysregulation o genes involved in infam-
this disease is rare, sporadic, and without an identi- mation. Genomic variation in the interleukin (IL)-6
able risk actor. Higher incidence in Asia is caused receptor (IL-6R), rs8192284 in exon 9 o IL-6R is asso-
by a greater risk o liver fuke inections with Opis- ciated with liver fuke–related cholangiocarcinoma in
thorchis viverrini and Clonorchis sinensis, particularly in Thailand. SNPs in IL-8 gene and IL-1 receptor antago-
Southeast Asia. Hepatolithiasis and choledochal cysts nist have been associated with susceptibility to biliary
are also more likely to be associated with cholangio- tract cancers.23 Although the above variants individu-
carcinoma in Asian countries.15 Other inectious risk ally have a low risk, collectively these may be impor-
actors include hepatitis B in Asia and hepatitis C in tant or prediction o individual risk and or uture
the West. Other important actors include primary surveillance strategies.
sclerosing cholangitis (PSC) associated with infamma-
tory bowel disease, cirrhosis, alcoholism, obesity, atty
liver disease, and smoking. Cirrhosis and nonalcoholic STAGING
steatohepatitis are most commonly associated with
ICC, whereas liver fuke inections are more likely to Staging o biliary tract cancers requires high-quality,
be associated with perihilar cholangiocarcinoma.16 multiphasic computed tomography (CT) or magnetic
In the Western countries, PSC is an important risk resonance imaging (MRI) o the abdomen and pelvis
actor or cholangiocarcinoma. The annual incidence to evaluate the extent o primary tumor and identiy
o cholangiocarcinoma in PSC is around 1%, with a metastases, particularly in the lymph nodes, liver,
reported lietime incidence o 20%.17 The median and peritoneum. CT o the chest, with or without
time rom PSC diagnosis to detection o cholangiocar- contrast, should be perormed to evaluate or pulmo-
cinoma is relatively short, at 4 to 6 years. There are nary and lymph node metastases. For patients with
no clear predictive actors identiable in patients with biliary obstruction, high-quality cross-sectional imag-
PSC that correlate with an increased risk o cancer, and ing should be perormed beore placement o biliary
stents, which can interere with tumor visualization. and elevated serum IgG4 levels in 74% o patients.27
Positron emission tomography (PET)/CT may be con- Concurrent autoimmune pancreatitis is ound in 92%
sidered when CT or MRI ndings are equivocal. o patients. Imaging eatures o IAC include long, mul-
Staging laparoscopy as a standalone procedure is tiocal strictures and smooth margins o the bile duct
not routinely recommended. For patients scheduled lumen.28 In contrast, cholangiocarcinoma is character-
or surgical resection o biliary tract tumors, staging ized by a solitary, irregular lesion with eccentric thick-
laparoscopy has been shown to identiy an unresect- ening o the bile duct wall.
able disease in 17% o patients, with a higher yield Estimated 5-year overall survival (OS) rates ater R0
in patients with gallbladder carcinoma and elevated resection are reportedly 43%, 40%, 48.5%, and 44% in
serum CA 19-9.24 Thereore, diagnostic laparoscopy gallbladder carcinoma, ICC, perihilar cholangiocarci-
beore open resection can be considered or patients noma, and distal bile duct cancer, respectively.29–32 Pre-
at risk or radiologically occult metastases, particularly dictors o worse survival ater surgery include lymph
peritoneal implants. node metastases, positive resection margin, vascular
The eighth edition o the American Joint Committee invasion, and multiocal disease. Contraindications
on Cancer Staging Manual has separate staging systems to surgery include distant metastases, local invasion
or gallbladder carcinoma, ICC, perihilar bile duct cancer, into critical vasculature that cannot be reconstructed,
and distal bile duct cancer (Table 29–3).25 For gallbladder poor perormance status, and insucient unctional
carcinoma, the T category is based on the depth o inva- liver remnant volume. In selected patients with locally
sion into the gallbladder wall and extension to surround- advanced disease or poor prognostic actors, such as
Chapter 29
ing structures. For ICC, tumor size, number, and vascular lymph node metastases or multiocal diseases, neo-
invasion dene the T stage. The T category or perihilar adjuvant therapy may be considered, particularly in
cholangiocarcinoma refects the central location o these the setting o a clinical trial. Systemic therapy beore
tumors, which can invade the portal vein, hepatic artery, surgery may allow assessment o tumor biology, treat-
and contralateral bile duct and/or vasculature. For distal ment o micrometastases, downsizing o tumors, and
cholangiocarcinoma, the T stage is based on the depth o increased chance o R0 resection.33,34
tumor invasion, measured in millimeters.
In biliary tract cancers, regional lymph nodes are
dened as those in the hepatoduodenal ligament. With
Gallbladder Cancer
the exception o ICC, the N category is separated by Among patients undergoing denitive surgery or
the number o positive regional nodes, with N1 dened gallbladder carcinoma, 61% o patients are diagnosed
as one to three regional nodes and N2 as our or more incidentally with cancer ater laparoscopic cholecys-
regional nodes. M1 disease includes distant lymph node tectomy or a presumed benign gallbladder disease.29
metastases, including aortocaval and celiac lymph nodes. For T1a tumors, simple cholecystectomy is sucient.
For incidentally diagnosed T1b–T3 tumors, reresec-
tion, also termed radical cholecystectomy, is recom-
SURGERY FOR BILIARY TRACT mended. Radical cholecystectomy entails resection o
CANCERS the gallbladder bed, typically partial hepatectomy o
segments 4B/5, and hepatoduodenal ligament lymph-
The goals o surgery are to evaluate or radiologically adenectomy. Bile duct resection is reserved or patients
occult distant metastases which contraindicate sur- who otherwise would have a positive cystic duct mar-
gery, resect the primary tumor with negative margins, gin. Routine resection o port sites rom prior laparo-
and perorm regional lymphadenectomy or adequate scopic cholecystectomy is not recommended.35
staging. Preoperative biopsy is not mandatory beore
surgery and can be dicult to obtain, particularly Intrahepatic Cholangiocarcinoma
in patients with malignant biliary strictures. Trans-
peritoneal biopsy is contraindicated in patients with Major or minor hepatectomy may be required or R0
perihilar cholangiocarcinoma who may otherwise be resection o ICC, depending on the anatomic extent
candidates or liver transplantation because o the risk o a disease. ICC oten presents as a large mass invad-
o peritoneal seeding.26 In most patients, suspicious ing the hepatic vein, inerior vena cava, and/or portal
clinical presentation and radiologic eatures, with or vein, requiring extended resection. Criteria or resect-
without elevated CA 19-9, are sucient or preopera- ability o hepatic tumors include adequate vascular
tive diagnosis. In rare patients, a dierential diagnosis infow and outfow, biliary drainage, and sucient
o immunoglobulin (Ig)G4-associated cholangitis (IAC) unctional remnant liver volume.36 For patients with
presents a diagnostic and therapeutic dilemma. IAC is inadequate liver volume, portal vein embolization is a
a broinfammatory disorder characterized by IgG4- strategy that induces hypertrophy o the remnant liver
positive plasma cell inltration o the bile duct wall to enable sae hepatectomy.
Chapter 29
652
Scion VI
Gastrointestinal Cancer
tbl 29–3 Staging Systema
Disease site
Stage Gallbladder cancer Intrahepatic cholangiocarcinoma Perihilar bile duct Distal bile duct
I IA T1N0: Invades lamina propria or T1aN0: Solitary tumor ≤ 5 cm without T1N0: Tumor conned to bile duct, T1N0: Invades bile duct wall
muscular layer vascular invasion with extension up to muscle layer with depth < 5mm
IB T1bN0: Solitary tumor >5 cm without or brous tissue
vascular invasion
II IIA T2aN0: Invades perimuscular T2No: Solitary tumor with intrahepatic T2N0: Invades beyond wall o bile T1N1: 1-3 regional nodes, or
connective tissue on peritioneal vascular invasion, or multiple duct to surrounding adipose tissue T2N0: invades bile duct wall with
side without involvement o serosa tumors, with or without vascular or adjacent hepatic parenchyma depth 5-12 mm
(visceral peritoneum) invasion
T2N1, or
IIB T2bN0: Invades perimuscular
T3N0; invades bile duct wall with
connective tissue on hepatic side
depth >12 mm, or T3N1
without extension into the liver
III IIIA T3 N0: Tumor perorates serosa and/ T3N0: Tumor perorating visceral T3N0: Invades unilateral branches o T1-3,N2: ≥ 4 regional nodes
or directly invades liver and/or peritoneum portal vein or hepatic artery
other adjacent organ or structure,
ie., extrahepatic bile duct, colon
IIIB T1-3, N1: 1-3 regional lymph nodes T4N0: Direct invasion o local T4N0: Invades main PV or branches T4, any N: Tumor involves celiac
extrahepatic structures, or any bilaterally, or CHA, or unilateral axis, superior mesenteric artery,
T, N1: regional lymph node 2nd-order biliary radicles with and /or common hepatic artery
metastasis contralateral PV or HA involvement
IIIC − − Any T, N1: 1-3 regional nodes −
IV IVA T4, N0-1: Tumor invades main portal Any T, any No, M1 Any T, N2: ≥ 4 regional nodes Any T, any N, M1
vein or hepatic artery, or invades ≥
2 extrahepatic organs or structures
IVB T1-4, N2: 4 ≥ regional nodes, or M1 Any T, any N, M1
a
Text describes underlined T or N category.
CHA, common hepatic artery; HA, hepatic artery; PV, portal vein.
Data rom Edge SB, Byrd DR, Byrd DR, et al: AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017
Perihilar Cholangiocarcinoma doses o radiation to the upper abdomen sae and eec-
tive through multiple radiation modalities: stereotactic
Perihilar cholangiocarcinoma, also termed hilar cholan- body RT (SBRT), intensity-modulated RT (IMRT), pro-
giocarcinoma or Klatskin tumor, is technically challenging ton therapy, and image-guided radiation, which have
to resect because o its central location and requent been reviewed previously.44–47
involvement o the portal vein, hepatic artery, and sec-
ond-order bile duct tributaries o both hepatic ducts.
Major hepatectomy and bile duct resection with recon- Growing Evidence or Radiation Therapy in
struction are required, and in some patients, vascular the Treatment o Biliary Cancers
resection and reconstruction are needed. Preoperative
Through a series o clinical trials, RT techniques, dose
biliary drainage and normalization o serum bilirubin
constraints, and specic indications were established
are necessary beore major hepatectomy. Endoscopic
that have demonstrated that RT can eectively ablate
biliary stents carry a risk o ascending cholangitis,
small liver tumors.48 Traditional SBRT can achieve
whereas percutaneous transhepatic biliary drainage
excellent results or small hepatic tumors (<5 cm), but
is associated with a risk o peritoneal seeding.37,38 For
it may not be an eective strategy or large liver tumors
patients with potentially resectable tumors, consulta-
(>7 cm). The ablative doses are dened as those that
tion with a hepatobiliary surgeon and high-quality
can achieve 2-year local tumor control rates greater
axial imaging are recommended beore placement o
than 90% and are termed stereotactic ablative RT. Stud-
biliary stents.
ies have shown that SBRT in 3 to 5 ractions can lead
Chapter 29
In patients with unresectable tumors, liver trans-
to high biliary stricture rates and toxicity to the cen-
plantation ater neoadjuvant therapy is associated with
tral hepatobiliary tract and should be avoided.49 An RT
a post-transplant 5-year recurrence-ree survival rate
dose o 58 Gy in 15 ractions is considered sae or the
o 65%.39 Eligibility criteria or liver transplantation
biliary tree. Delivery o lower RT doses has resulted in
include radial diameter smaller than 3 cm and absence
inadequate tumor control in primary ICC and proven
o a metastatic disease, including nodal metastases.
insucient or liver metastases.50
In a retrospective study involving 34 patients with
Distal Bile Duct Cancer 42 lesions, including 31 unresectable ICC and 11 hilar
cholangiocarcinomas treated with a median SBRT dose
The standard surgical procedure to achieve margin-
o 30 Gy in three ractions, an actuarial 4-year local
negative resection and adequate lymph node harvest
control o 79% was achieved.51 The median OS was
is pancreaticoduodenectomy (PD), which is associated
17 months, and the median progression-ree survival
with signicant morbidity and mortality. In highly
(PFS) was 10 months. However, 12% (4/34) o patients
selected patients with localized mid–bile duct cancer
experienced grade III adverse eects, including duode-
who are not candidates or PD, segmental bile duct
nal ulceration, cholangitis, and liver abscess.51 A phase
resection with lymphadenectomy has been shown to
2 trial o 128 patients included 46 patients with ICC,
result in comparable survival as PD.40
35 with HCC, and 47 with colorectal liver metasta-
ses.52 All patients received high-dose conormal RT
with a median dose o 60.75 Gy (1.5 Gy per raction,
RADIATION THERAPY twice daily) and concurrent hepatic artery foxuridine.
The median OS was 15.8 months or all patients, and
Previous studies have shown that the majority o patients 13.3 months or patients with ICC.
with unresectable ICC die rom liver ailure caused A retrospective dose-response analysis o patients
by vascular compromise (portal vein or hepatic vein treated with denitive IMRT or unresectable ICC at
obstruction) or biliary obstruction.41,42 In a retrospective MDACC identied 79 patients, most o whom had
study o 362 patients with unresectable ICC, local tumor large tumors (median size 7.9 cm).41 Eighty-nine per-
progression led to liver ailure in 89% patients, hal o cent o patients (n = 70) had received systemic che-
whom died rom tumor-related biliary obstruction and motherapy beore RT. The median RT dose was 58.05
the rest rom vascular compromise or a combination o Gy (range 35–100) in 3 to 30 ractions, with median
both.43 Although a higher proportion o patients with biologic equivalent dose (BED) o 80.5 Gy. The 1-year
ECC die rom extrahepatic disease than those with ICC, and 3-year OS rates were 87% and 44%, respectively,
local tumor-related complications remain an important and the median OS ater diagnosis was 30 months.41
actor in patient survival.42 For both ICC and ECC, radia- RT dose was the single most important prognostic ac-
tion therapy (RT) plays an important role in achieving tor, with a higher total dose correlating with improved
local control o the primary tumor. local control (P = .03) and OS (P = .02). No signicant
In recent decades, multiple advances in radiation treatment-related toxicities were reported. These
delivery technologies have made the delivery o high results suggest that BED o 80.5 Gy or greater may be
ablative or large ICC tumors, with long-term OS rates In contrast to the locally advanced setting, con-
comparing avorably to surgical resection. This requires solidative chemoradiation has shown promise in the
careul treatment planning with attention to organ earlier-stage resectable setting. SWOG’s S0809 study
motion control, protection o surrounding organs, daily investigated the use o gemcitabine and capecitabine
image guidance, and incorporation o conormal RT ollowed by consolidative chemoradiation.57 This
techniques such as IMRT and proton therapy. study is discussed below and showed that survival
A prospective study o hyporactionated proton RT rates were similar between R0 and R1 resection groups
or patients with either HCC or ICC urther validated ater radiotherapy.
the ndings o MDACC’s retrospective analysis. In a In summary, there is benet in the use o adjuvant
study o 44 patients with HCC, 37 patients with ICC, and denitive RT to achieve local control and pro-
and two patients with mixed HCC and ICC, patients longed survival or patients with ICC and ECC. The
received 15 ractions o radiation to a maximum o 67.5 assessment o response in these settings can be chal-
Gy in 15 ractions.53 The 2-year local control or ICC lenging, and rigorous standards remain to be dened.
was 94.1%, and the 2-year OS or ICC was 46.5%. There is also a strong rationale to combine RT with
Encouraging results were also noted or HCC. Toxici- systemic therapy to achieve both local and distant
ties in both ICC and HCC were very low. This study control. In recent years, various molecular targets have
led to two phase 3 randomized trials, NRG GI001 or been identied or cholangiocarcinoma. Preclinical
ICC (hyporactionated radiation vs observation ater data combining RT with targeted agents in these di-
initial chemotherapy; NCT02200042) and NRG GI003 erent molecular settings o cholangiocarcinoma may
Chapter 29
or HCC (protons vs photons; NCT03186898). The be ruitul; clinical trials in these areas are needed.
NRG GI001 was terminated because o lack o patient
accrual, and the NRG GI003 study is ongoing.
The results o escalated-dose RT in unresectable SYSTEMIC THERAPY
ECC have not been as clearly avorable as those or
ICC. In 1990, a multicenter, retrospective study o Neoadjuvant Therapy
patients with ECC reported an improved median sur-
vival in patients receiving more than 40.0 Gy compared The rationale or neoadjuvant therapy includes tumor
with those receiving 40.0 Gy or less.54 A retrospective downstaging, treatment o micrometastatic disease,
analysis o 52 patients with unresectable ECC treated and assessment o tumor biology beore resection.58–60
between 1957 and 2000 at MDACC shed light on the Neoadjuvant therapy enhances the R0 margins rate
limitations o conventional dosing in preventing local and prevents distant metastases, both o which are
progression.55 Although the study was limited in its associated with improved clinical outcomes.61–66 For
statistical power by its small patient number, it did example, a study o patients who had neoadjuvant
suggest a possible association between increasing radi- chemoradiation showed 100% o the margin-negative
ation dose and improved local control. surgical resection (R0) versus 54% in those who did
However, in a modern retrospective cohort o not have neoadjuvant therapy. Survival benet was
patients with unresectable ECC (2001–2015), there maniested in a study comparing patients who received
was no dose-response relationship.42 In this study, RT neoadjuvant concurrent chemoradiation with those
was given at a median dose o 50.4 Gy with a range who did not, and the 5-year survival rate was superior
o BED between 36–98 Gy (median 59.5). The cohort (53 vs 23%).67 Intrahepatic, combined intrahepatic and
was split into an escalated-dose RT (EDRT) group extrahepatic, and extrahepatic recurrence rates were
(>50.4 Gy in 28 ractions, BED >59.5) and a conven- 60.9%, 18.6%, and 21.0% in resected ICC.68 The sites
tional-dose group (BED ≤59.5). The EDRT group did o recurrence in 41% to 60% o resected hilar cholan-
not demonstrate improved OS or reedom rom local giocarcinoma were distant metastases69,70 and in 85%
progression, and showed worse reedom rom distant o patients with recurrent gallbladder carcinoma.70 In a
progression. In addition, EDRT was associated with study o 401 patients,71 the cumulative recurrence rate
the onset o grade 3 or higher lymphopenia, which has was higher in R1 than in R0 resections (86 vs 57% at 5
been shown to portend poor prognosis in other dis- years; P < .001). Other studies show that patients with
ease sites.56 Toxicity rates were comparable between a R0 resection had longer median OS and recurrence-
radiation dose groups. Thus, although dose escalation ree survival, and lower recurrence probability than
has shown promising results in unresectable ICC, the those with a R1 resection.72–75
results with ECC suggest that higher RT doses do not The ideal systemic chemotherapy regimen in the
provide the same local control and OS benets. The neoadjuvant setting is unclear. The combination o
proximity o ECC tumors to the bowel limit the abil- gemcitabine and cisplatin has been the most requently
ity to completely cover the tumor with higher doses o used chemotherapy regimen or resectable cholangio-
radiation and may explain the dierences in outcomes. carcinoma since the validation o clinical ecacy by
the ABC-02 trial.76 FOLFIRINOX (5-fuorouracil, iri- statistically signicant clinical benet with a trend toward
notecan, and oxaliplatin) resulted in avorable antitu- better survival, with the median recurrence-ree survival
mor activity in locally advanced or metastatic biliary o 30.4 versus 18.5 months with a HR o 0.88 (0.62–
tract cancer.77 More recently, the combination o gem- 1.25).82 The median OS was 75.8 versus 50.8 months with
citabine, cisplatin, and nab-paclitaxel was tested in a HR o 1.08 (0.70–1.66). Most patients included in this
advanced biliary tract cancers, and it showed promis- study had a R0 resection (86%). However, this trial was
ing OS and PFS superior to historical controls treated underpowered and may have missed a positive outcome
with gemcitabine-cisplatin alone.34 Objective response because o low patient numbers and heterogeneity o bili-
rates (ORR) in patients who received the doublet and ary cancers that were included. Another study rom Japan
triplet chemotherapy were 26.1%76 and 45%,37 respec- in patients with intravenous (IV) mitomycin C with 5-fu-
tively. This superior ecacy has led to the requent orouracil, ollowed by oral fuorouracil compared survival
use o the triple chemotherapy in the neoadjuvant set- with those who had surgical resection alone.79 It revealed
ting at MDACC. The National Comprehensive Cancer that patients who had resected gallbladder carcinoma had
Network (NCCN) ocially listed the triple combina- a statistically signicant 5-year survival rate and disease-
tion as one o the neoadjuvant chemotherapy options ree survival, whereas patients with pancreatic cancer,
(NCCN Guidelines, v. 2.2020). As o this writing, a cholangiocarcinoma, and ampullary cancer did not have
neoadjuvant clinical trial o gemcitabine, cisplatin, and survival benet.
nab-paclitaxel is underway at MDACC along with Adjuvant 5-fuorouracil or gemcitabine was com-
seven other institutions (NCT03579771). pared ater surgical resection with observation in an
Chapter 29
open-label, phase 3, randomized, controlled clinical
trial in patients with resected periampullary cancers
Adjuvant Therapy (ESPAC-3 trial).83 This study included patients with
Cholangiocarcinoma has a high recurrence rate at dis- cholangiocarcinoma (ampullary 297 and bile duct 96),
tant sites ater a curative surgical resection, and this both node-positive and -negative diseases, and R0 and
suggests the importance o adjuvant therapy in addi- R1 resections. 5-fuorouracil 425 mg/m2 IV was admin-
tion to neoadjuvant therapy (perioperative therapy). istered 1 to 5 days every 28 days, and gemcitabine 1000
Two large studies compared survival in patients who mg/m2 IV once a week or 3 weeks o every 4 weeks
underwent curative-intent resection alone, chemother- or 6 months. The median OS in the chemotherapy
apy alone, chemotherapy with RT, and RT alone.78,79 and observation groups was 43.1 and 35.2 months (HR
Overall, adjuvant therapy did not provide statistically 0.86, 95% CI 0.66–1.11), respectively. Ater adjusting
signicant survival benet with a trend toward better or independent prognostic variables, a HR was 0.75 (P
survival—the median recurrence-ree survival (odds = .03). When compared with the observational group,
ratio [OR] 0.74, 0.55–1.01). Chemotherapy (OR 0.39, the gemcitabine group (HR 0.77, 95% CI 0.57–1.05)
0.23–0.66) and chemoradiation therapy (OR 0.61, had better survival than the 5-fuorouracil group (HR
0.38–0.99) showed statistically signicant survival 0.95, 95% CI 0.71–1.28). O note, a R1 resection was a
benet, but RT alone did not, with an OR o 0.98 poor prognostic indicator, with a HR o 1.98.
(0.67–1.43). This study clearly demonstrated that any Capecitabine monotherapy was investigated in
orm o adjuvant therapies had survival advantage in a randomized, controlled, phase 3 study or patients
patients with R1 resection or a lymph node–positive with cholangiocarcinoma or gallbladder carcinoma
disease: margin-positive and node-positive patients who had undergone a surgical resection (BILCAP
had the ORs o 0.36 (0.19–0.68) and 0.49 (0.30–0.80), trial).84 Patients assigned to capecitabine 1250 mg/m2
respectively. Radiation therapy alone showed benet twice daily on days 1 to 14 o a 21-day cycle or eight
in patients with R1 resection (OR 0.33, 0.14–0.81). A cycles, and clinical outcomes were compared with
meta-analysis including 15 studies and 5060 patients patients who did not receive adjuvant chemotherapy
revealed that adjuvant chemotherapy was associated under observation. The study included patients with
with improved OS with a HR o 0.66 (0.55–0.79).80 R0 and R1 resections; positive and negative lymph
Survival benet was larger in high-risk patients with nodes; tumor grades I, II, and III; and ICC and ECC
positive margins and lymph nodes.81 Based on these and gallbladder carcinoma. This trial did not meet
strong clinical data, adjuvant therapy has been gen- its primary end point. The median OS by intention-
erally recommended in all the patients who undergo to-treat was 51.1 months (95% CI 34.6–59.1) in the
surgical resection or ICC, ECC, and gallbladder car- capecitabine arm compared with 36.4 months (95%
cinoma. However, phase 3 evidence was lacking until CI 29.7–44.5) in the observation arm (HR 0.81, 95%
recently. CI 0.63–1.04; P = .097). However, the survival benet
A randomized, phase 3 study (PRODIGE 12-ACCORD was signicant ater adjusting or nodal status, disease
18-UNICANCER GI) compared the ecacy o adju- grade, and sex (HR 0.71, 95% CI 0.55–0.92; P = .010).
vant gemcitabine and oxaliplatin, and it did not show The most common adverse events rom capecitabine
were hand-oot syndrome (20%), diarrhea (8%), and 1 and 8) and capecitabine (1500 mg/m2/d on days 1–14,
atigue (8%). In an unplanned subset analysis, no stain divided doses twice daily) every 21 days. Ater rei-
tistical benet was noted with capecitabine or patients maging, patients not experiencing disease progression
with hilar cholangiocarcinoma or muscle-invasive gall- then received capecitabine (1330 mg/m2/d, in divided
bladder carcinoma. doses twice daily, 7 days per week) concurrent with
Although there are no prospective randomized clin- radiotherapy (45 Gy to regional lymph nodes includ-
ical trials that are available to compare the ecacy o ing retro-pancreaticoduodenal, celiac, and portal vein
monotherapy with combination chemotherapy, most nodes and 54–59.4 Gy to a preoperative tumor bed).
clinicians use combination chemotherapy (eg, gem- The median OS was 35 months, and that o patients
citabine + cisplatin or gemcitabine + capecitabine), with R0 and R1 resections was 34 and 35 months (not
particularly in patients with a node-positive disease statistically dierent); the 2-year survival rate was
or R1 resection because combination therapy is better 67% and 60% in R0 and R1 resections (not statistically
established in the advanced or metastatic setting.76 The dierent). The median disease-ree survival was 26
NCCN guidelines recommend capecitabine as a pre- and 23 months in R0 and R1 resections, respectively.
erred medication in the adjuvant setting. Combination This study demonstrates that patients who received
regimens including 5-fuorouracil (or capecitabine) plus concurrent chemoradiation ater combination chemo-
oxaliplatin (or cisplatin), gemcitabine plus capecitabine therapy have similar OS and disease-ree survival in R0
(or cisplatin) are potential alternatives, as is gemcitabine and R1 resections.
or 5-fuorouracil (or capecitabine) monotherapy. In summary, adjuvant capecitabine is regarded as
Chapter 29
the standard o care ater surgical resection o bili-

ary tract cancer based on the BILCAP trial. The role
Concurrent Chemoradiation o adjuvant capecitabine or hilar cholangiocarcinoma
Adjuvant chemotherapy alone discussed above dem- remains controversial, and chemoradiation should be
onstrated improved survival in the BILCAP trial. Tra- considered, particularly or R1 resection. Adjuvant
ditionally, in the US, a combination o concurrent gemcitabine and cisplatin remains a potential option,
chemoradiation and chemotherapy has been used in because the phase 3 trial with this combination was
patients with high-risk eatures (positive node, R1 underpowered. The ongoing phase 3 ACTICCA-1 trial
resection, or lymphovascular and perineural inva- (NCT02170090) investigating gemcitabine and cispla-
sion).85–87 Adjuvant concurrent chemoradiation, tin versus capecitabine will be instructive in regard to
sequential chemotherapy ollowed by RT, and chemo- uture options.
therapy alone were compared in resected ICC.88 This
study demonstrated that patients had better clinical
outcomes when RT was added in the adjuvant set-
Incidental Gallbladder Carcinoma
ting. A HR or overall mortality at advanced patho- Better imaging techniques and assessment o risk ac-
logic stages III and IV were 0.55 (0.41–0.74) and 0.92 tors have led to a higher rate o preoperative diagno-
(0.70–1.33), respectively, in patients who received consis o gallbladder carcinoma.93 However, this cancer is
current chemoradiation and chemotherapy ollowed oten discovered incidentally during cholecystectomy
by radiation, compared with those who only received or benign diseases such as polyps or cholecystitis94–99;
chemotherapy. the incidence o gallbladder carcinoma in all cholecys-
Capecitabine (1650 mg/m2/day) and 5-fuoro- tectomies is 0.2% to 3%.100 In a retrospective analy-
uracil (225 mg/m2/day) are widely used as a radio- sis, 68% o patients underwent re-resection, with the
sensitizer in gastrointestinal malignancies including most common surgical procedures being gallbladder
pancreatic adenocarcinoma, rectal cancer, and chol- BED resection, liver 4B/5 segmentectomy, and hepa-
angiocarcinoma. 89,90 These agents are known to cause toduodenal ligament lymphadenectomy. Resection
direct and abscopal eects when combined with with T2/T3 diseases signicantly increased survival,
RT.89,91 Capecitabine is more requently used than whereas the resection o the common bile duct did not
5-fuorouracil because o the convenience o oral increase the R0 resection rate but increased postopera-
administration and elimination o catheter-related tive complications, unless the cystic duct was involved
complications.92 by cancer.95 The incidence o port-site metastases is
In ECC and gallbladder carcinoma, a phase 2 clini- about 10%, and routine resection o port sites has no
cal trial investigated adjuvant capecitabine and gem- eect on survival.101 I gallbladder carcinoma is deemed
citabine ollowed by concurrent chemoradiation unresectable perioperatively, systemic therapy is rec-
therapy (SWOG S0809).57 The study included patients ommended. Ater surgical resection is completed or
with stages pT2–4, lymph node–positive and –negative a resectable disease, adjuvant chemotherapy is recom-
diseases, and R0 and R1 margins. Treatment consisted mended, with radiation reserved or margin-positive
o our cycles o gemcitabine (1000 mg/m2 IV on days disease.
SYSTEMIC THERAPY FOR higher toxicity was neutropenia (33%), ollowed by

METASTATIC DISEASE anemia (16%). Nonhematologic toxicities ranged rom
2% to 6% or diarrhea, elevated alkaline phosphatase,
vomiting, constipation, and transaminitis. A phase 3,
First-Line Chemotherapy randomized clinical trial to compare gemcitabine, cis-
The standard-o-care rontline therapy or metastatic platin, and nab-paclitaxel with standard-o-care gem-
biliary tract cancer was established by the ABC-02 citabine and cisplatin is currently underway (SWOG
trial in 2010 which showed superiority o gemcitabine 1815 study; NCT03768414).
plus cisplatin compared with gemcitabine alone or Other rontline studies have assessed the addi-
advanced biliary cancers (Table 29–4).76 In this phase 3 tion o agents such as S-1, an oral fuoropyrimidine
study, 410 patients with cholangiocarcinoma, gallblad- derivative designed to enhance clinical use and reduce
der, or ampullary carcinoma were randomized in a 1:1 gastrointestinal toxicity (NCT02182778),103,104 or
ashion to receive gemcitabine alone (1000 mg/m2 on derivatives such as NUC-1031 (a phosphoramidate
days 1, 8, and 15 o a 4-week cycle) or cisplatin (25 transormation o gemcitabine) designed to overcome
mg/m2) ollowed by gemcitabine at above dose on day resistance mechanisms to gemcitabine (ABC-08 study,
1 and 8 o a 3-week cycle. At a ollow-up o median NCT02351765).105,106 As described urther below, there
8.2 months, medial OS was 11.7 months in the gem- has been a paradigm shit toward targeted therapy in
citabine plus cisplatin arm compared with 8.1 months biliary tract cancers, and targeted agents alone or in
with gemcitabine alone (HR 0.64, 95% CI 0.52–0.80; combination with chemotherapy are also being evalu-
Chapter 29
P < .001). Median PFS was 8.0 months in the doublet ated in the rontline setting.
arm compared with 5.0 months with gemcitabine
alone (P < .001). Rates o neutropenia were higher in
the doublet arm (25.3% vs 16.6% grade 3/4); however,
Second-Line Cytotoxic Chemotherapy
rates o inection were similar. Increased liver enzymes Ater progression on gemcitabine and cisplatin, stan-
occurred with gemcitabine alone (27.1% vs 16.7%; P dard-o-care second-line chemotherapy options are
= .01), which the authors concluded may have been limited. In the ABC-06 study (NCT01926236), patients
secondary to inerior control o the disease compared were randomly assigned 1:1 to modied (m) FOLFOX
with the doublet.76 Other toxicities were comparable. (olinic acid, fuorouracil, and oxaliplatin) with active
Gemcitabine and cisplatin compared with gemcitabine symptom control (ASC) versus ASC alone ater prior
alone was also tested in a Japanese population with gemcitabine-cisplatin therapy.107 O 162 patients, the
similar ndings.102 median OS was 6.2 versus 5.3 months or ASC with
A treatment regimen with better ecacy than mFOLFOX compared with ASC alone; the 6- and
gemcitabine and cisplatin has yet to be approved or 12-month OS rate was 50.6% and 25.9%, compared
clinical use, although several promising therapies are with 35.5% and 11.4%, respectively. Approximately
emerging. In a phase 2, open-label, single-arm study 59% o patients experienced grade 3 or 4 toxicity
o gemcitabine, cisplatin, and nanoparticle albumin- in the chemo-ASC arm compared with 39% in the
bound (nab)-paclitaxel (NCT0239263), patients were ASC-alone arm. Although survival was greater than
treated with gemcitabine 1000 mg/m,2 cisplatin 25 expected with ASC alone, the ndings indicate clinical
mg/m,2 and nab-paclitaxel 125 mg/m2 on days 1 and benet o mFOLFOX with ASC in the second-line set-
8 o a three-week cycle.34 Because o grade 3/4 hema- ting.107 Modied FOLFIRI (olinic acid, fuorouracil, and
tologic toxicities, doses were reduced to 800 mg/m2 irinotecan) has been compared with mFOLFOX in the
o gemcitabine, 25 mg/m2 o cisplatin, and 100 mg/m2 second-line setting via a 1:1 randomization ater pro-
o nab-paclitaxel (n = 28 in reduced-dose group). O gression on gemcitabine/cisplatin, and mFOLFIRI was
60 patients, the majority had ICC (63%), ollowed by noted to be tolerable but not superior to mFOLFOX
gallbladder carcinoma (22%), and ECC (15%). Patients in the second line (NCT03464968).108 Retrospective
who had prior chemotherapy were excluded (except in and meta-analyses o chemotherapy in the second or
the adjuvant setting >6 months prior). A median PFS o later line setting have shown a modest PFS o 2.4 to
11.8 months (95% CI 6–15.6) and disease control rate 3.2 months across studies, with an average median OS
o 84% was noted at 12.2 months ollow-up. Twelve average o 7 months.109–111
patients who had unresectable disease were converted
to resectable and underwent surgery. Median OS o
19.2 months (95% CI 13.2–unable to estimate) was
Targeted Therapy: Molecular Profling o
reported, which is an improvement compared with Biliary Tract Cancers
historical controls o gemcitabine and cisplatin.34 Grade The development o molecular proling technolo-
3 or greater toxicity was seen in 58% (61% high-dose, gies has led to increased genomic-proling studies o
54% low-dose group). The most common grade 3 or all cancers, including those o the biliary tract.112–119 At
Chapter 29
658
Scion VI
Table 294 Summary o pertinent systemic therapy trials in unresectable and metastatic biliary tract carcinoma
Trial Name (Clinical Trials Treatment Statusa
Identifer) Phase Molecular Target Regimen Patients Outcome Adverse Events [reerence]
ABC-02 Randomized, None – cytotoxic Cisplatin (25 N = 410 randomized mPFS: 8.0 vs 5.0 mo Gr 3/4: (gem/ Completed;
(NCT00262769) phase 2 mg/m2) + N = 204 assessed (P < .001) cis vs gem) standard
– rst line gemcitabine (gem/cis) mOS: 11.7 vs 8.1 mo (or neutropenia o care rst
(1000 mg/m2) N = 206 assessed gem/cis) (25.3 vs line76
D1, D8 (every 3 (gem) HR: 0.64% (95% CI 0.52–0.80; 16.6%), any
weeks) P < .001) hematologic
vs gemcitabine (32.3 vs
1000 mg/m2 D1, 23.6%); LFT
D8, D15 (every abnormal
4 weeks) (16.7 vs
27.1%); any
inection
(18.2 vs
19.1%)
Gemcitabine, cisplatin, Open-label, None – cytotoxic Gemcitabine 1000 N = 60 mPFS: 11.8 mo (95% Gr ≥3: Active, not
and nab-paclitaxel or single-arm, mg/m,2 cisplatin CI, 6.0–15.6) 58% total recruiting34
treatment o advanced phase 2 25 mg/m2, and mOS: 19.2 mo (95% (61% in
biliary tract cancers – 1st line nab-paclitaxel CI 13.2–not reached) high dose;
(NCT02392637) 125 mg/m2 PRR: 45% 54% dose
D1, D8 (21-day DCR: 84% reduced)
cycle) Gr3, Gr4:
Ater– neutropenia
N = 32, doses (30, 11%);
reduced: 800 diarrhea/
mg/m,2 elevated ALP/
25 mg/m,2 vomiting
100 mg/m,2 (4%)
respectively
ABC-06 Randomized, None – cytotoxic 1:1 randomization: N = 162 (81 per arm) ACS + mFOLFOX: mOS: 6.2 Gr 3/4: Completed107
(NCT01926236) multicenter, ACS + mo; 6 mo and 12 mo OS 59% (ACS +
controlled, oxaliplatin/5-FU rate: 50.6%, 25.9% mFOLFOX)
open-label (mFOLFOX) vs vs ACS alone: mOS: vs 39%
– second line ACS alone 5.3; 6 mo and 12 mo (ACS alone)
OS rate: 35.5%,
11.4%.
(Continued)
BGJ398 Open-label, FGFR2 usions Ingratinib N = 61 (FGFR2 ORR: 14.8% (18.8% or All Gr: Recruiting128,129
(Infgratinib; phase 2 or other FGFR PO 125 mg usions (48); FGFR2 usions) Hyperphos
NCT02150967) – 2nd line alterations once daily or mutations (8); DCR: 75.4% (83.3% FGFR2 (72.1%);
21 days; 7 days amplications usions) atigue
of (28-day (3) mPFS: 5.8 mo (95% CI (36.1%);
cycle) 4.3–7.6) stomatitis
(29.5%)
Gr 3/4:
hyperphos
(16.4%);
stomatitis
(6.6%); HFS
(4.9%)
Updated FGFR2 usions/ Ingratinib PO 125 N = 71 (FGFR2 ORR: 31.0% (95% All Gr:
results: open- translocations mg once daily usion/ CI 20.5–43.1) hyperphos
label, phase 2 only or 21 days; translocation cORR: 26.9% (95% (73.2%),
– second line 7 days of only) CI 16.8–39.1) atigue
(28-day cycle) mPFS: 6.8 mo (95% (49.3%),
CI 5.3–76) stomatitis
mOS: 12.5 mo (95% (45.1%),
CI 9.9–16.6) alopecia
(38%)
Gr 3/4: any
(66.2%);
hypophos
(14.1%),
hyperphos
(12.7%)
FLIGHT-202 Multicenter, COHORT: Pemigatinib PO N = 107 (FGFR2 Cohort 1: Gr 1/2: Active, not
Pemigatinib open-label, (1) FGFR2 usions/ 13.5 mg daily usion/ ORR: 35.5% (95% Hyperphos recruiting132
C 29 Biliary Tract Cancer

(NCT02924376) single-arm, rearrangements; or 14 days; rearrangements) CI 26.5–45.4; 3 CR and (55%);
phase 2 (2) other FGFR 7 days of N = 20 FGFR 35 PR) Alopecia
– 2nd line alterations (21-day cycle) alterations DCR: 82% (74%–89%) (46%);
(3) no FGFR N = 18 no FGFR OS: 21.1 (14.8–not reached) Dysgeusia
alterations N = 1 unknown FGFR Cohort 2: (34%); atigue
ORR: 0%; DCR: 40%; (31%)
mOS: 6.7mo (2.1–10.6) Gr 3: Hypophos
Cohort 3: (7%);
ORR: 0%; DCR: 22%; stomatitis
mOS: 4.0 (2.3–6.5) (5%);
arthralgia
and HFS (4%)
(Continued)
659
Chapter 29
Chapter 29
660
Scion VI
Table 294 Summary o pertinent systemic therapy trials in unresectable and metastatic biliary tract carcinoma (Cont.)
FOENIX-CCA2 Single-arm, FGFR2 gene Futibatinib once N = 103 enrolled ORR: 34.3% (PR, n = 23) All Grade: Active, not
Futibatinib (TAS120) multicenter, usions/ daily oral dose (interim analysis DCR: 76.1% Hyperphos recruiting133,134
(NCT02052778) phase 2 rearrangments continuous with n = 67; 82.1% mTTR: 1.6 mo (1.0–4.9) (79.1%),
– 2nd line with FGFR2 mDOR: 6.2 mo (2.1–14.2) Diarrhea
usions) (37.3%),
dry mouth
(32.8%)
Gr ≥3: Any
(73.1%);
Hyperphos
(25.4%)
ClarIDHy Multicenter, IDH1 mutations Ivosidenib 500 N = 185 (n = 124 mPFS: 2.7 mo (95% CI 1. Gr 1/2: nausea Active, not
Ivosidenib (AG120) randomized mg once daily ivosidenib; n = 61 6–4.2) or ivosidenib (33% vs 24%); recruiting142
(NCT02989857) (2:1), double- continuous placebo) vs 1.4 mo (1.4–1.6) diarrhea
blind, (28-day cycle) placebo (31% vs 15%);
placebo- vs matched HR: 0.37 (95% CI 0.25–0.54; atigue (23%
controlled, placebo P < .0001) vs 15%);
phase 3 (crossover mOS (ITT): 10.8 mo cough (21%
– 2nd line (up to permitted) (95% CI 7.7–17.6) vs 8%).
2 prior lines) vs 9.7 mo (4.8–12.1); Gr ≥3: Any (30%
HR 0.69 (95% treatment vs
CI 0.44–1.10; P = .06) 22% placebo)
Ascites (7%
both arms);
hyperbili
(6% vs 2%);
ALT elevation
(5% vs 0%).
My Pathway Open-label, HER2 Pertuzumab + N = 11 (HER2 Preliminary: No new signals Recruiting147
(NCT02091141) multicenter, amplication/ Trastuzumab amplied/ 4.2 mo ollow-up:
multi-basket, overexpression overexpressed) PR (n = 4); SD
phase 2a or activating N = 8 (HER2 (n = 3)
– reractory mutation mutated)
(Continued)
NCI-MATCH (EAY131) Approximately HER2 amplication T-DM1 N = 38 PR rate: 5.6% Gr 1/2: Anemia Recruiting148
(NCT02465060) 40 phase 2 (CN >7) 3 .6 mg/kg (n = 3 biliary tract) (noncholangiocarcinoma) (34%), AST
molecularly IV every 3 weeks SD rate: 47% increase/
targeted (noncholangiocarcinoma) low platelets
subprotocols (26%),
– reractory nausea/
(no prior vomiting
trastuzumab/ (21%)
pertuzumab/ Gr 3: Anemia
T-DM1) (8); atigue
(5%); low
platelets
(5%)
ROAR basket trial Open-label, BRAFV600E Dabraenib 150 N = 33 biliary ORR (investigator-assessed): Gr 3/4: Active, not
BRAF V600E-mutated phase 2 mutations mg PO BID + tract cancer 41% (95% CI 24–59). increased recruiting151
biliary tract cohort – second line trametinib mPFS: 7.2 mo GGT (9%);
(NCT02034110) or greater 2 mg PO daily (95% CI 4.6–10.1) leukopenia
mOS: 11.3 mo (9%)
(95% CI 7.3–17.6)
a
Clinicaltrials.gov status as o 6/27/2020.

ACS, active symptom control; ALT, alanine aminotranserase; BID, twice daily; BRAF, serine/threonine-protein kinase B-ra; Cis, cisplatin; DCR, disease control rate; FGFR, broblast growth actor receptor; Gem, gemcitabine; GGT,
gamma-glutamyl transerase; HFS, hand-oot syndrome (palmar-plantar erythrodysesthesia); HR, hazard ratio; hyperbili, hyperbilirubinemia; hyperphos, hyperphosphatemia; hypophos, hypophosphatemia; IDH1, isocitrate
dehydrogenase 1; ITT, intent to treat; LFT, liver unction test; mDOR, median duration o response; mOS, median overall survival; mPFS, median progression-ree survival; mTTR, median time to response; NCI-MATCH, National Cancer
Institute-Molecular Analysis or Therapy Choice; PO, oral; PRR, partial response rate; ROAR, rare oncology agnostic research; T-DM1, ado-trastuzumab emtansine.
661
Chapter 29
the chromosome level, initial studies o comparative WD repeat domain containing 7 (FBXW7), and cyclin-
genomic hybridization (CGH) shed light on chromo- dependent kinase inhibitor 2A (CDKN2A). In a larger
somal losses and gains and insight into the heterogene- study o patients (412 ICC, 57 ECC, and 85 gallbladder
ity o biliary tract cancer.113 A meta-analysis o ve CGH carcinoma), a similar prole was noted with commonly
studies encompassing a total o 98 ICCs showed re- altered genes in TP53, CDKN2A/B, KRAS, ARID1A,
quent gains in chromosomes 1q, 5p, 7p, 8q, 17q, and 20q IDH1, SMAD4, ERBB2, and broblast growth actor
in three or more studies (>20% overall change).113 Losses receptor (FGFR).115 O these, FGFR (11%) and IDH
o copy number on chromosome 1q, 4p, 8p, 9p, 17p, and (20%) alterations were predominantly ound in ICC
18p were also reported. The aggregate data noted pos- and noted to be mutually exclusive. KRAS and TP53
sible ethnic diversity between three Asian studies com- mutations were associated with poor prognosis, and
pared with a German study. Similarities were also noted FGFR2 alterations were associated with better progno-
to a previous CGH meta-analysis o HCC. sis and OS (HR 0.478; P = 0.03), emale gender, and
Comprehensive molecular proling technologies younger age (<40 years). IDH1/2 alterations were not
and high-throughput genomic-proling studies have ound to be prognostic. ERBB2 (16%) alterations were
shed light on commonly occurring alterations in bili- ound predominantly in gallbladder carcinoma. Broadly,
ary tract cancers.114–119 Next-generation sequencing o the unctionally validated genes can be categorized into
75 patients with cholangiocarcinoma that examined cell cycle–related (TP53, CDKN2A mutation/deletion,
236 cancer-related genes had shown tumor protein and CCND1 amplication), receptor tyrosine kinases
p53 (TP53) (35 and 45%) and KRAS (24 and 40%) (FGFR), MAPK pathway (KRAS, NRAS, and BRAF),
Chapter 29
as commonly occurring alterations in both ICC and chromatin modiying (ARID1A/B, BAP1, PBRM1), and
ECC, respectively.114 Other requently altered genes IDH1/2 alterations.116–121 BAP1 alterations also appear
in the intrahepatic subgroup include AT-rich interac- to coner a more aggressive phenotype, associated with
tion domain 1A (ARID1A), isocitrate dehydrogenase bone metastases, although case numbers have been
1 (IDH1), myeloid cell leukemia 1 (MCL1), Erb-B2 limited.114 A summary o commonly altered genes and
receptor tyrosine kinase 2 (ERBB2), SMAD4, F0box, their requencies are ound in Table 29–5.
tbl 29–5 Frequency o Genetic Alterations in Biliary Tract Carcinomas
Genetic Alteration Prevalence o Genetic Alterations
Intrahepatic Extrahepatic
Cholangiocarcinomaa Cholangiocarcinomaa Gallbladder Carcinomaa
Total Genomic 3.6 4.4 4.0
Alteration/Patient
TP53 25%–30% 40% 60%
RAS (KRAS/NRAS) 20%–25% 40%–45% 10%–15%
CDKN2A/B Loss 25%–30% 15%–20% 20%
ARID1A 15%–20% 10%–15% 10%–15%
BAP1 10%–15% 10% 6%
FGFR1-3 10%–15% <5% 3%–5%
ERBB2 (HER2/neu) 3%–5% 15% 15%–20%
Amplication
PBRM1 10% 5% n/ab
IDH1/2 20% 0% 0%
SMAD4 4%–7% 20%–25% 30%
PTEN 5% n/ab Up to 4%
BRAF Substitution 5% 3% 1%
PIK3CA Substitution 5%–6% 7% 10%–15%
BRCA1 0.4% 2% 0.3%
BRCA2 2.7% 2%–3% 4%
a
Rates o genetic alterations greater than 10 are rounded to the nearest 5 and provided in ranges.114,115
b
Consensus on prevalence unclear.
The results o these and other molecular proling diuretics.131 Ocular toxicity is also a potential unique
studies have led to a paradigm shit in the treatment side eect o FGFR inhibitors.
o advanced and metastatic biliary tract cancers with Pemigatinib is another FGFR1–3 oral inhibitor
development and use o targetable agents. An esti- investigated in a phase 2, multicenter, open-label study
mated 35% to 40% o biliary tract cancers contain tar- (FLIGHT-202; NCT02924376) or previously treated
getable genetic alterations.122 advanced or metastatic cholangiocarcinoma (89%
ICC) patients with FGFR alterations.132 The study
included three cohorts: (1) those with FGFR2 usions/
Targeted Therapies rearrangements, (2) those with other FGF pathway
FGFR Alterations alterations, and (3) patients without FGFR alterations.
Patients were treated with 13.5 mg pemigatinib orally
The FGFR signaling pathway is a amily o proteins once daily or 14 consecutive days on a 21-day cycle
consisting o our receptors (FGFR1–4) and 22 ligands, until progression or toxicity. O 146 patients enrolled
which, when activated, results in downstream signal- in the study, the majority (n = 107) had FGFR2 usions/
ing via the mitogen-activated protein kinase, phos- rearrangements. At median ollow-up o 17.8 months,
phoinositide 3-kinase (PI3K)/AKT, Janus kinase/signal an ORR o 38% (95% CI 26.5–45.4) was noted in the
transducers, and activators o transcription (JAK-STAT) FGFR2 usion/rearrangement–containing subset. No
pathways. This in turn leads to cell prolieration, responses were noted in the patients with other FGFR
growth, migration, and angiogenesis.123,124 alterations or in those without FGFR alterations. A
Chapter 29
FGFR alterations are ound in approximately 15% o DCR o 82% (range 74%–89%) or usion-contain-
ICCs and tend to be driver mutations. FGFR2 usions ing patients was noted, compared with 40% (range
or translocations are the most common type o altera- 19%–64%) and 22% (range 6%–48%) in other and no
tion, and two common usion partners identied have FGFR alteration groups, respectively. Median OS was
been the genes AHCYL1 and BICC1.125 These two 21.1 months (range 14.8–not reached) in patients with
usions have been shown as mutually exclusive with FGFR2 usions. A similar side eect prole to ingra-
KRAS and BRAF mutations and result in constitutive tinib was noted with hyper- and hypophosphatemia,
phosphorylation o mitogen-activated protein kinase arthralgias, and stomatitis.132 Based on these results,
in both in vitro and in vivo studies.126,127
pemigatinib was given a FDA-accelerated approval or
Several FGFR inhibitors are currently under investi- advanced or metastatic cholangiocarcinoma patients
gation. BGJ398, also known as ingratinib is an orally with FGFR2 gene usions or rearrangements ater pro-
bioavailable FGFR1–3 inhibitor and was studied in a gression on at least one prior line o therapy pending
multicenter, open-label, phase 2 trial in the second- verication in a conrmatory trial.
line setting or advanced or metastatic cholangiocar- TAS120 or utibatinib is a highly selective FGFR1–4
cinoma with FGFR alterations (NCT02150967).128 irreversible inhibitor that has completed phase 1/2 tri-
Ingratinib was dosed at 125 mg once daily or 21 als in cholangiocarcinoma. In an initial phase 1 study
days o a 28-day cycle. O the 61 patients reported at o TAS120 in advanced solid tumors, an ORR o 25%
data cuto, the majority (n = 48) had FGFR2 usions,
was noted in cholangiocarcinoma patients with FGFR2
but mutations were ound in eight patients and ampli- usions (n = 28).133 These initial results led to the FOE-
cation in three patients. An ORR o 14.8% (18.8% NIX-CCA2 (NCT02052778) phase 2, single-arm, mul-
or FGFR2 usion subset) and a median PFS o 5.8 ticenter study in second-line or greater advanced or
months (95% CI 4.3–7.6), and a disease control rate metastatic cholangiocarcinoma patients with FGFR2
(DCR) o 75.4% (83.3% in the FGFR2 usion subset) gene usions/rearrangements.134 O 103 patients,
was reported.128 An update with 71 patients with an interim analysis o 67 patients with more than 6
FGFR2 usions showed an ORR o only 31.0% (95% months o ollow-up showed an ORR o 34.3% and
CI 20.5–43.1) and disease control rate o 83.6% (95% DCR o 76.1%. Median duration o response o was
CI 72.5–91.5). Median PFS was 6.8 months (95% CI 6.2 months (range 2.1–14.2) with a 1.6-month (range
5.3–7.6) and median OS o 12.5 months (95% CI 1.0–4.9) median time to response. Side eect prole
9.9–16.6) was noted.129 Overall the therapy was well was similar to the other FGFR inhibitors above.
tolerated, with hyperphosphatemia (73.2%), atigue Multiple other nonselective tyrosine kinase inhibi-
(49.3%), and stomatitis (45.1%) noted as the most tors with anti-FGFR activity are also under inves-
common adverse events. Hyperphosphatemia is a tigation in the second-line setting in patients with
common class eect o FGFR inhibitors secondary FGFR-altered cholangiocarcinoma.124,135–139 All three o
to the role o the FGFR pathway in renal phosphate the agents above (ingratinib, pemigatinib, and utiba-
metabolism and is considered an on-target eect.130,131 tinib) are also under investigation in the rst-line setting
As o this writing, hyperphosphatemia is managed in phase 3, randomized clinical trials compared with
with phosphate binders, low-phosphate diets, and standard-o-care gemcitabine-based chemotherapy in
this patient population (NCT03773302, NCT03656536, predominantly seen in gallbladder carcinoma (16%),
and NCT04093362).140 The results o these studies can ollowed by ECC (11%), and ICC (3%).115,145
potentially lead to a chemotherapy-ree option or A multihistology trial o ado-trastuzumab emtansine
patients with advanced or metastatic cholangiocarci- (T-DM1) at a dose o 3.6 mg/kg IV given once every 3
noma harboring FGFR2 usions/rearrangements. weeks in HER2-amplied solid cancers included 6 (n =
58) patients with biliary tract cancer (NCT02675829).146
IDH Inhibitors ORR was 26%, and 1 o 6 (17%) in biliary cancer. No
signicant correlation was ound between the degree
Approximately 20% o cholangiocarcinomas (pre- o HER2 amplication and response. MyPathway is an
dominantly intrahepatic) contain IDH1/2 muta- ongoing open-label, multicenter, phase 2a basket study
tions.114,115,119 IDH1 and 2 are essential or production (NCT02091141) aimed at evaluating saety and ecacy
o metabolic enzymes that prevent cellular oxidative o targeted therapies across tumor types.147 In a sub-
damage via conversion o isocitrate to alpha-ketoglu- set o 11 patients with advanced biliary tract cancer,
tarate.141 Mutations in these genes increase the produc- with eight HER2 amplications/overexpression and
tion o D-2-hydroxyglutarate, an oncometabolite, and three mutations, our partial responses were seen at
decreased α-ketoglutarate production, which in turn 12 months, with three others achieving disease stabil-
increases oncogenesis. The most common IDH1 muta- ity. The National Cancer Institute–Molecular Analysis
tion seen in cholangiocarcinoma is R132C.141 or Therapy Choice is a national study using genomic
The phase 3, multicenter, randomized, double-blind testing or matching patients with reractory disease to
Chapter 29
study ClarIDHy (NCT02989857) investigated the e- potential targeted therapies.148 In a subprotocol evaluat-
cacy o ivosidenib in IDH1-mutated cholangiocarci- ing T-DM1 in 36 patients with HER2-amplied non-
noma ater progression on prior therapy. Patients were breast and nongastroesophageal cancers, three biliary
randomly assigned 2:1 to receive ivosidenib 500 mg or adenocarcinoma patients were included. In this study, a
placebo with the possibility or crossover on progres- trend toward increased tumor shrinkage was seen with
sion.142 At 6.9 months, median PFS was 2.7 months higher levels o gene copy number. Although the above
or the ivosidenib group (95% CI 1.6–4.2) versus 1.4 studies had small sample sizes and a small number o
months (95% CI 1.4–1.6) with a HR o 0.37 (95% CI responders, basket trials are particularly useul or iden-
0.25–0.54; P < .0001). A signicant dierence in OS was tication o signals to targeted therapy in rare tumors to
not noted between the treatment and placebo groups warrant urther investigation.148,149
(10.8 months in intent-to-treat [95% CI 7.7–17.6] vs 9.7
months [range 4.8–12.1], HR 0.69 [95% CI 0.44–1.10;
BRAF Blockade
P = .06]). Correcting via rank-preserving structural
ailure time method had noted a median OS o 6.0 BRAF alterations are ound in approximately 1% to
months (HR 0.46 [range 0.28–0.75]; P = .0008). Objec- 5% o biliary tract cancer. In the histology-indepen-
tive response rates were low (n = 3/124 patients [2%]) dent, phase 2 basket study (NCT01524978) with BRAF
with 51% achieving stable disease compared with 28% V600–containing nonmelanomatous cancers, a total o
in the placebo group.142 The 12-month OS rate o this 122 patients were enrolled.150 O these, eight patients
study (48%) when compared with historic controls o with advanced cholangiocarcinoma were included. No
regoraenib and mFOLFOX in second line (27% and CRs were noted; a partial response lasting more than
25.9%, respectively) show comparable results.108,143,144 12 months was noted in one (12%) patient, and stable
The most common grade 1/2 adverse events in the disease was achieved in our (50%) patients.150 Com-
treatment group included nausea (33%), diarrhea bination BRAF + MEK inhibition (dabraenib and tra-
(31%), and atigue (23%). Grade 1/2 ascites was noted metinib) in BRAFV600-mutated rare tumors was studied
in 13% o the treatment group and 8% in the placebo in the phase 2, open-label “ROAR” basket trial, where
group. Ascites was the most common grade 3 or greater 33 patients with biliary tract cancer were included
adverse event, although rates were the same between (NCT02034110).151 O 32 evaluable patients, investiga-
the treatment and placebo groups (7%).142 tor-assessed ORR was 41% (95% CI 24–59). Median PFS
o 7.2 months (95% CI 4.6–10.1 months) and median
HER2 Blockade OS o 11.3 months (95% CI 7.3–17.6 months) was seen,
warranting urther clinical investigation in this patient
Overexpression o human epidermal growth actor population.
receptor 2 (HER2) encoded by ERBB2 is a well-estab-
lished driver o oncogenesis in multiple cancer types
Other Targetable Pathways
and approved or use in breast and gastric/gastro-
esophageal carcinoma. In biliary tract cancer, genetic Neurotrophic tropomyosin-related kinase gene
alterations (amplications or mutations) in ERBB2 are usions are present in approximately 3% to 5% o
cholangiocarcinomas, and larotrectinib tissue agnostic barriers o response to ICIs.161 Key immunotherapy
approval or all solid tumors in the reractory setting trials with dosing schedules and outcomes are sum-
without known acquired mutation is also applicable marized in Table 29–6 and highlighted below.
to biliary tract cancers.152 Anti–angiogenesis-directed In the KEYNOTE-028 phase 1b study (NCT02054806)
therapies have also been highly studied in advanced o pembrolizumab in advanced or metastatic biliary
biliary tract cancers, including vascular endothelial tract cancers in the second line or greater with at least
growth actor inhibitors and multi-tyrosine kinase 1% PD-L1 expression, an ORR o 13% (all PR, 95%
inhibitors. Overall, results have not shown signi- CI 2.8–33.6) was seen among 23 patients at a median
cant added benet to the chemotherapy backbone in ollow-up o 5.7 months (range 0.6–55.4). This trans-
unselected patients with cholangiocarcinoma.153–160 lated to a median OS and PFS o 5.7 months (95% CI
Taken together, the identication o targeted 3.8–9.8) and 1.8 months (95% CI 1.4–3.1), respectively.
genetic alterations in biliary tract cancer and the No grade 4 or 5 adverse events were noted, although
development o targeted agents have revolutionized 16.7% had grade 3 toxicities.162,163 PD-L1 positivity
therapy in the advanced and metastatic setting. Perti- was not a requirement or inclusion in KEYNOTE-158
nent trial data have been summarized in Table 29–5. (NCT02628067), a phase 2 study o 200 mg pembroli-
Sequencing o these agents and urther studies into zumab given once every 3 weeks ater progression on
resistance mechanisms in terms o gatekeeper muta- prior standard-o-care therapy. O 104 patients included
tions and development o other secondary genetic in this study, 61 were positive or PD-L1 expression.
alterations is an area o active research. In addition, ORR was 5.8% (all PR, including 1 PD-L1–negative
Chapter 29
with multiple FGFR inhibitors now being stud- patient; 95% CI 2.1–12.1) in all patients (6.6% among
ied in the rst-line setting compared with standard PD-L1 expressors vs 2.9% among nonexpressors).
o care, a chemotherapy-ree rontline option may Median duration o response had not been reached;
soon become available in the metastatic setting or however, an estimated 50% had duration o response
the FGFR-altered population (particularly those with at 24 months or longer. Median OS and PFS were 7.4
FGFR2 gene usions). months (95% CI 5.5–9.6) and 2.0 months (95% CI 1.9–
2.1), respectively. One patient had grade 5 renal ailure,
and grade 3 or higher adverse events were reported
Immunotherapy in 13.5%. Taken together, these data suggest modest
Immune checkpoint inhibitors (ICIs) have revolu- activity o pembrolizumab monotherapy without new
tionized the treatment o multiple cancer types; saety signals noted162,163
however, their role in biliary tract cancer is not well A multicenter, phase 2 study o nivolumab in 54
established. Certain genetic actors have shown to patients with biliary tract cancer who had received
predict response to ICIs such as tumor mutation between one and three prior lines (NCT02829918)
burden (TMB), program death-ligand/program cell showed a 22% investigator-assessed ORR had been
death protein 1 (PD-L1/PD-1) expression, and mis- noted with a DCR o 59% (central independent review;
match repair (MMR) gene deciency. These actors ORR 11%, DCR 50%). All responses were in patients
are indicative o high microsatellite instability (MSI- with procient MMR. Median PFS was 3.68 months
H) and an increased likelihood o tumor-specic (95% CI 2.3–5.69) and median OS was 14.24 (95% CI
neoantigen that can be recognized by the immune 5.98–not reached). PD-L1 expression was signicantly
system.161 The majority o biliary tract cancers have a associated with prolonged PFS (P < .001). Grade 3/4
low-to-intermediate TMB. Comprehensive genomic toxicities included hyponatremia (6%) and elevated
proling o 3634 cholangiocarcinomas showed an alkaline phosphatase (4%).164
approximately 1% rate o MSI-H.119 Global loss o Preliminary data rom a randomized, phase 2, mul-
heterozygosity (gLOH) higher than 16% was seen in ticenter study (BilT-01; NCT03101566) o nivolumab
11% o studied cases. Approximately 3.5% and 1.4% with gemcitabine-cisplatin (Arm A) or nivolumab
o evaluated cases had TMB higher than 10 and more with anticytotoxic T-lymphocyte–associated protein
than 20 mutations/megabase, respectively. PD-L1 4 (CTLA-4) agent ipilimumab (Arm B) in untreated
positivity was seen in 9% o tested cases, and PD-L1 advanced or metastatic biliary tract cancer was
amplication was present at a rate o 0.27%. 119,161 reported.165 O 71 eligible patients (n = 35 Arm A;
Stages o chronic infammation and inectious/viral n = 36 Arm B), the 6-month PFS rate was 70% in arm
etiologies are associated with cholangiocarcinoma. A and 18.6% in Arm B. This translated to a median PFS
Although other virally-associated cancer types have o 8.8 months (95% CI 6.1–11.3) and median PFS o 4.1
shown encouraging response rates to ICI therapies, months (95% CI 2.4–5.2)), respectively.165 Although
it is unclear whether this pattern is evident in bili- the combination immunotherapy arm appears to be
ary tract cancer. The highly heterogeneous nature o inerior to the nivolumab with chemotherapy arm,
these cancers and desmoplastic stroma may also be the preliminary data are comparable with historical
Chapter 29
666
Scion VI
Table 296 Summary o Pertinent Immunotherapy Therapy Trials in Unresectable and Metastatic Biliary Tract Carcinoma
Trial Name
(Clinical Trials Treatment Statusa
KEYNOTE-028 Phase 1b, PD-L1 positive Pembrolizumab N = 24 ORR: 13.0% (95% Gr 3–5: 16.7% Active, not
(NCT02054806) basket study 10 mg/kg CI 2.8–33.6) Any Gr: pyrexia recruiting162
IV every mDOR: not (16.7%), nausea/
2 weeks reached pruritis (12.5%),
mOS: 5.7 mo hypothyroid
(3.1–9.8) (8.3%), severe
mPFS: 1.8 mo skin reaction/
(1.4–3.1) colitis (4.2%)
KEYNOTE-158 Phase 2, Unselected or Pembrolizumab N = 104 ORR: 5.8% (95% Gr 3–5: 13.5% Recruiting163
(NCT02628067) multicohort PD-L1 200 mg (PD-L1 expressor, CI 2.1–12.1); Any Gr: atigue
IV every n = 61; PD-L1 (6.6% PD-L1 pos; (14.4%), rash
3 weeks nonexpressor, 2.9% (PD-L1 (11.5%),
n = 24) neg) hypothyroidism
mDOR: not (7.7%),
reached pneumonitis
mOS: 7.4 mo (5.8%)
(95% CI 5.5–9.6)
mPFS: 2.0 mo
(95% CI 1.9–2.1)
Nivolumab or Multicenter, PD-L1 positivity Nivolumab 240 N = 54 (n = 46 ORR: 22% Any Gr: increased Active, not
patients with phase 2 not required mg IV every assessed) (investigator- ALP (24.1%), recruiting164
advanced/ 2 weeks • PD-L1+: assessed); 11% lymphopenia
reractory biliary (16 weeks), n = 18 (central review) (22.2%), AST
tract cancer then 480 mg • PD-L1 + increase/atigue
(NCT02829918) IV every investigator (20.4%), anemia
4 weeks assessed: 50% (18.5%)
DCR: 59% Gr 3: hypoNa (5.6%),
mPFS: 3.68 mo HTN/ALP increase
(95% (3.7%)
CI 2.3–5.69)
mOS: 14.24 mo
(95% CI 5.98–
not reached)
(Continued)
Trial Name
BilT-01 Multicenter, Unselected Arm A: N = 71 PFS rate, 6 mo: Pending Active, not
(NCT03101566) randomized, gemcitabine (35 Arm A, 70% (A); 18.6% recruiting
phase 2 1000 mg/m2 36 Arm B) (B). 165
+ cisplatin 25 mPFS (A): 8.8

mg/m2 D1, D8 mo (95% CI
every 3 weeks + 6.1–12.3)
nivolumab 360 mPFS (B): 4.1 mo
mg D1 every (95% CI 2.4–5.2)
3 weeks (6 mo mOS (A): 10.6
and 240 mg mo (6.8–not
every 2 weeks) reached)
Arm B: mOS (B): 8.3 mo
Nivolumab (5.9–16.9)
240 mg every
2 weeks + 1
mg/kg every
6 weeks (6
mo and then
nivolumab
240 mg every
3 weeks)
Durvalumab +/- Phase 1, Unselected Cohort 1: N = 42 PR (D): n = 2 Any Gr: 64% (D); 82% Active, not
tremelimumab open-label, Durvalumab (Durvalumab) PR (D+T): n = 7 (D+T) recruiting166
biliary tract multicenter 0 mg/kg every N = 65 DCR (D): 16.7%

cancer 2 weeks (Durvalumab + DCR (D+T): 32.2%
expansion Cohort 2: tremelimumab) mOS (D): 8.1
cohort Durvalumab mo (95% CI
(NCT01938612) 20 mg/kg + 5.6–10.1)
tremelimumab mOS (D+T):
1 mg/kg every 10.1 (95%
4 weeks CI 6.2–11.4)
(Continued)
667
Chapter 29
Chapter 29
668
Scion VI
Table 296 Summary o Pertinent Immunotherapy Therapy Trials in Unresectable and Metastatic Biliary Tract Carcinoma (Cont.)
Trial Name
Durvalumab with Phase 2, Unselected Cohort 1: Cohort 1: N = 30 ORR (95% CI): Any Gr: neutropenia Recruiting
167
gemcitabine- open-label, (Biomarker) Biomarker: 50% (54.5%), nausea
cisplatin +/ rst line gem 1000 mg/ Cohort 2: N = 45 (31.1–67.9) (59.5%), pruritus
tremelimumab m2 + cisplatin Cohort 2: 73.4% (55.4%)
(NCT03046862) 25 mg/m2 D1, Cohort 3: N = 46 (60.5–86.3) Gr 3/4: neutropenia
D8, → gem/cis Cohort 3: 73.3% (50.4%), anemia
+ durvalumab (60.4–86.2) (35.5%),
(1120 mg) + DCR: thrombocytopenia
tremelimumab Biomarker: (16.5%)
(75 mg) every 96.7%
3 weeks Cohort 1: 100%
Cohort 2: gem/cis Cohort 2: 97.8%
+ durvalumab
Cohort 3: gem/cis
+ durvalumab +
tremelimumab
a
Clinicaltrials.gov status as o 6/27/2020.
ALP, alkaline phosphatase; ALT, alanine aminotranserase; AST, aspartate aminotranserase; D, durvalumab; DCR, disease control rate; HTN, hypertension; HypoNa, hyponatremia; mDOR, median duration o response; mOS, median
overall survival; mPFS, median progression-ree survival; ORR, objective response rate; PD-L1, program death-ligand 1; PR, partial response; T, tremelimumab.
controls o PFS or gemcitabine-cisplatin alone, sug- Routine endoscopies to rule out other primary sites are
gesting unclear survival benet o nivolumab to stan- not perormed in the absence o symptoms. High-qual-
dard-o-care chemotherapy at this time. Response ity liver protocol imaging is mandated or all patients,
rates, saety proles, and survival data are pending and PET/CT is used to examine ambiguous ndings.
maturity, which will shed urther light on the clinical Surgical resection with nodal dissection, ollowed by
benet and utility o the above combinations. adjuvant capecitabine or gemcitabine and cisplatin is
Durvalumab with or without tremelimumab has oered or patients with early-stage disease. Neoadju-
also been studied in the phase 1 setting (NCT01938612) vant chemotherapy with gemcitabine and cisplatin or
in an Asian population.166 A DCR and median OS o gemcitabine, cisplatin, and nab-paclitaxel is considered
16.7% and 8.1 months, and 32.2% and 10.1 months or high-risk cases such as multiocal and radiologic
in the durvalumab (n = 42) arm compared with the node-positive diseases. Postoperative radiotherapy is
durvalumab and tremelimumab (n = 65) arm, respec- usually reserved or margin-positive ICC.
tively, was reported at 12 weeks. Both the mono- Extrahepatic biliary tract cancers, particularly hilar
therapy and combination therapy arms were noted to cholangiocarcinoma (Klatskin tumor) requires a com-
show encouraging clinical benet warranting urther plex, multispecialty approach that includes endoscopy;
investigation. interventional radiology; and medical, surgical, and
Preliminary data rom a phase 2 study o dur- radiation oncology teams. Complications rom this
valumab and gemcitabine-cisplatin with or without cancer include biliary obstructions and cholangitis with
tremelimumab in patients naïve to prior chemother- sepsis, and thereore, establishment and maintenance
Chapter 29
apy (NCT03046862)167 has also been reported. Patients o biliary drainage is critical. Specialized imaging to
were enrolled in three cohorts as detailed in Table detect a hilar mass, vascular approximation, and nodal
29–6. Initial biomarker analyses noted requent muta- spread is required, and specic CT/MRI protocols have
tions in ataxia telangiectasia–mutated (ATM), BRCA2, been established. A tissue diagnosis or these cancers is
DNA polymerase epsilon, mutS homolog 2 (MSH2), established with brush cytology or biopsy using endo-
and CDKN2A genes with distinct somatic variants in scopic ultrasound. Core biopsy o the hilar stricture
responders compared with nonresponders. TMB had carries a risk o peritoneal dissemination and is there-
not correlated with survival outcomes (PFS or OS); ore discouraged. A minority o patients are candidates
however, interestingly, early reductions in cell-ree or surgery and adjuvant therapy. Given the relatively
circulating tumor (ct) DNA allele requencies on cycle limited benet with adjuvant capecitabine or hilar
3 on day 1 were signicantly associated with ORR cholangiocarcinoma, chemotherapy with gemcitabine
(P < .015). Response rates (73.4% and 73.3%) were and capecitabine, ollowed by chemoradiation with
similar in the three- and our-combination cohorts, and capecitabine as per prior phase 2 data (SWOG 0809)
the triple combination (gemcitabine-cisplatin and dur- are encouraged. Select patients with hilar tumors
valumab) has moved orward to phase 3 testing com- larger than 3 cm and tting the Mayo Clinic criteria are
pared with gemcitabine-cisplatin alone in the rst line oered orthotopic liver transplantation. Gallbladder
(TOPAZ-1; NCT03875235). cancer in the early stages is oten detected incidentally
In summary, the treatment o biliary tract cancer has during cholecystectomy. For these cases and or sur-
evolved rapidly in the last decade. An understanding gically resectable tumors, radical cholecystectomy is
o the diversity o these cancers and their molecular perormed, ollowed by adjuvant chemotherapy. Peri-
underpinnings, and access to novel therapies have led operative chemotherapy is oten considered or a high-
to transormative changes or patients with this cancer. risk disease, such as with nodal disease, T3 tumors,
and regional spread.
All patients with biliary tract cancer, regardless o
MD ANDERSON APPROACH TO stage or histology, are oered molecular proling using
BILIARY TRACT CARCINOMA next-generation sequencing. Furthermore, patients
receiving targeted therapies are also oered serial liq-
Our approach to biliary tract cancer is guided by its uid biopsies. Given the timeline or these analyses,
clinical and molecular diversity and ocuses on mul- targeted therapy is typically oered in the second or
tidisciplinary management. Given the guarded prog- subsequent lines o treatment. Typical rst-line regi-
nosis o these cancers, clinical trials are encouraged mens or biliary tract cancers include gemcitabine-
in all clinical settings. The majority o cases o biliary cisplatin and gemcitabine-cisplatin-nab-paclitaxel, or
tract cancer treated at our center are ICC, a trend that clinical trials such as currently with a rst-line FGFR
is commonly seen in all cancer centers in the United inhibitor versus chemotherapy. Sequencing o thera-
States. The diagnosis o ICC is established by a core- pies based on clinical outcomes, such as systemic che-
needle biopsy and includes an immunohistochemical motherapy ollowed by consolidative IMRT or SBRT,
analysis to exclude other sites o primary invasion. is commonly used in cholangiocarcinoma at MDACC.
Continuous chemotherapy until progression is not usions. Biliary tract cancers without actionable muta-
encouraged because this aects quality o lie. tions are usually treated with FOLFOX as per the
The choice o systemic therapy in the second-line ABC-06 clinical trial. The role o immunotherapy with
setting is guided largely by molecular proling results. checkpoint inhibitors is considered as experimental
ICC, in particular, is enriched with FGFR, IDH1, BRAF, or biliary tract cancers, other than those tumors with
and other actionable targets and has many options MSI-H. However, several clinical trials are currently
available as clinical trials; pemigatinib was recently investigating the role o checkpoint inhibitors com-
FDA approved in this setting or ICC with FGFR2 bined with systemic chemotherapy or radiotherapy.

J Treatment is guided by clinical and molecular J Select patients meeting the Mayo Clinic criteria
diversity and uses a multidisciplinary approach. with hilar tumors smaller than 3 cm are candidates
J In early-stage ICC, surgical resection with nodal or orthotopic liver transplantation.
dissection is ollowed by adjuvant capecitabine J All patients with biliary tract cancer are ofered molec-
or gemcitabine-cisplatin; radiation therapy is ular proling using next-generation sequencing.
given postoperatively or positive margins.
Chapter 29
J The choice o systemic therapy in the second-line

J Neoadjuvant chemotherapy is considered or metastatic setting is guided largely by molecular
disease with high-risk eatures, including pres- proling results and actionable targets. FGFR, IDH1,
ence o a multiocal disease or radiographic node HER2, and BRAF alterations are among the most
positivity. enriched and numerous clinical trial options avail-
able or these patients.
CYP genes in gallbladder cancer predisposition. Tumour Biol.

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Chapter 29
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30 Hepatocellular Carcinoma
Sunyoung S. Lee
Hao Chi Zhang
Hop S. Tran Cao
Sudha Kodali
Joshua D. Kuban
Eugene J. Koay
Rony Avritscher
Ahmed O. Kaseb
KEY CONCEPTS
 Risk actors or liver cirrhosis and hepatocellular carcinoma  Targeted therapy (anti-vascular endothelial growth
(HCC) include chronic hepatitis B and C inections, metabolic actor and tyrosine kinase inhibitors) and immune check-
syndrome, and alcohol abuse. Hepatology management o point inhibitors are two main backbones o systemic
risk actors reduces the risk o cancer recurrence. therapy. These include soraenib, lenvatinib, atezolizumab
 Treatment or HCC is multidisciplinary and involves hepa- with bevacizumab, nivolumab with and without ipi-
tology; interventional radiology; and medical, surgical, limumab, pembrolizumab, cabozantinib, regoraenib, and
and radiation oncology. ramucirumab.
 Surgical resection is considered or patients who have  There are no established guidelines or brolamellar
small-volume disease without portal hypertension. Those HCC (FLHCC) and combined HCC-cholangiocarcinoma
with portal hypertension receive locoregional and/or radi- (cHCC-CC). Systemic therapy such as 5-uorouracil plus
ation therapy, and liver transplantation is considered. intereron-α2b or FLHCC and platinum-based chemo-
therapy or cHCC-CC is combined with surgical resection
 Systemic therapy is recommended or patients with
and locoregional and radiation therapy.
advanced or metastatic HCC, and locoregional and radia-
tion therapy are combined in eligible patients.
Hepatocellular carcinoma (HCC) is a malignancy o 4 million US individuals who are HCV-seropositive

worldwide signicance and has become increasingly and the known latency o HCC development rom the
important in the United States (US). It is the most initial HCV inection, which may take two to three
common primary liver malignancy, the sixth most decades.10 However, given the improved treatment
common cancer, and the third most common cause regimens now available or patients with chronic HCV,
o cancer-related deaths worldwide.1 Eighty percent HCV-related HCC incidence may decrease in the next
o new cases occur in developing countries, but the ew years.11 It is also known that NAFLD-associated
incidence is rising in economically developed regions, cirrhosis is on the rise in the US.12–14 A majority o
including Japan, Western Europe, and the US.2–5 Liver patients diagnosed with HCC present with advanced
cirrhosis is the seventh leading cause o death in the disease that is not amenable to curative procedures.
world, the tenth most common cause o death in the
US, and is acknowledged as a premalignant condition
or developing HCC.6,7 EPIDEMIOLOGY
In the US, hepatitis C virus (HCV), alcohol use, and
nonalcoholic atty liver disease (NAFLD) are the most Hepatocellular carcinoma represents approximately
common causes o cirrhosis.8 The incidence o HCC 85% o all primary liver cancers.15 The distribution o
doubled between the years 1975 to 1995 and con- HCC varies signicantly by geography; it is endemic
tinued to rise through 1998.9,10 This trend was previ- in parts o the world where hepatitis B virus (HBV)
ously expected to continue because o the estimated is also endemic. In Western countries, HCV inection
677
and alcoholic cirrhosis are the principal risk actors or Chronic Hepatitis B Inection
HCC. Because o the rising incidence o HCV inec-
tion in American subpopulations, the incidence has Chronic inection HBV remains common and well rec-
increased.10 Moreover, HCC incidence increases with ognized as a strong risk actor or HCC. An important
age, with the age o peak incidence varying somewhat mechanism in HBV is the integration o HBV DNA
with the population. The median age group or devel- into the cellular DNA o hepatocytes.29,30 Eects on
opment o HCC is between the th and sixth decades transcription actors, JAK/STAT pathways, and DNA
o lie. The disease is also seen in children and young repair, even in the absence o brosis, may be a cul-
adults in areas where HBV is endemic, and most o prit in the pathogenesis.29,31 In vitro studies suggest
these inections occur perinatally. In all populations that the X protein encoded by HBV plays a role in the
worldwide, there is a strong male predominance in pathogenesis o HCC through the mechanism o HBV
HCC incidence. In the US, the male-to-emale ratio binding to and inhibiting p53-mediated transcriptional
is 2.7:1, and HCC incidence rates are higher among activity and downregulating DNA repair ability.32 It is
Blacks than Whites (6.1 vs 2.8 per 100,000 in men). hypothesized that this mechanism is related to poten-
Hispanics, Asians, Pacic Islanders, and Native tial carcinogenesis, augmented by HBV replication in
Americans have a higher HCC requency. Indepen- the case o active chronic HBV.
dent o HBV status, a amily history o HCC in rst- The estimated 5-year cumulative requency o pro-
degree relatives carries a relative risk o 2.4 and overall gression to cirrhosis ranges rom 8% to 20% without
risk (OR) o 2.9. 16 Hepatoblastoma is the most com- treatment or HBV, at higher requencies in HBV e-anti-
Chapter 30
mon type o childhood liver cancer, and Beckwith- gen (HBeAg)-negative patients relative to HBeAg-positive
Wiedemann syndrome is known to be associated with patients.29 The incidence o HCC in patients with chronic
this.17 Familial aggregation and germline mutations HBV without cirrhosis is estimated to be 0.1 to 0.8 per
o the APC (adenomatous polyposis coli) gene have 100 person-years, in contrast to 2.2 to 4.3 per 100 person-
also been reported in hepatoblastoma.18 Hereditary years in the context o cirrhosis.33 Based on the examina-
tyrosinemia, type 1 glycogen storage disease, Alagille tion o ethnicity, geographic origin, and medical history,
syndrome, Fanconi anemia, and ataxia-telangiectasia certain high-risk groups have been identied in the rec-
increase the risk o HCC.19–25 ommendations to implement HCC screening.26,29,33
Hepatitis B virus replication also correlates with
HCC risk.34 Patients with active chronic HBV with
ETIOLOGY AND RISK FACTORS ongoing viremia should also be screened, although
chronic HBV treatment is available and considered sae.
HCC develops commonly, but not exclusively, in a set- However, achieving viral suppression may not reduce
ting o liver cell injury, which leads to infammation, the risk o HCC to nil, and this population continues to
hepatocyte regeneration, liver matrix remodeling, be screened. Inactive carriers who are HBeAg-negative
brosis, and ultimately cirrhosis. The major etiolo- also bear a higher risk or HCC compared with controls
gies o liver cirrhosis are diverse and include chronic who are HBsAg-negative.34,35 Although not tested or
hepatitis B and chronic hepatitis C inections, chronic routinely, genotype C in Asians, genotype F in Alas-
alcohol consumption, certain medications or toxic kans, and mutations in precore or basal core promoter
exposures, and genetic metabolic diseases. Nonalco- regions have been implicated in increased HCC risk.31,34
holic atty liver disease, especially in association with The at-risk population in chronic HBV with or
obesity and diabetes, is emerging as a recognized risk without cirrhosis should undergo routine HCC screen-
actor or HCC, even in patients without cirrhosis. The ing.29,30,33 Screening also applies to patients who have
mechanisms by which these varied etiologies lead to achieved viral suppression (ie, undetectable HBV
HCC are not ully elucidated. The principal risk actors DNA levels, normal serum alanine aminotranserase
that have been associated with cirrhosis and HCC are level) who are HBsAg-positive because ongoing treat-
listed in Table 30–1. As such, the populations deemed ment does not entirely eliminate the risk or HCC.
to bear a signicant risk or HCC generally refect the The REACH-B scoring system allows the clinician to
same population or which routine screening is tar- readily input data including gender, age, serum alanine
geted (Table 30–2). The recommendations or the tar- aminotranserase level, HBeAg status, and HBV DNA
get population are also deemed to be cost-eective.26 levels to generate a 3-, 5-, and 10-year estimates or the
The ability o the clinician to identiy at-risk patients risk o development o HCC.36,37
eligible or HCC screening should be emphasized
because utilization o HCC screening is revealed to be Chronic Hepatitis C Inection
suboptimal, even among patients with a gastroenterol-
ogy subspecialist.27,28 This has signicant implications Hepatocellular carcinoma in the context o chronic
or early detection o HCC and treatment options. HCV is diagnosed more requently in the cirrhotic liver
C 30 Hepatocellular Carcinoma 679
tbl 30–1 Etiologic Factors Associated with an Increased Risk o Cirrhosis and Hepatocellular Carcinoma
Category Specifc Etiology Comment

Inectious (77% o cases Chronic hepatitis B virus Underlying etiology in a signicant majority o HCC cases
o HCC worldwide inection worldwide, primarily in Asia, sub-Saharan Arica; patients
attributed to viral without cirrhosis are at increased risk o HCC
hepatitis)
Chronic hepatitis C virus Principal underlying etiology in Japan, the United States, Western
inection Europe, Mediterranean basin countries; may account or 20%–
25% HCC cases worldwide
Metabolic disorders Hereditary Phlebotomy in patients whose disease has progressed to cirrhosis
deciency hemochromatosis does not alter or improve the HCC risk
Wilson disease
α-1 antitrypsin deciency
Porphyria cutanea tarda
Glycogen storage disease HCC risk is best described in GSD type I via adenoma
(GSD) transormation
Citrullinemia
Chapter 30
Familial intrahepatic
cholestasis
Other Alcohol Signicant cause o cirrhosis; synergistic coactor with HCV
Aatoxin B1 Coactor with HBV that increases risk o developing HCC; relative
risk varies rom 2- to 4-old in nonendemic regions
Androgenic steroids Some association reported, primarily case reports and small
series
Oral contraceptives
Autoimmune hepatitis
Primary biliary cholangitis Elevated HCC risk is pertinent when disease progresses to
(PBC) cirrhosis or in male patients with PBC
Nonalcoholic atty liver Increasing evidence or association with HCC with or without
disease (NAFLD)/ cirrhosis; incidence o NAFLD is rising in the United States
nonalcoholic
steatohepatitis (NASH)
Tobacco Weak association suggested that it is independent o HBV
inection, alcohol
than in the non-cirrhotic liver.38 Unlike HBV, HCV does cohort allows or identication o the undiagnosed
not integrate into the host DNA. The exact mechanism population. As such, eligible patients can be promptly
o carcinogenesis is not well understood. The risk o treated to achieve sustained viral remission (SVR),
developing HCC urther increases with concomitant preerably beore cirrhosis develops, thereby curtailing
alcohol use, which may act in synergy.39 the progression to cirrhosis and, subsequently, the risk
Pertinent risk actors or acquiring HCV include but or developing HCC.
are not limited to intravenous drug use, sexual expo- With intereron (IFN)-based therapies, the annual
sure, chronic hemodialysis, blood transusions beore incidence o HCC could be reduced rom 1% to 8%
year the 1992, perinatal transmission, and acquiring to 0.07% to 1.2%.31,44 The motivation or treatment
tattoos/piercings at unregulated establishments.40,41 is urther driven by the advent and ecacy o direct-
In the US, the birth cohort o patients born between acting antivirals (DAAs) used to treat chronic HCV.33
1945 and 1965 directed prior screening recommen- DAAs have become the standard or chronic HCV
dations.41,42 In 2020, the US Services Preventative treatment since 2014, supplanting IFN-based treat-
Task Force updated the screening recommendation ment, which was raught with limitations including
to include general screening o patients ages 18 to 79 genotype coverage and adverse eects. DAAs have
years or HCV inection.43 Expanding the screening better tolerance and improved adverse eect proles
Table 302 Patients at Highest Risk or HCC with Recommendations or Screening
Threshold Incidence or Ecacy

o Surveillance
Population Group (>0.25 LYG; % per year) Incidence o HCC (% range per year)
Surveillance Beneft
Asian male hepatitis B carriers over age 0.2 0.4–0.6
40 y
Asian emale hepatitis B carriers over 0.2 0.3–0.6
age 50 y
Hepatitis B carrier with amily history 0.2 Incidence higher than without amily
o HCC history
Arican and/or North American Blacks 0.2 HCC occurs at a younger age
with hepatitis B
Hepatitis B carriers with cirrhosis 0.2–1.5 3–8
Hepatitis C cirrhosis 1.5 3–5
Stage 4 PBC 1.5 3–5
Chapter 30
Genetic hemochromatosis and cirrhosis 1.5 Unknown, but probably >1.5

Alpha-1 antitrypsin deciency and 1.5 Unknown, but probably >1.5
cirrhosis
Other cirrhosis 1.5 Unknown
Surveillance Beneft
Hepatitis B carriers younger than 40 y 0.2 <0.2
(males) or 50 y (emales)
Hepatitis C and stage 3 brosis 1.5 <1.5
NAFLD without cirrhosis 1.5 <1.5%
LYG, lie-years gained; PBC, primary biliary cholangitis.
Reproduced with permission rom Marrero JA, Kulik LM, Sirlin CB, et al: Diagnosis, Staging, and Management o Hepatocellular Carcinoma: 2018 Practice Guidance by
the American Association or the Study o Liver Diseases, Hepatology 2018 Aug;68(2):723-750.
to allow or achieving SVR ater 8 to 12 weeks o treat- o patients.47 Another study reported recurrence o
ment. Eective pan-genotypic coverage by glecaprevir/ HCC in 27.6% o the examined cohort.48 Additional
pibrentasvir and soosbuvir/velpatasvir has overcome studies, however, did not support the aoremen-
the challenges o treating some patients with HCV, tioned concern. 49,50 Nonetheless, ater achieving SVR,
such as those with genotype 3. Several DAAs, includ- these patients continue to undergo HCC screening or
ing these two medications, have also been approved surveillance.30,33
or treatment in patients with compensated cirrhosis. Although some data have suggested that HCC
In non-cirrhotic patients, SVR may curtail the risk o can potentially arise in the non-cirrhotic liver, a or-
progression to cirrhosis and even potentially reduce mal recommendation about routine screening in this
the extent o brosis. In cirrhotic patients, SVR reduces population is not established.51,52 Specically, there is
but does not eliminate the risk o HCC.44 risk observed in patients with bridging brosis with-
Once SVR is achieved, the risk o HCC persists. In out rank cirrhosis.52 The American Association or the
a Veterans Aairs study, SVR led to a reduced risk o Study o Liver Diseases (AASLD) recognizes chronic
HCC to an annual incidence o 0.90%, in contrast to HCV with advanced brosis (stage 3) without cirrhosis
a higher annual incidence o 3.45% in those who did as being at an increased risk.33 The decision o whether
not achieve SVR. 45 In comparison, in patients who to screen this population is also predicated on the cli-
achieved SVR ater receiving IFN-based therapies, nician’s ability to reliably ascertain the brosis stage.
the annual incidence was estimated to be 0.33%.45,46 Several noninvasive methods (such as the NAFLD
Direct-acting antiviral treatment was not without con- brosis score, serologic brosis tests, and elastogra-
troversy in the eld o HCC. One study was concerned phy) are available.
that SVR with DAA still led to a 3.16% rate o devel- Some o the principal dierences between hepatitis
oping de novo HCC; or the patients already treated B- and hepatitis C-associated HCC are listed in Table
or HCC, the study reported recurrence in 28.81% 30–3.
Table 303 Comparison Between Hepatitis B Viral Inection and Hepatitis C Inection and Hepatocellular
Carcinoma
Factor HBV HCV

Mean age (y) o HCC presentation 55 (31–76) 66 (38–83)
(range)
Highest incidence 400 million carriers in Asia and Arica 170 million inected worldwide;
accounts or 50% o HCC cases in
Japan, the United States, and Western
Europe
Cirrhosis Cirrhosis presents in 88% o HBV Cirrhosis presents in 93% o HCV
inection inection
Morphology Solitary lesions Multiocal lesions, more severe
inammation
Rate o progression to HCC (y) 10–30 >30
Percentage likely to develop HCC 4% per year 1–7% per year
Chapter 30
Metabolic Factors Nonalcoholic Fatty Liver Disease
Diabetes The widespread prevalence o NAFLD has prompted
concern or its implications in patients whose disease
The association o diabetes with the increased risk o evolves into a state o steatohepatitis and transorms
HCC has been previously described, although with to cirrhosis. These considerations have garnered par-
limitations inherent in the published studies, includ- ticular interest in dening the degree o HCC risk in
ing conounding actors such as viral hepatitis C.31,53 A this population.
study o VA patients comparing diabetic and nondia- Certain genetic actors have been implicated in the
betic patients, the majority comprised o men, demon- pathophysiology o NAFLD/nonalcoholic steatohepa-
strated a doubling o the risk (HR 2.16), independent titis (NASH). Genetic variants o the PNPLA3 (patatin-
o alcoholic history, viral hepatitis, or demographics like phospholipase domain–containing 3) gene are
eatures.53 Despite achieving SVR in HCV, diabetes is hypothesized to play a role in the progression o
still a risk actor or HCC.46 NAFLD.58–60 For instance, the PNPLA3 polymorphism
rs738409[G] (genotype GG), encoding I148M, is linked
Obesity
to increased hepatic at levels and hepatic infamma-
The high prevalence o obesity in the US has real tion.59 The prevalence o PNPLA3 genotype CC (wild-
clinical implications on liver health. Body mass index type) is decreased in cases o NAFLD-related HCC.61
(BMI) alone, however, does not adequately account In patients with NAFLD or alcoholic liver disease,
or the increased risk in developing HCC. One sys- wherein 11.5% o patients with NAFLD had HCC, the
tematic review showed a positive association in 7 o KCNQ1 genotype TT was ound to be signicant in
10 cohort studies, no associations in two studies, and patients with HCC.61
even one study suggesting an inverse relationship.54 NAFLD is increasingly recognized as a common
The association between BMI and HCC may instead etiology o cirrhosis. Some patients diagnosed with
be claried by identication o intermediary actors “cryptogenic” cirrhosis are also elt to have potentially
known as “proximal” associations, including abdomi- undiagnosed NASH as an underlying etiology.62 In
nal at (instead o BMI, which is considered a “distal” these cases, HCC tended to present as a single nodule
association), humoral mechanisms, and steatohepa- and with lower rates o portal vein thrombosis, com-
titis.55 Abdominal visceral at, or instance, correlates pared with the other three underlying conditions.62
with the waist-to-hip ratio. An elevated waist-to-hip Consequently, delineating the potential risks in the
ratio may coner up to about a 3.5-old higher risk or NAFLD population without cirrhosis is important.
development o HCC, implying that abdominal vis- Broadly, the absolute risk in this population is not
ceral at plays a major role.56,57 Because patients with known; small studies indicate an estimated annual
obesity and/or metabolic syndrome are also at risk or incidence less than 1% versus 2.6% in cirrhosis related
NAFLD, careul evaluation or NAFLD should be made to NASH.33,63–65 The AASLD recognizes NAFLD with-
in conjunction. out cirrhosis as bearing increased risk.33
The observation that HCC could arise in non- markers such as serum α-etoprotein (AFP) may be
cirrhotic NAFLD has generated newound vigi- normal despite the presence o HCC, and ultrasonog-
lance.64–66 The prevalence o HCC in patients with raphy may not always be sensitive enough to detect
non-cirrhotic NASH was 38% (odds ratio [OR] o 2.61 small hepatic adenomas, which presents a challenge
vs the non-cirrhotic control).67 From the national Vet- in screening or surveillance.72 Recommendations or
erans Aairs database, or those diagnosed with HCC screening in patients with GSDs is initially abdominal
in the absence o cirrhosis, both NAFLD and metabolic ultrasonography every 12 to 24 months in the pediat-
syndrome conerred increased risk with odds ratios o ric population, with transition to interval surveillance
5.4 and 5.0, respectively, when compared with HCV- with contrast-enhanced magnetic resonance imaging
related HCC.68 Male gender, alcohol consumption, and (MRI) or computed tomography (CT) o the abdomen
the FIB-4 index (brosis score) are recognized risk ac- in older patients (starting at age 18 years).72,76,77
tors.69 One study suggested cumulative HCC mortality
o potentially 0% to 3% over 20 years in patients with-
out cirrhosis, and that NASH-related cirrhosis bore a
Alcoholic Liver Disease
cumulative risk o 2.4% over 7 years to 12.8% over 3 Excessive alcohol consumption can lead to cirrhosis
years; yet, the risk remained lower than that o cirrho- and thus is a risk actor or development o HCC. The
sis related to hepatitis C.70 autopsies o patients with alcoholic cirrhosis have
Even i the risk is perceived to be relatively lower reported up to 10% undiagnosed HCC. In the US,
than some other risk actors or HCC, the population- alcoholic cirrhosis is associated with about 15% o
Chapter 30
attributable raction may argue or NAFLD being a HCC and cholangiocarcinoma.78,79 One meta-analysis
more salient risk actor, especially when viewed in suggested that there was a dose-dependent eect o
conjunction with metabolic syndrome.33,55 The obser- alcohol on the risk o HCC, where drinkers o three or
vation o an apparently increased HCC risk in patients more alcoholic beverages per day bore a 16% increased
with non-cirrhotic NAFLD emphasizes the importance risk compared with nondrinkers.80 A recent review
o estimating brosis, identication o other concur- compares the epidemiology and reported incidences
rent HCC risk actors, and ongoing ollow-up to con- o HCC in alcoholic and nonalcoholic liver disease.81
tinuously reassess risk and candidacy or undergoing As in studies o NAFLD, genetic actors have also
an HCC screening program. These patients would been studied in alcoholic liver disease. Like NAFLD-
benet rom engaging in related conversations with a associated HCC, the KCNQ1 genotype TT was also
hepatologist. Liver brosis estimation tools allow or observed to be signicant.61
a noninvasive way o risk-stratiying these patients in As previously introduced, alcohol use appears to
those clinical discussions.71 Weight loss eorts remain have an adverse synergistic eect in patients with
the rst-line recommendation or patients to poten- concurrent chronic HCV, such that alcohol increases
tially reduce steatosis, improve steatohepatitis, and in circulating HCV viral titer and HCC risk.39 Similar
some cases reverse brosis, to secondarily reduce the eects could be said in the context o metabolic syn-
risk o developing cirrhosis and HCC. drome. Other types o cirrhosis and parenchymal liver
diseases—such as primary biliary cholangitis (PBC),
hemochromatosis, Wilson disease, α-1 antitrypsin
Glycogen Storage Diseases deciency, and GSD—signicantly increase HCC risk
Glycogen storage diseases (GSDs) represent disorders when alcohol is a coactor.
o inborn errors related to glucose or glycogen metabo-
lism. Cases o HCC have been described in GSD type I,
a rare autosomal recessive genetic disease. The associ-
Cirrhosis
ation between GSD subtype Ia (related to deciency in The status o cirrhosis alone, regardless o etiology, is
the glucose-6-phosphatase enzyme) and HCC is most recognized as an inherent predisposition or increased
commonly recognized. Hepatic malignancy in the con- risk o developing HCC. However, as previously sug-
text o GSD type I is hypothesized to arise rom an gested, dierences in the magnitude o that risk depend
adenoma-to-HCC transormation sequence.72–74 The on the etiology. For instance, chronic HBV or chronic
prevalence o hepatic adenomas is estimated to be up HCV appears to pose a higher risk than NAFLD/NASH.
to 75% o adults with GSD type I and urther increases In general, societies recommend routine screening or
with age.72,75,76 The pathogenesis o these hepatic ade- HCC every 6 months i the patient has a diagnosis o
nomas are thought to be related to inadequate meta- cirrhosis.30,33,82
bolic control; improved metabolic control could lead to The clinician should be attentive to specic condi-
some degree o regression o the adenomas.72,75 With tions aecting the liver that may progress to severe
hepatic adenomas, the risk is estimated to be about brosis and cirrhosis, including PBC, hereditary hemo-
10% or malignant transormation.75 However, tumor chromatosis, Wilson disease, and α-1 antitrypsin
deciency. In Wilson disease, copper accumulation in upper quadrant abdominal pain. Anorexia or early
the liver is thought to induce oxidative stress, which satiety with weight loss is the second most common
is likely complicit in malignant transormation, as sug- symptom. HCC may present with various paraneo-
gested in animal studies.29,83 In patients with PBC, the plastic symptoms through the secretion o numerous
increased risk o HCC is elt to be pertinent when cir- hormones. Late-stage symptoms include jaundice,
rhosis develops, at which point routine HCC screen- tumor ever, bone pain caused by metastatic lesions,
ing is recommended.33 The AASLD also recommends and complications rom portal venous hypertension,
HCC screening in men with PBC even outside the con- such as esophageal varices, hypoalbuminemia, ascites,
text o cirrhosis.84 thrombocytopenia, and coagulopathy.
On physical examination, hepatomegaly is present
in more than 90% o patients. A hepatic arterial bruit
Afatoxin B1 or a riction rub, ascites, splenomegaly, and jaundice
Food contaminated with afatoxin, a mycotoxin ound are ound in up to 50% o patients. Muscle wasting,
in grains, can induce HCC in animals. Peanuts, corn, ever, and dilated abdominal veins are also common.
and soybeans stored in damp environments increase The Budd-Chiari syndrome is caused by malignant
the risk o exposure to afatoxin. Exposure to Aspergil- invasion and occlusion o the hepatic veins. AFP is
lus favus and Aspergillus parasiticus are important risk oten elevated to above 400 ng/mL.
actors, especially in Asia and Arica.29 Moreover, a
strong synergistic association exists between afatoxin
Chapter 30
exposure and HBV carrier status.29 Relative risks o PATHOLOGY
HCC are three-old or afatoxin, nine-old or chronic
HBV inection, and 59-old or concurrent afatoxin and Based on the growth pattern, HCC is classied into
chronic HBV inection. The underlying mechanism is our major gross anatomic types: spreading, multio-
polymorphism variants o glutathione S-transerase cal, encapsulated, and combined patterns.89 Normal
M1 and epoxide hydrolase genes and G-to-T point liver parenchyma is shown in Fig. 30–1. The spread-
mutation o the p53 gene.85–87 ing type o HCC grows in nodular, pseudolobular, or
invasive patterns with poorly dened margins, occurs
in the setting o hepatic cirrhosis, and accounts or
Other Environmental Factors nearly 50% o cases in the US. The multiocal type
The use o oral contraceptive pills signicantly increases has numerous tumors o similar size that make it di-
the incidence o benign hepatic adenomas. There is cult to determine whether the lesions are intrahepatic
some evidence that they also increase HCC risk. Mul- metastases or second primary tumors (Fig. 30–2A, B).
tiple studies o tobacco smoking and HCC risk have The encapsulated type o tumor grows by expanding,
yielded mixed conclusions. Occupational exposure to compressing, and distorting the surrounding liver tis-
arsenic or vinyl chloride signicantly increases the risk sue. Satellite or metastatic lesions are seen in late-stage
o liver angiosarcoma. Exposure to the radiograph con- disease. This type is most common in Asia and Arica
trast medium thorium dioxide rom the years 1930 to but seen in only 13% o cases in the US. The combined
1955 is associated with a very high risk o hemangio- patterns o the three are seen in up to 25% o cases.
sarcoma, cholangiocarcinoma, and HCC.88 Figure 30–3 shows an HCC histopathology specimen.
CLINICAL PRESENTATION
Most cases o HCC are identied incidentally or
through screening programs o high-risk individuals. It
is common or patients to be asymptomatic until their
disease is very ar advanced. The only potentially cura-
tive modalities or HCC include liver resection (par-
tial hepatectomy) and transplantation. Unortunately,
the actual number o patients who qualiy or these
modalities is small (~10%–30%) because most patients
present with locally advanced and metastatic disease
or have signicant liver dysunction that precludes
curative options. Many patients present with symp-
toms o advanced liver dysunction rom both cirrhosis
and HCC. The most common initial symptom is right FIGURE 30–1 Photomicrograph o normal parenchyma.
A B
Liver cancer
FIGURE 30–2 A. Gross pathologic specimens o multiocal HCC. B. Gross appearance o HCC. (Reproduced with permission
rom Cooke RA, Stewart B: Colour Atlas o Anatomical Pathology, 3rd ed. Edinburgh, Churchill Livingstone; 2004. Photo con-
tributor: Dr RA Cooke, Brisbane, Australia.).
Chapter 30
Variants o Hepatocellular Carcinoma

Hepatocellular carcinoma variants with dierential
molecular and prognostic signicance include com-
bined HCC and cholangiocarcinoma (cHCC-CC)
and brolamellar HCC (FLHCC). cHCC-CC is a rare
combination o cholangiocarcinoma and HCC and
staged as intrahepatic cholangiocarcinoma, not HCC.
This was believed to behave in a ashion similar to
cholangiocarcinoma, but growing evidence suggests
that cHCC-CC has intermediate clinical eatures and
prognosis between HCC and CC.91,92 A comprehen-
sive molecular characterization o cHCC-CC demon-
strates three main subclasses93: (1) a subtype sharing
the molecular characteristics o both HCC and intra-
FIGURE 30–3 Photomicrograph with standard hematoxylin
and eosin stain o hepatocellular carcinoma cells in hepatic
hepatic cholangiocarcinoma arising rom a common
parenchyma. clonal origin; (2) cholangiolocellular carcinoma rep-
resenting a distinct biliary-derived entity, with sig-
nicant upregulation o transorming growth actor-β
signaling and enrichment o infammation-related and
Approximately 60% to 70% and 80% to 90% o immune response signatures; and (3) stem cell–like
HCC in Whites and Asians, respectively, show ele- eatures with enrichment o progenitor-like signa-
vated AFP, which is the most useul marker or HCC. tures, leading to more aggressive tumor behavior and
Originally, AFP is produced by the etal liver and yolk poor clinical outcome.
sac but alls to below 10 ng/mL in adult serum. A tran- FLHCC is predominantly seen in the right hepatic
sient elevation o AFP to 20 to 400 ng/mL may occur lobe, accounts or 2% to 4% o HCC and occurs
when there is hepatocyte regeneration, as in cirrhosis, equally in men and women. It typically occurs in ado-
active hepatitis, or partial hepatectomy. The HCC pos- lescents and young adults; the etiology is unknown.
itive predictive value o an AFP level o 400 ng/mL is Histologically, it is characterized by brosis arranged
over 95%, and normal AFP levels may exist in patients in lamellar ashion around HCC cells, consisting o
with low tumor burden. The lectin-reactive isoenzyme large polygonal tumor cells with eosinophilic granular
o AFP (AFP-L3) has shown increased sensitivity. As cytoplasm, large vesicular nuclei, and prominent nucle-
o this writing, serum AFP level and ultrasonography oli. Immunohistochemistry proles are similar to that o
are the “gold standard” or HCC screening in high-risk HCC and shows positive staining or hepatocyte para-
populations.90 n 1 (HepPar1), glypican-3 (GPC3), arginase-1, polyclonal
carcinoembryonic antigen (pCEA), and CD10 positiv- serum or complete blood cell count, electrolytes, liver
ity. CD68 and epithelial membrane antigen are specic unction tests, albumin level, prothrombin time, hepa-
or FLHCC.94–96 It is associated with DNAJB1-PRKACA titis B and C serologies, and tumor markers (AFP and
usion, mainly seen in younger patients, and BAP1 muta- CA 19-9). The medical history should include a thor-
tion is commonly seen in older patient groups.97,98 ough review o potential HCC risk actors: transu-
Rare primary liver neoplasms include hepatoblas- sions, tattoos, intravenous drug abuse, high-risk sexual
toma, sarcoma, angiosarcoma, rhabdomyosarcoma, practices, amilial syndromes, oral contraceptive pills
and epithelioid hemangioendothelioma. Patients or hormone replacement use, androgenic steroid use,
may present with atigue, anorexia, weight loss, and chemical exposures.
and abdominal pain. Hemorrhagic ascites is com- Several radiographic imaging modalities are useul
mon, and AFP level is usually normal. Angiography in evaluating a patient with HCC. Ultrasonography
and contrast-enhanced CT o the liver are the best oten serves as the initial screening modality, ollowed
diagnostic tools. Open or percutaneous liver biopsy by triple-phase CT scan or MRI. Randomized studies
is needed or diagnosis. Surgical resection is still the have shown that hepatic ultrasonography has 78%
principal means o therapy i tumors are diagnosed sensitivity and 93% specicity to detect HCC in high-
at relatively early stages. They are oten resistant to risk populations, especially or patients with normal
chemotherapy and radiotherapy (RT), and the overall AFP levels.104 Color-fow Doppler can assist preopera-
prognosis is poor. tive assessment and planning.
Abdominal CT has relatively higher sensitivity
Chapter 30
and specicity than ultrasonography. With special
Benign Liver Tumors
arterial- and venous-phase scans, CT also makes it
Hemangiomas are the most common benign tumors possible to evaluate the blood supply o the normal
o the liver. Their size ranges rom a ew millimeters liver parenchyma (portal vein) and neoplastic lesions
to 25 cm. They appear as calcied solitary lesions in (hepatic artery). MRI is useul in distinguishing
up to 7% o the general population. Magnetic reso- benign lesions rom malignant tumors by the combi-
nance imaging is better than CT at distinguishing nation o T2-weighted phase-contrast and spin-echo
HCC rom hemangioma on heavily T2-weighted sequences. MRI can also demonstrate atty degenera-
images. Surgical resection is used or symptomatic tion o tumor and vascular invasion. 105
lesions or when malignancy cannot be excluded. Hepatic radionuclide imaging has low spatial reso-
Hepatic artery ligation is an alternative or large, cav- lution and is only about 70% sensitive in demonstrat-
ernous hemangiomas. 99 Hepatic adenoma is another ing neoplasms. Using the glucose metabolic dierence
common benign solitary tumor seen in women who between neoplastic and normal cells, positron emis-
have used estrogen-containing medications such as sion tomography dierentiates benign lesions rom
oral contraceptive pills or more than 10 years. It malignant tumors, detects extrahepatic metastasis, and
is composed o sinusoids, central veins, and arter- evaluates response to therapy.
ies without well-dened portal tracts or bile ducts. In summary, ultrasonography is the most cost-
Hepatic angiography is the most valuable diagnostic eective HCC screening test in high-risk populations.
tool. Small adenomas usually regress when contra- Abdominal CT with liver protocol (with and with-
ceptive pills are discontinued. Symptomatic lesions out contrast) is the most helpul in accurately staging
are treated with resection.100,101 Focal nodular hyper- patients beore surgery. No single diagnostic modality
plasia (FNH) occurs predominantly in young women. has greater than 50% to 60% sensitivity in detecting
Liver unction studies and the serum AFP level are lesions less than 1 cm in size. The combination o AFP
normal. A technetium sulur colloid radioisotope level, ultrasonography, and CT provides the best hope
scan o the liver shows increased radioisotope o early diagnosis.
uptake in FNH compared with hepatic adenomas or A variety o staging and prognostic systems has
carcinomas. The prognosis is excellent. Female sex been developed to evaluate patients with HCC. Four
hormones such as oral contraceptive pills are not staging systems (Okuda; CLIP, Cancer o the Liver
associated with FNH.102,103 Italian Program; CUPI, Chinese University Prognostic
Index; BCLC, Barcelona Clinic Liver Cancer Stage; and
AJCC, American Joint Committee on Cancer TNM)
DIAGNOSTIC EVALUATION, have evolved since the 1980s. Currently, we use the
STAGING, AND PROGNOSIS AJCC-TNM and BCLC at MDACC (Table 30–4).106
The Child-Pugh Classication System provides an
In addition to perorming a complete medical history estimate o a patient’s unctional liver reserve and is
and physical examination, the diagnostic workup or used principally to assist in evaluating a patient’s suit-
a patient suspected o having HCC should include ability or hepatic resection.
Table 304 TNM Staging System or Hepatocellular Carcinoma
Stage Group TNM Scheme

Stage IA T1aN0M0 Single tumor ≤2 cm
Stage IB T1bN0M0 Single tumor >2 cm without vascular invasion
Stage II T2N0M0 Single tumor >2 cm with vascular invasion, or multiple tumors, none >5 cm
Stage IIIA T3N0M0 Multiple tumors, at least one o which is >5 cm
Stage IIIB T4N0M0 Single tumor or multiple tumors o any size involving a major branch o the portal
vein or
hepatic vein or tumor(s) with direct invasion o adjacent organs other than the
gallbladder or
with peroration o visceral peritoneum
Stage IVA T1–4NN1M0 Regional lymph node metastasis
Stage IVB T1–T4N0–N1M1 Distant metastasis
Fibrosis score 0–4, none to moderate; 5–6, severe brosis/cirrhosis
TNM, tumor, node, metastasis; UICC, Union or International Cancer Control.
Data rom Edge SB, Byrd DR, Byrd DR, et al: AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017
Chapter 30
TREATMENT diameter, and thrombocytopenia. Additional investiga-

tional tools may include upper endoscopy to rule out
HCC is treated in the multidisciplinary ashion. There esophageal varices and measurement o portal venous
are ve options: surgical resection, liver transplant, pressure. This heightened ocus on portal hyperten-
locoregional therapy, radiation, and systemic therapy. sion is based on the act that this condition is associ-
They are summarized in Table 30–5. ated with increased risk o both long- and short-term
mortality and postoperative decompensation and liver
ailure.109 As such, patients with Child-Pugh class A cir-
Surgical Resection rhosis with portal hypertension are oten treated in the
Ater liver transplantation, surgical resection oers the same ashion as those with class B disease.
next best chance at long-term survival, with 5-year sur- In addition to the condition o the underlying liver
vival exceeding 50% in well-selected patients.107 How- disease, tumor characteristics must also be considered.
ever, recurrence is common, with more than 70% o Under the BCLC system, surgical resection is only rec-
patients experiencing tumor recurrence at 5 years.26 In ommended or single tumors without evidence o vas-
considering surgery or patients with HCC, several ac- cular invasion in the setting o normal liver unction.110
tors must be balanced, including patient perormance Additional actors associated with greater risk o dis-
status, the condition o the underlying liver parenchyma, ease recurrence and worse outcomes include tumor size
tumor characteristics, and the uture liver remnant (FLR). larger than 5 cm and elevated AFP levels.108 Thus, in our
When properly selected, surgery or HCC is sae, with group’s experience, no rm limits on either tumor size
modern series demonstrating perioperative mortality or AFP exist to contraindicate resection, because survival
below 5% compared with rates o 20% in the 1980s.108 or these patients is improved compared with alternative
Patients with poor perormance status, especially in approaches. Instead, these high-risk actors are taken
the setting o severe uncontrolled comorbidities, and into account during treatment planning, which may
those with advanced, uncompensated cirrhosis (Child- then consider preoperative adjunctive treatments or dis-
Pugh class C) are not suitable candidates or hepatec- ease control and assessment o tumor biology. Likewise,
tomy and are best served with nonsurgical options. multiocality and limited vascular invasion, although
Instead, surgery is reserved or patients with preserved strongly associated with risk o disease recurrence, do
liver unction. As a general rule, patients with Child- not represent strict contraindications to hepatectomy,
Pugh class A cirrhosis may be candidates or major hep- which must be considered with extreme care and should
atectomy, whereas those with class B cirrhosis should only be oered selectively in this patient population.
only be considered or more limited resections. Yet, A nal, but critical, element to consider when plan-
because the Child-Pugh score does not ully account or ning any liver resection is liver volumetry. In particular,
portal hypertension, it is important to careully review the standardized FLR is predictive o the risk o postop-
the patient’s chart or evidence thereo, including the erative liver ailure. In the case o HCC, because o the
presence o varices, splenomegaly, ascites, recana- presence o cirrhosis o the background liver, a standard-
lization o the umbilical vein, enlarged portal vein ized FLR o at least 40% is required or sae resection.111
Table 305 Treatment Options or Management o Hepatocellular Carcinoma
Treatment Option Comments

Liver transplantation Historically low survival rates (20%–36%)
Recent improvement (75%–80% 5-year survival), likely related to adoption o Milan criteria
at US transplant centers
Currently HCC represents 25% or more o liver transplants perormed annually in the
United States.
Surgical resection Historic 5-year survival rates 30%-40%
Recent series indicated 5-year progression-ree survival as high as 48%. A majority o
patients develop recurrence or second primary tumors.
Resection in cirrhotic patients carries high morbidity and mortality and is reserved or
those with compensated disease: major hepatectomy is an option or Child-Pugh class
A without portal hypertension; only minor hepatectomy or Child-Pugh class B or Child-
Pugh class A with portal hypertension.
Transarterial Modest survival benet demonstrated or repeated TACE (82% 1-year survival) vs
chemoembolization (TACE) supportive care (63%) in patients with preserved liver unction, PS 0, small tumor burden
Improvement in 1-year survival rom 32% in control (supportive care) to 57% or TACE
Chapter 30
shown in randomized study o 279 primarily HBV patients with tumors <7 cm
Locoregional therapy and Improvement in time-to-progression (26 months) with Y-90 compared with conventional
radiation therapy TACE (6.8 months). Phase 3 clinical trials have shown mixed data on survival benet rom
Y-90 combined with soraenib. Ongoing trials will provide more inormation about a role
o Y-90.
Percutaneous treatments RFA similar recurrence rates to resection or small tumors. Higher recurrence rate than
(RFA, MWA, ethanol injection) resection in tumors > 3cm. Ethanol injection has high rate o recurrence.
External beam radiation therapy It can be delivered with stereotactic radiation therapy (3–5 ractions) to achieve 80%–90%
local control at 1 year or with hyporactionated radiation therapy (10–15 ractions) to
achieve 95% local control at 2 years. Ongoing phase 3 trials (RTOG1112 and NRG GI003)
will help dene a role o radiation therapy.
Molecular targeted therapy Soraenib, lenvatinib, cabozantinib, regoraenib, bevacizumab (combined with
atezolizumab), and ramucirumab (or patients with AFP ≥ 400)
Immune checkpoint inhibitors Nivolumab, nivolumab with ipilimumab, pembrolizumab, and atezolizumab (combined
with bevacizumab)
MWA, microwave ablation; RFA, radiorequency ablation; TACE, transarterial chemoembolization; Y-90, Yttrium-90.
Portal vein embolization (PVE) can be used to induce increasing.114,115 A large retrospective study using the
hypertrophy o the FLR i it alls below this threshold and United Network o Organ Sharing showed that among
improve postoperative outcomes.112 The procedure has 109,018 registrants between January 2004 and Decem-
been shown to be sae and well tolerated, and response ber 2015, 18.5% were registered or LT because o
to PVE, especially in cirrhosis, is refective o the regenera- HCC. In 2015, HCC was the leading diagnosis among
tive potential and physiologic reserve o the liver. Indeed, registrants (23.9% o registrations) and recipients
degree o hypertrophy below 5% ater PVE is associated (27.2% o recipients).114 LT is the treatment o choice
with increased mortality and poor outcomes.113 In the or patients with advanced cirrhosis and clinically sig-
event o inadequate liver growth, although attempts at nicant portal hypertension and decompensated liver
urther augmenting the FLR may be considered with the disease where surgical resection is not possible, i the
addition o hepatic vein embolization and/or Yttrium-90 tumors are within Milan criteria (one tumor up to 5
(Y-90) radioembolization, these patients may be better cm, or two to three tumors with the largest being <3
served with nonoperative treatment. cm).116,117 Beore universal acceptance o the Milan cri-
teria or listing, the lack o good selection criteria led to
poor outcomes, high recurrence rates (32%–54%), and
Liver Transplantation low survival at 5 years.118 Patients with small, unre-
With the increase in number o cases o HCC, the num- sectable HCC within the Milan criteria have excel-
ber o patients listed or liver transplantation (LT) is also lent long-term survival, and hence LT is an eective
and ecient therapy.33,116 Patients who are listed with In the era o DAAs, two important actors that need
tumors within Milan Criteria (T2HCC) have exception to be considered in deciding timing o treatment or
points, and patients with larger tumors (T3HCC) can HCV include anticipated waitlist time and whether the
be successully downstaged and are eligible or excep- patient has compensated or decompensated cirrhosis.
tion (see https://optn.transplant.hrsa.gov/media/1200/ Initiation o DAA may be withheld until ater LT i LT
optn_policies.pd). is imminent (ie, <3–6 months), whereas treatment pre-
In the last two decades, multiple studies have shown LT may be considered or patients who may be on the
good survival with larger tumors, based on the Univer- waitlist longer than 6 months. Patients with decom-
sity o Caliornia–San Francisco criteria (a solid tumor pensated cirrhosis should be treated and monitored at
<6.5 cm in size or up to three tumors with <4.5 cm a transplant center. Recommendations guiding HCV
as the largest diameter and a total tumor burden o treatment decisions in dierent scenarios are outlined
8 cm) with similar survival results.119,120 Tumor markers in a review by Terrault et al.137
including AFP, AFP-L3, and des-gamma-carboxy pro- In summary, LT can be considered as the rst-line
thrombin have shown a predictive value along with an treatment option or unresectable HCC with accept-
AFP cuto value o 300 ng/mL or delisting patients to able perioperative mortality and one-year mortality
improve outcomes and reduce risk o recurrence post- o 3% and less than 10%, respectively.33,117 Locore-
LT.121–124 A recent large series o LT or patients beyond gional therapies can be used or treating tumors within
University o Caliornia–San Francisco criteria showed the Milan criteria and or downstaging larger tumors
overall survival (OS) and recurrence-ree survival or listing. Aggressive post-LT surveillance scans and
Chapter 30
(RFS) to be comparable with that o patients trans- immunosuppression with mTOR inhibitors is recom-
planted within the Milan criteria.125 A waitlist time mended or patients who are at a higher risk o recur-
o more than 9 months with aggressive locoregional rence based on explant pathology.
therapies while waiting or transplant was used as a
bridge or these patients.125 Recurrence rates o 11%
to 18% have been reported post-LT in patients with
Locoregional Therapy
HCC, and recurrence rates are higher in patients with Hepatocellular carcinoma derives its blood sup-
bigger tumors that were downstaged.125–128 Based on ply almost exclusively rom the hepatic artery. This
explant liver pathology, the risk o recurrence is higher important anatomic eature oers unique advantages
with vascular invasion, poorly dierentiated tumors, or catheter-based therapies, because arterial emboli-
history o hepatectomy, AFP at the time o transplant, zation interrupts blood fow to the tumor while pre-
and viable tumors.125,127,129 A multicenter risk stratica- serving the portal vein and normal liver parenchyma.
tion scoring system (RETREAT) has been validated and Transarterial therapies or HCC include transarterial
takes into account AFP at the time o transplant, micro- chemoembolization (TACE), bland hepatic artery
vascular invasion, and largest viable tumor size with a embolization (HAE) and selective internal radiation
score o 0–5, where a score o 0 had 3% and a score therapy (SIRT) using Y-90.
o 5 had a more than 75% risk o recurrence. This The combination o tissue ischemia with highly
has been used to determine surveillance protocols or concentrated chemotherapy delivered into the
patients post-LT,129 like requent CT scans o the chest hepatic artery enhances tumor necrosis. TACE was
and abdomen every 6 months or the rst 3 years post- rst described by Yamada et al and incorporates these
LT.33 Given the highest rates o recurrence in the rst 2 concepts.138 It has since become one o the most com-
to 3 years o transplant, avoiding calcineurin inhibitors monly used procedures in interventional radiology
that are known to be tumorigenic and instead select- practice. Landmark, prospective, randomized clini-
ing mammalian target o rapamycin (mTOR) inhibi- cal trials published in 2002 validated the use o che-
tors having antiprolierative properties against HCC moembolization or unresectable advanced HCC. In
is recommended.130–132 Sirolimus is a mTOR inhibitor, the multicenter study including 112 patients, when
has an anti-angiogenic activity that decreases the pro- compared with bland embolization or best supportive
duction o vascular endothelial growth actor (VEGF), therapy, patients who underwent TACE with a com-
and inhibits a response o vascular endothelial cells to bination o doxorubicin and iodized oil ollowed by
stimulation by VEGF.133,134 Sirolimus has been shown gelatin sponge demonstrated a clear survival advan-
to reduce the risk o HCC recurrence ater LT: in a large tage, leading to premature stoppage o the trial. 139
prospective, randomized, open-labeled, international Survival in the chemoembolization group at 1 and 2
trial, there was an improvement in RFS in the rst 3 years was 82% and 63%, respectively. Survival in the
to 5 years.135 In the case o recurrence post-LT, surgical bland embolization group was 75% and 50%, respec-
resection, ablation, liver-directed therapy, stereotactic tively; in the best supportive care group, survival was
radiation, or therapy tailored to the site o recurrence 63% and 27%, respectively, and reached statistical
can be considered.128,136 signicance.
A single-center study compared 80 patients with at el reviewed 60 patients treated with radiorequency
unresectable HCC randomly assigned to undergo ablation (RFA), TACE, Y-90, and stereotactic body radi-
TACE with cisplatin and iodized oil ollowed by gela- ation therapy (SBRT), showing pathologic CR rates o
tin sponge or best supportive care.140 Survival in the 28.5% in SBRT, 41% in TACE, 60% in RFA, and 75%
chemoembolization group at 1 and 2 years was 57% in Y-90.154 A recent study published long-term results
and 31%, respectively. Survival or the patients ran- o 207 patients with HCC who had eective bridging
domly assigned to the supportive care group was 32% or downstaging therapy with Y-90 beore liver trans-
and 11%, respectively, also reaching statistical signi- plant.155 Notably, most studies on Y-90 have not mea-
cance. The dierence in survival rates between the sured the dose delivered to the tumor, but only the
Llovet and Lo studies can be attributed to the inclusion administered dose. The dose delivered to the tumor
o a larger proportion o patients with more advanced has been shown to predict treatment response, and
stages o underlying chronic liver disease in the latter urther advances in Y-90 dosimetry have the potential
study. Besides iodized oil used in those seminal studies, to urther increase the ecacy and saety prole o
TACE using drug-eluting beads that enable controlled Y-90.
and sustained release o chemotherapeutic agents into Percutaneous therapy or patients with HCC
the surrounding tumor was made available.141 This includes heat-based thermal ablation (microwave
device enables delivery o a higher concentration o ablation [MWA], radiorequency ablation [RFA],
drugs with low systemic toxicity.142–144 cryoablation, ethanol injection, and irreversible
Bland HAE is similar to TACE in its embolic eect electroporation [IRE]). Heat-based thermal ablation
Chapter 30
but is done without mixed or suspended chemothera- with RFA and MWA is the contemporary, preerred
peutic. A small, randomized clinical trial comparing approach, owing to improved ecacy and saety.
embolization with microspheres alone versus drug- RFA and MWA both cause tissue necrosis by the
eluting beads loaded with doxorubicin 150 mg in 101 controlled deposition o thermal energy and are tra-
patients with HCC did not show signicant dier- ditionally used or nonresectable disease or lesions
ences in progression-ree survival (PFS) or OS between smaller than 5 cm, or three lesions smaller than 3 cm.
the groups.145 These techniques are highly eective in the treat-
Selective interval radiation therapy with Y-90 has ment o small and early HCC, with outcomes simi-
been in clinical use since 1999 when Y-90–impreg- lar to surgical resection.156 Recurrences ater RFA are
nated glass microspheres (Therasphere, BTG) were usually attributable to a microsatellite disease and
given a humanitarian device exception rom the FDA the limitation o ablation size that can be obtained
owing to studies showing saety and ecacy o glass with RFA. MWA is an alternative hyperthermic abla-
microspheres in patients with HCC.146 Y-90 had rst tive technique that has recently become the avored
been used in patients with portal vein thrombosis ablative modality or HCC. The main reason or
because o the nonembolic nature o glass micro- this is that MWA does not rely on heat conduction
spheres compared with TACE and HAE. A long-term through the tissue and similarly is not limited by
outcomes study o 291 patients with HCC who were the “heat sink” eect that surrounding vessels may
treated with Y-90 showed the objective response rate impart,157 allowing or the creation o larger ablation
o 57%, time-to-progression (TTP) o 7.9 months, zones. Furthermore, combination therapy consisting
and median OS o 17.2 months (Child-Pugh class A) o hyperthermic ablation with arterial HAE/TACE
and 7.7 months (Child-Pugh class B).147 Y-90 has also can improve cell death because an occlusion o blood
been used in patients with more advanced disease fow leads to larger ablation zones. 158,159 Both RFA
who were not eligible or TACE or other local thera- and MWA are limited by lesion proximity to adjacent
pies. Hilgard et al demonstrated saety and ecacy o critical structures, such as lung, gallbladder, colon,
Y-90 in patients with advanced HCC, with TTP o 10 and central bile ducts. However, with the exception
months and median OS o 16.4 months without lung o lesions adjacent to a central bile duct, utilization o
or visceral toxicity.148 Multiple comparison trials have advanced organ displacement techniques allows most
been perormed between Y-90 and TACE149,150 and lesions to be treated with MWA or RFA.
soraenib.151,152 Cohort OS with Y-90 therapy has not At MDACC, or nonsurgical patients, ablation is the
been signicantly dierent rom TACE or soraenib in preerred strategy or lesions less than 3 cm. TACE is
these trials, but has oered the advantages o improved routinely used or patients with HCC with more than
response rates, lower rates o adverse events, and three lesions measuring up to 3 cm each, or a single
improved quality-o-lie measurements. In addition, lesion greater than 5 cm. In patients with portal vein
Y-90 has shown survival benets in some subgroups thrombosis, inltrative diseases, or more than our
(age <65 years, nonalcoholic cirrhosis, and non- lesions, Y-90 SIRT is preerred. SIRT is also used to
cirrhotic liver disease).153 Y-90 has been shown to be an treat patients with single lesions up to 7 cm who do
eective tool to downstage to transplant. Mohamed not have signicant extrahepatic arterial supply.
Radiation Therapy results.168 In this study, the median maximum dimen-

sion or patients with HCC was 5.0 cm, and 27.3% o
Technological advances in RT delivery have enabled patients had multiple tumors; 29.5% o patients had
the sae escalation o radiation doses to ocal parts o portal vein tumor thrombus, and the majority o the
the liver. Specically, these technologies include image patients were treatment naïve (30/44). For the HCC
guidance, respiratory motion management, and highly group (n = 44), the 2-year local control rate was 94.8%,
conormal radiation delivery techniques. Retrospec- and the 2-year OS rate was 63.2%.
tive and prospective data demonstrate that the com- Our own MDACC experience refects these obser-
bination o these technologies results in high rates o vations that higher doses are associated with bet-
local control and promising rates o survival in several ter overall, in-eld progression-ree and biochemical
dierent settings o HCC management. Collectively, PFS.169,170 Across all partial liver radiation paradigms,
these promising clinical data rom multiple studies the most common site o rst recurrence is intrahe-
demonstrate that HCCs are radiosensitive. Sustained patic but outside the high-dose irradiated volume,
local control rates ranging rom 71% to 100% have and toxicities are more common in Child-Pugh class
been reported ater 30 to 90 Gy delivered over 1 to 8 B patients.
weeks.160,161 Given the excellent local control rate as noted with
Historically, investigators rom Michigan used RT alone, RT has been combined with TACE to over-
conormal RT (1.5 Gy twice daily over 6–8 weeks) come treatment resistance. Korean researchers initially
with concurrent hepatic arterial 5-fuorodeoxyuridine noted more than 60% response rates and a signicant
Chapter 30
to treat HCC saely to doses as high as 90 Gy and drop in tumor marker levels using this combination
achieved a median survival duration o 15.2 months.162 treatment strategy.171,172 It was reported that TACE ol-
Analysis o these data suggested that doses greater lowed by RT improved OS over TACE alone in a ret-
than 75 Gy resulted in more durable in-eld local con- rospective analysis o this experience. Similar results
trol than lower doses. have been reported by other groups as well.173–175
A prospective French phase 2 trial administered 66 For the treatment o unavorable tumors, multiple
Gy in 33 ractions to HCC in patients ineligible or groups have reported avorable outcomes in patients
curative therapies and noted 92% tumor responses and with portal venous tumor thrombus (PVTT) treated
78% one-year local control rates.163 Using higher doses with RT.176–185 Response rates rom these older stud-
and ewer ractions (hyporactionated RT), Canadian ies ranged rom 37.5% to 100%, and median survival
researchers have noted excellent local control rates durations ranged rom 3.8 months to 10.7 months. Our
ranging rom 70% to 90% when the radiation beam retrospective data rom MDACC indicate that patients
can be directed rom multiple planes (stereotactic body with PVTT who received higher doses o RT had bet-
RT, SBRT) converging on the tumor. Oten with SBRT, ter rates o local control and longer survival compared
the majority o the liver can be spared rom irradiation with those who received lower doses.186 Most recently,
using image guidance and respiratory motion manage- neoadjuvant 3D conormal RT beore hepatectomy or
ment.160,164,165 The ongoing RTOG 1112 randomized patients with limited PVTT and resectable HCC dem-
study o soraenib versus soraenib with SBRT or onstrated an OS advantage with strong eect compared
patients with HCC is ongoing and has OS as the pri- with hepatectomy alone in a multicenter, random-
mary end point. ized controlled trial in Japan.187 On multivariable Cox
In contrast to photon irradiation, or which the dose regression analyses, the hazard ratio was 0.35 (range
delivered to the tumor is limited by the entrance and 0.23–0.54), avoring the preoperative RT regimen.
exit doses that can potentially harm normal tissues, Future directions or RT with photons and protons
accelerated proton beams deposit a dose within the will include use o unctional imaging or biomarkers
tumor without exiting through normal tissues beyond to personalize therapy or patients. Proo o concept
the tumor.166 Japanese investigators have reported has been demonstrated in a phase 2 study o SBRT or
mature results o the treatment o 162 patients with patients with advanced cirrhosis or impaired liver unc-
192 unresectable HCCs with 72 Gy in 16 ractions tion.188 The investigators used indocyanine green as a
o proton beam therapy.167 The 5-year local control readout o liver unction during SBRT to decide whether
rate o 87% and OS rate o 23.5% in the absence o it was sae to deliver the ull ve-raction course o SBRT
signicant toxicity are clinically noteworthy. Further- or stop ater three ractions. Sixty-two o 90 enrolled
more, an impressive 5-year survival rate o 53.5% patients completed all ve ractions using this person-
was achieved in a subset o 50 patients with solitary alized strategy. Six o the patients (7%) experienced a
tumors and Child-Pugh class A cirrhosis. A prospective 2-point decline in Child-Pugh score within 6 months,
multicenter phase 2 trial o hyporactionated radiation which was lower than historical data that used a non-
therapy (58.05–67.5 Gy in 15 ractions) or HCC and adaptive approach. The 2-year local control rate was
intrahepatic cholangiocarcinoma demonstrated similar 95%.
Taken together, these advances have permitted the double-blind, placebo-controlled trial.197 The median
escalation o radiation dose to unresectable HCCs OS was 10.7 months in the soraenib group (vs 7.9
without causing undue toxicity in multiple clinical months in the placebo group) with a HR o 0.69 (range
scenarios rom resectable to unresectable disease, as 0.55–0.87). The median time-to-radiologic progression
well as in the context o patients with limited hepatic was 5.5 months (vs 2.8 months). The ORR was 2%,
reserve. Strategies that combine RT with other thera- and the disease control rate (DCR) was 43%. The most
pies merit continued evaluation to maximize the rela- common grade 3–4 adverse events were diarrhea, pal-
tive benets o each approach. mar-plantar erythrodysesthesia, and atigue. Based on
this study, soraenib was approved in November 2007
or patients with unresectable HCC. Soraenib was the
Systemic Therapy only option or advanced HCC until April 2017, when
A majority (>80%) o patients diagnosed with HCC regoraenib was approved or the second-line therapy
have advanced disease at presentation and—based on and the only rontline medication, until lenvatinib was
the number, size, location o lesions, and the severity o approved in August 2018.
the underlying cirrhosis—are not candidates or trans-
plantation, surgical resection, or locoregional therapies.
Systemic therapy is recommended or patients with Lenvatinib
adequate liver unction as demonstrated by Child-Pugh Lenvatinib is a tyrosine kinase inhibitor o VEGFR 1, 2,
class A or B cirrhosis. Those with Child-Pugh class C cir- 3; broblast growth actor receptor (FGFR) 1, 2, 3, and
Chapter 30
rhosis have insucient liver unction to tolerate medica- 4; and PDGFRα, KIT, and RET. It has been approved or
tion treatment, locoregional therapy, radiation therapy, patients with endometrial cancer, renal cell carcinoma,
or surgical intervention.189,190 Thereore, best supportive and thyroid cancer.198–200 It was initially investigated
care is recommended or this patient population. in a phase 2 clinical trial or patients with advanced
Since the approval o soraenib in 2007, several HCC, and saety and ecacy were validated.201 This
medications have been investigated, approved by study demonstrated that lenvatinib had an ORR and
the FDA, or recommended by the National Compre- DCR o 37% and 78%, respectively. Median OS and
hensive Cancer Network guideline. Soraenib, lenva- TTP were 18.7 and 7.8 months, respectively. The e-
tinib, atezolizumab plus bevacizumab, and nivolumab cacy o lenvatinib was urther investigated in a phase
monotherapy (or patients considered ineligible or 3, randomized, nonineriority study to compare the
intolerant to other rontline medications) are recom- ecacy versus soraenib as a rontline treatment.202
mended in the rst-line setting; nivolumab mono- Patients were Child-Pugh class A only and BCLC stage
therapy, nivolumab plus ipilimumab, pembrolizumab, B/C. Patients with portal vein tumor thrombosis and
cabozantinib, regoraenib, and ramucirumab (patients 50% or higher liver occupation were excluded rom
with AFP >400) are recommended in the subsequent- the study. Lenvatinib dose was 12 mg or patients with
line therapy. Systemic therapy is recommended or a body weight o 60 kg or more and 8 mg or those
patients with Child-Pugh class A except or nivolumab weighing less than 60 kg. The primary end point, the
(Child-Pugh class A/B) and soraenib (Child-Pugh medial OS, was 13.6 months (range 12.1–14.9), and
class A/B7) by the National Comprehensive Cancer it was noninerior to soraenib (12.3 months, range
Network. 10.4–13.9). The median PFS was 7.4 months (range
Hepatocellular carcinoma is inherently chemo- 6.9–8.8), and ORR and DCR were 24% (1% complete
therapy resistant191 and known to express the multi- response) and 75%. Based on this promising result, the
drug-resistance gene MDR-1.192,193 5-fuorouracil plus FDA approved lenvatinib 12 mg daily in patients with
oxaliplatin versus doxorubicin as palliative chemo- 60 kg or greater body weight or 8 mg in those less than
therapy was navigated, and it showed the median OS 60 kg in August 2018. Lenvatinib was the rst rontline
and PFS o 6.4 versus 5.0 months and 2.9 versus 1.8 systemic therapy approved by the FDA ater soraenib
months, respectively.194 Other chemotherapeutic med- in 2007.
ications showed similar results, and chemotherapy is
rarely considered outside a setting o a clinical trial.
Atezolizumab and Bevacizumab Combination
Atezolizumab is a ully humanized, monoclonal anti-
Soraenib
body o IgG1 isotype against the programmed cell
Soraenib is a tyrosine kinase inhibitor o VEGFR 1, death-ligand 1 (PD-L1). Atezolizumab has a proven
2, and 3 and platelet-derived growth actor receptor–β ecacy in patients with triple-negative breast can-
(PDGFR-β). It was approved by the FDA or patients cer, non–small cell lung cancer, small cell lung can-
with renal cell carcinoma.195,196 Soraenib was later cer, and urothelial carcinoma.203–210 Bevacizumab is a
tested in patients with advanced HCC in a phase 3, humanized antibody binding to VEGF and prevents
angiogenesis. It has shown antitumor ecacy in mul- 3 complete responses and 19 partial responses. The
tiple tumors including cervical cancer, colorectal can- DCR was 64%. The median OS and PFS were 15.0
cer, glioblastoma, non–small cell lung cancer, ovarian and 4.0 months, respectively. The duration o response
cancer, renal cell carcinoma, and endometrial can- ranged rom 3.2 to 38.2+ months; 91% o responders
cer.209,211–215 A phase 1b study o atezolizumab and bev- had responses lasting 6 months or longer, and 55%
acizumab in patients with unresectable HCC showed had responses lasting 12 months or longer. The most
an ORR o 36% and a median PFS o 7 months.216 This common grade 3–4 adverse events were increased
combination was recently validated in a global, phase lipase, aspartate aminotranserase, and alanine ami-
3 clinical trial, and patients were randomized to this notranserase, as well as atigue. The FDA approved
combination or soraenib in patients with unresect- nivolumab 240 mg every 2 weeks in the second-line
able HCC.217 Patients were Child-Pugh class A5 or A6, setting in September 2017. It is also recommended in
and 82% o patients were BCLC stage C. Primary end the rontline setting i patients are considered ineligible
points were OS and PFS. The median OS o patients or intolerant to other rontline medications.
in the combination arm could not be evaluated at the
time o data collection (over 17 months), and that o
Pembrolizumab
those who received soraenib was 13.2 months (range
10.4–NE). HR or death was 0.58 (range 0.42–0.79). The Pembrolizumab is a humanized monoclonal antibody
median PFS was 6.8 months (range 5.7–8.3) versus 4.3 binding to PD-1 and inhibiting the binding o PD-1 to
months (range 4.0–5.6) in the respective groups, with its ligand PD-L1 and PD-L2. Its clinical activities have
Chapter 30
a HR o 0.59 (range 0.47–0.76). The ORR was 33.3% been proven in several dierent cancers that include
(10.2% and 23.1%, complete and partial response triple-negative breast cancer, cervical cancer, endome-
rates, respectively) versus 13.3% (range 1.9% and trial cancer, esophageal and gastric cancers, head and
11.4%), and the DCR was 72.3% and 55.1%, respec- neck squamous cell carcinoma, Hodgkin lymphoma,
tively. The most common grade 3–4 adverse events melanoma, Merkel cell carcinoma, mycosis ungoides
included hypertension (15.2%), increased aspartate and Sézary syndrome, non–small cell lung cancer, pri-
aminotranserase (7%), thrombocytopenia (3.3%), mary mediastinal large B-cell lymphoma, renal cell car-
and proteinuria (3%) in the combination arm. O note, cinoma, small-cell lung cancer, urothelial carcinoma,
atezolizumab monotherapy and bevacizumab mono- and microsatellite unstable cancers.198,233–250 Pembro-
therapy also showed antitumor activity or advanced lizumab was investigated in Keynote 224, a single-
HCC, with an ORR o 17% and 13% to 14%, respec- arm trial or patients with Child-Pugh class A and
tively.216,218–220 This combination is the rst regimen disease progression on or intolerance to soraenib.251
in HCC showing better survival than soraenib as all The median PFS and OS were 4.9 (range 3.4–7.2) and
other FDA-approved medications showed similar out- 12.9 months (range 9.7–15.5), respectively. The ORR
comes when compared with soraenib. and DCR were 17% (range 11%–26%) and 67%. The
duration o response ranged rom 3.1 to 16.7 months.
Fatigue (4%) and increased aspartate aminotranser-
Nivolumab
ase (7%) and alanine aminotranserase (4%) were
Nivolumab is a ully human IgG4 antibody inhibiting the most common grade 3–4 adverse events. Pem-
programmed cell death-1 (PD-1) rom binding to the brolizumab 200 mg every 3 weeks was approved or
ligands PD-L1 and PD-L2. It is an immune checkpoint advanced HCC in the second-line setting by the FDA
inhibitor with known activities in multiple cancer in November 2018.
types including microsatellite unstable colorectal can-
cer, head and neck squamous cell carcinoma, Hodgkin Nivolumab and Ipilimumab Combination
lymphoma, melanoma, non–small cell lung cancer,
small cell carcinoma, renal cell carcinoma, and urothe- Nivolumab was tested in combination with ipi-
lial carcinoma.221–231 It was tested in a phase 1/2, open- limumab, a recombinant human IgG1 antibody
label trial (CheckMate 040).232 Forty-eight patients binding to the cytotoxic T lymphocyte–associated
and 214 patients were treated in the dose-escalation antigen 4 (CTLA-4) or advanced HCC. Ipilimumab
phase and the dose-expansion phase or patients with showed clinical eicacy in microsatellite unstable
Child-Pugh class A cirrhosis. Nivolumab 3 mg/kg was colorectal adenocarcinoma, melanoma, renal cell
chosen or dose expansion. The ORR was 20% (range carcinoma, and small-cell lung cancer.117,222,227,252,253
15%–26%) in the dose-expansion phase and 15% This combination was investigated in cohort 4 o
(range 6%–28%) in the dose-escalation phase. A total CheckMate 040. 254 A total o 50 and 49 patients
o 154 patients received soraenib and progressed on received nivolumab 1 mg/kg plus ipilimumab 3 mg/
or were intolerant to it. The conrmed ORR in this kg and nivolumab 3 mg/kg plus ipilimumab 1 mg/
patient group was 14.3% (range 9.2%–20.8%) with kg every 3 weeks ollowed by nivolumab 240 mg
every 2 weeks. Most patients had advanced HCC investigated in a randomized, double-blind, placebo-
at baseline: 88% o patients had vascular invasion controlled trial or patients with advanced HCC.263
or extrahepatic spread, and 91% had BCLC stage Patients were Child-Pugh class A and BCLC stage B/C.
C. This combination showed the ORR o 32% Patients in the regoraenib arm had a median OS o
and 31%, and DCR o 54% and 43% in respec- 10.6 months (vs 7.8 months in the placebo arm; range
tive arms. The median OS was 23 months and 12 9.1–12.1) with a HR o 0.63 (range 0.5–0.79) and a PFS
months, respectively. Response duration ranged o 3.1 months (vs 1.5 months in the placebo arm) with
rom 4.6 to 30.5+ months, with 31% o responses a HR o 0.46 (range 0.37–0.56). The ORR and DCR
lasting at least 24 months. As discussed above, the were 11% and 65%, respectively. The most common
ORR and median OS o nivolumab monotherapy grade 3–4 adverse events were hypertension (15%),
demonstrated in CheckMate 040 were 14% and 16 palmar-plantar erythrodysesthesia (13%), atigue (9%),
months, and the combination o nivolumab and ipi- and diarrhea (3%). The FDA approved regoraenib
limumab clearly showed clinical beneit. The com- 160 mg once a day ater a low-at meal or 21 days on
bination showed that 37% o patients had grade and 7 days o o each 28-day cycle or patients with
3–4 adverse events, with the most common being advanced HCC in the second-line setting in April 2017.
pruritus and rash, as well as other known immune-
related adverse events reported in clinical studies Ramucirumab
or other cancers. Based on this result, nivolumab
1 mg/kg in combination with ipilimumab 3 mg/kg Ramucirumab is a recombinant monoclonal antibody
Chapter 30
every 3 weeks or our doses, ollowed by single- inhibiting VEGFR2 and blocking ligand-receptor inter-
agent nivolumab 240 mg every 2 weeks or 480 mg action with VEGF-A, -C, and -D. It causes reduced
every 4 weeks was approved by the FDA in March cancer vascularity and growth.264 It has been used
2020 in the second-line setting. in metastatic non–small cell lung cancer, esophageal
and gastric cancers, and colorectal cancer. 264–267 Ramu-
cirumab was investigated in a randomized, double-
Cabozantinib blind, placebo-controlled, phase 3 trial or HCC
Cabozantinib is an inhibitor o VEGFR 1, 2, and 3; patients with Child-Pugh class A, BCLC stage B/C,
MET; and AXL. It has shown its clinical ecacy in and AFP >400 ng/mL.268 The medication was used or
renal cell carcinoma and thyroid cancer.255–257 It was patients who had received soraenib. The median OS
initially tested in a phase 2 trial or patients with was 8.5 months (vs 7.3 months in the placebo arm;
advanced HCC, regardless o previous treatment range 7.0–10.6) with a HR o 0.71 (range 0.53–0.95).
with soraenib.258 Patients with Child-Pugh class B/C The PFS was 2.8 months (range 2.8–4.1) versus 1.6
were excluded. This showed a median OS o 11.5 months with a HR o 0.45 (range 0.34–0.60). The ORR
months and a median PFS o 5.2 months. This was and DCR were 5% and 59.9%, respectively. Grade
validated in a randomized phase 3 trial, and a total 3–4 adverse events included hypertension (13%),
o 707 patients were assigned in a 2:1 ratio to receive hyponatremia (6%), and increased aspartate amino-
cabozantinib 60 mg daily or placebo. 259 The primary transerase (3%). Ramucirumab 8 mg/kg once every
end point was OS, and the secondary end points 2 weeks was approved by the FDA in May 2019 or
were PFS and ORR. A median OS was 10.2 months patients with AFP o ≥400 ng/mL in the second-line
versus 8.0 months in the cabozantinib and placebo setting.
arms, with a HR o 0.76 (range 0.63–0.92). Median
PFS and ORR were 5.2 months with a HR o 0.44 Neoadjuvant Systemic Therapy
(range 0.36–0.52) and 4% (P = .009). The DCR was
64%. The most common grade 3–4 adverse events The only potentially curative modalities or HCC
were palmar-plantar erythrodysesthesia (17%), include liver resection and transplantation. How-
hypertension (16%), and increased aspartate amino- ever, the actual number o patients who qualiy or
transerase (12%). Based on this trial, cabozantinib these modalities is small (~10%–30%) because most
was approved by the FDA in January 2019 in the patients present with locally advanced or metastatic
second-line setting. disease or have signicant liver dysunction that pre-
cludes curative options. In addition, or those who
Regoraenib undergo resection, tumor recurrence is common,
with a 5-year recurrence rate o more than 70%,26,269
Regoraenib is a multikinase inhibitor o multiple targets and the 5-year survival rate or patients with resected
including VEGFR 1, 2, and 3; KIT; and PDGFRα and β. HCC has been reported to be 30% to 70%.270–272 The
It had been approved or patients with metastatic colon potential reasons or recurrence ater surgical resec-
cancer and gastrointestinal stromal tumor.260–262 It was tion involve the presence o micrometastases not
seen on conventional imaging or the dissemination platorms including lymphocyte inusion, tumor-
o tumor cells during surgery. Patients who initially directed vaccines, cytokine-induced killer cells, and
are surgical candidates at diagnosis could have sig- autologous cytokine-induced killer cells have been
nicant progression during the time between initial investigated with mixed results.282–285 As o this writ-
diagnosis and surgery and do not quality or surgery ing, multiple clinical trials o tyrosine kinase inhibitors
at a later time. and immune checkpoint inhibitors are underway, but
In this regard, preoperative therapy has been pro- no systemic therapy is considered a standard o care in
posed and has theoretical benets including tumor the adjuvant setting.286
downsizing and reduction in micrometastases.
Recently, soraenib was tested in the neoadjuvant set-
ting. In the open-label, phase 2 study reported at the Combined Hepatocellular Carcinoma and
Gastrointestinal American Society o Clinical Oncol- Cholangiocarcinoma (cHCC-CC)
ogy (GI ASCO) in 2016, our weeks o soraenib given
Surgical resection is the only curative option in
beore surgical resection resulted in 50% or higher
cHCC-CC, similar to intrahepatic cholangiocarci-
tumor necrosis in 24% o surgical specimens.273 In
noma and HCC. There are limited data on the role o
addition, this small study yielded a 32% ORR by
LT. For example, two o three patients with cHCC-
mRECIST.
CC underwent LT, and two patients survived at 25
Immune checkpoint inhibitors can be saely admin-
and 35 months287,288; another report shows that 8 o
istered in the preoperative setting as demonstrated by
Chapter 30
14 patients had tumor recurrence at a median ollow-

preoperative trials o an anti–CTLA-4 antibody beore
up o 32 months, with a median DFS o 8 months
curative surgery in bladder cancer and other can-
status post-LT.289 For unresectable tumors, systemic
cers.274,275 In addition, immune checkpoint inhibitors
therapy is the main backbone o treatment. However,
investigated in the preoperative setting at MDACC
there is no consensus o opinions about chemother-
indicated an impressive signal o activity in patients
apy or molecular targeted therapy. A retrospective
with resectable HCC.276 In this pilot, randomized trial
analysis o patients with unresectable cHCC-CC who
o perioperative immunotherapy with nivolumab
received systemic treatment including gemcitabine
with and without ipilimumab or resectable HCC,
monotherapy, gemcitabine with platinum with or
ve o 21 resected cases (two treated with nivolumab
without bevacizumab, and soraenib showed poor
and three with nivolumab and ipilimumab) demon-
responses, with 71% having disease progression on
strated the complete pathologic response. However,
the rst radiographic scan.290 The median OS and
there are no standard, systemic preoperative therapies
the tumor control rate were 8.3 months and 21%.
or resectable HCC as o this writing. Ongoing trials
Another retrospective analysis revealed the median
with tyrosine kinase inhibitors or immune checkpoint
OS or gemcitabine plus cisplatin, 5-fuorouracil
inhibitors will provide more inormation in the neo-
plus cisplatin, and soraenib o 11.9, 10.2, and 3.5
adjuvant setting.
months, respectively,291 whereas another case report
o soraenib monotherapy showed patients achieved
Adjuvant Systemic Therapy remission ater progression on chemotherapy.292
Overall, gemcitabine plus platinum (cisplatin or oxali-
Early studies o adjuvant chemotherapy published
platin) with and without bevacizumab or molecular
in the late 1990s to early 2000s demonstrated mixed
targeted therapy including soraenib is considered the
results. For example, randomized studies o adjuvant
main backbone o systemic therapy.293 Locoregional
capecitabine and 5-fuorouracil showed the improved
therapy or external beam radiation can also be con-
time-to-recurrence and 5-year OS rate277,278; other stud-
sidered in a similar ashion to the treatment in HCC
ies o adjuvant epirubicin, tegaur, or carmour did
or intrahepatic cholangiocarcinoma.
not show survival benet or decrease in the recur-
rence rate.279,280 More recently, soraenib was tested as
adjuvant treatment in a phase 3, randomized clinical Fibrolamellar Hepatocellular Carcinoma
trial.281 This study included more than 500 patients
in the soraenib and placebo groups. The investiga-
(FLHCC)
tors did not nd a dierence in the median RFS (33.3 In our recent publications294,295 with the largest sin-
vs 33.7 months; HR 0.94, range 0.78–1.13), whereas gle-institution sample o 94 patients, the patients
patients in the soraenib arm showed increased adverse who received neoadjuvant (n = 34) or adjuvant ther-
events including palmar-plantar erythrodysesthesia apy (n = 10) had the longest median OS—60 and
and elevated liver enzymes. Adjuvant immunotherapy 110.5 months, respectively—in the entire cohort.
The median age was 23 years (range 14–75), the regarding the ideal chemotherapeutic regimen or
median OS was 57.2 months (range 36.4–77.9), and FLHCC, platinum-based chemotherapy regimens,
the median RFS was 13.9 months (range 8.8–18.9). as well as combination regimens including IFN-α2b
White race, emale gender, early tumor stage, and have been used with some success. 304–306 A phase
tumor resection (including metastasectomy) were 2 trial reported complete or partial responses in 5
positively associated with a longer OS, whereas o 8 patients treated with 5-luorouracil and IFN-
emale gender was the only signicant positive pre- α2b.306 In this trial, patients received 5-luorouracil
dictor o longer RFS. The 5-fuorouracil plus IFN-α2b at a dose o 200 mg/m 2 inused continuously over
combination was the most requently used systemic 21 days with IFN-α2b at a dose o 4 million U/m 2
therapy.294 three times weekly during 5-luorouracil inusion
Surgical resection remains the standard o care in on a 28-day cycle. The median OS was 23.1 months
patients with resectable and locally advanced FLHCC. (range 10.3–35.9). Approximately 9% o patients
In a systematic review that evaluated data rom 575 had grade 3–4 neutropenia, thrombocytopenia, or
patients with FLHCC, the authors noted that patients anemia. Nonhematologic toxicities were mostly
who underwent surgical resection had a 5-year sur- grade 1–2 mucositis (39.5%), diarrhea (13.9%),
vival rate o 70% compared with 0% among patients nausea and vomiting (13.9%), atigue (34.9%), and
who did not undergo resection.296 However, recur- skin reaction (23.3%). Since that publication, the
rence could be as high as 100% ater surgical resection; 5-luorouracil plus IFN-α2b combination has been
moreover, chemotherapy options in neoadjuvant and established as the most requently used systemic
Chapter 30
adjuvant settings are not well dened.295,297 None o therapy.294 There is limited and conlicting evidence
the presently used chemotherapy regimens are based demonstrating the eicacy o immune checkpoint
on randomized clinical data because o the limited inhibitors.307,308 However, the addition o an immune
number o patients with FLHCC. For patients with checkpoint inhibitor to 5-luorouracil plus IFN-α2b,
an unresectable disease, LT can be considered, and which is known to augment immune cell iniltra-
3-year survival approaches 75% to 80% ater trans- tion, increases PD-L1 expression and restores the
plantation,298 whereas transplantation is much more INF-γ–producing capacity o CD8+ T cells and may
commonly indicated or patients with HCC than or prolong survival. 309,310 As o this writing, there is a
those with FLHCC. This is likely because HCC is clinical trial or patients with FLHCC at MDACC: a
more common than FLHCC, and a regional lymph phase 1/2 study o atezolizumab plus bevacizumab
node metastasis, a relative contraindication to trans- with 5-luorouracil and IFN-α2b or unresectable
plant, is more common in FLHCC (42.2%) compared FLHCC.
with patients with HCC (22.2%). 299
Although not well studied, radiation therapy has
been used to treat recurrent FLHCC in case reports and MD ANDERSON APPROACH TO
small case series300,301: in one case report, Peacock et HEPATOCELLULAR CARCINOMA
al demonstrated an 85% decrease in tumor volume o
FLHCC metastases ater treatment with 40 Gy in 10 Hepatocellular carcinoma and other primary liver
ractions over a 13-day period. In a retrospective study tumors require multidisciplinary input, and patients
o 10 patients with metastatic FLHCC treated with benet rom clinical care that integrates the expertise
external beam radiation in addition to chemotherapy, o surgical oncology, LT, diagnostic and interventional
three patients had partial responses, six patients had radiology, gastroenterology and hepatology, radia-
stable disease, and one patient had early progression. tion oncology, and medical oncology. New cases o
The use o liver-directed therapies (eg, chemoemboli- HCC are reviewed at a weekly multidisciplinary liver
zation, Y-90, and ablation) in FLHCC remains poorly tumor conerence to develop a consensus approach
dened. Recently, Maeld et al reported a patient to each patient’s case. Careul attention is paid to
with successul downstaging o an initially unresect- precise tumor staging, histopathologic diagnosis,
able FLHCC with TACE ollowed by Y-90. The tumor and each patient’s perormance status. Figure 30–4
decreased in volume rom 350 to 20 cm3, allowing cura- depicts the general approach ollowed by the mul-
tive or microscopically margin-negative (R0) resection tidisciplinary hepatobiliary team in treating patients
with an extended let hepatectomy and reconstruction with HCC. MDACC has multiple clinical trials o
o the inerior vena cava.302 combined approaches with systemic therapy, radia-
FLHCC is not typically responsive to chemo- tion therapy, and locoregional therapy, and clinical
therapy.294,303 Although there is no consensus trials are oered at dierent levels o treatment.
1 INITIAL EVALUATION
TREATMENT 5 SURVEILLANCE
• History and physical
• CBC with differential, liver function test • History and physical
(LFTs), creatinine, electrolytes, PT/INR, 4 • CBC with differential, LFTs, electrolytes, PT/INR, AFP
lipid profile, hemoglobin A1C, 3 Yes Surgery • Triple phase CT (preferred) or MRI abdomen and CT
alpha-fetoprotein (AFP) 2 chest every 4 months for 2 years, than every 6 months
• Viral serologies if not known (HBV core Liver-only Resectable or
for 3 years, then annually
and surface antibody (Ab); HBV DNA disease transplantable ?
6
titer if HBV core and antigen positive; No See Page 2 for unresectable tumors
HCV Ab or RNA if Ab positive; HIV
serology if HCV Ab positive or HBV core
Ab positive) 9 10
• Diagnostic imaging: Consider loco-regional therapies if primary Further treatment based
8 Yes
° Triple phase CT (preferred) or tumor is resectable in select cases on primary liver lesions
MRI abdomen and pelvis 7
° CT chest with contrast Metastatic Solitary 11 12
• Consider consult if indicated: disease metastasis ? Performance status 0-2, CLIP 0-3, and Child-Pugh A-B
Systemic treatment
° Hepatology for chronic liver disease or and bilirubin less than or equal to 3 mg/dL
HBV treatment
° Infectious Diseases for HCV or HIV No
treatment 13 14
• Lifestyle risk assessment Performance status greater than 2, CLIP 4-6, or
Best supportive care
Child-Pugh C or bilirubin greater than 3 mg/dL
Note: Consider Clinical Trials as treatment options for eligible patients.
19 TREATMENT
CLINICAL PRESENTATION STAGING • Ablation (preferred or clinical trial if appropriate)
FOR NOT CONSIDERED FOR 18 • Other alternative loco-regional therapies
Up to 3 lesions that
RESECTION OR ° TACE ° Radiation therapy
are less than or equal
TRANSPLANTATION TUMORS ° Combination of ablation and ° Neoadjuvant PIAF when
to 3 cm in size TACE when clinically appropriate clinically appropriate
° Radioembolization
RE-STAGING
21 WORKUP
Chapter 30
28
17 Early/ 20 • TACE (preferred or clinical trial if appropriate)
Intermediate • Single lesion greater than • History and physical
• Other alternative loco-regional therapies
disease 3 cm up to 6.5 cm • CBC with differential,
15 ° Combination of TACE and ° Radiation therapy LFTs, AFP, electrolytes
• Multiple lesions (up to 3-4)
Performance ablation when appropriate ° Neoadjuvant PIAF when
• Overall tumor burden <25% • Triple phase CT
status 0-2, 16 Yes ° Radioembolization clinically appropriate
abdomen and CT
CLIP 0-3, Well 23 chest every 2 months
Child-Pugh A-B defined 22
• Single lesion • Radioembolization or radiation therapy (preferred or clinical trial if appropriate) until stable disease,
and bilirubin less lesions? then every 3 months
25-50% tumor burden • Other alternative loco-regional therapies
than or equal to No for 2 years, then every
• Single lesion > 6.5 cm ° Neoadjuvant PIAF when clinically appropriate ° TACE
3 mg/dL 6 months for 3 years,
29 25 then annually
Advanced disease ° Multiphasic MRI
• Radioembolization with or without systemic therapy (preferred or
(extensive vascular 24 abdomen with
clinical trial if appropriate)
involvement, infiltrative Multiple lesions extracellular
• Other alternative loco-regional therapies
morphology, ill-defined greater than 4 contrasr agent if
° Neoadjuvant PIAF when histology is confirmed to be fibrolamellar HCC
disease, high tumor steatosis present
° TACE in select cases where lesions grouping allows for selective TACE
burden >50%, or • Consider resection,
metastatic disease) 27 transplantation or
26
Any tumor burden • Systemic therapy with or without radioembolization or radiation therapy another loco-regional
above with portal (preferred or clinical trial if appropriate) therapy
vein or hepatic vein Other alternative loco-regional therapies
PIAF = cisplatin,
tumor thrombus ° TACE in select cases where lesions grouping allows for selective TACE interferon-alfa, 5-fluorouracil
30 and doxorubicin
TACE = transcatheter
Apply treatment options pathways for early/intermediate disease but consider adding systemic arterial chemoembolization
31 therapy as a stand alone option or in combination with local therapy if feasible NED = no evidence of
Performance status disease
greater than 2, CLIP 4-6, 32
Child-Pugh C or bilirubin greater Best supportive care
than 3 mg/dL
FIGURE 30–4 MDACC approach to HCC treatment. (Adapted with permission rom the University o Texas MD Anderson Cancer
Center.)

J Patients with HCC are co-managed by a multidisci- J For patients with early-stage liver cancer, locore-
plinary approach with hepatology, medical oncol- gional therapy, radiation therapy, surgical resection,
ogy, surgical oncology, radiation oncology, and and LT are considered. Clinical trials o neoadjuvant
interventional radiology. and adjuvant therapy are ofered.
J MDACC collaborates with transplant hepatology at J Systemic therapy is the main backbone o cancer
Houston Methodist and Baylor College o Medicine treatment or patients with advanced or metastatic
or transplant-eligible patients. HCC. Clinical trials are ofered or eligible patients, and
J Liver unction (eg, Child-Pugh score or liver cirrho- locoregional and radiation therapy are combined.
sis) and portal hypertension, as well as the stage o J All patients with HCC are ofered pathologic
liver cancer, are assessed beore a treatment deci- and molecular proling using next-generation
sion is made. sequencing.
23. Patil MM, Patil SV. Ataxia telangiectasia with hepatocellular

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Chapter 30
31 Small Bowel Cancer and
Appendiceal Tumors
Pat Gulhati
John Paul Shen
Kanwal P. Raghav
Michael J. Overman
KEY CONCEPTS
 Small bowel neoplasms are rare with roughly 12,000 new  Appendiceal neoplasms are very rare consist o two major
cases per year in the United States. The two most common types: appendiceal carcinoid tumors and appendiceal epi-
histologies are adenocarcinoma (30%–40%) and carcinoid thelial tumors, each accounting or roughly hal all cases.
tumors (40%–45%).  No clear risk actors or appendiceal neoplasms have been
 Inammatory bowel disease, Peutz-Jeghers, amilial ade- identifed.
nomatous polyposis, celiac disease, and hereditary non-  Surgery is the mainstay o curative therapy or all patients
polyposis colorectal cancer and all increase the risk o with appendiceal neoplasms. Patients with adenocarcino-
developing small bowel adenocarcinomas. mas are more likely to present with advanced disease in
 Surgery is the mainstay o curative therapy; however, comparison with those with carcinoid tumors.
patients oten present with more advanced disease, espe-  The histologic subtypes o epithelial appendiceal neo-
cially with adenocarcinomas. plasms include low- and high-grade appendiceal muci-
 There is no frmly established adjuvant therapy or patients nous neoplasms and invasive adenocarcinomas that may
with either carcinoid tumors or adenocarcinoma. be mucinous (low or high grade), nonmucinous, or with
 Systemic therapy or patients with advanced disease mir- signet ring cell eatures.
rors treatment or neuroendocrine tumors or carcinoids,  Metastatic low-grade mucinous tumors have a more
whereas FOLFOX (modifed 5-uorouracil and oxalipla- indolent disease course, respond poorly to systemic ther-
tin), CAPOX, and regimens with irinotecan are active or apy, and are primarily managed with surgical cytoreduc-
patients with adenocarcinoma. tion and hyperthermic intraperitoneal chemotherapy
 The molecular deects in adenocarcinomas are being (HIPEC).
elucidated. To date, however, no targeted therapy has an  Metastatic high-grade adenocarcinomas, which include
established role in advanced disease. Mismatch repair all tumors with signet ring cell eatures, are oten treated
deects (even more requent than in colorectal cancer) are with systemic chemotherapy. The beneft rom cytoreduc-
predictive o response to immune checkpoint blockade. tive surgery and HIPEC is uncertain.
SMALL BOWEL CANCER adenocarcinoma (SBA) and the difculty in imaging

the small bowel, most patients with SBA present with
Small bowel cancer is a rare malignancy represent- lymph node involvement or distant metastases. Even
ing approximately 3% o gastrointestinal (GI) neo- in patients with localized disease who undergo resec-
plasms.1 In 2020, it was estimated that 11,110 new tion with curative intent, the prognosis is poor, and
cases o small bowel cancer and 1700 small bowel no studies have yet demonstrated a clear beneft rom
cancer–related deaths would occur.1 The two most adjuvant therapy. However, there have been some
common histologies seen in cancers o the small intes- recent advances in molecular profling as well as the
tine are carcinoids and adenocarcinomas.2 Because o use o chemotherapy, targeted therapy, and immuno-
the nonspecifc clinical presentation o small bowel therapy as palliative treatments. In this chapter, the
707
708 Scion VI Gastrointestinal Cancer
epidemiology, diagnosis, and treatment o small bowel retroperitoneal. The second (descending) segment o
cancers, in particular SBA, are reviewed. the duodenum contains the ampulla o Vater, through
which the pancreatic and biliary secretions exit. The
third (horizontal) segment o the duodenum is the lon-
Epidemiology gest, and as it crosses the let border o the aorta, the
Based on an analysis o the Surveillance, Epidemiol- ourth (ascending) segment o the duodenum begins.
ogy, and End Results (SEER) database, the age-adjusted The duodenal–jejunal junction is characterized by
incidence rate or small bowel cancers slowly increased the attachment o the suspensory ligament o Treitz.
rom 0.9 per 100,000 persons in the years 1973 to 1982 The next segment o the small bowel, the jejunum, is
to 2.4 per 100,000 persons in the years 2013 to 2017.3,4 approximately 2.5 m long, and the nal segment, the
The majority o this increase has been attributed to an ileum, is approximately 3.5 m long.
increase in the incidence o carcinoid tumors. Carci-
noids account or 39% to 45% o all cases, whereas
SBA accounts or 31% to 40% o all small intestinal
Etiology
cancer diagnoses.5 Most primary tumors arise in the Little is known about the etiology o SBA. As seen in
duodenum (60%), with 25% to 29% arising in the jeju- CRC, SBA undergoes a similar phenotypic adenoma–
num and 10% to 13% in the ileum.5 The incidence o carcinoma transormation.8–10 An increase in the size o
histologic subtypes varies in the dierent sections o small bowel adenomas and the presence o a villous
the small intestine, with adenocarcinomas represent- histology are risk actors or the development o inva-
Chapter 31
ing 59% o duodenal cancers and carcinoids represent- sive adenocarcinoma.

ing 57% o ileal cancers.2,5 The median age at diagnosis Common underlying genetic or environmental ac-
is 60 years, and there is slightly increased incidence tors o both large and small intestine adenocarcinomas
seen in men and Blacks.5,6 have been suggested by studies that have demon-
One o the more interesting aspects o SBA is its strated an increased risk o SBA in patients with colon
rarity in comparison with large intestine adenocar- adenocarcinoma and vice versa.11 SBA has a higher
cinoma. Even though the small intestine represents likelihood o microsatellite instability (7.6%) and high
approximately 70% to 80% o the length and more tumor mutational burden (9.5%) compared with CRC
than 90% o the surace area o the alimentary tract, (4.0% and 4.3%, respectively).12
the incidence o SBA is 50- to 100-old less than the The possible role o pancreaticobiliary secretions
incidence o colorectal carcinoma (CRC). Numer- in the development o adenocarcinoma o the duode-
ous theories have been proposed to explain the small num has been suggested by the anatomic clustering o
intestine’s relative protection rom the development duodenal carcinomas in the periampullary area. For
o malignancy. Proposed protective actors have cen- example, in patients with amilial adenomatous pol-
tered on two concepts. First, the rapid turnover time o yposis (FAP), 80% o SBAs occur in the second portion
small intestinal cells results in epithelial cell shedding o the duodenum. One study evaluating 213 cases o
beore the necessary acquisition o multiple genetic duodenal carcinomas identied rom the Los Angeles
deects. Second, the small bowel’s exposure to the car- County tumor registry determined that 57% o the
cinogenic components o our diet are limited because cases originated in the second part o the duodenum. 13
o rapid small bowel transit time; the lack o bacterial
degradation activity that occurs in the small bowel;
the relatively dilute, alkaline environment o the small
Environment and Dietary Risk Factors
bowel; and greater lymphoid inltrate in small intes- A number o case-control studies have analyzed asso-
tinal mucosa. In a population-based comparison o ciations between environmental and dietary actors and
adenocarcinomas o the large (n = 261,521) and small the development o SBA. Two studies have demon-
(n = 4,18) intestine identied rom the SEER registry, strated that there is an association between the ingestion
SBA demonstrated a distinctly worse stage-adjusted o smoked or salt-cured oods and the development o
cancer-specic survival than CRC.7 SBA.14,15 An association between tobacco use and cancer
risk has been inconsistently demonstrated. Case-control
studies have demonstrated an association between an
Anatomy increased risk o SBA and high alcohol intake, high
The small intestine is divided into three sections. The sugar intake, high red meat intake, low ber intake,
duodenum represents the rst 25 cm o the small intes- celiac disease, peptic ulcer disease, and prior cholecys-
tine and is subdivided into our anatomic segments. tectomy14–18 Studies o the relationship with obesity
The proximal portion o the rst (ascending) segment have been conficting, although a case-cohort study o
o the duodenum is intraperitoneal, and then the distal 500,000 participants with 134 incident cases o small
portion, as well as the rest o the duodenum, becomes bowel cancer showed a statistically nonsignicant trend
C 31 Small Bowel Cancer and Appendiceal Tumors 709
toward increased risk in subjects with high body mass SMAD4 have been implicated in the adenoma–dys-
index (BMI) with a hazard ratio (HR) o 1.5 (95% con- plasia–carcinoma sequence o SBA.2 In a pivotal study
dence interval [CI], 0.76–2.96) or BMIs greater than comparing chromosomal copy number aberrations in
27.5 kg/m2 compared with BMIs o 22.6 to 25.0 kg/m2.19 85 gastric cancer, CRC, and SBAs, hierarchical cluster-
ing revealed a substantial overlap o SBA copy number
proles with matched CRCs but less overlap with pro-
Genetic Cancer Syndromes les o gastric adenocarcinomas, indicating a genetic
The genetic cancer syndromes hereditary nonpolypo- prole similar to CRC.27 However, SBA is a unique
sis colorectal cancer (HNPCC), FAP, and Peutz-Jeghers molecular entity with distinct dierences compared
syndrome (PJS) are all associated with SBA. The esti- with other GI cancers, including CRC and gastric ade-
mated lietime risk or SBA is 1% to 4% in patients nocarcinoma. The most commonly noted alterations
with HNPCC, 5% in those with FAP, and 13% in were TP53 (58.4%), KRAS (53.6%), APC (26.8%),
those with PJS20–23 Patients with HNPCC develop SBA SMAD4 (17.4%), PIK3CA (16.1%), CDKN2A (14.5%),
at a younger age, with a median age at diagnosis o and ARID1A (12.3%).12 The low rate o APC altera-
49 years. Patients with PJS, an autosomal dominant tions in patients with SBA compared with those with
polyposis disorder characterized by multiple hamarto- CRC is a undamental genomic dierence between
matous polyps throughout the intestinal tract, have a these malignancies. The most common potentially tar-
markedly increased risk or SBA, with one meta-anal- getable alterations in SBA were identied in PIK3CA
ysis demonstrating a 520-old increased relative risk.24 (16.1%), ERBB2/HER2 (9.5%), BRAF (9.1%), ATM
Chapter 31
Duodenal adenomas are seen in approximately 80% (7.6%), FBXW7 (6.9%), ERBB3 (6.3%), NF1 (6.0%),
o patients with FAP, and regular endoscopic screening CTNNB1 (5.7%), MDM2 (5.7%), and PTEN (5.7%).
or the development o adenocarcinoma is required or Although in CRC, most BRAF alterations are V600E,
these patients. The optimal requency o endoscopic this codon is inrequently altered in patients with SBA.
screening depends on a number o actors, such as the Similarly, despite equivalent rates o ERBB2 altera-
number o polyps, polyp size, polyp histology, and tions, only 23% alterations are amplications in SBA,
amount o dysplasia present.20 With the early use o but 69% o alterations are amplications in gastric
colectomy in patients with FAP, duodenal adenocarci- adenocarcinoma. Interestingly, whereas tumor rom
nomas and desmoid tumors are now a more common patients with IBD associated SBA had higher requen-
cause o death in this population than CRC. cies o CDKN2A/B, CASP8 and ATRX mutations, APC
mutations were exclusively noted in non–IBD-associ-
ated SBA. Moreover, celiac disease–associated SBA has
Inammatory Bowel Disease and Celiac high rates o microsatellite instability, ranging rom
Disease 50% to 73%.
Infammatory bowel disease (IBD), particularly Crohn
disease, is associated with the development o SBA.
The increase in risk varies depending on both the Presentation and Diagnosis
extent and duration o small bowel involvement. In Clinical Presentation
one study, the cumulative risk o SBA in patients with
Crohn disease was 0.2% at 10 years and 2.2% at 25 The symptoms associated with SBA are nonspecic
years.25 Because Crohn disease requently involves the and requently do not occur until advanced disease is
ileum, 70% o the small bowel cancers in patients with present. The most commonly reported symptoms are
Crohn disease occur in the ileum. Patients with Crohn abdominal pain (45%–76% o patients), nausea and
disease who develop SBA appear to have a worse vomiting (31%–52%), weight loss (22%–29%), and GI
prognosis, with one study o 37 patients with SBA bleeding (8%–34%). Delays in diagnosis are common,
demonstrating signicantly shorter overall survival with one retrospective study reporting a mean delay o
(OS) in patients with Crohn disease.26 Celiac disease 7.8 months rom the time o initial physician evalua-
is another proinfammatory condition that increases tion until a nal diagnosis was made.28 Unortunately,
the risk o developing SBA 34-old.5 In general, these SBA tends to be diagnosed at a later stage compared
patients may be younger at disease onset and have bet- with CRC. Unlike CRC, SBA has no population-based
ter OS compared with those with SBA caused by other screening given its rarity, which creates low value or
disorders.5 screening among the general population. According to
SEER–Medicare data, 33.7% o patients present with
stage I/II disease compared with 52.3% o those with
Molecular Profle CRC, and 32.1% o patients with SBA are initially diag-
Accumulation o genetic deects such as loss o E-cad- nosed with stage IV disease compared with 15.6% o
herin and SMAD4 and mutations in KRAS, TP53, and those with CRC.29
Diagnosis rom a SEER–Medicare study identied advanced age,

Black race, advanced stage, poor tumor dierentiation,
Given the nonspecic presenting symptoms, a high
high comorbidity index, and distal location as poor
index o suspicion is a crucial rst step in diagnosis.
prognostic actors. In other studies, the histopathologic
Because imaging o the small intestine is dicult, mul-
actors reported to be correlated with poor survival
tiple tests may be needed. Unortunately, there are ew
were poorly dierentiated histology, positive margins,
prospective, randomized trials comparing dierent
lymphovascular invasion, lymph node involvement,
visualization modalities. However, with the availabil-
and T4 tumor stage.26,34–36
ity o wireless capsule endoscopy, the need or older
small bowel imaging techniques has declined.
A barium small bowel ollow-through study was Treatment
previously the radiographic gold standard or small
Surgical Management
bowel evaluation. In patients with advanced-stage dis-
ease, this technique has a sensitivity o approximately For patients with localized disease, complete removal
60% or diagnosing small bowel tumors. Enteroclysis, o the tumor with negative surgical margins and local
in which contrast material is inused directly into the lymph node removal are critical or a potentially cura-
small intestine through a nasogastric tube, provides tive resection. For jejunal and ileal lesions, an oncologi-
a slightly higher sensitivity than small bowel ollow- cally successul resection requires a wide local excision
through. Endoscopic evaluation o the small intestine, with lymphadenectomy. Lesions located in the duo-
Chapter 31
or enteroscopy, requires expertise and is requently denum generally require a pancreaticoduodenectomy;

unable to evaluate the entire small intestine. however, or small distal lesions in the third and ourth
The incorporation o wireless capsule endoscopy has portions o the duodenum, a wide local excision may
allowed improved evaluation o the lumen o the small be an option. In a surgical series o 68 patients with
intestine. This technique has primarily been applied to duodenal adenocarcinoma, no dierences in the 5-year
the evaluation o obscure GI bleeding, or which it has OS rates, local recurrence rates, or margin-negative
shown superiority over other imaging and endoscopy resection rates were seen between the 50 patients who
techniques.30 In one study evaluating capsule endos- underwent pancreatic resections and the 18 patients
copy in 60 patients with suspected small bowel pathol- who underwent distal duodenal segmental resections.37
ogy but without GI bleeding, the overall diagnostic The presence o locoregional lymph node involvement
yield o capsule endoscopy was 62%.31 In that study, all should not deter surgical intervention because well
patients had undergone upper and lower GI endoscopy, over one third o patients will survive long term.29,38
and many had undergone enteroclysis, small bowel This is in contrast to patients with lymph node–posi-
ollow-through, push enteroscopy, and abdominal com- tive pancreatic cancer, o whom only 7% survive 5
puted tomography (CT). In a large, single-center, retro- years.39 As is seen with CRC, the total lymph nodes
spective review o 562 patients who underwent capsule (TLNs) assessed during surgery and the number o
endoscopy, small bowel tumors were ound in 8.9% o positive lymph nodes (PLNs) have prognostic implica-
cases.32 The major limitations o capsule endoscopy are tions in SBA. In a SEER registry retrospective review o
inability to obtain biopsy and lack o therapeutic inter- 1991 patients, the 5-year disease specic survival rate
vention capability (eg, in case o bleeding). Moreover, or patients with stage II disease appeared to be asso-
patients cannot have bowel obstruction, which could ciated with the TLNs assessed (44%, 69%, and 83%
result in the capsule’s becoming trapped in the bowel. or 0 TLNs, 1 to 7 TLNs, and >7 TLNs, respectively).40
Three-dimensional imaging with either CT or mag- Furthermore, the 5-year DSS with stage III disease was
netic resonance imaging is useul in identiying locore- associated with the number o PLNs (58% and 37%
gional lymph node involvement and the presence o or <3 PLNs and ≥3 PLNs, respectively).40
distant metastatic disease. For tumors o the duode-
num, endoscopic ultrasonography can be useul in Patterns o Recurrence
assessing both the tumor and nodal status. Although
not directly studied or duodenal adenocarcinomas, Recurrence ater potentially curative resection o SBA
endoscopic ultrasonography has been demonstrated occurs most commonly at distant sites. In a series o
to improve staging accuracy or both ampullary and 146 patients with SBA who underwent resection, 56
pancreatic cancers. patients relapsed at a median o 25 months, with the
sites o relapse reported as distant in 59%, peritoneum
in 20%, abdominal wall in 7%, and local in 18%.41 In
Staging and Prognosis
a second study o 30 patients who underwent poten-
The TNM (tumor, node, metastasis) staging system or tially curative resection or SBA, 21 patients experi-
SBA is shown in Table 31–1.33 A multivariate analysis enced a relapse, with the sites o relapse being the liver
taBLe 311 Tumor, Node, Metastasis Staging or Adenocarcinoma o the Small Intestine
Primary Tumor (T)

T0 No evidence o primary tumor
Tis High-grade dysplasia or carcinoma in situ
T1a Tumor invades lamina propria
T2 Tumor invades muscularis propria
T3 Tumor invades through the muscularis propria into the subserosa or into the
nonperitonealized perimuscular tissue (mesentery or retroperitoneum) without serosal
penetration
T4 Tumor perorates the visceral peritoneum or directly invades other organs or structures
(includes other loops o small intestine, mesentery o adjacent loops o bowel, and
abdominal wall by way o serosa; or duodenum only, invasion o pancreas or bile duct)
Chapter 31
N1 Metastasis in one or two regional lymph nodes
N2 Metastasis in three or more regional lymph nodes
Distant Metastasis (M)
Stage Grouping
Stage 0 Tis N0 M0
Stage I T1 N0 M0
T2 N0 M0
Stage IIA T3 N0 M0
Stage IIB T4 N0 M0
Stage IIIA Any T N1 M0
Stage IIIB Any T N2 M0
Stage IV Any T Any N M1
Used with permission o the American College o Surgeons, Chicago, Illinois. The original source or this inormation is the AJCC Cancer Staging System (2020).
in 67% o the patients, lung in 38%, retroperitoneum Adjuvant Therapy

in 29%, and peritoneum in 25%.34
Patients with duodenal adenocarcinoma have a Currently, there is no evidence demonstrating a ben-
higher rate o locoregional ailure than patients with et rom adjuvant therapy in patients with SBA who
jejunal and ileal adenocarcinoma, with one study undergo potentially curative resection. However,
reporting a 39% rate o locoregional ailure among 31 owing to the rarity o SBA, only a limited number o
patients ater curative resection o duodenal adenocar- primarily small retrospective studies have been con-
cinoma.42 In that study, positive margin status was the ducted (Table 31–2). Selection bias is the major limita-
strongest predictor o local recurrence, with our o the tion o these retrospective studies because the patients
ve patients who had a margin positive resection devel- selected to receive adjuvant therapy were those
oping a local recurrence. However, distant recurrences believed to be at highest risk or disease recurrence.
are still predominant, with a retrospective review o One prospective phase III study conducted by the
recurrence patterns in 67 patients with resected duode- European Organization or Research and Treatment o
nal adenocarcinoma revealing local recurrences in 33% Cancer randomized 93 eligible patients with periam-
o the patients and distant recurrences in 67%.43 pullary carcinoma (dened as adenocarcinoma o the
Chapter 31
712
Scion VI
TABLE 31–2 Reported Overall Survival o Patients Who Received Adjuvant Therapy Ater Resection o Small Bowel Adenocarcinoma
Median Overall Survival

Patients (n)
(Months)
Type o No No
Tumor Adjuvant Adjuvant Adjuvant Adjuvant Adjuvant
Reerence Time Period Study Type Location Therapy Total Therapy Therapy Therapy Therapy P Value
Agrawal et al34 1971–2005 Retrospective review Small bowel Not specied 30 19 11 41 56 NR
Aydin et al114 2003–2013 Retrospective review Small bowel Chemotherapy 20 10 10 64 59 0.57
41
Dabaja et al 1978–1998 Retrospective review Small bowel Not specied 120 62 58 36 19 0.49
Ecker et al115 1998–2011 Propensity score– Small bowel Chemotherapy 4746 3072 1674 44.5 63.2 <0.001
matched analysis
Fishman et al54 1986–2004 Retrospective review Small bowel Not specied 60 45 15 28 22 NR
47
Haldanarson et al 1970–2005 Retrospective review Small bowel Chemotherapy/ 58 60 45 26.5 30.2 0.36
radiation
Kelsey et al42 1975–2005 Retrospective review Duodenum 5-FU/radiation 32 16 16 44%a 57%a 0.42
44
Klinkenbiji et al 1987–1995 Randomized phase Periampullary 5-FU/radiation 93 49 44 40 40 0.74
III trial
Neoptolemos et al45 2000–2008 Randomized phase Periampullary Chemotherapy 428 144 284 35.2 43.1 0.25
III trial
Overman et al46 1990–2008 Retrospective review Small bowel Chemotherapy/ 54 24 30 NR NR 0.84
radiation
Sohn et al38 1984–1996 Retrospective review Duodenum 5-FU/radiation 48 37 11 35 27 0.73
Solaini et al116 2000–2013 Retrospective review Duodenum Not specied 150 NR NR 52 84 0.83
Swartz et al117 1994–2003 Retrospective review Periampullary Not specied 25 11 14 21 41 NR
a
Five-year overall survival rate.
5-FU, 5-uorouracil; NR, not reported.
distal common bile duct, ampulla o Vater, or duode- be discussed with the patient. However, the rationale
num) to receive either no adjuvant therapy or con- or considering adjuvant chemotherapy is based on
current 5-fuorouracil (5-FU) and radiation therapy.44 1. The known poor prognosis o patients with high-
The 5-year OS rates were similar in the two groups, risk disease
but 30% o the patients assigned to receive adjuvant 2. The predominantly systemic relapse pattern or
therapy did not actually receive it, and no descrip- small intestinal adenocarcinoma
tion o the results in the duodenal adenocarcinoma 3. The proven activity o chemotherapy in the treat-
subgroup were reported. Another randomized phase ment o metastatic small intestinal adenocarcinoma
III trial, European Study Group or Pancreatic Cancer 4. The known benet o adjuvant chemotherapy in
(ESPAC-3), randomized 428 patients with periampul- large intestinal adenocarcinoma, which appears
lay carcinoma ater resection to receive no adjuvant to have a number o similarities to small intestinal
therapy or 5-FU or gemcitabine.45 Although primary adenocarcinoma
analysis did not identiy signicant survival benet 5. The extremely limited amount o high-quality
with either adjuvant chemotherapy compared with data to support or reute the role o adjuvant
observation, multivariate analysis ater adjusting or therapy or SBA
prognostic variables, including age, bile duct cancer,
Based on the substantial activity o a 5-FU and plati-
poor tumor dierentiation, and PLNs, demonstrated a
num combination in the metastatic disease setting, we
statistically signicant survival benet associated with
generally use the combination o capecitabine and oxali-
adjuvant chemotherapy.
platin (CAPOX) as adjuvant therapy or nonmetastatic
Chapter 31
In a series by Kelsey et al,42 no dierences in the
SBA. In addition to systemic chemotherapy, radiation
5-year OS rates were seen between the patients who
therapy is considered or patients with duodenal adeno-
did or did not receive adjuvant therapy ater resection
carcinoma who are at high risk or a local recurrence
o duodenal adenocarcinoma. However, in the sub-
based on the presence o positive margins or T4 disease.
group o patients who had undergone a margin-neg-
ative resection, the 5-year OS rates were 53% in the
patients who underwent resection only and 83% in the Metastatic Disease
patients who had resection and adjuvant chemoradia- In general, chemotherapy or metastatic SBA has been
tion therapy (P =.07). A trend toward improvement o based on the principles used or treating patients with
disease-ree survival (DFS) and OS was seen in patients colon cancer. Several single-institution retrospective
receiving adjuvant therapy in a retrospective series at series have demonstrated a survival benet in patients
MD Anderson Cancer Center (MDACC) (n = 54).46 with metastatic or unresectable SBA who received
However, in the subgroup analyses in patients with chemotherapy compared with patients who did not
high-risk disease, dened by a lymph node ratio o receive chemotherapy.41,48
10% or greater, adjuvant therapy was associated with Most o the studies evaluating chemotherapy or SBA
signicant improvement in OS.46 In contrast, in a sin- have been retrospective, with only seven prospective
gle-institution retrospective review at Mayo Clinic, no phase II studies reported (Table 31–3). One multicenter
benet o adjuvant chemotherapy or chemoradiother- study conducted by the Eastern Cooperative Oncology
apy was seen in patients with resected SBA.47 Group reported on the combination o 5-FU, doxorubi-
Limited data are available regarding a neoadjuvant cin, and mitomycin C (FAM) in 39 patients with adeno-
(preoperative) treatment approach or patients with carcinomas o the duodenum, jejunum, ileum, or ampulla
duodenal adenocarcinoma. In one report in which o Vater. The overall response rate (ORR) was 18%, with
11 patients underwent neoadjuvant chemoradiation a median OS o 8 months.49 A single-institution study
therapy ollowed by resection or duodenal adenocar- conducted at MDACC evaluated CAPOX in 30 patients
cinoma, a complete pathologic response was seen in with metastatic or locally advanced small bowel or
two patients, and none o the 11 patients had histo- ampullary adenocarcinomas. The ORR was 50%, with a
pathologic nodal involvement at the time o surgery.42 median time to progression (TTP) o 9.8 months and OS
o 20.3 months.50 An example o a response to CAPOX
The MD Anderson Approach to chemotherapy in a patient treated in that study is shown
in Figure 31–1. In 33 patients treated with continuous
Nonmetastatic Disease inusional 5-FU and leucovorin in combination with
At MDACC, patients with high-risk, resected SBA are oxaliplatin (modied 5-FU and oxaliplatin [FOLFOX]
typically oered postoperative adjuvant chemother- regimen), the ORR was 48.5%, and the median OS was
apy. In general, patients who are considered to be at 15.2 months.51 Another prospective, multicenter, rst-
high risk are those with lymph node involvement and line study (n = 23) using CAPOXIRI (capecitabine, oxali-
positive resection margins. The lack o proven benet platin, and irinotecan) showed an ORR o 39% and a
rom adjuvant chemotherapy or this tumor type must median OS o 12.7 months.52
Chapter 31
714
Scion VI
TABLE 31–3 Reported Response and Overall Survival or Patients Treated with Systemic Chemotherapy, Targeted Therapy, or Immunotherapy
or Metastatic Small Bowel Adenocarcinoma
Patients Overall Response Median Overall

Reerence Year Study Type Disease Status (n) Type o Systemic Therapy Rate (%) Survival (Months)
Aldrich et al57 2019 Retrospective review Metastatic 20 Taxane-based therapy 30 10.7
Pedersen et al5 2019 Prospective phase II trial Metastatic 30 Pembrolizumab 8 6.9
59
Gulhati et al 2018 Prospective phase II trial Metastatic 8 Panitumumab 0 5.7
Gulhati et al58 2017 Prospective phase II trial Metastatic 23 CAPOX + bevacizumab 48 12.9
McWilliams et al52 2012 Prospective phase II trial Metastatic 23 CAPOXIRI 39 12.7
Xiang et al51 2012 Prospective phase II trial Metastatic 33 FOLFOX 49 15.2
48
Zaanan et al 2010 Retrospective review Metastatic 93 5-FU–based therapy 26 17.8
Overman et al50 2009 Prospective phase II trial Metastatic, LAD 30 CAPOX 50 20.3
56
Overman et al 2008 Retrospective review Metastatic 29 5-FU + platinum 41 14.8
56
Fishman et al 2006 Retrospective review Metastatic, LAD 44 Various agents 29 18.6
Locher et al55 2005 Retrospective review Metastatic, LAD 20 5-FU + platinum 21 14.0
49
Gibson et al 2005 Prospective phase II trial Metastatic 38 FAM 18 8
Enzinger et al118 2005 Prospective phase I trial Metastatic 4 5-FU + cisplatin + irinotecan 50 NS
Czaykowski et al119 2007 Retrospective review Metastatic, LAD 16 5-FU–based therapy 6 15.6
Goetz et al120 2003 Prospective phase I trial Metastatic, LAD 5 5-FU + oxaliplatin + 40 NS
irinotecan
Polyzos et al121 2003 Case series Metastatic 3 Irinotecan 0 NS
Crawley et al53 1998 Retrospective review Metastatic, LAD 8 ECF +5-FU–based therapy 37 13
122
Jigyasu et al 1984 Retrospective review Metastatic 14 5-FU–based therapy 7 9
Ouriel et al123 1984 Retrospective review Metastatic 14 5-FU–based therapy NS 10.7
Morgan et al124 1977 Retrospective review Metastatic 7 5-FU–based therapy 0 NS
Rochlin et al125 1965 Retrospective review NS 11 5-FU 36 NS
CAPOX, capecitabine and oxaliplatin; CAPOXIRI, capecitabine, oxaliplatin, and irinotecan; ECF, 5-FU, epirubicin, and cisplatin; FAM, 5-FU, doxorubicin, and mitomycin C; FOLFOX, 5-uorouracil and oxaliplatin; 5-FU, 5-uorouracil;
LAD, locally advanced, unresectable disease; NS, not signicant.
A B
Chapter 31
FIGUre 31–1 Radiographic response to capecitabine and oxaliplatin (CAPOX) chemotherapy in a patient with locally advanced
small bowel adenocarcinoma. Pretreatment (A) and posttreatment (B) computed tomography scans.
Several retrospective studies have conrmed the Irinotecan-based chemotherapy is also active against
substantial activity o 5-FU combined with a platinum metastatic SBA. One retrospective study reported that
agent or metastatic SBA, with response rates o 18% ve o 12 patients responded to irinotecan-based ther-
to 46%.53–56 In one o the largest retrospective stud- apy (three patients responded to 5-FU plus irinotecan,
ies to date, a total o 80 patients with metastatic SBA one responded to capecitabine plus irinotecan, and one
were treated with various regimens: 29 received 5-FU responded to single-agent irinotecan).54 A second study
with a platinum (19 received cisplatin, our received o salvage therapy with irinotecan in the second-line
carboplatin, and six received oxaliplatin), 41 received setting noted stable disease (SD) in our o eight treated
5-FU–based therapy without a platinum (32 received patients.55 Among the 19 patients in the Association des
5-FU alone, three received FAM, three received 5-FU Gastro-Entérologues Oncologues (AGEO) study treated
and mitomycin, and three received other 5-FU com- with 5-FU plus irinotecan, one had a partial response (PR),
binations), and 10 received non–platinum-based and and SD was seen in seven patients.48 Responses to gem-
non–5-FU–based therapy.56 Patients who received citabine-based therapy have also been noted, although
5-FU combined with a platinum agent had a higher the number o patients treated has been small. Although
ORR (46% vs 16%; P <.01) and longer median pro- taxanes have not been classically used or treatment o
gression-ree survival (PFS) (8.7 vs 3.9 months; P <.01) patients with SBA, a recent single-center retrospective
than patients who received other chemotherapy regi- study evaluating the activity o taxanes in SBA dem-
mens. Although not statistically signicant, there was onstrated clinical activity with responses noted in 30%
also a trend toward improved median OS times in patients, SD in 35%, and PD in 35% patients.57 Median
patients who received 5-FU plus a platinum agent (14.8 TTP and OS were 3.8 and 10.7 months, respectively.
vs 12.0 months; P =.1). A French multicenter study in The remaining prospective phase II studies evalu-
SBA receiving rontline chemotherapy with 5-FU (n = ated the role o targeted therapy and immunotherapy in
10), FOLFOX (n = 48), (5FU + irinotecan) (n = 19), and patients with metastatic SBA. A single-institution study
5-FU-cisplatin (n = 16) demonstrated median PFSs o conducted at MDACC evaluated CAPOX with bevaci-
7.7, 6.9, 6.0, and 4.8 months, respectively.48 The cor- zumab (anti–vascular endothelial growth actor [VEGF]
responding median OSs were 13.5, 17.8, 10.6, and antibody) in 30 patients with advanced small bowel
9.3 months, respectively.48 In the subgroup analysis, or ampullary adenocarcinomas. The ORR was 48.3%,
patients treated with 5-FU–cisplatin had decreased PFS with a median PFS o 8.7 months and median OS o
(P <.01) and OS (P =.02) compared with those treated 12.9 months.58 An exploratory analysis comparing this
with oxaliplatin-based chemotherapy.48 regimen to a prior phase II clinical trial o CAPOX alone
rom the same institution did not demonstrate signi- APPENDICEAL TUMORS
cant dierence in ORR or PFS. Another phase II study
conducted at MDACC evaluated the ecacy o panitu- Appendiceal tumors encompass a rare and diverse
mumab (anti–epidermal growth actor receptor [EGFR] group o neoplasms. Epidemiologic studies based on
antibody) in metastatic RAS wild-type SBA or ampul- the SEER database have shown a steady increase in
lary adenocarcinoma given the known benets o EGFR incidence rom approximately 0.2 cases per 100,000
antibodies in metastatic CRC.59 The study was stopped in the 1970s, to approximately 0.6 per 100,000 in
early because o utility with no responses in nine 2000, to current estimates o between 1 and 4 per
patients, SD in two patients, and PD in seven patients. 100,000.61–63 There are no denitive risk actors or
Median PFS and OS were 2.4 and 5.7 months, respec- developing appendiceal cancer. 64 In comparison,
tively. No patients had extended RAS mutations (exons this is 10- to 40-old less common than colon can-
2/3/4), but two patients had BRAF G469A, and one cer, which in the United States has an incidence o
patient had PIK3CA H1074R mutations. The authors approximately 40 per 100,000. Historically, appendi-
proposed that these ndings may relate to the primarily ceal tumors have been grouped together with CRCs,
midgut and oregut derivation o the small bowel and and as o 2020, the National Comprehensive Cancer
ampulla. Finally, the ZEBRA trial was a prospective, Network guidelines still suggest that patients with
multicenter phase II study evaluating pembrolizumab appendiceal tumors should be treated similar to those
(anti–programmed cell death protein 1 [PD-1] antibody) with colon tumors. However, there is a growing body
in SBA patients given the more requent microsatel- o evidence that appendiceal tumors, in which out-
Chapter 31
lite instability, greater programmed cell death ligand comes are strongly determined by histologic subtype,
1 expression compared to CRC.60 Median PFS and OS are quite distinct rom CRC at the molecular level. 65,66
were 2.8 and 6.9 months, respectively. Both microsatel- Recognizing the clear dierences in biology, natural
lite instability–high (MSI-H) patients achieved PR and history, and response to therapy between CRC and
remained alive without progression. O patients with appendix cancer, there is now an eort underway to
microsatellite SD, disease control rate was 50% with a develop national guidelines specically or appendi-
PR noted. The ndings rom these studies taken together ceal tumors. Appendiceal tumors comprise two major
with the dierences in mutational proles between SBA types: appendiceal carcinoid tumors and appendiceal
and CRC described previously suggest that approaches epithelial tumors, each accounting or roughly hal o
to SBA should not be extrapolated rom CRC but should all appendiceal neoplasms.67 This section on appen-
be based on data derived rom SBA. diceal tumors discusses the management o these
two tumor types (carcinoid and epithelial) as well
The MD Anderson Approach to Metastatic as the unusual clinical syndrome o pseudomyxoma
Disease peritonei (PMP).
The substantial response rates and prolonged OS
reported with modern-day chemotherapy combina-
Incidence
tions in SBA strongly argue or an aggressive approach Data derived rom the SEER database o the National
in treating patients with metastatic SBA. Given the Cancer Institute between 1973 and 1998 revealed that
encouraging results with CAPOX and FOLFOX or the most common histologic subtypes o malignant
metastatic SBA, we generally recommend these regi- tumors o the appendix were adenocarcinomas (67%)
mens at MDACC. Ater rontline CAPOX or FOLFOX and carcinoids (33%).68 However, this SEER analysis
chemotherapy, patients are then treated with an irino- captured neither adenomatous tumors nor benign car-
tecan-based regimen. In addition, patients with limited cinoids. The SEER subtypes o adenocarcinoma were
metastatic disease who respond to initial chemother- mucinous type (56%), nonmucinous intestinal type
apy are considered or surgical resection i all disease (38%), and signet ring cell type (6%). A more recent
sites can be successully excised. Data or use o anti- SEER-based analysis o 7170 tumors again ound muci-
VEGF and anti-EGFR targeted antibodies in SBA are nous adenocarcinoma most common (39%) ollowed
limited, and urther investigation into their clinical by nonmucinous adenocarcinoma (also called colonic
benet is indicated. Although anti–PD-1 immunother- type) (33%), goblet cell carcinoid (13%), malignant
apy is approved or use in MSI-H SBA, urther studies carcinoid (9%), and signet ring cell carcinoma (6.5%).62
are needed to comprehensively evaluate the benet Alternatively, in a separate study o 7970 appendec-
rom these agents in microsatellite-stable SBA. More tomy specimens, tumors were identied in 1% o
eective treatments or patients with SBA remain specimens, with carcinoids representing 57% o all
needed, and participation in clinical trials or this rare tumors identied.67 Adenomas and adenocarcinomas
tumor type is strongly encouraged. A proposed treat- represented 18% and 11% o the identied tumors,
ment algorithm or SBA is presented in Figure 31–2. respectively.
Small bowel
adenocarcinoma
Pathology review
and chest, abdominal,
and pelvic CT
Locoregional Symptomatic
No Distant metastasis Yes
disease primary tumor
Locally advanced Medically Oligo liver Consider

Resectable Metastatic disease
unresectable inoperable metastasis metastasectomy
Obstruction
Multidisciplinary bleeding
Unresectable PS 0–2
discussion
PS 3–4
Palliative chemotherapy
PS 3–4
• CAPOX (preferred)
Best supportive care
C 31 Small Bowel Cancer and Appendiceal Tumors

Neoadjuvant therapy • FOLFOX (preferred)
• Chemo-XRT (5-FU) Revisit or hospice
• FOLFIRI • Palliative resection (PS < 2)
• FOLFOX or CAPOX surgery Progressive
Clinical trial • Enteric stenting (PS ≥ 2)
disease
(duodenum)
• Palliative XRT (duodenal)
Progressive PS 3–4
PS 0–2
disease
No Observation Progressive
Clinical trial disease
Pancreaticoduodenectomy
• Duodenum Palliative chemotherapy
Wide segmental resection + regional Nodal • FOLFIRI (preferred)
lymphadenectomy involvement • Gemcitabine PS 0–2
• Jejunum or Ileum
Clinical trial
• Duodenum (third or fourth portion)
Yes Adjuvant chemotherapy Clinical trial

• 5-FU/capecitabine
• FOLFOX/CAPOX
FIGUre 31–2 Treatment algorithm or small bowel adenocarcinoma. (Reproduced with permission rom Raghav K. and Overman M. J. Small bowel adenocarcinomas—
existing evidence and evolving paradigms. Nat Rev Clin Oncol. 2013 Sep;10(9):534-544.)
717
Chapter 31
Presentation and Prognosis a consensus classication and reporting system was

adopted that has greatly helped to standardize the
Appendiceal tumor presentation is bimodal; tumors histopathologic categorization o appendix cancer.70
are generally either identied incidentally at the time Importantly, these guidelines distinguished mucinous
o pathological review o appendectomy specimens neoplasms without inltrative invasion as a separate
or only ater the tumor has spread to the peritoneal entity rom adenocarcinoma, which by denition had
space. Symptoms o appendicitis are most oten the presence o inltrative invasion. Mucinous neoplasms
presenting symptom or early-stage tumors, espe- without inltrative invasion were urther subdivided
cially with tumors located at the base o the appendix into low grade (low-grade appendiceal mucinous neo-
where obstruction is more likely to occur. Presenting plasm [LAMN]) and high grade (HAMN). Uniorm cri-
symptoms o advanced appendiceal disease refect teria or PMP, a unique clinical syndrome with spread
the nonspecic abdominal symptoms associated o tumor and ascites within the peritoneal cavity but
with peritoneal involvement: abdominal pain and not to distant organs, were also developed dierentiat-
distention, altered bowel motility, and early satiety. ing PMP rom acellular mucin.69
Metastatic carcinoid tumors may also present with As would be expected, patients with early-stage
symptoms related to the carcinoid syndrome such as tumors identied incidentally at the time o appendec-
episodic fushing, wheezing, and diarrhea. Patient age tomy have a better prognosis than patients who are
at presentation diers depending on histologic sub- diagnosed ater symptoms develop. For these early-
type o the tumor, with carcinoid tumors occurring in stage patients, the distinction between LAMN and
Chapter 31
younger patients (goblet cell carcinoid, 54 years; malig- adenocarcinoma has important prognostic implica-
nant carcinoid, 43 years) relative to adenocarcinomas tions. In a study o 107 patients with localized LAMN
(mucinous, 59 years; nonmucinous, 64 years; signet o adenocarcinoma, no LAMNs conned to the appen-
ring, 58 years).62 dix experienced recurrence at a median ollow-up
The prognosis or patients with appendiceal cancer period o 6 years.71 LAMNs that had extra-appendiceal
is strongly dependent on the histopathologic subtype spread did recur and had OS rates o 100%, 86%, and
o the tumor, with patients who have carcinoids hav- 45%, at 3, 5, and 10 years, respectively. In contrast,
ing a signicantly better survival than do patients with mucinous adenocarcinomas were more likely to have
adenocarcinomas (Fig. 31–3).68 However, longitudinal extra-appendiceal spread and had worse OS, o 90%
data in appendiceal cancer can be dicult to interpret and 44% at 3 and 5 years, respectively.
because o inconsistent terminology in describing the The importance o grade is captured in the eighth
multiple subtypes o appendiceal tumors.69 In 2016, edition o the American Joint Committee on Cancer
100
Malignant carcinoid
80
Goblet cell carcinoid
60
Survival (%)
Colonic-type adenocarcinoma
40
Mucinous adenocarcinoma
20
Signet ring cell carcinoma
0
0 1 2 3 4 5 6 7 8 9 10
Years after diagnosis
FIGUre 31–3 Overall survival o malignant appendiceal cancers according to the Surveillance, Epidemiology and End Results
registry (SEER), stratied by histological subtype. (Reproduced with permission rom McCusker ME, Coté TR, Clegg LX, et al.
Primary malignant neoplasms o the appendix, Cancer 2002 Jun 15;94(12):3307-3312.)
(AJCC) staging or appendix cancer, which dieren- to the prognostic impact in appendiceal adenocarcino-
tiates between stages IVA and IVB (Table 31–4).33,66 mas.66 Among carcinoid tumors, pure malignant carci-
There have been conficting reports regarding the noids have the best OS (median, 396 months) ollowed
prognosis o patients with mucinous adenocarcinoma by goblet cell carcinoids (median, 162 months). Gob-
relative to those with nonmucinous or colonic-type let cell carcinoids, also called goblet cell tumor (GCT),
adenocarcinoma,72 with recent report that mucinous adenocarcinoma ex goblet cell carcinoid, or mixed
moderately dierentiated adenocarcinomas appear to adenoneuroendocrine carcinoma, have a mixed his-
have a prognosis more akin to mucinous well-dieren- tologic appearance that includes neuroendocrine cells
tiated carcinomas as opposed to mucinous poorly di- and goblet cells, as well as eatures o adenocarcinoma,
erentiated carcinomas.73 Despite these nuances, grade increasing percentage o the adenocarcinoma propor-
trumps all clinico-molecular parameters with regards tion associated with worse outcomes.74
taBLe 314 Tumor, Node, Metastasis Staging or Appendiceal Carcinomas
Primary Tumor (T)

T0 No evidence o primary tumor
Chapter 31
Tis Carcinoma in situ (intramucosal carcinoma; invasion o the lamina propria or extension into but not
through the muscularis mucosae)
Tis(LAMN) LAMN conned by the muscularis propria; acellular mucin or mucinous epithelium may invade into
the muscularis propria
T1 and T2 are not applicable to LAMN; acellular mucin or mucinous epithelium that extends into the
subserosa or serosa should be classied as T3 or T4a, respectively
T1 Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria)
T2 Tumor invades the muscularis propria
T3 Tumor invades through the muscularis propria into the subserosa or the mesoappendix
T4 Tumor invades the visceral peritoneum, including the acellular mucin or mucinous epithelium
involving the serosa o the appendix or mesoappendix, and/or directly invades adjacent organs or
structures
T4a Tumor invades through the visceral peritoneum, including the acellular mucin or mucinous
epithelium involving the serosa o the appendix or serosa o the mesoappendix
T4b Tumor directly invades or adheres to adjacent organs or structures
N1 One to three regional lymph nodes are positive (tumor in lymph node measuring ≥0.2 mm) or any
number o tumor deposits is present, and all identiable lymph nodes are negative
N1a One regional lymph node is positive
N1b Two or three regional lymph nodes are positive
N1c No regional lymph nodes are positive, but there are tumor deposits in the subserosa or mesentery
N2 Four or more regional lymph nodes are positive
Distant Metastasis (M)
M1aa Intraperitoneal acellular mucin, without identiable tumor cells in the disseminated peritoneal
mucinous deposits
M1b Intraperitoneal metastasis only, including peritoneal mucinous deposits containing tumor cells
M1c Metastasis to sites other than peritoneum
a
For specimens containing acellular mucin without identiable tumor cells, eforts should be made to obtain additional tissue or thorough histologic examination
to evaluate or cellularity.
(Continued)
taBLe 314 Tumor, Node, Metastasis Staging or Appendiceal Carcinomas (Cont.)
Histologic Grade (G)

GX Grade cannot be assessed
G1 Well diferentiated
G2 Moderately diferentiated
G3 Poorly diferentiated
Stage Grouping
Stage 0 Tis or Tis(LAMN) N0 M0
Stage I T1 N0 M0
T2 N0 M0
Stage IIA T3 N0 M0
Stage IIB T4a N0 M0
Stage IIC T4b N0 M0
Stage IIIA T1 N1 M0
T2 N1 M0
Stage IIIB T3 N1 M0
Chapter 31
T4 N1 M0
Stage IIIC Any T N2 M0
Stage IVA Any T Any N M1a
Any T Any N M1b G1
Stage IVB Any T Any N M1b G2, G3, Gx
Stage IVC Any T Any N M1c Any G
LAMN, low-grade appendiceal mucinous neoplasm.
Used with permission o the American College o Surgeons, Chicago, Illinois. The original source or this inormation is the AJCC Cancer Staging System (2020).
Appendiceal Carcinoid Tumors entail a right hemicolectomy with complete removal

Similar to other intestinal carcinoid tumors, appendi- o the base o the appendix, mesoappendix, and drain-
ceal carcinoid tumors arise rom neuroendocrine cells ing lymph nodes.
within the lamina propria and submucosa. Appen- The most useul criteria or determining the need
diceal carcinoid tumors can secrete serotonin and or a complete right hemicolectomy are tumor size (≥2
vasoactive substances responsible or the carcinoid cm in diameter) and mesoappendix involvement.77 In
syndrome, although this is rarely seen in patients in a retrospective study o appendiceal carcinoids, Moer-
the absence o extensive liver metastases. Appendiceal tel et al78 reported no metastases in 127 patients with
carcinoid tumors are usually seen in young patients tumors smaller than 2 cm, whereas metastatic disease
and are seen slightly more oten in women.75,76 Goblet was seen in three o the 14 patients with tumors 2 to
cell carcinoids or GCT, overall a rare histologic variant 3 cm in size and our o the nine patients with tumors
o carcinoid tumors, are actually more common in the 3 cm or larger. Patients with GCT are generally treated
appendix than pure carcinoid tumors. Characterized as having an appendiceal adenocarcinoma. O note,
by malignant cells that demonstrate both exocrine and a small study ound no benet in using 68Ga-DOT-
neuroendocrine characteristics, GCTs have outcomes ATATE positron emission tomography–computed
in between that o a carcinoid and that o an adenocar- tomography (PET-CT) or ollow-up in these patients.79
cinoma (see Fig. 31–3). For patients with metastatic malignant carcinoid
tumors, the use o somatostatin analogues can alle-
viate the symptoms o the carcinoid syndrome but
Management o Appendiceal Carcinoids rarely causes objective tumor regression. Given the
Because most appendiceal carcinoid tumors are dis- slow-growing nature o appendiceal carcinoid tumors,
covered incidentally rom an appendectomy speci- local modality therapies such as hepatic embolization
men, a critical and somewhat controversial oncologic or surgical resection may also be benecial in selected
question relates to the need or perorming a more patients with metastatic disease. For additional inor-
complete surgical staging procedure. For appendiceal mation on management o this type o tumor, please
cancers, a complete surgical staging procedure would reer to Chapter 34 on neuroendocrine cancers.
Appendiceal Epithelial Tumors a patient with a ruptured ovarian cystadenoma who

had copious gelatinous intraperitoneal ascites (Fig.
Little is known about the risk actors or cause o epi- 31–4).84 This term has been applied broadly to include
thelial tumors o the appendix. Historically viewed as any mucinous tumor type involving the peritoneal
a subset o CRC, epithelial tumors o the appendix cavity with any histologic grade o dierentiation.
have a markedly dierent biology and natural history PMP is a clinical syndrome o malignant mucinous
relative to that o adenocarcinomas o the colorectum peritoneal dissemination and can sometimes arise
and do not align with any o the consensus molecu- rom tumors other than the appendix (colon, ovary,
lar subtype (CMS) o CRC.80 In particular, a subset o urachus, pancreas); notably, it does not reerence
appendiceal epithelial tumors that have disseminated the histopathologic characteristics o the tumor o
peritoneal mucinous deposits derived rom a ruptured origin. 69 To reduce conusion and better segregate
appendiceal mucinous adenoma can demonstrate patients by clinical outcome, PMP is now subdivided
excellent long-term survival with aggressive cytoreduc- into three groups: low-grade mucinous PMP, high-
tive surgery (CRS) and hyperthermic intraperitoneal grade mucinous PMP, and high-grade mucinous PMP
chemotherapy (HIPEC).81,82 This contrasts the result with signet ring cells.
o the recent PRODIGE (Partenariat de Recherche en
Oncologie Digestive) 7 trial in patients with CRC that
showed no additional benet to HIPEC in addition to Low-Grade Mucinous Pseudomyxoma Peritonei
CRS.83 It is thought that most appendiceal epithelial Low-grade mucinous PMP, previously reerred to as
Chapter 31
tumors begin as a mucinous adenoma with appendi- disseminated peritoneal adenomucinosis (DPAM),85 is
ceal distention caused by excessive mucin production. characterized by peritoneal lesions composed o abun-
On gross inspection or radiographic evaluation, this dant extracellular, mucin-containing, scant, and simple
dilated mucin-lled appendix is requently reerred to to ocally prolierative mucinous epithelium with little
as a mucocele. With progressive growth, the appen- cytologic atypia or mitotic activity, with or without
diceal lumen can become obstructed and result in an associated appendiceal mucinous adenoma.85 In
increased intraluminal pressure within the appendix, essence, the underlying epithelium in low-grade muci-
which can cause the appendix to rupture. Appendiceal nous PMP may have low-grade adenomatous changes
rupture represents the critical step in the dissemination but may not have any evidence o inltrative invasion
o the mucinous appendiceal tumor to the peritoneal or carcinoma. However, there must be observed neo-
cavity. For this reason, it is critical that care is taken plastic cells; mucin without neoplastic cells is termed
when surgically removing an appendiceal mucocele to acellular mucin. Notably, in the setting o an appendiceal
prevent rupture and peritoneal seeding during a rou- primary tumor, acellular mucin within the abdominal
tine appendectomy.71 When resecting an appendiceal cavity is classied pM1a by the AJCC Cancer Staging
mucocele, the peritoneum should be inspected closely Manual, eighth edition, whereas deposits with tumor
to evaluate any evidence o dissemination to the peri- cells are classied M1b.33 Low-grade mucinous PMP
toneal cavity. During pathological examination o the
appendix, any fuid or mucus in the peritoneal spaces
surrounding the appendix should undergo cytologic
examination.77 In patients with localized disease, the
presence o carcinoma (as opposed to LAMN, which
does not have invasive eatures) requires a completion
right hemicolectomy or oncologic staging.
Histopathologic Subtypes o Epithelial

Appendiceal Tumors
As noted previously, the oten inconsistent and ambig-
uous terminology o appendiceal tumors was updated
with consensus guidelines in 2016.70 Here we will use
the new consensus terminology but also list historical
terminology or reerence.
Pseudomyxoma Peritonei
PMP, literally translated rom Latin as “alse mucinous
tumor o the peritoneum,” is a term originally used by FIGUre 31–4 Peritoneal mucin in a patient undergoing
Werth in 1884 to describe the pathological ndings in surgical cytoreduction.
subgroup o tumors demonstrates the classic PMP clin- should be conducted.86 When molecular and immu-
ical syndrome o massive amounts o benign-appear- nohistochemical evaluations have been perormed on
ing mucinous ascites that over time slowly ll the patients with both appendix and ovarian involvement,
entire peritoneal cavity (Fig. 31–5). Although spread to these evaluations have generally demonstrated the pri-
the peritoneal cavity is present, these tumors do not mary site o disease as the appendix87–89
metastasize to regional lymph nodes or via hematog-
enous spread to the liver or other distant sites. High-Grade Mucinous Pseudomyxoma Peritonei
Patients with low-grade mucinous PMP typically and Pseudomyxoma Peritonei-Grade Mucinous
present with gradually increasing abdominal girth. For Pseudomyxoma Peritonei with Signet Ring Cells
women, DPAM may present as a new ovarian mass,
and or men, it may present as a new-onset hernia. In I evidence o destructive, inltrative invasion or high-
women, secondary involvement o the ovaries is com- grade cytologic atypia is present, then the pathologi-
mon, and because the histopathologic eatures o low- cal diagnosis o high-grade mucinous PMP should be
grade mucinous PMP rom a primary ovarian tumor used69 Previously reerred to as peritoneal mucinous
can be quite similar to those o appendiceal origin, a carcinomatosis (PMCA),85 these tumors are character-
thorough pathological examination o the appendix ized by peritoneal lesions composed o more cellular
mucinous epithelium with the architectural and cyto-
logic eatures o carcinoma, with or without an associ-
ated primary mucinous adenocarcinoma. I high-grade
Chapter 31
eatures are ound, even ocally, the lesion should be

A
classied as high grade, which makes adequate sam-
pling and review o the complete resected specimen
critical. High-grade mucinous PMP with signet ring
cells, previously called peritoneal mucinous carcino-
matosis with signet ring cells (PMCA-S), is included as
a separate category given the worse prognosis associ-
ated with signet ring cells. In an analysis o 109 patients
with clinical eatures o PMP, the 5- and 10-year sur-
vival rates or patients with low-grade disease were
75% and 68%, respectively. This was in stark contrast
to those with high-grade disease, who had 5- and
10-year survival rates o 14% and 3%90 (Fig. 31–6).
Mucinous Appendiceal Adenocarcinoma

B
The most common type o epithelial appendiceal
tumor, like PMP, mucinous appendiceal adenocarci-
noma really behaves like two distinct disease entities
with low-grade tumors having a much more indolent
clinical course relative to high-grade tumors. These
tumors are dierentiated rom LAMN and HAMN by
the presence o inltrative invasion and by denition
more than 50% o the cross-sectional area histologically
comprises extracellular mucin.69 The consensus guide-
lines recognize a trinary well-, moderately, or poorly
dierentiated grading scheme with poorly dierenti-
ated carcinomas showing little or no gland ormation.
A study o 201 mucinous appendiceal carcinomas has
shown the trinary grading systems is strongly predic-
tive o survival with 94%, 71%, o 30% o patients
FIGUre 31–5 Histology rom a patient with well dier-
alive at 5 years or well-, moderately, and poorly di-
entiated mucinous appendiceal adenocarcinoma with the
erentiated tumors, respectively.91 Although mucinous
clinical syndrome o pseudomyxoma peritonei (PMP). A.
Adenoma-like epithelium with acellular mucin pools dissect- appendiceal adenocarcinoma are invasive tumors with
ing through the brous stroma with chronic infammation distant metastatic potential, the majority o these
(×40). B. Adenoma-like epithelium with abundant acellular tumors remain localized to the peritoneal cavity. Even
mucin (×400). in the subset o patients with aggressive-appearing
1.00
Survival probability
0.75
0.50
0.25
0.00
0 20 40 60 80 100 120
Months after diagnosis
Well differentiated Moderately differentiated

Poorly differentiated Undifferentiated
Unknown
FIGUre 31–6 Overall survival o appendiceal adenocarcinoma stratied by histological grade. (Reproduced with permission
Chapter 31
rom Overman MJ, Fournier K, Hu CY, et al: Improving the AJCC/TNM staging or adenocarcinomas o the appendix: the prog-
nostic impact o histological grade, Ann Surg 2013 Jun;257(6):1072-1078.)
histologies, the rate o distant hematogenous metas- Similarly, appendix tumors have less requent TP53
tases remains low. In one retrospective study o 90 mutation (Fig. 31–7).66 The requency o GNAS muta-
appendiceal adenocarcinomas with either poor di- tion is much higher in appendix cancer, with a particu-
erentiation or signet ring cell morphology, the rate o larly strong enrichment in low-grade tumors. Nearly
extraperitoneal metastases was only 17%.92 all GNAS mutations occur in codon R201, with R201H
and R201C being the most common substitutions. O
note, Although GNAS-specic chemical inhibitors do
Nonmucinous or Colonic-Type not yet exist, the cystine in the R201C mutation could
Adenocarcinoma be targeted similar to that in KRAS G12C. The re-
Occurring somewhat less requently than mucinous quency o KRAS mutation is similar in appendix can-
tumors, nonmucinous or colonic-type adenocarcinomas cer and CRC. Unortunately, the incidence o currently
o the appendix demonstrate a dierent tumor biol- “actionable” mutations in genes such as HER2 and
ogy than mucinous appendiceal tumors. These cancers EGFR is quite rare in appendiceal tumors, as is mic-
are generally more aggressive and less likely be well rosatellite instability. Importantly, low-grade appendi-
dierentiated and appear to behave more like colonic ceal adenocarcinomas have distinct molecular prole
adenocarcinomas. In a study by Kabbani et al,93 43% rom high-grade tumors characterized by requent
o patients with nonmucinous appendiceal adenocarci- mutation in GNAS and KRAS and absence o TP53
noma had evidence o extraperitoneal metastases. The mutation (Fig. 31–8).65,66 These molecular dierences
patients with nonmucinous carcinomas in this study had and the distinct indolent disease course o low-grade
a signicantly worse OS and DFS than those with muci- tumors suggests strongly that low-grade appendix
nous carcinomas, although given the critical importance adenocarcinoma is a distinct disease entity rom high-
o grade in determining survival in mucinous tumors, it grade appendix adenocarcinoma.
is dicult to make this direct comparison. There are limited transcriptomic data on appendi-
ceal cancer, although a pilot study o microarray gene
Molecular Profles expression proling o 26 appendiceal adenocarcino-
mas showed clear dierences between appendiceal
Recent large sequencing studies, including indepen- adenocarcinoma and CRC.94 A second study o 24 addi-
dent cohorts o 703 and 266 appendiceal tumors have tional tumors identied a 139 gene signature associated
revealed several key molecular dierences between with poor prognosis specically in low-grade tumors.95
appendiceal tumors and CRC and between dier- Unsupervised clustering o appendiceal tumors with
ent subtypes o appendiceal tumors.65 Most notably, all o the TCGA tumors and cancer cell lines rom the
APC mutation, which is a hallmark eature o CRC, Cancer Cell Line Encyclopedia96 using the Celligner
is uncommon in all subtypes o appendix cancer. method97 has shown that appendiceal tumors cluster
80
72.5
Proportion of cases (%) with mutation

70 67.5 AA
62.4
60 All CRC
56.2 56.9 57.2
55.4
50.8
Right-sided CRC 51.5
50
45.3 Left-sided CRC
40
30 28.1 26.9
23.4
20 16.9 17.8 16.6

13.6 13.4
11.7 12.0
10 9.1
4.2
2.0 1.0
0
RAS GNAS TP53 SMAD4 PIK3CA APC
FIGUre 31–7 Frequency (percentage) o mutations (>3% incidence) in tumor tissue rom patients with appendix cancer (a)
and distribution o mutation (top six most requently mutated genes) by grade or dierentiation as compared to colorec-
Chapter 31
tal cancer (CRC). (Reproduced with permission rom Raghav K, Shen JP, Jácome AA, et al: Integrated clinico-molecular pro-
ling o appendiceal adenocarcinoma reveals a unique grade-driven entity distinct rom colorectal cancer, Br J Cancer 2020
Oct;123(8):1262-1270.)
70 69.2
64 Well-D Mod-D Poor-D All
Proportion of cases (%) with a mutation
60
54.8
50 48.7
41.8
40
32
30 27.8
26
25.6
22.6 20 19.0
20 17.7
16
12.8 17.3 12.8
2.8
10.1 13.1
10 8.3
7.7 7.6
7.
4
0.0
0
RAS GNAS TP53 SMAD4 PIK3CA APC
FIGUre 31–8 Frequency o the top six cancer mutations in appendiceal adenocarcinomas stratied by grade. Comparisons
are shown or only signicant dierences (P <.05). D, dierentiated; Mod, moderately; Poor, poorly. (Reproduced with permis-
sion rom Raghav K, Shen JP, Jácome AA, et al: Integrated clinico-molecular proling o appendiceal adenocarcinoma reveals a
unique grade-driven entity distinct rom colorectal cancer, Br J Cancer 2020 Oct;123(8):1262-1270.)
closely together, away rom any other tumor type and (eIF4E) as well as RAF and EGFR in the RAS-MAPK
also away rom any cell line model. This indicates that (mitogen-activated protein kinase) pathway.
appendiceal cancer is a distinct entity rom CRC and The ability to measure circulating tumor DNA
that currently, there are no representative cell line mod- (ctDNA) in the blood has proven valuable in many GI
els o appendix cancer. Gene Set Enrichment Analysis malignancies; however, the sensitivity o these “liq-
o appendix cancer transcriptomes has shown upregu- uid biopsies,” particularly in low-grade appendiceal
lation o the eukaryotic translation initiation actor 4E tumors, seems to be low. The ultimate answer to this
question will require a cohort o patients with paired only 26% developed recurrence.100 The median time to
blood and tissue sequencing; however, a 73-gene panel recurrence was 26 months. Repeat CRS was attempted
identied a mutation in blood in only 61% o patients in 26% o these patients and was associated with bet-
versus an expected 94% based on tissue sequencing.65,98 ter survival than or recurrent patients who did not
Interestingly, the disparity was much greater or muta- undergo a second CRS. These data suggest that in
tions in gene characteristic o low-grade tumors, such patients who develop recurrence ater an extended dis-
as GNAS (34% vs 2.6%, 13-old), relative to mutations ease-ree interval, repeat CRS can be attempted with
characteristic o high-grade tumors, such as TP53 (35% avorable results or at least some patients.
vs 23%, 1.5-old), suggesting that low-grade tumors are
less likely to shed DNA into the blood. The prognostic Hyperthermic Intraperitoneal Chemotherapy
implications o having detectable ctDNA in the blood
remain unknown, but this could potentially have value In an attempt to diminish the rate o disease recur-
as a biomarker o high-risk disease. rence ater CRS, the administration o intraperitoneal
chemotherapy ater a surgical cytoreduction has been
used to try to treat any residual microscopic disease in
Treatment the peritoneal cavity. Historically, a number o meth-
Cytoreductive Surgery ods o delivering intraperitoneal chemotherapy have
been used, although the most commonly used method
Because o the relative rarity o this disease, prospec- is HIPEC administered at the time o cytoreduction.
Chapter 31
tive randomized clinical trials studying the treatment o At MDACC, ater complete CRS, the standard proce-
appendiceal epithelial tumors are lacking. The major- dure is to administer heated mitomycin C at a dose
ity o data evaluating the various treatment modalities o 25 mg/m2 or patients who are chemotherapy naïve
in this disease have been derived rom retrospective, or 20 mg/m2 or patients who have received previous
single-institution studies. Surgical cytoreduction has chemotherapy in a volume o 5 to 6.5 L o electrolyte
been the primary mode o therapy or these tumors solution at a fow rate o 3 to 3.5 L/min. Intraoperative
based on the ollowing actors: hemodynamic monitoring and thermal monitoring
1. Lack o extraperitoneal disease spread are essential or optimal outcomes in these patients.
2. Primarily mucinous nature o peritoneal deposits The HIPEC is continued or 90 minutes with vigor-
3. Indolent growth rate (or low-grade tumors) ous shaking o the closed abdomen. On completion o
4. Limited activity o systemic chemotherapy HIPEC, necessary bowel anastomoses are perormed,
5. Lack o an eective systemic mucolytic agent and gastrostomy and jejunostomy tubes are placed or
The goal o surgical cytoreduction is complete postoperative management o nutritional deciencies
tumor removal rom the peritoneal cavity. Because o and prolonged gastric ileus.
the large surace area o the peritoneum, surgical cyto- Intraperitoneal administration o chemotherapy
reduction to remove all visible sites o disease can be oers an advantage o providing high local concen-
challenging. Optimal CRS may involve removal o the trations o drug directly to the targeted peritoneal
appendix, right colon, intraperitoneal tumor debulk- suraces, and hyperthermia provides a synergistic anti-
ing, resection o multiple abdominal and pelvic organs tumor eect when combined with chemotherapy.101
with peritoneal tumor studding, and stripping o all However, as a locally applied modality, the maximum
involved parietal peritoneum.99 Ater successul surgi- penetration into tumor tissue is usually limited to 2 to
cal cytoreduction, patients can experience reaccumula- 5 mm rom the surace.102 At present, no randomized
tion o mucinous peritoneal implants, which may be study has compared the benet o adding HIPEC to sur-
complicated by brosis rom prior surgery, requiring gical cytoreduction, although single-institution series
repeated surgical cytoreductive procedures. have indirectly suggested a benet when DFS rates
In a 97-patient series rom Memorial Sloan Kettering o patients treated with surgical cytoreduction and
Cancer Center, in which surgical resection alone repre- HIPEC (37%–57%)87,103 are compared with the histori-
sented the primary treatment modality in more than cal rates o surgical cytoreduction alone (9%–12%).81,88
two thirds o the patients, the 5-year OS rates were CRS with HIPEC represents an aggressive treat-
90% or patients with low-grade and 50% or patients ment requiring signicant surgical expertise and
with high-grade tumors.81 In the 55% o patients who should only be conducted at centers experienced in
underwent a complete cytoreduction o all visible perorming peritoneal cytoreduction. Operation time
tumors, 91% had recurrent disease. The average num- is approximately 8 to 12 hours, with an average hos-
ber o surgical cytoreductions that patients underwent pital stay o 20 to 25 days. The 30-day postoperative
in this study was 2.2, with a range o 1 to 6.81 These mortality and morbidity rates range rom 0% to 12%
ndings are contrasted by a retrospective analysis o and 12% to 56%, respectively.87,89 In one o the larg-
512 peritoneal metastatic appendiceal tumors in which est retrospective multi-institutional registry-based
study o 2298 patients with PMP originating rom an nodules on the peritoneal surace; the previous surgi-
appendiceal mucinous neoplasm undergoing CRS, the cal score, a measure o the extent o prior cytoreduc-
reported median OS was 16.3 years, with a 10-year tion; and the extent o disease on the small bowel and
survival rate o 63%.104 The treatment-related mor- small bowel mesentery.81,82,105,106 The prognostic value
tality was 2%, and major operative complications o these dierent actors relates primarily to their abil-
occurred in 24% o cases.104 A high peritoneal carcino- ity to predict the likelihood o obtaining a complete
matosis index (PCI), lack o complete cytoreduction, cytoreduction. For patients who cannot undergo com-
and lack o HIPEC were associated with poorer PFS plete CRS, the benet obtained rom an incomplete
and OS.104 cytoreduction remains uncertain. I complete CRS can-
The prognosis or patients undergoing CRS with not be perormed, a surgical cytoreduction is gener-
HIPEC is primarily dependent on two critical ac- ally considered only i there are particular symptoms
tors: histologic classication and completeness o that can be palliated by tumor debulking. Given that
surgical resection. A quantitative score, the com- HIPEC has limited tumor penetration, use o HIPEC
pleteness o cytoreduction (CC) score proposed by should be limited to patients with a complete or near-
Sugarbaker and colleagues, 82 categorizes the CC complete CRS.
based on the size o nodules remaining at the end
o surgery: CC-0 (no visible disease), CC-1 (nod- Systemic Chemotherapy
ules <0.25 cm), CC-2 (nodules 0.25 to <2.5 cm),
and CC-3 (nodules ≥2.5 cm). In an analysis o 224 The role o systemic chemotherapy has not been well
Chapter 31
patients with low-grade histology, Sugarbaker et al 82 delineated in appendiceal epithelial tumors and has
ound that whereas patients with complete cyto- generally been used in patients who are not candidates
reduction (CC-0 or CC-1) had a 5-year OS rate o or surgical cytoreduction.99 The challenges o using
86%, patients with incomplete cytoreduction (CC-2 systemic chemotherapy to treat appendiceal tumors
or CC-3) had a 5-year OS rate o 20% (P <.0001) are numerous. Because it is a rare disease, it has been
(Fig. 31–9). The importance o CC has been condicult to conduct clinical trials specically or appen-
rmed by other authors, although various methods diceal tumors. Factors urther complicating the devel-
o categorizing CC have been used.87,103 opment o eective chemotherapy include the marked
Additional prognostic measures include the PCI, a heterogeneity between low- and high-grade tumors,
quantitative measure o the size and distribution o the relatively slow-growing nature o the disease,
the primarily mucinous component o the tumors,
and challenges in radiographically measuring disease
response. In the absence o data specic to appendiceal
adenocarcinoma, chemotherapy developed or CRC
1.0 has traditionally be used or these tumors. Tradition-
Complete (n = 250) ally, PMP has been considered resistant to systemic
Incomplete (n = 135) chemotherapy, although a phase II study evaluating
0.8
the use o concurrent mitomycin C and capecitabine
in patients with advanced, unresectable high- or low-
0.6
Survival
grade mucinous PMP has suggested a role or sys-

temic chemotherapy.107 In this study o 39 patients,
0.4 a clinical benet rate o 38% was determined based
P = 0.0001
on the denition o either semiquantitative reductions
0.2 in mucinous deposition or stabilization o previously
progressive disease, with a 2-year cancer-related mor-
0.0 tality rate o 39%.107
0 1 2 3 4 5 6 7 8 9 10 There is now growing recognition that given di-
Years erences in natural history, somatic mutation proles
and gene expression high- and low-grade appendi-
FIGUre 31–9 Overall survival or 385 cases with the ceal tumors need to be treated as separate entities
mucinous epithelial tumors o the appendix according to
with respect to chemotherapy. A 2016 review o
completeness o surgical cytoreduction (CC). Complete cyto-
reduction dened as a CC score o CC-0 or CC-1, and an incom-
25,992 tumors rom the SEER database ound stage
plete cytoreduction is dened as a score o CC-2 or CC-3. IV well-dierentiated mucinous appendiceal adeno-
(Reproduced with permission rom Sugarbaker PH. Results o carcinomas demonstrated no benet rom systemic
treatment o 385 patients with peritoneal surace spread o chemotherapy. 108 This nding was conrmed by a
appendiceal malignancy. Ann Surg Oncol. 1999;6(8):727-731.) similar study o 639 metastatic well-dierentiated
mucinous appendiceal adenocarcinoma patients o ascites and should be considered in patients with
showing 5 year survival benet rom surgical resec- reractory ascites.
tion (HR, 0.4) but not chemotherapy (HR, 1.1).109 Given the indolent nature o well- to moderately
Currently, a randomized trial or well-dierentiated dierentiated mucinous adenocarcinoma, systemic
appendiceal tumors is underway at MDACC to chemotherapy is generally reserved or patients
conrm these ndings prospectively; reporting is who either have clear evidence o disease progres-
expected in 2021. sion on radiographic imaging or have signicant
Although colon cancer chemotherapy—namely, fu- tumor-related symptoms. Frontline chemotherapy is
oropyridines (5-FU, capecitabine) oxaliplatin, and/or fuoropyrimidine based, and additional agents may
irinotecan—is commonly used or patients with high- be added based on the perceived tolerance o more
grade appendiceal cancer, there are ew published data aggressive combinations. Given the generally good
to support this practice. Shapiro et al99 retrospectively prognosis o these patients and limited data support-
reviewed data collected rom 54 patients (26 moderate ing the ecacy o CRC-like chemotherapy in these
or poorly dierentiated) who were suboptimal surgi- tumors, it is critical that treatment is closely aligned
cal cytoreductive candidates, showing radiographic with quality o lie and that cumulative toxicities are
stabilization or response to therapy in 55% o patients kept to a minimum.
with median PFS o 7.6 months and median OS o 56 The use o multiagent systemic chemotherapy,
months. The largest study specically o high-grade as administered in patients with CRC, is the treat-
appendiceal adenocarcinoma is a retrospective review ment o choice or patients who have signet ring cells,
Chapter 31
o 142 patients by Lieu et al.92 This showed a response poorly dierentiated tumors, or nonmucinous tumors.
rate o 44%, median PFS o 6.9 months, and median OS Because patients with poorly dierentiated or signet
o 1.7 years. Patients with response to chemotherapy ring cell appendiceal adenocarcinomas have consis-
and complete CRS were associated with improved PFS tently shown worse outcomes ater aggressive CRS,
and OS. A small Japanese case series showed disease our approach has been only to consider surgical cyto-
control in 6 o 8 patients with FOLFOX.110 Regarding reduction in these patients ater initial treatment with
the combination o systemic treatment with surgery, systemic chemotherapy. In a retrospective study rom
in a study o 109 high-grade tumors, adjuvant chemo- MDACC, Lieu et al showed that patients with stage
therapy ater CRS plus HIPEC was associated with IV poorly dierentiated or signet ring cell morphology
improved PFS (12.6 months vs 6.8 months; P <.01), appendiceal adenocarcinomas had a median OS o 24
but interestingly, no benet was seen rom neoadju- months, similar to the known OS or patients with
vant treatment.111 There are also retrospective reports metastatic CRC.92 With regard to targeted agents, it is
suggesting that combining bevacizumab with chemo- not standard practice at MDACC to use either VEGF
therapy may improve survival outcomes in surgically inhibitors or EGFR inhibitors in appendiceal epithelial
unresectable appendiceal epithelial neoplasms.112,113 tumors. MSI-H is rare in appendiceal cancer, but these
patients are treated with immunotherapy similar to
those with MSI-H colon cancer. Given the lack o data
The MD Anderson Approach to Epithelial supporting systemic chemotherapy and lack o a true
Appendiceal Tumors standard-o-care regimen, patients should be enrolled
Unlike CRC, appendiceal epithelial malignancies on clinical trials whenever possible. To help acilitate
have a more indolent natural history that is deter- trial enrollment, all metastatic appendiceal tumors are
mined primarily by their underlying histopathol- routinely molecularly proled or somatic mutation
ogy. At MDACC, patients with LAMN and well- to in common cancer genes, microsatellite instability,
moderately dierentiated mucinous adenocarcinoma and HER2 overexpression. Now that it is possible to
are evaluated initially or CRS. Patients with a com- obtain these data in a Clinical Laboratory Improve-
plete cytoreduction (CC-0 or CC-1) are treated with ment Amendments (CLIA) ashion, moving orward
HIPEC using intraperitoneal mitomycin at 42°C. I a this molecular proling will include RNA_Seq.
complete CRS is not obtained, i radiographic imaging Because o the rarity o appendiceal tumors, our
indicates that obtaining a complete cytoreduction is understanding o these tumors is limited, and urther
highly unlikely, or i medical comorbidities preclude research into the molecular characteristics o these
a surgical procedure, then patients are considered tumors is needed. The role o CRS is well established
or systemic chemotherapy. Also, HIPEC is used at or appendiceal epithelial tumors. The use o systemic
MDACC or the control o reractory ascites in select chemotherapy in patients with appendiceal epithelial
patients with low-grade tumors. We have ound that tumors needs urther study, in particular or low-grade
the use o HIPEC in patients who have undergone tumors in which CRC-like chemotherapy seems to pro-
an incomplete CRS can provide long-term control vide no benet.
MD ANDERSON PRACTICE TIPS: SMALL BOWEL CANCER

J Predisposing conditions or SBA should be consid- J For metastatic SBA, start with 5-FU–based chemo-
ered; specically, testing or both mismatch repair therapy (FOLFOX, FOLFIRI, or FOLFOXIRI). Use o
and celiac disease should be done. concomitant bevacizumab can be considered, but
J Approach adjuvant therapy or SBA similar to the use o anti-EGFR drugs (cetuximab and panitu-
general principles rom colon adenocarcinoma, but mumab) appears to have limited activity.
stage or stage, outcomes or SBA tend to be worse. J Taxane-based therapy has demonstrated activity
J All patients with metastatic disease should be pro- and can be considered in later lines o therapy in the
led as a number o targetable alterations can be absence o clinical trials, but reerral to clinical trials
identied such as HER2 alterations and mismatch is always preerred.
repair deciency.
MD ANDERSON PRACTICE TIPS: APPENDICEAL TUMORS

Chapter 31
J Grade is critical in all mucinous appendiceal neo- avorable prognostic entity that is best managed
plasms or both prognosis and management. Ensure with surgery.
adequate sampling has occurred, and i uncertainty J Avoid use o chemotherapy in patients with low-
exists, consider discussion with pathology. grade (well-diferentiated) mucinous adeno-
J Given the mucinous nature o these cancers in most carcinomas because these tumors tend to be
cases (especially low-grade tumors) and the desire nonresponsive to chemotherapy.
or peritoneal cavity evaluation, PET scans should J In nonmucinous and high-grade mucinous appen-
not be used in routine care. diceal adenocarcinomas, systemic 5-FU–based
J For low-grade (well-diferentiated) mucinous ade- chemotherapy should be used because these his-
nocarcinomas, ensure multidisciplinary discussions tologic types are chemoresponsive, and the benet
and early surgery reerral because they represent a rom upront CRS is uncertain.
23. Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in amilies
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drug sensitivity. Nature. 2012;483(7391):603-607. zumab in advanced small bowel adenocarcinoma. Clin Colorec-
97. Warren A, Chen Y, Jones A, et al. Global computational align- tal Cancer 2017;16:78-83.
ment o tumor and cell line transcriptional proles. Nat Com- 115. Ecker BL, McMillan MT, Datta J, et al. Ecacy o adjuvant
mun. 2021;12(1):22. chemotherapy or small bowel adenocarcinoma: A propensity
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rent chemoradiation or node-positive adenocarcinoma o the salvage chemotherapy or advanced small bowel adenocarci-
duodenum. Arch Surg. 2007;142(3):285-288. noma: a series o three patients. J Chemother. 2003;15(5):503-506.
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nding and Pharmacologic Study o Cisplatin, Irinotecan, mary adenocarcinoma o the small bowel. Cancer 1984; 53(1):
and either capecitabine or inusional 5-FU in Patients with 23–5.
Advanced Gastrointestinal Malignancies [abstract 28]. Ameri- 123. Ouriel K, Adams JT. Adenocarcinoma o the small intestine.
can Society o Clinical Oncology Gastrointestinal Cancers Am J Surg. 1984;147(1):66–71.
Symposium. 2005. 124. Morgan DF and Busuttil RW. Primary adenocarcinoma o the
119. Czaykowski P and Hui D. Chemotherapy in small bowel small intestine. Am J Surg. 1977;134(3):331-333.
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120. Goetz MP, Elrichman C, Windebank AJ, et al. Phase I and phar-
macokinetic study o two dierent schedules o oxaliplatin,
Chapter 31
32 Colorectal Cancer
Arvind Dasari
Benny Johnson
Christine Parseghian
Kanwal P. Raghav
Scott Kopetz
KEY CONCEPTS
 Although the overall incidence o incidence o colorectal All patients with mCRC should be evaluated or resectable
cancer (CRC) has decreased, its incidence in those younger disease at diagnosis and at each restaging.
than 50 years o age (ie, early-onset CRC) has signicantly  Most patients with mCRC are treated with fuoropyrimidine-
increased over the past 2 to 3 decades, accounting or based combination chemotherapy with oxaliplatin, irinote-
an estimated one o every 10 cases currently being diag- can, or both in the rst- and second-line settings. Monoclonal
nosed in the United States. antibodies (mAbs) against the vascular endothelial growth
 Surgery is the cornerstone o curative therapy in locore- actor axis or epidermal growth actor receptor (EGFR) may
gional CRC. Adjuvant chemotherapy with a fuoropyrimidine be used in combination with such chemotherapy. The use
typically in combination with oxaliplatin is standard-o- o anti-EGFR antibodies should be limited to RAS wild-type
care adjuvant therapy or patients with stage III and IV and patients and to those with tumors arising in the let colon
high-risk stage II colon cancer. Recent data support tailor- at least in the rst-line setting. Patients with incurable meta-
ing duration o therapy (3 months vs 6 months) based on static disease should be considered or periods o less inten-
pathologic stage or stage III colon cancer. sive therapy during their treatment course as the clinical
 In patients with locally advanced rectal adenocarcinoma, situation warrants. Patients with mismatch repair–decient
the paradigm has shited to a total neoadjuvant therapy mCRC are responsive to immunotherapy and should be
approach in which systemic chemotherapy in addition to treated with such agents, including in the rst-line setting.
neoadjuvant radiation is administered beore surgery. Ongo-  A biologic doublet therapy o encoraenib (BRAF inhibitor)
ing studies are evaluating deintensiying such trimodality in combination with cetuximab (EGFR mAb) is now stan-
therapy by omitting surgery or radiation in select patients. dard o care or patients with previously treated BRAFV600E
 Biomarker testing that includes mismatch repair deciency mutant mCRC. Regoraenib and TAS-102 are oral agents
should be perormed in all patients with CRC; expanded or patients with reractory disease in later lines o therapy.
RAS (KRAS and NRAS exons 2,3, 4), BRAFV600E mutation, and Ongoing trials are evaluating role o anti-Her2neu therapy
HER2neu amplication should be perormed in all patients in patients with Her-2neu amplication and rechallenge
with metastatic CRC. NTRK usion and POLE mutations are with anti-EGFR antibodies in patients with prior clinical
rare but targetable aberrations in metastatic CRC (mCRC). benet and subsequent progression.
Colorectal cancer (CRC) is currently the third most com- EPIDEMIOLOGY AND ETIOLOGY OF
mon cancer in incidence in the United States and accounts COLORECTAL NEOPLASIA
for about 8.5% of all cancer-related deaths (nearly 148,000
new cases and 53,000 deaths each year).1 This chapter
reviews our current understanding of CRC; describes the
Carcinogenesis: The Adenoma–
known genetic mutations and risk factors; and outlines
Adenocarcinoma Sequence
emerging screening, prevention, and therapeutic strate- Colorectal neoplasia results from three different
gies, with particular emphasis on the approach taken at pathways driving carcinogenesis, including chro-
MD Anderson Cancer Center (MDACC). mosomal instability, microsatellite instability (MSI),
733
734 Secion VI Gastrointestinal Cancer
TABLE 32–1 Lietime Risks o Colorectal Cancer
Characteristic Incidence (%)

General population 5
Personal history o colorectal cancer 15–20
Inammatory bowel disease 15–40
Adenomatous polyps: personal Variable
Hereditary nonpolyposis colorectal 70–80
cancer mutation
Familial adenomatous polyposis >95
Risk Factors
Genetic predisposition, acquired (somatic) or inherited
FIGURE 32–1 Photomicrograph o a tumor with microsat- genetic (germline) mutations, interplay with urther
ellite instability. Upper arrows point to poorly dierenti-
environmental, dietary, or other less-well-understood
ated malignant cells with some glandular dierentiation
actors in CRC carcinogenesis. Personal or amily his-
ChaptER 32
and mucin. Lower arrow shows peritumoral lymphocytes

clustering near areas o malignant cells and permeating tories o CRC or polyps, older age, and infammatory
the local stroma. CAPOX, capecitabine and oxaliplatin; bowel disease (IBD) have all been associated with an
dMMR, deicient mismatch repair; 5-FU, 5-luorouracil; increased risk o CRC (Table 32–1).
FOLFOX, 5-luorouracil, leucovorin calcium, and oxalipla-
tin; LV, leucovorin.
Modiable Risk Factors
A diet rich in saturated at, tobacco use, and excess
alcohol use have been associated with an increased
and CpG island methylation. The chromosomal risk o colon cancer. Fiber has previously been associ-
instability pathway identies early mutations in ated with lower CRC risk; however, ater correction
genes such as the tumor suppressor APC and the or other dietary actors, it is no longer considered
K-ras oncogene and later genetic events, including protective.4
PIK3CA oncogene and the tumor suppressor gene
p53. Histology that suggests an MSI tumor may Obesity and Insulin Resistance
include mucinous eatures, poor dierentiation,
or the presence o tumor-inltrating lymphocytes Increased body mass index (BMI) and central obesity
(Fig. 32–1). are risk actors or CRC. The Framingham Study ound
that a BMI above 30 increases the risk o colon cancer
by 50% among middle-aged (30–54 years) individuals
Consensus Molecular Subtype and by 2.4-old or those aged 55 to 79 years, and waist
Classication circumerence was a stronger predictor than BMI.5
Patterns in RNA expression have been shown to Independent o body mass index, insulin resistance and
dene our molecular subtypes o CRC, with impor- diabetes mellitus have also been associated with CRC.6
tant prognostic dierences. 2 The rst consensus
molecular subtype (CMS), CMS1, denes a sub- Adenomatous Polyps
group with immune activation, and encompasses
Carcinoma is present in 5% o adenomas, in which the
the majority o MSI and BRAF-mutated tumors.
potential or malignant transormation is 8 to 10 times
CMS2, or the canonical subgroup, is the most com-
higher or villous and tubulovillous adenomas than
mon and includes eatures o MYC activation and
tubular adenomas. Just over 1% o adenomatous pol-
TP53 mutations. CMS3 is a less common subtype
yps smaller than 1 cm in size are malignant, whereas
with metabolic dysregulation and high rates o
up to 40% o adenomas larger than 2 cm are malignant.
KRAS mutation. CMS4 is an immune-excluded sub-
type with active stromal eatures, including trans-
orming growth actor β signaling. The ability o Inammatory Bowel Disease
these subgroups to dene treatment response has Patients with IBD (ulcerative colitis or Crohn dis-
been proposed but is not yet integrated into treat- ease) are at increased risk o developing CRC based
ment guidelines. 3 on the duration and extent o active disease, colitis,
Cer 32 Colorectal Cancer 735
and mucosal dysplasia. Recognizing the increased risk SCREENING FOR COLORECTAL
o CRC or patients with IBD, appropriate screening NEOPLASIA
should be instituted.
The current recommendation o the US Preventative
Familial Syndromes Services Task Force is to use any accessible screening
method, recognizing the major hurdles to improving
About 20% o all CRC cases are attributed to inherited outcomes are caused by poor screening compliance and
autosomal dominant syndromes, including amilial less about specic testing characteristics.8 At MDACC,
adenomatous polyposis (FAP), Gardner syndrome, and we recommend colonoscopy screening starting at the
hereditary nonpolyposis colorectal cancer (HNPCC) age o 45 to 50 years as a preerred modality.
(see Table 32–1).
Familial Adenomatous Polyposis Detection Methods

FAP is caused by a mutation o APC leading to the
Stool-Based Testing
unctional loss o both APC alleles, one inherited as Meta-analysis o our randomized trials investigat-
a germline mutation and the other mutated in early ing the role o etal occult blood testing (FOBT) dem-
childhood. FAP has high penetrance, maniesting as onstrated an increased detection o early-stage CRCs
thousands o adenomatous polyps; some invariably and a reduction in CRC mortality.9 Fecal immunohis-
ChaptER 32
progress to cancer, thereby warranting a prophylac- tochemistry tests (FITs) use antibodies or hemoglobin
tic colorectal resection. The onset o malignancy in and appear more sensitive than FOBT; however, studies
untreated patients occurs at about 42 years, with inva- demonstrating mortality reduction have not been com-
sive cancer developing 20 to 30 years later. pleted. DNA testing o stool uses detection o mutation
and methylation markers rom shed epithelial cells rom
adenomas or adenocarcinomas. Although sensitivity
Hereditary Nonpolyposis Colorectal Cancer
appears higher than FIT, mortality reduction has not
HNPCC (also known as Lynch syndrome) is caused been directly conrmed with this screening approach.
by germline mutations in the DNA mismatch repair
genes. Additional mutations involving tumor suppres- Blood-Based Testing
sor genes and oncogenes rapidly accumulate within
these DNA repair–decient cells, leading to malignant Carcinoembryonic antigen (CEA) is not recommended
transormation in only 3 to 5 years. as a screening test because o poor sensitivity and spec-
icity. Septin 9 DNA testing in blood is approved by
the Food and Drug Administration (FDA) or patients
MUTYH-Associated Polyposis reusing a colonoscopy but not recommended as a
MutY homolog–associated polyposis is caused by screening method because o low sensitivity.
biallelic mutations in the base excision repair gene
MUTYH. Patients with the syndrome are character- Sigmoidoscopy
ized by oligopolyposis, usually more than 15 but Flexible sigmoidoscopy is relatively sae and inexpen-
ewer than 100 polyps. The onset o adenomas is older sive suitable or screening large populations at low risk
than in those with classic FAP but similar to attenuated in combination with FOBT. However, adenomas in
adenomatous polyposis (45–55 years o age). the distal colon are not indicative o proximal lesions,
and sigmoidoscopy may miss nearly 50% o all colonic
lesions.10 Patients with adenomas detected by fexible
Early-Onset Colorectal Cancer
sigmoidoscopy should have a ull colonoscopy.
In contrast to the declining incidence o CRC in screen-
ing-eligible patient (age older than 45–50 years), the Computed Tomography Colonography (Virtual
incidence o CRC in younger adults has substantially Colonoscopy)
increased over the past 2 to 3 decades. It is now esti-
mated that 1 in 10 diagnoses in the United States are Virtual colonoscopy (VC) involves reconstruction o
in younger patients, with the number o young patients three-dimensional images o the colon rom the two-
with rectal cancer representing as much as 1 in 5 diag- dimensional data obtained by a spiral computed tomog-
noses.7 The cause o this increase in not clear because raphy (CT) scanner. Bowel preparation is required, but
hereditary syndromes do not appears commonly in these the technique is less invasive and does not require seda-
patients. Eorts to understand the environmental expo- tion. However, VC lacks the advantage o a colonos-
sures, comorbidities, and liestyle actors are ongoing. copy or direct access to colonic tissue or biopsies.
Colonoscopy CRC. Consequently, primary preventive strategies may

have a signicant impact on the overall incidence o CRC.
Colonoscopy not only enables ull visualization o the
entire colon but also allows or biopsy or removal o
Nonsteroidal Antiinammatory Drugs
any suspicious lesions.
Despite widespread use, the colonoscopy or the For more than 20 years, data suggested that nonsteroidal
purposes o cancer screening has not been studied in a antiinfammatory agents such as sulindac slow or prevent
randomized prospective trial until the Nordic-European the ormation o adenomatous polyps, particularly in
Initiative on CRC (Nordic) study (NCT00883792). This patients with FAP.15 Prostaglandin E2, an important mod-
multinational trial randomized patients aged 55 to 64 ulator o cell prolieration and malignant transormation,
years to either once-only screening colonoscopy with is ormed by the catalytic activity o two predominant
removal o all lesions or no screening, which is the stan- isoorms o cyclooxygenase. Cyclooxygenase 1 (COX-1)
dard o care in these trial countries.11 Ater a 15-year is constitutively active and widely expressed; it appears
ollow-up period, the primary endpoints o cumulative to regulate tissue repair and homeostasis. COX-2 is an
CRC–specic death and incidence will be evaluated. inducible enzyme that appears to play a role in infam-
Preliminary results showed that 0.5 o the participants mation and tumor promotion. In a study o patients with
were diagnosed with CRC, and 30.7% had adenomas, FAP, the selective COX-2 inhibitor celecoxib at a higher
o which 10.4% were high-risk adenomas. Detection dose signicantly reduced the number o adenomas com-
rates were similar in the proximal and distal colon.12 pared with placebo or a lower dose o celecoxib.16 A pro-
ChaptER 32
spective, placebo-controlled study o 600 mg aspirin per

Genetic Testing and Counseling day in patients with HNPCC, a secondary per protocol
analysis suggested that it may reduce cancer incidence,
Genetic testing or APC mutations, MUTYH mutations, although urther validation is required.17
and DNA mismatch repair gene mutations are now However, the increased incidence o stroke and
available to identiy carriers. A patient with classic FAP myocardial inarctions make the use o COX-2 inhibi-
or with oligopolyposis but negative APC mutation test- tors as primary chemoprevention unclear.16 Aspirin has
ing should undergo MUTYH mutation testing given the primary chemopreventive properties, with the risk o
incidence (7%–29%) o biallelic MUTYH in patients CRC substantially reduced among women who were
with polyposis with negative APC testing results.13 regular users o aspirin or at least 20 years.18 An addi-
All patients with CRC at MDACC are screened or tional prospective cohort study o male physicians
MSI. MSI, which is a hallmark o HNPCC, also occurs ollowed over 4 years showed that regular users o
in about 15% o spontaneous colon cancers. aspirin (≥2 times per week) had a lower risk o devel-
Immunohistochemical (IHC) stains done on sec- oping CRC during the study period (relative risk [RR],
tions rom the diagnostic biopsy assess tumors or loss 0.68; 95% condence interval [CI], 0.52–0.92).19
o heterozygosity in hMSH2, hMSH6, or hMLH1 gene
loci. Further testing or germline mutations may ollow Secondary Prevention
an uninormative IHC stain. In particular, the absence
o the MLH1 protein on IHC staining calls or the test- Aspirin also has secondary chemopreventive benets.
ing o the BRAF gene, in which a BRAF mutation sig- In a large randomized, placebo-controlled trial, aspirin
nies the downregulation o MLH1 gene expression demonstrated a benet or patients with a prior his-
not through a germline mutation but rather somatic tory o CRC, showing a signicantly reduced risk o
promoter hypermethylation. Furthermore, up to 10% developing adenomatous polyps compared with the
o all MSIs may be missed through conventional IHC placebo group (RR, 0.65; 95% CI, 0.46–0.91), a nding
methods, highlighting MSI testing by polymerase that was conrmed in other studies.20,21 In contrast, the
chain reaction (PCR) i suspicion is high.14 At MDACC, Cancer and Leukemia Group B (CALGB)/SWOG 80702
all young patients with CRC are oered the opportu- study evaluating the role o celecoxib or prevention o
nity to meet with a genetic counselor to discuss the recurrence did not show any improvement in progres-
option and implications o genetic testing. sion-ree survival (PFS) or overall survival (OS) in the
adjuvant setting in patients with stage III colon cancer.22
PREVENTION STRATEGIES DIAGNOSTIC EVALUATION AND

STAGING
Primary Prevention
In primary prevention, broad-based interventions may Clinical Presentation
decrease the risk o CRC or those at average risk. Ameri- Colonic lesions in any location can cause change in
cans currently have a 1 in 20 lietime risk o developing bowel habits and bleeding, which may maniest as
melena, hematochezia, a positive hemoccult test preoperative staging. At MDACC, patients also receive
result, or iron deciency anemia in addition to weight a CT scan o the chest and abdomen, with a dedicated
loss, anorexia, and other constitutional symptoms. MRI o the pelvis with rectal protocol in the preopera-
Unexplained iron deciency anemia warrants an eval- tive setting.
uation o the gastrointestinal (GI) tract.
Pathology
Preoperative Staging or Colonic More than 95% o all colorectal malignancies are ade-
Neoplasms nocarcinomas that are well dierentiated, moderately
In patients ound to have a colonic neoplasm not requir- dierentiated, poorly dierentiated, and undierenti-
ing urgent surgery, a complete history, physical exami- ated. Other subtypes include mucinous and signet ring
nation, and ull colonoscopy with biopsies should be cell, which coner a poorer prognosis. These tumors
perormed. Laboratory evaluation should include a are more likely to be present in younger patients and
complete blood cell count with dierential, electro- more commonly spread to the peritoneum. Treatment,
lytes, liver unction studies, CEA level, serum urea however, does not dier rom the more typical adeno-
nitrogen (BUN), and creatinine. Imaging studies should carcinoma subtypes.
include CT o the chest and CT scan or magnetic reso-
nance imaging (MRI) o the abdomen and pelvis. Pathologic Staging
ChaptER 32
Currently, the widely accepted system is the American
Rectal Cancer Staging Joint Committee on Cancer tumor, node, metastasis
Patients with newly diagnosed rectal cancer at classication system (Table 32–2) to guide treatment.
MDACC are staged with endorectal ultrasonography
(EUS) or pelvic MRI. The EUS is more accurate than
CT or assessing the depth o tumor invasion into the MANAGEMENT OF NONMETASTATIC
bowel wall and perirectal lymph node involvement. COLON CANCER
A pelvic MRI to evaluate the mesorectal planes and
perirectal lymph nodes allows improved accuracy o Although surgery is the cornerstone o curative intent
therapy or patients with CRC, almost hal o such
patients undergoing curative resection will ultimately
die o subsequent development o metastatic disease.
TABLE 32–2 Tumor (T), Node (N), Metastasis (M) Further systemic therapy is administered in these
Staging o Colorectal Cancer patients to improve survival by eliminating residual
microscopic disease not evident at the time o surgery.
T N M Stage
Tis N0 M0 0 Surgical Management o Colon Cancer
T1, T2 N0 M0 I Resection or localized colon cancer involves en bloc
T3 N0 M0 IIA removal o the aected segment o bowel along with
T4a N0 M0 IIB the adjacent mesentery to the origin o the primary
T4b N0 M0 IIC eeding vessel inclusive o the draining lymph nodes.
Care should be taken to have proximal and distal mar-
T1–T2 N1/N1c M0 IIIA
gins o at least 5 to 7 cm and at least 12 lymph nodes
T1 N2a M0 IIIA in the resected specimen. In patients with locally
T3–T4a N1/N1c M0 IIIB advanced T4 tumors involving adjacent organs, en bloc,
T2–T3 N2a M0 IIIB multivisceral resection without disturbing the plane o
T1–T2 N2b M0 IIIB adherence is vital and is associated with improved local
and distant relapse rates.23–27 Colectomy may done via
T4a N2a M0 IIIC
open or laparoscopic approaches; multiple, random-
T3–T4a N2b M0 IIIC
ized trials and meta-analyses suggesting comparable
T4b N1-N2 M0 IIIC outcomes with the two approaches but with aster
Any T Any N M1a IVA recovery with the latter. In the Clinical Outcomes o
Any T Any N M1b IVB Surgical Therapy (COST) trial, 872 patients with colon
Any T Any N M1c IVC adenocarcinoma were randomly assigned to open ver-
sus laparoscopic colectomy. In the laparoscopic group,
Used with permission o the American College o Surgeons, Chicago, Illinois. The
original source or this inormation is the AJCC Cancer Staging System (2020). although the operative time was longer, duration o
hospital stay and parenteral analgesia were slightly o oxaliplatin (69% vs 64%; HR, 0.82; 95% CI, 0.69–
shorter.28,29 O note, 21% o the laparoscopic cases had 0.93).40 However, this was at a cost o increased GI
to be converted to an open procedure however.28,29 toxicities related to bFU/LV (≥grade 3 diarrhea, 32%
Other studies have also shown improved quality o vs 38%; vomiting, 8% vs 13%; and dehydration 12%
lie and higher likelihood o initiating adjuvant chemo- vs 17% with bFU/LV vs FLOX) and thus the preerred
therapy with laparoscopic over open colectomy.30 The method o administration o 5-FU is ambulatory inu-
COST trial and several other randomized studies have sional therapy.40 Both the MOSAIC and National Sur-
also shown no dierence in long-term outcomes includ- gical Adjuvant Breast and Bowel Project (NSABP) CO-7
ing local recurrence, disease-ree survival and OS rates trials mandated a total duration o adjuvant therapy or
between the two approaches.28,29,31–34 Data also sug- 6 months that is associated with signicant toxicities,
gest that outcomes are signicantly better in hospitals especially oxaliplatin-related neuropathy. More than
with higher annual case volumes.29 Such data highlight 90% o patients in the MOSAIC trial developed neu-
the importance o adequate experience with this tech- ropathy during chemotherapy, including 13% with
nique or optimizing outcomes. More recently, robotic grade 3 or greater symptoms. Ater a ollow-up period
approaches have been evaluated against laparoscopic o 48 months, grade 1, 2, or 3 neuropathy was persis-
approaches in observational studies. These studies tent in 12%, 3%, and 0.7% o patients, respectively.
suggest that robotic approaches are more expensive Although all these trials used 5-FU, other randomized
and are associated with longer operating time but pos- trials and pooled analyses convincingly support the
sibly with better short-term outcomes such as blood substitution o 5-FU with capecitabine in the adjuvant
ChaptER 32
loss, hospital stay, and return o postoperative bowel setting.45–47

unction.35–38 Our recommendation is that minimally The IDEA (International Duration Evaluation o
invasive surgeries only be perormed in centers with Adjuvant Chemotherapy) Collaboration was a pro-
high volumes and by experienced surgeons. These spective combined analysis o six international phase
approaches should be avoided in complex situations III trials investigating nonineriority o 3 versus 6
involving extensive adhesions, obstruction, perora- months o adjuvant chemotherapy (either FOLFOX
tion, or involvement o adjacent organs. or CAPOX [capecitabine and oxaliplatin] per physi-
cians’ choice) or stage III colon cancer with the pri-
mary endpoint o 3-year DFS.48 The study narrowly
Evidence Regarding Adjuvant Therapy or ailed to show nonineriority o 3 months o adjuvant
Colon Cancer therapy compared with 6 months (3-year DFS, 74.6%
Although there are no randomized data dening the vs 75.5%; HR, 1.07; 95% CI, 1.00–1.15; nonineriority
optimal time interval to starting adjuvant therapy ater HR boundary, 1.12). However, prespecied subgroup
surgery, it is usually started ater complete recovery analyses based on type o regimen suggested that non-
rom surgery, typically 4 to 8 weeks ater surgery and ineriority or 3 months was noted with CAPOX (0.95;
as mandated by most completed adjuvant trials.39–44 95% CI, 0.85–1.06) but not with FOLFOX (HR, 1.16;
Patients with stage III colon cancer typically receive 95% CI, 1.06–1.26). Furthermore, an exploratory anal-
3 to 6 months o adjuvant chemotherapy with a ysis in low-risk (T1–T3 and N1) patients demonstrated
fuoropyrimidine in combination with oxaliplatin. nonineriority o 3 versus 6 months (3-year DFS, 83.1%
Improvement in DFS with addition o oxaliplatin to and 83.3%, respectively; HR, 1.01; 95% CI, 0.90–1.12)
fuoropyrimidine was demonstrated by two large and superiority o 6 months over 3 months in those
phase III trials. The European MOSAIC (Multicenter with high-risk (T4 or N2) disease (3-year DFS, 64.4%
International Study o Oxaliplatin/5-Fluorouracil/Leu- vs 62.7%; HR, 1.12; 95% CI, 1.03–1.23).48 Ater a lon-
covorin in the Adjuvant Treatment o Colon Cancer) ger ollow-up period, updated results showed that the
trial randomized 2246 (60% with stage III) patients to 5-year DFS was 69.1% versus 70.8% (HR, 1.08; 95%
FOLFOX (inusional 5-fuorouracil [5-FU], leucovorin CI, 1.01–1.15; alse discovery rate adjusted P = .22);
calcium, and oxaliplatin) versus 5-FU and leucovorin. 5-year OS rate was 82.4% versus 82.8% (HR, 1.02;
This trial demonstrated an improvement in the primary 95% CI, 0.95–1.11), and absolute 5-year OS rate dier-
endpoint o 5-year DFS rom 67% to 73% or patients ence was -0.4% (95% CI, -2.1% to 1.3%).49 Together,
with the addition o oxaliplatin to 5-FU.43 An OS ben- these data suggest highlight the implications o risk
et was noted in the stage III subgroup (10-year, OS stratication based on the pathologic and the potential
67% vs 59%; hazard ratio [HR], 0.80; P = .016).43 The or shortening duration o therapy with CAPOX, espe-
North American NSABP C-07 trial that randomized cially in low-risk patients.
2407 patients (70% with stage III) to bolus weekly The evidence or adjuvant therapy or patients with
5-FU/LV bolus 5FU, leucovorin (bFU/LV) with (FLOX) stage II disease is less robust (Fig. 32–2). To date, the
or without oxaliplatin also showed an improvement in largest randomized study o patients with stage II
the primary endpoint o 5-year DFS with the addition disease, QUASAR (Quick and Simple and Reliable),
Resected colon cancer
Stage II Stage III
Yes
Low risk dMMR
T4 and/or N2
No No Yes
No therapy! Clinical or Intermediate risk High risk

pathologic
high risk
No Yes
No therapy! 5-FU–LV
3 months of CAPOX 6 months of
or capecitabine
or FOLFOXa or
or 3 months of
6 months of FOLFOXa CAPOXa
CAPOX
Consider 5-FU/capecitabine Consider observation
ChaptER 32
aNCCN category 1.
FIGURE 32–2 Decision algorithm or adjuvant therapy in colon cancer.
showed a modest survival benet o 3.6% in patients analyses o 3273 patients with high-risk stage II colon
receiving adjuvant 5-FU versus observation ater surgi- cancer rom our trials within the IDEA collaboration
cal resection.50 However, this study had several critical ailed to show nonineriority o 3 versus 6 months o
limitations, including enrollment o patients with rectal adjuvant therapy (80.7% vs 84%; DFS HR, 1.18; 80%
cancer (29%), limited number o lymph nodes evalu- CI, 1.05–1.31; P = .404; nonineriority boundary, 1.2).
ated (median, 6) and use o radiation in some patients As with the stage III patients, toxicities were signi-
(14%).50 Other pooled analyses have shown small cantly lower in the 3-month group, and there appeared
improvements in DFS (5%–10%) but without improve- to be a trend toward dierence in DFS based on type
ment in OS or adjuvant 5-FU over observation in stage o regimen (CAPOX: HR, 1.02; 80% CI, 0.88–1.17;
II colon cancer.51–54 Subgroup analyses o stage II patients P = .087 and FOLFOX: HR, 1.42; 80% CI, 1.19–1.70;
rom the MOSAIC and NSABP C-07 trials showed no P = .894).59
statistically signicant benet in either OS or DFS with Approximately 20% to 25% o stage II and 10%
the addition o oxaliplatin to 5-FU.43 These ndings to 15% o stage III patients are MSI-H decient mis-
were also supported by a pooled analysis o the Adju- match repair (dMMR) that has prognostic and perhaps
vant Colon Cancer End Points (ACCENT) database.55–57 predictive implications or adjuvant therapy.60–62 Sub-
However, a subset o stage II patients at a higher risk stantial data suggest that patients with dMMR have a
o recurrence may be identied based on histopatho- decreased likelihood to develop recurrent disease with
logical eatures. These eatures are dened by the some studies suggesting that the recurrence rate may
National Comprehensive Cancer Network (NCCN) as be as low as hal that o procient mismatch repair
T4 tumors (stage IIB/IIC); poorly dierentiated histol- (pMMR) tumors.63 This positive prognostic eect o
ogy (excluding microsatellite instability–high [MSI-H] dMMR also appears to be more pronounced in stage II
cancers); lymphovascular invasion; perineural invasion; rather than in stage III colon cancer.60–62 Some o these
bowel obstruction; localized peroration; margins that studies have also suggested that dMMR may also be
are close, indeterminate, or positive; and inadequate a negative predictive marker or benet rom single-
sampling o lymph nodes (<12 nodes examined).58 agent fuoropyrimidine, although some other studies
Data rom randomized trials suggest that such patients have suggested otherwise.60,64–66
with high-risk stage II colon cancer may derive modest Irinotecan has no established role in the adjuvant
benet rom the additional o oxaliplatin to a fuoropy- setting. Three randomized phase III trials ailed to
rimidine. In exploratory analyses o the MOSIAC trial, show an improvement in DFS or OS in the adjuvant
there was a trend toward improvement in DFS (82% vs setting. Furthermore, data have not supported the
77%) and OS (85% vs 83.3%) without reaching statis- addition o bevacizumab, cetuximab, or panitumumab
tical signicance in this subset.43 A preplanned pooled in the adjuvant setting.41,44,67–72
Emerging Directions used or de-escalation o adjuvant therapy in stage III

patients. Together, we anticipate that these data will
Role o Immunotherapy in Adjuvant Therapy likely establish ctDNA as an integral biomarker in the
Although immunotherapy is rapidly emerging as the adjuvant setting.80,81
cornerstone or management o patients with meta-
static dMMR CRC, whether it has benet in the The MDACC Approach to Nonmetastatic
adjuvant setting is being explored in an ongoing trial Colon Cancer
(Alliance A021502; NCT02912559).
When patients present to MDACC with a diagnosis
Role o Neoadjuvant Therapy o colon cancer, a detailed history, including amily
history; routine laboratory tests, including CEA level;
The role o neoadjuvant chemotherapy in colon can- and imaging (CT o the chest; CT or MRI o the abdo-
cer is unclear but may be considered in patients with men and pelvis) are obtained. Previous endoscopic
locally advanced tumors in whom margins may be ndings and pathology are reviewed and are tested or
compromised or in whom surgery may need to be MSI. Patients without metastatic disease or contrain-
delayed because o comorbidities or other causes. The dications to surgery should undergo primary resection
FOxTROT trial randomized 1052 patients with T3–T4 with curative intent (Fig. 32–3). Surgery may consist
N0-2 colon cancer to surgery upront ollowed by 6 o segmental resection or subtotal colectomy, depend-
months o adjuvant oxaliplatin-based chemotherapy ing on the underlying colonic pathology (multiocal
ChaptER 32
or to 6 weeks o preoperative oxaliplatin-based che- cancer, FAP, HNPCC, and so on); pathologic staging is
motherapy ollowed by surgery and then 18 addi- then determined rom the surgical specimens. Patients
tional weeks o chemotherapy. There was only a with stage 0 or I tumors are placed on surveillance
trend toward improvement in the primary endpoint only. Patients with stage II colon cancer have a 75%
o 2-year DFS (13.6% vs 17.2%; HR, 0.75; 95% CI, to 80% chance o long-term DFS with surgical resec-
0.55–1.04). However, the preoperative chemotherapy tion alone. For stage II patients, a thorough discussion
group had lower rates o incomplete resection (5% vs regarding the evidence and morbidity associated with
10%; P = .001) and improved histologic downstaging treatment while taking into consideration high-risk
o both pathologic tumor and nodal stage (including a eatures, mismatch repair (MMR) testing results, and
4% pathological complete response rate [pCR]) with- patient preerences. In patients with dMMR stage II
out increased perioperative complications.73 colon cancer and without high-risk eatures, observa-
tion is recommended. Few data are available or the
Role o Circulating Tumor DNA benet o adjuvant therapy in dMMR stage II patients
with high-risk eatures, and a thorough discussion
Circulating tumor DNA (ctDNA) are short ragments is required, especially in those with T4b tumors. All
o DNA (130–150 base pairs) released by cancer cells patients with dMMR undergoing adjuvant therapy
through apoptosis, necrosis, or secretion into the should receive a fuoropyrimidine in combination
circulation.74 Given the short hal-lie between 16 with oxaliplatin. In patients with standard-risk pMMR
minutes to 2.5 hours, ctDNA is a sensitive real-time stage II colon cancer, a thorough discussion is recom-
marker o tumor burden.74 The presence o ctDNA mended, and patients are advised that any 5-year sur-
ater curative intent therapy, minimal residual disease vival benet is likely to be less than 5%. Ater such a
(MRD) likely represents existence o radiographically discussion, i wishing to proceed with adjuvant ther-
undetectable micrometastases.75–79 Rapidly accumu- apy, they are oered single-agent fuoropyrimidine
lating data suggest very high specicity and positive or 3 to 6 months. Patients with pMMR and high-risk
predictive value (90%–100% or both) or clinical stage II colon cancer may be oered adjuvant chemo-
recurrence in patients with ctDNA-dened MRD.75–80 therapy or 3 to 6 months, and the inclusion o oxalipl-
The sensitivity o ctDNA or detection o MRD is also atin needs to be individualized based on the observed
improving with newer methods and assays providing risk actors, patient preerences, and comorbidities.
increasing lead time between detection o ctDNA and Stage III patients are oered combination chemother-
clinical recurrence approaching 8 to 9 months cur- apy with fuoropyrimidine and oxaliplatin irrespective
rently.75,76,81 Given the high specicity and positive o MMR status. Patients with low-risk disease (T1–
predictive value coupled with the lead time allowing T3 and N1) are oered 3 months o CAPOX or 3 to
or intervention, ongoing trials are evaluating escala- 6 months o FOLFOX. Patient with high-risk disease
tion o therapy in patients with stage II MRD-positive are oered 3 to 6 months o CAPOX or 6 months o
colon cancer and similar eorts are being planned FOLFOX. Adjuvant therapy should begin within 4 to
in stage III colon as well. 80,81 As sensitivity o MRD 8 weeks ater surgery unless postoperative complica-
assays urther improves, it is likely that they may be tions warrant a delay.
Diagnosis
History and physical examination;

stage CT scan of the chest, abdomen,
and pelvis; and CEA level
No metastatic disease Metastatic disease
Endoscopic Significant pain, bleeding,

ultrasound or impending obstruction
T1-2N0 T3, N0, or TANYN+ No Yes
ChaptER 32
Surgical Neoadjuvant If patient is ChemoXRT
resection chemotherapy responding to +/– stent
and/or radiation systemic +/– laser
chemotherapy, +/– diversion
consider systemic
Pathologic Surgical resection therapy only +/–
staging +/– ileostomy chemoradiation
Subsequent
Adjuvant therapy if Adjuvant chemotherapy chemotherapy
T3, N0, M0, and/or radiation if
or TANYN + M0 needed
Ileostomy closure
FIGURE 32–3 Diagnostic and therapeutic algorithm or rectal cancer. CEA, carcinoembryonic antigen; Chemo-XRT, chemo-
therapy and radiation; CT, computed tomography.
Surveillance or Patients with Resected MANAGEMENT OF NONMETASTATIC

Colon Cancer RECTAL CANCER
Ater active therapy is completed, patients undergo clini-
cal evaluations every 3 to 6 months or the rst 3 years Given the higher risk o locoregional recurrence with
during the period o highest risk o recurrence, then every rectal cancer compared with colon cancers, most
6 and 12 months or the ollowing 2 years, and annually patients with stages II and III rectal cancer undergo
thereater. O all recurrences, 80% occur within the rst neoadjuvant therapy ollowed by surgery with total
3 years ater surgical resection.56 Colonoscopy is recom- mesorectal excision (see Fig. 32–3). A total mesorec-
mended 1 year ater surgery and every 3 years thereater tal excision (TME) involves an en bloc removal o the
at a minimum. Laboratory studies, including CEA level, mesorectum through sharp dissection, including asso-
are checked every 3 to 6 months; abdominopelvic CT ciated vascular and lymphatic structures, atty tissue,
or MRI and chest radiography or CT o the chest are and mesorectal ascia, while sparing the autonomic
obtained every 6 to 12 months. At 5 years, patients are nerves. In general, more than two thirds o the patients
ollowed with surveillance colonoscopy (every 3 years), with rectal cancer will be able to have a sphincter-sav-
annual physical examination, and CEA level. ing procedure, whether it is a low anterior resection
or a proctectomy with a coloanal anastomosis. An (TNT) in which systemic chemotherapy is adminis-

abdominoperineal resection (APR), which includes tered beore surgery in addition to neoadjuvant radia-
removal o the rectum, anus, sphincter muscles, and tion. The rationales or this approach are to improve
a permanent colostomy, is reserved or patients with downstaging o tumors in the short term and to
tumor involvement o sphincter muscles or with poor improve DFS and OS by better treatment o systemic
preoperative sphincter unction. disease through increased compliance to chemother-
apy that is also administered earlier in the treatment
course. The phase III PRODIGE (Partenariat de Recher-
Perioperative Therapy or Rectal Cancer che en Oncologie Digestive) 23 trial randomized 461
Two European studies have supported the use o pre- patients with locally advanced rectal cancer to neoad-
operative therapy or resectable rectal cancer. The juvant long-course chemoradiation versus induction
German Arbeitsgemeinschat Internistische Onkologie FOLFIRINOX or six cycles ollowed by long-course
(AIO) trial comparing preoperative and postoperative chemoradiation beore surgery.112 Patients were
chemoradiation in T3 or T4 tumors showed a lower allowed to receive additional adjuvant chemotherapy
pelvic recurrence rate in the preoperative chemoradia- (capecitabine or FOLFOX) or a total o 6 months o
tion arm (6% vs 13% postoperatively, respectively; perioperative chemotherapy. This trial showed an
P = .0006).82 In patients who were believed to require improvement in the primary endpoint o 3-year DFS
APR, chemoradiation also led to increased sphincter with the TNT approach (75.7% vs 68.5%; HR, 0.69;
preservation rates (39% vs 19%; P = .004). Only 54% 95% CI, 0.49–0.97). There was also an improvement
ChaptER 32
o patients in the postoperative arm received the ull in the pCR rate (27.5% vs 11.7%; P < .001) with the
radiation dose, and 50% received ull-dose chemother- TNT approach.112 The phase III RAPIDO (Rectal Can-
apy compared with 92% and 89%, respectively, in the cer And Pre-operative Induction Therapy Followed by
preoperative arm (P <.001).82 Dedicated Operation) trial randomized 920 patients
Standard radiotherapy doses are 45 Gy in 25 rac- with locally advanced rectal cancer to long-course
tions ollowed by a 5.4-Gy boost. Concurrent chemo- chemoradiation versus short-course radiation ol-
therapy with a fuoropyrimidine, typically capecitabine lowed by consolidation FOLFOX or CAPOX ollowed
(over inusional 5-FU) is recommended as a radiosen- by surgery and subsequent adjuvant chemotherapy
sitizer. Addition o agents other than a fuoropyrimi- (or a total o 6 months o perioperative chemother-
dine to chemoradiation must be within the context o apy).113 Similar to the PRODIGE 23 trial, the TNT arm
clinical trials. Results o multiple, large, randomized in the RAPIDO trial also showed a statistically signi-
trials that evaluated addition o oxaliplatin and irino- cant improvement in the primary endpoint o 3-year
tecan to a fuoropyrimidine during chemoradiation disease-related treatment ailure (19.8% vs 26.6%; HR,
have all shown increased toxicities without a convinc- 0.69; 95% CI, 0.53–0.89) and in the pCR rate (27.7%
ing improvement in pCR, DFS, or OS.83–96 Data rom vs 13.8%; P <.001).113 Both trials showed that the TNT
small, nonrandomized trials suggest that addition o approach did not aect compliance to chemoradiation,
anti–vascular endothelial growth actor (VEGF) agents adjuvant therapy, or risk o surgical complications.
may increase pCR rates but at the cost o postopera- Together, these data show the saety and benet o
tive complications. However, studies with anti-EGFR the TNT approach. However, the optimal sequencing
antibodies are mixed, perhaps related to lack o appro- o radiation and chemotherapy (“induction” vs “con-
priate biomarker-based patient selection.97–101 solidation” chemotherapy), modality o radiotherapy
Preoperative short-course radiotherapy (ie, 25 Gy (short course vs long course), and chemotherapy regi-
administered over ve ractions) has consistently men (fuoropyrimidine with oxaliplatin with or with-
shown to improve local control over surgery alone.102– out irinotecan) remain to be dened.
105
However, the initial studies that evaluated this Alternative approaches aiming to eliminate a com-
approach suggested high rates o long-term toxicities, ponent o the trimodality approach, either radiation
including ecal incontinence, bowel obstruction, and or surgery, are also under investigation. Data rom
sexual dysunction.106–109 ore recent trials have allayed multiple nonrandomized studies suggest that patients
these concerns and have also provided additional data with a complete clinical response (cCR) at the com-
suggesting that this approach is comparable to conven- pletion o neoadjuvant therapy may undergo careul
tional long-course chemoradiation or rates o local, observation (ie, “watch and wait”) in lieu o radical sur-
distant recurrences, DFS, OS, and toxicities.110,111 gery.114–120 The largest o these studies was a registry
An alternative approach to preoperative therapy, that included 880 patients with cCR who underwent
especially in patients with high-risk tumors such as watch and wait. Ater a median ollow-up period o
those at risk or margin-positive resection, advanced 3.3 years, 88% o all local regrowth was diagnosed
disease (T4, node positive) or with low-lying tumors within 2 years with the 2-year cumulative incidence
may be considered or total neoadjuvant therapy o local regrowth being 25.2% (97% within the bowel
wall).121 O the 213 patients with local recurrence, In patients treated with TNT and receiving neoad-
details regarding salvage surgery was available in 148 juvant chemotherapy or at least 4 months, no urther
with 78% o these patients requiring a TME and the adjuvant chemotherapy is recommended.
rest having local excision. Five-year disease-specic
survival or the entire group was 94%, and 5-year OS
was 85%.121 Some studies have raised concern about
The MDACC Approach to Nonmetastatic
increased risk o distant recurrence with the wait-and- Rectal Cancer
watch approach compared with those noted to have Patients are evaluated with history, including amily
pCR with surgery; whether these distant recurrences cancer history, physical examination with a digital rec-
may have be prevented with surgery is uncertain. Sev- tal examination, inguinal lymph node exam, proctos-
eral randomized trials are current underway evaluating copy, and cross0sectional imaging studies o the chest,
this approach in patients with cCR. abdomen (typically CT with contrast) and pelvis. MRI
Given the concern or radiation related side eects o the pelvis (and EUS as needed) are obtained in all
in both the short and long terms, upront chemo- patients as pretreatment staging. The patency o the
therapy to enable selective use o radiation in those colonic lumen is evaluated by proctoscopy, fexible sig-
with inadequate response is also being evaluated. moidoscopy, or colonoscopy beore starting therapy.
This approach is being tested in the ongoing phase II/ Given the limitations with delivery o adjuvant ther-
III Alliance (N0148) trial that is evaluating chemora- apy as discussed and robust prospective data showing
diation therapy versus induction FOLFOX in patients improvement in both sphincter preservation and DFS
ChaptER 32
with mid–high-lying rectal cancers (NCT01515787). with neoadjuvant chemotherapy, our practice patterns
have increasingly shited toward the TNT approach.
Adjuvant Therapy or Rectal Cancer Treatment decisions are based on risk stratication
and made in a multidisciplinary ashion involving
In patients receiving neoadjuvant short-course radia- radiation, medical, and surgical oncologists; patholo-
tion or chemoradiation without urther neoadjuvant gists; radiologists; and gastroenterologists. In patients
systemic chemotherapy, most expert groups and con- with rectal cancer deemed low risk (T3N0, mid–high
sensus guidelines recommend adjuvant chemotherapy rectum, without EMVI or threatened CRM) neoad-
or up to 4 months. Although data rom randomized juvant chemotherapy with FOLFOX or CAPOX is
trials comparing adjuvant therapy with observation do oered or 3 months ollowed by surgery. For patients
not convincingly show a survival benet, these trials with low-risk but low-lying tumors wanting sphinc-
have several limitations. First, a signicant proportion ter preservation and or those with high-risk eatures,
o patients (25%–50%) never start adjuvant therapy the TNT approach with chemotherapy or 4 months
because o postoperative complications, slow recov- in addition to radiotherapy is recommended. In these
ery, patient preerence, or other actors.85,86,122 Second, patients, the choices o chemotherapy (FOLFOX,
even in those starting adjuvant therapies, there may be CAPOX, FOLFIRINOX), radiotherapy regimens (long-
a signicant delay in initiating therapy. There is also course chemoradiation vs short-course radiation) and
signicant debate whether adjuvant chemotherapy sequencing modalities are made based on the clinical
may be tailored based on the degree o pathological situation and patient preerences while awaiting ur-
response. Robust nonrandomized data convincingly ther data.
show that patients with pCR have a very low risk o In patients receiving neoadjuvant chemoradiation,
recurrence and adjuvant therapy maybe deintensied capecitabine is given as the radiation sensitizer (825
in these patients to fuoropyrimidine alone. Whether mg/m2 twice daily, Monday–Friday, on days o radia-
adjuvant therapy may be omitted completely with pCR tion therapy only). Bowel exclusion techniques dur-
is uncertain. In patients with poor pathologic response, ing simulation minimize the small bowel in the eld.
data show benet with addition o oxaliplatin. The We conduct a toxicity evaluation every 1 to 2 weeks
ADORE (Adjuvant Oxaliplatin in Rectal cancer) trial during radiation to ensure symptom control. Electro-
randomized 321 patients with pathologic stage stage lytes, renal unction, and hematologic parameters are
II or III tumors postoperatively (and hence avoiding checked weekly. Topical barrier creams are prescribed
dropout beore initiation o adjuvant therapy) to 5-FU or grades 1 to 3 perineal radiation dermatitis. I grade
or FOLFOX and showed an improvement in the pri- 2 or higher nonhematologic toxicity develops (exclud-
mary endpoint o 3-year DFS (71.6% vs 62.9% 0.657; ing radiation dermatitis), concurrent chemotherapy is
95% CI, 0.434–0.994; P = .047).123 These ndings were held until resolution, but radiation is continued. Ater
also supported by a meta-analysis o three randomized chemoradiation, perianal pain and ulceration, anorexia,
trials comparing adjuvant 5-FU with or without oxali- and diarrhea typically subside within 2 to 3 weeks.
platin ater neoadjuvant chemoradiation with improve- Approximately 8 to 10 weeks ater completion o
ment in DFS (HR, 0.85; 95% CI, 0.73–0.99).124 neoadjuvant therapy, patients undergo repeat evaluation
with physical examination, proctoscopy, MRI o the pel- collective experience at MDACC suggests that systemic
vis, and then surgical resection. therapy has limited activity against locally recurrent dis-
In the adjuvant setting, chemotherapy is oered to ease with ew durable responses. Palliative radiation is
those who received radiotherapy alone as neoadjuvant delivered as external-beam radiotherapy or brachyther-
therapy. Patients with stage III rectal cancer and no apy catheters. Aggressive use o narcotics and intrathecal
contraindication to oxaliplatin are advised to receive it analgesics or neurolytic blocks is used or pain control
as a component o FOLFOX or CAPOX. Patients with concurrently with aggressive bowel management.
a pCR ater preoperative 5-FU–based chemoradiation For the subset o patients who may be surgical can-
may receive single-agent 5-FU–based adjuvant therapy didates, treatment planning is vetted in our multidis-
rather than FOLFOX. The choice o adjuvant therapy ciplinary conerence. In our experience, pelvic MRI
may vary based on degree o response to single-agent is superior to CT or distinguishing posttreatment
fuoropyrimidine-based therapy and the patient’s changes rom viable tumor while identiy resectable
underlying comorbidities. disease. Biopsy conrmation o recurrence is always
recommended; EUS has not been particularly useul
with locally recurrent rectal tumors.
Postoperative Chemoradiation Beore salvage surgery, additional chemoradia-
Patients who have undergone surgery as their initial tion may be considered using a hyporactionated
intervention may require postoperative chemora- schedule to a total dose o 39 Gy (i at least 1 year
diation and systemic therapy when they present to has elapsed since prior pelvic radiation). Radiosen-
ChaptER 32
MDACC ater surgery. For patients with T3N0M0 sitization with 5-FU or capecitabine is also consid-
or T2N1 disease, radiotherapy is oten omitted i the ered. Approximately 6 to 8 weeks ater completion
tumor was located in the high pelvis (>10 cm rom the o chemoradiation, a nal decision about surgery is
anal verge), there is good nodal sampling (>12 lymph made. In most cases, the operative strategy may also
nodes), and the radial margin is negative (>2 mm) include intraoperative radiotherapy or insertion o
because pelvic tumor control is excellent without the brachytherapy catheters or high-dose aterloading.
use o chemoradiation.125,126 In all other stage II and III Postoperative chemotherapy ater aggressive pre-
rectal cancer cases, local ailure is high enough to war- operative chemoradiation is at the discretion o the
rant the use o chemoradiation. In addition, 4 months treating physician. However, there is broad agree-
o systemic therapy with either capecitabine or 5-FU– ment that surgery or locally recurrent disease is not
leucovorin is typically integrated with chemoradia- indicated in patients with unresectable metastatic
tion. Patients at higher risk o distant metastasis oten disease, given the overall poor prognosis, signicant
receive chemotherapy rst with FOLFOX. morbidity, and prolonged recovery associated with
this complex pelvic surgery.
Surveillance or Patients with Rectal
Cancer SYSTEMIC THERAPY FOR
Follow-up or patients with resected rectal cancer is very METASTATIC DISEASE
similar to that or colon cancer. Patients with a sphinc-
ter-preserving procedure also require periodic proctos- Since the late 1950s, systemic chemotherapy with 5-FU
copies or local relapses and anastomotic strictures. has been the mainstay o palliative treatment or patients
A rising CEA without other clinical or CT evidence with metastatic disease. During the ensuing decades, a
o relapse prompts a pelvic MRI or positron emission variety o 5-FU schedules have been used, including bolus
tomography (PET)–CT, particularly or local recurrence. injections administered either weekly (Roswell Park regi-
In patients with cCR dened as no apparent residual men) or daily or 5 days (Mayo regimen) and continuous
tumor on endoscopy, MRI and CT ater completion o inusion given via central catheter and portable pump.
neoadjuvant therapy wishing or a watch-and-wait When 5-FU is administered as a bolus injection, leucovo-
approach, a thorough discussion o the pros and cons, rin is oten added to enhance binding o 5-FU to its target,
including the current evidence, is done. Patients are thymidylate synthase. Ater a long period o uncertainty
additionally monitored with a proctoscopy every 3 to regarding the optimal dose and schedule o 5-FU with
4 months or the rst 2 years and every 6 months or leucovorin, inusional 5-FU regimens have been recog-
the next 3 years. nized as superior to bolus regimens.
Oncologists now have access to several drugs with
Management o Locally Recurrent Disease activity in the rst-, second-, and third-line settings. It
is important or oncologists to have a general under-
Locally recurrent rectal cancer presents a therapeutic chal- standing o these drugs and their roles in the treatment
lenge or which salvage surgery may not be easible. The o metastatic disease.
Capecitabine: An Orally Bioavailable leucovorin. These results prompted the FDA in 2000
Fluoropyrimidine to approve the use o these irinotecan-based combina-
tions or rst-line treatment o patients with CRC.
Capecitabine is an oral fuoropyrimidine that is con-
verted to 5-FU primarily in tumor tissues by the
enzyme, thymidine phosphorylase (TP). Concentra- Oxaliplatin
tions o TP are relatively higher in tumor tissue than Oxaliplatin is a third-generation platinum derivative
normal tissue, which accounts or the preerential that has shown additive or synergistic antitumor activ-
intratumoral release o 5-FU. Two large phase III trials ity in combination with a variety o antineoplastic
compared capecitabine with a bolus regimen o 5-FU, agents, including 5-FU; oxaliplatin is ineective without
and the results were subsequently pooled.127,128 The 5-FU.132 In 2000, de Gramont and colleagues133 reported
response rates were superior with capecitabine, and the the results o a phase III trial o inusional 5-FU–leucovo-
median survival was equivalent, with less neutropenia rin and oxaliplatin (FOLFOX4) versus 5-FU–leucovorin
and mucositis among patients receiving capecitabine. alone as rst-line treatment in patients with advanced
In patients with contraindications to combination CRC. PFS and response rates were signicantly bet-
chemotherapy, capecitabine monotherapy is a reason- ter or the FOLFOX arm compared with the 5-FU–leu-
able alternative to 5-FU and leucovorin in the metastatic covorin arm (9.0 months and 50% vs 6.2 months and
setting. However, caution should be taken when pre- 22%, respectively). Even though the FOLFOX arm expe-
scribing capecitabine to patients with end-stage renal rienced more grade 3 and 4 neutropenia, diarrhea, and
ChaptER 32
disease, and capecitabine should be held i the creatinine neurosensory toxicity, this did not impair quality o lie.
clearance is lower than 30 mL/min. Furthermore, it is o Goldberg and associates134 subsequently compared
note that patients in the United States do not tolerate the activity and toxicity o three dierent drug com-
the capecitabine doses used in Asian and European trials, binations in untreated patients with mCRC. A total o
perhaps because o the higher nutritional olate intake in 795 patients were randomized to receive IFL, FOLFOX,
the United States.129 Thus, we commonly dose-reduce or IROX (irinotecan + oxaliplatin). The results avored
capecitabine by about 20% without any apparent FOLFOX or all endpoints, including time to progres-
decrease in ecacy but with greatly improved tolerance. sion, response rate, and OS. Median survival times in
the FOLFOX, IFL, and IROX groups were 19.5, 15.0,
and 17.4 months, respectively.
IRINOTECAN Tournigand and colleagues135 answered the impor-
tant question o how to sequence these regimens. They
Irinotecan, an inhibitor o topoisomerase I, is a com- reported the results o a phase III study investigating
ponent o rontline therapy in patients with metastatic 5-FU, leucovorin, and irinotecan (FOLFIRI) ollowed by
CRC (mCRC). Two large, randomized trials were con- FOLFOX6 (Table 32–3) on progression o disease versus
ducted in the United States and Europe comparing 5-FU the opposite sequence (FOLFOX6 ollowed by FOLFIRI).
and leucovorin with 5-FU, leucovorin, and irinotecan as The two sequences were equivalent in terms o PFS and
rst-line treatment o patients with mCRC.130,131 Both OS, although the toxicity proles were dierent. The
studies demonstrated that the response and OS rates median survival times were 21.5 months in the FOLFIRI-
or the group treated with triple-drug therapy were FOLFOX arm (n = 109) and 20.6 months in the FOLFOX-
superior to those or the group treated with 5-FU and FOLFIRI arm (n = 111) (P = .99).
TABLE 32–3 Summary o Common Chemotherapy Regimens Used at MD Anderson Cancer Center or
Patients with Colorectal Cancer
Adjuvant Chemotherapy
Capecitabine: 1000 mg/m2 by mouth twice daily on days 1–14 (3-week cycle, total eight cycles)
5-FL–leucovorin: leucovorin 400 mg/m2 IV on day 1; 5-FU 400 mg/m2 IV bolus on day 1 ollowed by 5-FU 2400 mg/m2 IV
continuous inusion over 46 hours (2-week cycle, total 12 cycles)
Modied FOLFOX 6: oxaliplatin 85 mg/m2 IV on day 1; leucovorin 400 mg/m2 IV on day 1; 5-FU 400 mg/m2 IV bolus on day 1
ollowed by 5-FU 2400 mg/m2 IV continuous inusion over 46 hours (2-week cycle, total 12 cycles)
CAPOX: oxaliplatin 130 mg/m2 on day 1; capecitabine 850 mg/m2 by mouth twice a day on days 1–14 (3-week cycle, total eight cycles)
Therapy or Metastatic Disease
Capecitabine: 1000 mg/m2 by mouth twice a day on days 1–14 (3-week cycle)
• With or without bevacizumab (7.5 mg/kg IV every 3 weeks)
(Continued)
TABLE 32–3 Summary o Common Chemotherapy Regimens Used at MD Anderson Cancer Center or
Patients with Colorectal Cancer (Cont.)
5-Fluorouracil–leucovorin: leucovorin 400 mg/m2 IV on day 1; 5-FU 400 mg/m2 IV bolus on day 1 ollowed by 5-FU 2400 mg/m2
IV continuous inusion over 46 hours (2-week cycle)
• With or without bevacizumab (5 mg/kg IV every 2 weeks)
Modied FOLFOX 6: oxaliplatin 85 mg/m2 IV on day 1; leucovorin 400 mg/m2 IV on day 1; 5-FU 400 mg/m2 IV bolus on day 1
ollowed by 5-FU 2400 mg/m2 IV continuous inusion over 46 hours (2-week cycle)
• With or without cetuximaba (400 mg/m2 IV rst inusion ollowed by 250 mg/m2 IV weekly or 500 mg/m2 IV every 2 weeks)
or panitumumaba (6 mg/kg IV every 2 weeks)
CAPOX: oxaliplatin 130 mg/m2 on day 1; capecitabine 850 mg/m2 by mouth twice a day on days 1–14 (3-week cycle)
• With or without bevacizumab (7.5 mg/kg IV every 3 weeks)
• With or without cetuximaba (400 mg/m2 IV rst inusion ollowed by 250 mg/m2 IV weekly or 500 mg/m2 IV every 2 weeks)
or panitumumaba (9 mg/kg IV every 3 weeks)
Modied FOLFIRI: irinotecan 180 mg/m2 IV on day 1; leucovorin 400 mg/m2 IV on day 1; 5-FU 400 mg/m2 IV bolus on day 1
ollowed by 5-FU 2400 mg/m2 IV continuous inusion over 46 hours (2-week cycle)
ChaptER 32
• With or without cetuximaba (400 mg/m2 IV rst inusion ollowed by 250 mg/m2 IV weekly) or panitumumaba (6 mg/kg IV
every 2 weeks)
Irinotecan: 180 mg/m2 IV on day 1 (2-week cycle) or 300–350 mg/m2 IV on day 1 (3-week cycle)
Cetuximaba–irinotecan
• Cetuximaba 400 mg/m2 IV rst inusion ollowed by 250 mg/m2 IV weekly plus irinotecan 350 mg/m2 IV on day 1 (3-week
cycle) or 180 mg/m2 IV on day 1 (2-week cycle)
• Cetuximaba 500 mg/m2 IV every 2 weeks ± irinotecan 180 mg/m2 IV every 2 weeks
Panitumumaba: 6 mg/kg IV every 2 weeks or 9 mg/kg IV every 3 weeks
FOLFOXIRI: oxaliplatin 85 mg/m2 IV on day 1; irinotecan 165 mg/m2 IV on day 1; leucovorin 400 mg/m2 IV on day 1; ollowed by
5-FU 2400 mg/m2 IV continuous inusion over 46 hours (2-week cycle)
• With or without cetuximaba (400 mg/m2 IV rst inusion ollowed by 250 mg/m2 IV weekly or 500 mg/m2 IV every 2 weeks) or
panitumumaba (6 mg/kg IV every 2 weeks)
Triuridine–tipiracil: triuridine–tipiracil 35 mg/m2 (triuridine component) orally twice daily on days 1–5 and 8–12 (28-day cycle)
Regoraenib: regoraenib 160 mg once daily or 21 days; then 1 week o (28 day cycle). Recommend starting with 80 to 120 mg
once daily or 21 days; then 1 week o or rst cycle to determine tolerability
Pembrolizumabb: pembrolizumab 2 mg/kg IV every 3 weeks (21-day cycle); or pembrolizumab 200 mg IV every 3 weeks (21-day
cycle); or pembrolizumab 400 mg IV every 6 weeks (6-week cycle)
Nivolumabb: nivolumab 3 mg/kg IV on day 1 every 14 days (14-day cycles); or nivolumab 240 mg IV on day 1 (14-day cycle); or
nivolumab 480 mg IV on day 1 every 28 days (28-day cycle)
Nivolumab–ipilimumabb: nivolumab 3mg/kg (30-minute IV inusion) on day 1; ipilimumab 1 mg/mg (30-minute IV inusion)
on day 1 (21-day cycle) or our doses; then nivolumab 3 mg/kg IV every 14 days or nivolumab 240 mg IV every 14 days or
nivolumab 480 mg IV every 28 days
Cetuximab–encoraenibc: cetuximab 400 mg/m2 IV rst inusion ollowed by 250 mg/m2 IV weekly; encoraenib 300 m PO daily;
binimetinib 45 mg PO twice daily (28-day cycle)
Pertuzumab–trastuzumabd: pertuzumab 840 mg IV loading dose cycle 1 day 1, with subsequent doses 420 mg IV every 21 days;
trastuzumab 8 mg/kg IV loading dose cycle 1 day 1, with subsequent doses 6 mg/kg IV every 21 days (21-day cycle)
Larotrectinibe: 100 mg PO twice daily (28-day cycle)
Entrectinibe: 600 mg PO once daily (28-day cycle)
a
Cetuximab and panitumumab are indicated only in patients with RAS wild-type tumors.
b
Pembrolizumab, nivolumab, and ipilimumab are only indicated in patients with decient mismatch repair (dMMR)/microsatellite instability–high tumors.
c
The combination o cetuximab and encoreenib is only indicated in patients with BRAF V600E mutated tumors.
d
The combination o pertuzumab and trastuzumab is only indicated or HER2 amplied tumors that are RAS and BRAF wild type.
e
Larotrectinib and entrectinib are only Indicated In patients with an NTRK gene usion.
Concurrent chemotherapy and radiation therapy (rectal cancer):
Continuous inusion o 5-uorouracil (5-FU): 250–300 mg/m2 IV daily (Monday–Friday on days o radiation therapy only).
Capecitabine: 825 mg/m2 by mouth twice a day (Monday–Friday on days o radiation therapy only)
FOLFOX, 5-uorouracil, leucovorin calcium, and oxaliplatin; FOLFIRIIV, 5-FU, leucovorin, irinotecan, oxaliplatin; intravenous; PO, oral; CAPOX, capecitabine and
oxaliplatin.
An aggressive approach is the combination o oxali- a TP inhibitor, tipiracil hydrochloride, which prevents
platin, irinotecan, and 5-FU–leucovorin (FOLFOXIRI).136 the degradation o trifuridine. Results o the double-
In the randomized phase III TRIBE study, upront use o blind, randomized, controlled, international phase
FOLFOXIRI plus bevacizumab resulted in an improve- III RECOURSE trial were published in 2015 ollowed
ment in RR, PFS, and OS compared with FOLFIRI plus shortly thereater by approval o TAS-102 by the FDA.142
bevacizumab (OS, 29.8 months vs 25.8 months). In The primary endpoint o OS was met in 800 patients
the RAS/RAF wild-type (WT) population, there was an receiving TAS-102 in the third-line setting versus pla-
even greater benet, with an OS o 37.1 months com- cebo (7.1 months vs 5.3 months, respectively; P <.001).
pared with 25.6 and 13.4 months in the RAS MT and Improvement, albeit slight, was also seen in the second-
BRAF MT populations treated with FOLFOXIRI plus ary endpoint o PFS (2.0 months vs 1.7 months; HR,
bevacizumab, respectively.137 Concerns about this regi- 0.48; P <.001). The most common adverse events were
men are largely due to discussion o limited options or grade 3/4 neutropenia (38%) and leukopenia (21%).
second-line therapy i the patient’s disease progresses. Thus, TAS-102 and regoraenib, are reasonable sal-
However, this was disproven in the TRIBE2 trial that vage therapies, FDA approved in mCRC to be used
evaluated upront FOLFOXIRI plus bevacizumab ol- ater ailure o 5-FU, oxaliplatin, irinotecan, VEGF
lowed by the preplanned reintroduction o the same inhibitor, and an anti-EGFR monoclonal antibody
agents ater progressive disease. This approach was (mAb) in RAS WT.
shown to provide statistically signicant, and clini- Common chemotherapy regimens or both colon
cally relevant PFS and OS benets compared with the and rectal carcinoma are listed in Table 32–3.
ChaptER 32
preplanned sequential administration o FOLFOX plus
bevacizumab and FOLFIRI plus bevacizumab (PFS, 19.1
months vs 16.4 months; P = .002; and OS, 27.6 months
vs 22.6 months; P = .033, respectively).138
Cetuximab
Cetuximab is a chimeric immunoglobulin G1 (IgG1)
Regoraenib mAb directed against the epidermal growth actor
Regoraenib, a small-molecule inhibitor o multiple receptor (EGFR). Compared with BSC in a treatment-
kinases that are involved with various processes, includ- reractory patient population, single-agent cetuximab
ing tumor growth and angiogenesis, has documented resulted in superior OS (6.1 months vs 4.6 months) and
ecacy in a salvage therapy setting in advanced CRC. quality o lie. Two phase III randomized trials subse-
The phase III CORRECT trial randomized 760 patients quently conrmed the ecacy o cetuximab in combi-
who progressed on standard therapy to best supportive nation with irinotecan in previously treated patients,
care (BSC) or regoraenib. The trial met its primary end- with response rates o approximately 20%.143,144
point o OS (6.4 months vs 5.0 months or regoraenib Improvement in OS versus BSC has since been vali-
and placebo, respectively; HR, 0.77; P = .005). PFS was dated in heavily pretreated patients.145
also signicantly but modestly improved (1.9 months However, anti-EGFR mAbs do not benet patients
vs 1.7 months; P <.001).139 Unortunately, although with mCRC with oncogenic RAS mutations.146,147
response rates to regoraenib are low, adverse events are KRAS mutations initially identied in codons 12
high. The most common severe toxicities observed with and 13 o exon 2 result in constitutive activation o
regoraenib were hand-oot skin reaction, atigue, diar- the RAS-RAF-MEK-ERK (mitogen-activated protein
rhea, and hypertension. In a meta-analysis o our stud- kinase [MAPK]) pathway.148–150 Activating mutations in
ies, the incidence o all-grade hand-oot skin reactions in KRAS are detected in approximately 40% o mCRC
500 patients with CRC was 46.6%.140 To address this, cases151,152 with good concordance between primary
the phase II ReDOS trial investigated the use o an alter- tumors and distant metastases.153 Expanded RAS
native dosing schedule to reduce the toxicities related to mutations in KRAS exon 3 or 4 or in NRAS exon 2, 3,
regoraenib treatment. Rates o several o the most com- or 4 have also been noted to predict a lack o benet
mon adverse events were lower among the dose-esca- rom anti-EGFR mAbs, increasing the prevalence o all
lation group compared with the standard dosing group. innate RAS mutations to 50% to 55%.148,154,155
Based on these results, the dose-escalation strategy is The phase III trial CRYSTAL randomized nearly
an appropriate alternative approach or regoraenib 1200 patients with untreated mCRC to FOLFIRI with
dosing.141 or without cetuximab. Median PFS (8.9 months vs 8.0
months) and RR (47% vs 39%) were modestly improved
with cetuximab. Unplanned retrospective analyses
Trifuridine–Tipiracil (TAS-102) showed that clinical benet was limited to patients with
Trifuridine–tipiracil is an oral combination drug con- KRAS WT tumors. In this group o patients, cetuximab
sisting o a cytotoxic thymidine analog trifuridine and improved the RR rom 43% to 59%, median PFS rom 8.7
months to 9.9 months, and OS rom 20.0 months to 23.5 result in secondary resistance. Growing use o plasma
months.149,156 In addition, OPUS, a randomized phase II ctDNA testing has allowed or the noninvasive detec-
trial in treatment-naïve patients, compared FOLFOX4 tion o heterogeneous molecular alterations underly-
plus cetuximab with FOLFOX4 alone and showed ing the evolution o resistance to targeted therapies in
improvement in response rate and PFS with cetuximab. advanced CRC.162,163 Such analyses have uncovered the
Again, analysis revealed that this benet was restricted to role o acquired RAS mutations in resistance to anti-
patients without KRAS mutations.157 EGFR mAbs but have also implicated subclonal muta-
The most signicant toxicities associated with cetux- tions in the EGFR ectodomain in the development o
imab include diarrhea, hypomagnesemia, hypocalce- acquired resistance to anti-EGFR therapy.164
mia, and an acneiorm rash. Traditionally, the risk o an Several groups have shown that in the absence
allergic hypersensitivity reaction is reported to be less o continued selective pressure rom EGFR inhi-
than 5%. However, lie-threatening anaphylactic hyper- bition, the prevalence o RAS and EGFR mutant
sensitivity reactions have been reported in up to 30% o clones declines with a hal-lie o approximately 4
patients residing in select geographic locations.158 months.165,166 These data are consistent with several
Cetuximab is currently FDA approved with FOL- prospective trials demonstrating clinical benet with
FIRI in rst line, in combination with irinotecan ater anti-EGFR rechallenge. In the CRICKET single-arm
progression o disease (although it is routinely used in phase 2 study, patients with tissue-based RAS and
combination with FOLFOX as well), as monotherapy BRAF WT tumors with a PR and PFS o at least 6
or patients with mCRC who are intolerant o irinote- months to rst-line cetuximab plus irinotecan were
ChaptER 32
can-based regimens, and in combination with irinote- studied and ound to have RR, SD, and DCR rates
can ater progression o disease. o 21%, 32%, and 54%, respectively, to anti-EGFR
rechallenge. There was a statistically signicant cor-
relation between benet rom the rst anti-EGFR
Panitumumab
therapy and rechallenge.167 All patients achieving a PR
Panitumumab is a ully human IgG2 mAb directed were ctDNA RAS WT beore rechallenge with EGFRi,
against EGFR. In a randomized phase III trial, patients and these patients experienced a signicantly longer
with reractory metastatic disease received BSC with or PFS compared with patients with ctDNA RAS MT (4
without panitumumab. The RR and SD rate with pani- months vs 1.9 months). There are several large-scale
tumumab were 10% and 27% compared with 0% and clinical trials currently ongoing that will hopeully
10%, respectively, with BSC alone. An OS dierence better inorm the rechallenge practice.
could not be demonstrated in this trial, likely because
o crossover rom the BSC group.159 Subsequent analy-
Tumor Sidedness
sis revealed that only patients with KRAS WT tumors
beneted rom panitumumab.146 Although cetuximab Primary tumor location in mCRC is now considered
and panitumumab have not been compared head to a clear prognostic and predictive tool to guide man-
head, they appear to have similar ecacy and toxicity agement. Right-sided tumors are dened as those
in patients. Inusion reactions are uncommon with pani- that arise in the cecum to the hepatic fexure, and
tumumab because it is a ully human mAb. A large ran- let-sided tumors represent those rom the splenic
domized phase II trial (ASPECCT) (n = 1010) ound that fexure to the rectum. The initial indication that sid-
panitumumab is noninerior to cetuximab (Z score, -3.19; edness impacted clinical outcomes were noted in a
P = .0007) and that these agents provide similar OS bene- rst-line chemotherapy trial highlighting right-sided
t in patients with chemotherapy-reractory disease (10.0 tumors exposed to 5-FU–based chemotherapy had
months vs 10.4 months, respectively). Thus, it is now worse survival than let-sided tumors, with a di-
FDA approved as a single agent or patients ailing irino- erence o at least 5 months.168 More recently, these
tecan- and oxaliplatin-based chemotherapy. Two phase ndings have been urther supported by analysis o
III trials have also been reported o FOLFOX or FOLFIRI two randomized phase III clinical trials using ront-
with or without panitumumab or both treatment-naïve line chemotherapy with bevacizumab or treatment-
and previously treated patients, respectively.160,161 Both naïve mCRC, AVF2107g and NO16966. Interestingly,
studies reported superior response and PFS or the com- right-sided tumors were identied as negative prog-
bination and resulted in approval in combination with nostic indictors regardless o mutational status or
chemotherapy in the ront- and second-line settings. tumor histology.169 Furthermore, post-hoc analysis o
FIRE-3, PEAK, PRIME, and CRYSTAL all ound that
OS and PFS benet rom anti-EGFR therapy or RAS
Anti-EGFR Antibody Rechallenge
WT mCRC was limited to let-sided tumors alone.169–
172
Among patients with mCRC who initially respond to To date, CALGB/SWOG 80405 represents the
EGFRi, acquired abnormalities eventually develop and most compelling evidence or predicting the lack o
response to anti-EGFR therapy in relation to tumor The ecacy o bevacizumab as an adjunct to che-
sidedness.173 In this trial, among patients with RAS motherapy has been validated in the second-line set-
WT tumors treated with chemotherapy and cetux- ting as well. ECOG 3200 randomized more than
imab, a statistically signicant reduction in OS o 13.6 800 patients with mCRC previously treated with
months or right-sided cancers was noted compared 5-FU and irinotecan (but not oxaliplatin or beva-
with 39.3 months or let-sided cancers (P = .001; HR, cizumab) to one o three arms: FOLFOX4, bevaci-
0.55). O note, this stark dierence was not appreci- zumab, or the combination.177 The arm receiving
ated or bevacizumab exposure, consistent with an bevacizumab as monotherapy was closed to accrual
agnostic impact on survival outcomes between RAS ater an interim analysis revealed inerior outcomes
WT let-sided versus right-sided tumors (P = .50) with compared with the other two arms. Ultimately, the
anti-VEGF therapy. addition o bevacizumab to chemotherapy resulted
because o the retrospective analysis o CALGB in improved PFS (median, 7.3 months vs 4.7 months;
80405 highlighting sidedness as a biomarker o P <.0001) and OS (median, 12.9 months vs 10.8
response and selection criteria or EGFR inhibition, months; P = .0011).
both the NCCN and ESMO guidelines support deer- Bevacizumab is now FDA approved or use in com-
ring anti-EGFR therapy or patients with RAS WT bination with fuorouracil-based regimens as a rst- or
right-sided tumors in the rst-line setting. To date, second-line treatment or patients with mCRC.
there is no clear consensus on therapy ater the ront- Two large phase III trials (CAIRO2 and PACCE)
line setting; however, one trial, CO.17, solidied a examined the ecacy o dual biologic therapy (beva-
ChaptER 32
lack o benet with cetuximab compared with best cizumab with anti-EGFR antibody and chemotherapy)
supportive care or reractory KRAS mutant tumors. in mCRC. Both trials unexpectedly showed worse out-
Patients with right-sided tumors had no statistically comes with the combination approach.178,179 In light o
signicant benet with cetuximab compared with these data, dual VEGF and EGFR inhibition currently
let-sided tumors.174 Additional studies are needed to has no role in the treatment o patients with CRC and
determine whether patients with RAS WT right-sided should not be pursued outside a clinical trial.
tumors can glean any benet rom EGFR inhibition in
subsequent lines o therapy.
Ramucirumab
Bevacizumab Ramucirumab, another antiangiogenic agent, is a
human mAb that blocks VEGF signaling. In the multi-
Bevacizumab is a humanized mAb that binds all iso- center, phase III RAISE trial, 1072 patients with mCRC
orms o circulating VEGF, thereby inhibiting perme- whose disease progressed on rst-line therapy with
ability and angiogenesis mediated by this actor. 5-FU, oxaliplatin, and bevacizumab were randomized
In the phase II TREE-2 study, Hochster and col- to FOLFIRI with either ramucirumab or placebo. The
leagues175 demonstrated the saety and ecacy o primary endpoints o OS were met at 13.3 months and
bevacizumab in combination with oxaliplatin-based 11.7 months in the ramucirumab and placebo groups,
chemotherapy (mFOLFOX6, bFOL, or CAPOX). respectively (P = 0.02). PFS was also improved slightly
This trial was not powered or direct comparisons with the addition o ramucirumab (5.7 months vs 4.5
among the three arms, but time to progression (9.9 months, P <.0005).180
and 10.3 months, respectively) and OS (26.1 and 24.6
months, respectively) were virtually identical in the
mFOLFOX6 and CAPOX arms. In the NO16966 trial, Aibercept
untreated patients were randomized in a 2 × 2 design Afibercept is a recombinant usion protein o por-
to FOLFOX4 or CAPOX (nonineriority) with or with- tions o human VEGFR 1 and 2 extracellular domains
out bevacizumab.176 The pooled analysis revealed used to the Fc portion o human IgG1. In the phase
superior median PFS (9.4 months vs 8.0 months; P = III VELOUR trial, 1226 patients with oxaliplatin-rerac-
.002) in the bevacizumab-containing groups, but a di- tory mCRC were randomly assigned to afibercept or
erence in response and OS did not achieve statistical placebo plus FOLFIRI. Median OS, the primary end-
signicance. Surprisingly, when PFS was stratied by point was signicantly longer in patients treated with
chemotherapy regimen, the CAPOX regimen ared afibercept irrespective o prior bevacizumab exposure
better. In both o these trials, bevacizumab did not (13.5 months vs 12.1 months).181
increase the toxicities o chemotherapy. The most sig- Considering the results o the RAISE and VELOUR
nicant adverse events associated with bevacizumab trials, ramucirumab or afibercept are second-line
were hypertension; proteinuria; thrombosis; and treatment options in combination with FOLFIRI or
rare instances o bleeding (mostly epistaxis), delayed irinotecan ater progression on therapy not containing
wound healing, and GI peroration. irinotecan and are FDA approved or this indication.
Biomarkers and Targeted Therapy or among patients with dMMR mCRC compared with
Colorectal Cancer Management 0% and 11% or those with pMMR mCRC. At the
time o the report, the median PFS and OS were not
Microsatellite Instability–High Metastatic reached or the dMMR cohort and were 2.2 and 5.0
Colorectal Cancer months or the pMMR cohort, respectively.
Decient mismatch repair (dMMR) or MSI-H account Based on this data, MSI status is a denitive pre-
or only 4% to 5% o all patients with mCRC but dictive biomarker or response to immune check-
represent a unique cohort with a distinct prognosis point blockade (Figs. 32–4 and 32–5). NCCN has
and treatment option in the orm o immunotherapy included single-agent pembrolizumab, nivolumab, or
(Table 32–4).182 nivolumab plus ipilimumab as viable treatment options
Considering the hypermutated phenotype o dMMR or patients with dMMR mCRC in a second- or third-
tumors, the use o checkpoint inhibitors has oered line setting as well as those deemed “not appropriate
an exciting new treatment strategy or patients with or intensive therapy.”58
advanced CRC. Targeting programmed death ligand O note, the randomized open-label international
1 (PD-L1) on tumor cells or programmed cell death phase III KEYNOTE-177 trial comparing the anti–PD-1
protein 1 (PD-1) on T-cells has dramatically impacted antibody pembrolizumab with investigator’s choice
patient outcomes. Pembrolizumab and nivolumab are standard chemotherapy in combination with biologic
two IgG4 mAbs that target PD-1, both FDA approved therapy (anti-EGFR or anti-VEGF) or 307 patients with
treatment-naïve MSI-H mCRC has been presented.185
ChaptER 32
or patients with MSI-H mCRC ater demonstrating

durable clinical activity. The CheckMate-142 study The study met its primary endpoint o PFS with a
investigated the use o nivolumab alone or in combi- statistically signicant improvement to 16.5 months
nation with ipilimumab, a ully human IgG1 mAb that with pembrolizumab compared with 8.2 months
targets cytotoxic T-cell lymphocyte antigen-4 (CTLA- with chemotherapy (HR, 0.60; P = .0002). ORR was
4). The overall response rate (ORR) was 31.3% with also improved to 43.8% with the pembrolizumab arm
nearly 70% o patients achieving disease control at 12 compared with 33.1% with chemotherapy (P = .0275).
weeks and a median OS o 73% at 1 year or the mono- OS analysis is pending. Based on these results, the
therapy arm.183 In the doublet arm, although grade 3 FDA has now approved pembrolizumab or patients
and 4 treatment-related adverse events were increased with unresectable or metastatic MSI-H/dMMR CRC
to 32%, the ORR was 55% with a disease-control as rst-line treatment.
rate o 80% and a 1-year OS o 85%.184 Single-agent
data or pembrolizumab was rst reported in a land- BRAFV600E Mutation
mark phase II study investigating its ecacy among
41 patients with advanced CRC with or without mis- BRAF is a serine threonine kinase that is downstream
match-repair deciency.182 Both immune-related ORR o RAS in the MAPK pathway and is predominantly
and PFS were noted to be 40% and 78%, respectively, mutually exclusive rom concurrent RAS mutations.
The most common BRAF mutation occurs at codon
600 with a valine to glutamic acid change (c.1799T>A
TABLE 32–4 Prognostic and Predictive or p.V600E) producing a constitutively active protein.
Biomarkers in Metastatic Colorectal Cancer In clinical practice, approximately 7% to 14% o all
patients with mCRC carry a BRAFV600E mutation,
Biomarker Prognostic Predictive and this portends a poor prognosis.186 Patients with
dMMR/MSI-H + + BRAFV600E mCRC have a distinct clinical presentation
Tumor sidedness + + (or let-sided accompanied with hallmark pathologic eatures that
RAS WT) include older women, right-sided T4 tumors, high-
RASWT + + grade mucinous histology, sporadic MSI-H phenotype,
and predominantly distal nodal involvement with peri-
RAS mutant - +
toneal disease.187
V600E
BRAF + + BRAFV600E mCRC is associated with tumorigenesis
HER2 - + via the serrated/methylated pathway traditionally
amplication through a serrated adenoma precursor. This results in
NTRK usions Unknown + a hypermethylated phenotype with subsequent inac-
Atypical Unknown Unknown tivation o MLH1 yielding sporadic MSI-H/dMMR.188
non-V600 BRAF Thereore, it is critical to be aware o the MMR sta-
POLE Unknown Likely tus o all patients with BRAFV600E because o can have
dMMR, decient mismatch repair; MSI-H, microsatellite instability–high; WT, wild
clear clinical implications regarding sequencing o their
type. cancer therapy. Additionally, BRAF mutational status
mCRC: Screen all patients for dMMR and MSI, obtain comprehensive genomic profiling, obtain germline testing for young-onset mCRC
BRAFV600E RAS mutated RAS/RAF wild type
MSI-H/dMMR Right sided Left sided
FOLFOXIRI–
bevacizumab
First or
line doublet pMMR/MSS → FOLFOX / FOLFIRI
pMMR and MSS → FOLFOX, FOLFIRI, or FOLFOXIRI
chemotherapy +
+ bevacizumab
(for poor PS) Anti-EGFR (preferred) or Bevacizumab
dMMR or MSI-H: first-line dMMR or MSI-H: first-line

HER2 amplified?
anti–PD-1 monotherapy anti–PD-1 monotherapy
BEACON Alternate doublet + HER2 (+) clinical

Alternate Screen for NTRK Alternate doublet
regimen Bevacizumab or trials
doublet + gene fusions; if (+) +
(preferred) consider anti-EGFR or
bevacizumab → TRK inhibitor alternate biologic
Second or combination therapy trastuzumab
line VIC regimen +
ChaptER 32
or lapatinib or
BRAF (+) pertuzumab
clinical trials
Third Check ctDNA;

line or Novel targeted therapeutic clinical trials preferred or regorafenib or TAS-102 considere rechallenge
above of anti-EGFR
FIGURE 32–4 Biomarker-based decision algorithm or systemic therapy in metastatic colorectal cancer. BEACON; ctDNA,
circulating tumor DNA; dMMR, decient mismatch repair; EGFR, epidermal growth actor receptor; FOLFIRI, ????; FOLFOX,
5-fuorouracil, leucovorin calcium, and oxaliplatin; FOLFOXIRI, ????; mCRC, metastatic colorectal cancer; MSI, microsatellite
instability; MSI-H, microsatellite instability–high; PD-1, programmed cell death protein; pMMR, procient mismatch repair; PS,
perormance status; TAS-102, trifuridine–tipiracil; VIC, vemuraenib, irinotecan, cetuximab.
A B
C D
FIGURE 32–5 Radiographic and pathologic response o a microsatellite instability–high colon tumor treated with immuno-
therapy. A. Pretreatment computed tomography (CT) image o the abdomen with arrow depicting a bulky right colon mass
(arrow). B. CT image obtained ater 26 months o therapy with ipilimumab and nivolumab demonstrating complete radio-
graphic resolution o the colonic tumor (arrow). C. Photomicrograph o a right hemicolectomy specimen resected ater immu-
notherapy. The normal muscularis propria bundles are interrupted by broelastic tissue containing areas o eosinophilic
necrosis, as well as a polymorphic infammatory inltrate including cholesterol clets surrounded by giant resorptive cells (×25
magnication). D. The brous scar contained many vessels, some with associated thrombosis. Acellular mucin was also vis-
ible. (Reproduced with permission rom Ludord K, Cohen R, Svrcek M, et al: Pathological Tumor Response Following Immune
Checkpoint Blockade or Decient Mismatch Repair Advanced Colorectal Cancer, J Natl Cancer Inst 2021 Feb 1;113(2):208-211.)
remains a prognostic actor in terms o OS in both the mechanism o resistance in mCRC ater single-agent
early-stage and advanced settings.189 In the metastatic BRAF inhibition supporting the development o ratio-
setting, patients with a BRAFV600E mutation are rerac- nal combination therapies.194,195 Initial clinical studies
tory to traditional chemotherapy with an OS o only exploring the ecacy o BRAF and EGFR targeted
10 to 12 months.186,190 therapies revealed disease response in 52% and 67%
Considering this, initial therapeutic decisions are o treatment-reractory patients.196,197 Most notably,
paramount or patients presenting with metastatic when this dual targeted approach was combined with
disease. There are data to support the use o triplet chemotherapy (vemuraenib, irinotecan, cetuximab) in
chemotherapy in combination with bevacizumab or the SWOG 1406 study, superior PFS (4.4 months vs 2.0
BRAFV600E mCRC based on the TRIBE study, which months) and ORR (16% vs 4%) were achieved among
compared FOLFOXIRI–bevacizumab versus FOL- patients exposed to the three-drug combination arm
FIRI–bevacizumab or treatment-naïve patients with compared with those who received irinotecan and
mCRC.137 In this study, the primary endpoint o PFS cetuximab alone, supporting its initial insertion into
was met with an improvement o 2.4 months or all treatment guidelines.198,199
patients who received the triplet regimen compared MEK is a downstream eector o BRAF, and ini-
with doublet. Specically regarding BRAF,V600E 28 tial eorts exploring dual BRAF and MEK inhibi-
patients were included in this trial o which 16 were ran- tion reported modest ecacy with response rates o
domized to the triplet arm. Subgroup analysis revealed 12% and one complete response (CR) in a cohort o
that the triplet regimen resulted in improvement o OS 43 treated patients.200 The rst randomized phase III
ChaptER 32
to 19 months compared with 10.7 months with the trial or previously treated BRAFV600E mCRC, known
doublet regimen or BRAFV600E patients. Thereore, in as the BEACON CRC study, has been completed and
the rst-line setting or BRAFV600E mCRC patients with published with updated survival data reported.201 This
adequate perormance status, FOLFOXIRI in addition pivotal trial evaluated the ecacy o a BRAF inhibitor
to bevacizumab is a reasonable treatment choice. O encoraenib plus cetuximab with or without the MEK
note, in this same study, the RAS/RAF WT cohort that inhibitor binimetinib compared the control arm o iri-
received triplet therapy had a median OS o nearly notecan–FOLFIRI plus cetuximab. Initial saety lead-in
42 months, highlighting the innate aggressiveness o data reported an ORR o 48% with good tolerability
BRAFV600E mCRC. among 29 patients who received the triplet regimen.202
In addition to its underlying resistance to stan- Interestingly, updated survival data revealed that the
dard chemotherapy, the use o anti-EGFR therapy doublet regimen (encoraenib–cetuximab) was no
or BRAFV600E mCRC is no longer recommended as less ecacious than the triplet regimen. The doublet
monotherapy or in combination with chemotherapy arm revealed an improved median OS o 8.4 months
because o a lack o benet. This is based on the col- compared with 5.4 months or the control arm (HR,
lective assessment o multiple studies because individ- 0.60; P = .0003) as well as an improved median PFS
ual studies were limited by retrospective nature and o 4.2 months compared with 1.5 months or control
small numbers.191 A meta-analysis o nine phase III (HR, 0.40; P <.0001). Additionally, ORR was noted to
and 1 phase II trial (six rst-line studies, two second- be 20% or the doublet arm compared with 2% or
line studies, and two chemotherapy-reractory studies) the control arm (P <.0001). Based on these data, FDA
evaluated 463 BRAFV600E patients to address the impact approval was granted or the doublet regimen on April
o EGFR mAbs. This revealed that when anti-EGFR 8, 2020. Considering these data, the NCCN has rec-
therapy was added to chemotherapy or best sup- ommended the BEACON regimen o encoraenib in
portive care, there was no improvement in PFS, OS, combination with cetuximab or previously treated
or response rate compared with control regimens.192 patients with BRAFV600E mCRC, refecting the rst time
Based on these available data, NCCN, ESMO, and a completely targeted therapeutic approach is available
ESMO Asia all recommend the use o EGFR antibodies or these high-risk patients.
exclusively or RAS/BRAF WT mCRC patients.
In light o the limitations o chemotherapy and EGFR
HER2 Amplifcation
inhibition or BRAFV600E mCRC, the need to develop
eective targeted therapies against the mutated pro- Human epidermal growth actor receptor (HER2) is a
tein itsel was clear. Unortunately, although exciting member o the EGFR receptor amily and aberrant sig-
results or BRAFV600E mutant metastatic melanoma was naling is known to occur via genomic amplications
achieved with BRAF inhibition, this success was not promoting upregulation o phosphoinositide 3-kinase
realized with either vemuraenib or encoraenib in (PI3K) and MAPK pathways. In CRC, HER2 ampli-
early-phase studies or mCRC, with response rates o cation is noted in 3% to 5% o patients, mutually
5% and 0%, respectively.193 Distinct rom melanoma, exclusive rom RAS/RAF mutations and may be associ-
reactivation o EGFR signaling is the most prominent ated with de novo resistance to EGFR mAbs. In breast
cancer, HER2 amplications occur at an increased re- landmark study, 55 adult and pediatric patients with
quency and has been a ocus o therapeutic targeting NTRK usions achieved an ORR o 75% with 55% o
via mAbs trastuzumab and pertuzumab. Serving as a patients remaining progression-ree at 1 year. Among
precedent, this approach was pursued in CRC trials three patients enrolled with CRC, two achieved an
with success. The HERACLES trial accrued patients objective response.207 These data have resulted in FDA
with CRC with HER2 positivity dened as 3+ HER2 accelerated tissue agnostic approval to use larotrectinib
score in greater than 50% o tumor cells by immuno- or all patients with reractory solid tumors and an NTRK
histochemistry (IHC) or with 2+ HER2 score and a usion. The NCCN has since recommended testing or
HER2:CEP17 ratio greater than 2 in more than 50% NTRK gene usions in mCRC and supports the admin-
o cells by fuorescence in situ hybridization (FISH). istration o larotrectinib or this rare cohort o patients.
In this study, trastuzumab in combination with lapa-
tinib (an oral dual HER2–EGFR kinase inhibitor) was Evolving Biomarkers o Interest in
used to treat 27 patients with reractory HER2 mCRC. Metastatic Colorectal Cancer
Nearly 30% o patients had an objective response with
1 patient developing a CR.203 In the phase II MyPath- BRAFnon–V600 Mutation
way study, 57 reractory HER2-amplied patients Atypical, non-V600 BRAF mutations are an increas-
with mCRC were treated with a combination dual- ingly recognized molecular subset, representing nearly
HER2 targeted approach o pertuzumab and trastu- 2.2% o all patients with mCRC.208 Unlike BRAF,V600E
zumab, revealing a 32% ORR and 1 patient with a patients with atypical BRAF mCRC have a distinct
ChaptER 32
CR.204 Considering these two positive landmark stud- clinicopathologic prole with most patients having
ies, the NCCN has added HER2 targeted therapy with microsatellite stable (MSS) disease, let-sided primary
trastuzumab and lapatinib or trastuzumab and pertu- tumors, lower grade histology, and nonperitoneal dis-
zumab as viable options or patients with reractory ease and are commonly co-mutated with RAS. Patients
HER2-amplied mCRC. Based on early reports o with atypical BRAF mCRC have been reported to have
HER2 amplication representing a negative predictive an improved median OS o 60.7 months compared with
biomarker or EGFR mAbs, we await results rom the 11.7 months or those with traditional BRAFV600E muta-
ongoing phase II SWOG 1613 study (NCT03365882) tions.208 Furthermore, preclinical data have described
evaluating patients with chemotherapy-reractory,
BRAF mutations as unique classes based on their
anti-EGFR-naïve, HER2-amplied, RAS/RAF WT
underlying signaling biology. Whereas class I refects
mCRC randomizing to trastuzumab and pertuzumab
traditional BRAFV600E mutations that signal via BRAF
versus cetuximab and irinotecan.
monomers with high kinase activity and are non–RAS
The DESTINY-CRC01 trial evaluated trastuzumab
dependent, atypical non-V600 BRAF mutations signal
deruxtecan (T-DXd), an antibody–drug conjugate
via BRAF dimerization and have been categorized into
consisting o an anti-HER2 antibody, a cleavable tet-
class II and III subtypes.209,210 Whereas class II muta-
rapeptide-based linker, and a cytotoxic topoisomer-
tions have intermediate to high kinase activity without
ase I inhibitor, in 78 patients with previously treated
RAS dependency, class III mutations have low kinase
unresectable or mCRC that was HER2 expressing and
activity and are RAS dependent.
RAS/BRAF WT mCRC with a primary endpoint o RR.
Currently, there are no guidelines to direct the man-
Patients with HER2-positive with IHC scoring 3+ or
agement o patients with atypical BRAF mutations
IHC 2+/in situ hybridization+ had RR o 45.3% and
with clinical trials recommended ater ailure o stan-
stable disease in another 37.7%. Median PFS was 6.9
dard cytotoxic chemotherapy. Regarding biologic ther-
months in cohort A, and median OS was not reached.
apy, although there have been some data to suggest
O note, interstitial lung disease is an important
class III mutations may benet rom EGFR inhibition,
adverse event with T-DxD noted in 6.4% o patients
additional studies have been less convincing.210,211
in this trial.205
POLE Mutations
NTRK Fusions
The POLE gene is located in 12q24.33 and encodes
Neurotrophic receptor tyrosine kinase usion (NTRK) the prooreading exonuclease domain o polymerase
genes encode or TrkA, TrkB, and TrkC receptor tyro- epsilon.212 Somatic mutations in POLE are a rare
sine kinases that are responsible or baseline unction event in CRC, estimated at less than 1%.213 However,
in human neuronal tissue with activation via MAPK POLE mutations are important to highlight consider-
and PI3K pathways. Fusions can be aberrant resulting ing patients with these mutations have an increased
in oncogenic addiction with a rare prevalence o 0.2% rate o hypermutated tumors with higher neoantigen
to 2.4% o all CRC with data suggesting higher yield load, thereby potentially representing a predictive bio-
(approaching 3%) in the MSI-H subpopulation.206 In a marker to immunotherapy in a non–MSI-H setting,
although deciphering between passenger and driver recommended cross-sectional imaging modality. PET-
POLE mutations is o importance in regards to pre- CT may be used or inconclusive ndings or i a ris-
dicting successul outcomes with checkpoint inhibi- ing CEA level is noted without measurable disease on
tion.214,215 Although an evolving area in CRC, there are CT or MRI. All patients are encouraged to maintain a
no guidelines because o limited data to date. How- relationship with a primary care physician or optimal
ever, in clinical practice, identiying the presence or surveillance and health care.
absence o these mutations refects a potential thera-
peutic target in the reractory setting.
CHALLENGING CLINICAL
MANAGEMENT PROBLEMS
DECISION MAKING FOR POTENTIAL
SURGICAL RESECTION IN PATIENTS Management o the Older Adult
WITH METASTATIC COLORECTAL Population and Colorectal Cancer
CANCER Age-related decline in organ unctions and reserves,
medical comorbidities, and quality o lie consider-
Despite therapeutic advances, the estimated 5-year OS ations oten complicate management o older adult
or patients unable to be surgically resected remains less patients with CRC. Although essential principles o
than 15%. Although randomized data are limited, ret- management in CRC do not vary with age, increased
ChaptER 32
rospectively, surgery has shown 5-year OS in excess o risks o chemotherapy in older adult patients, some-
30%.216,217 Thereore, multidisciplinary discussions or times perceived and sometimes palpable, may alter the
surgical resection in mCRC should be initiated early i approach to these patients. Despite their underrepre-
there is a potential or surgery with curative intent. Diag- sentation in clinical trials, a systematic review o phase
nostic imaging (MRI, PET-CT, and volumetric) has an III randomized trials (n = 345) or older adult patients
important role when considering surgical resection. The (65 years o older) demonstrated that appropriately
use, choice, and duration o neoadjuvant chemotherapy selected patients can derive equivalent benets rom
should be determined by the treating medical oncolo- therapy without a substantial increase in toxicity.224
gist and surgeon in a multidisciplinary ashion and is The AVEX study in older adult patients (aged 70
typically limited to less than 3 months. Patients who years and older) with untreated mCRC, deemed not to
have response or stable disease on neoadjuvant therapy be candidates or aggressive chemotherapy showed that
are better than those with progression.218 Perioperative combination bevacizumab and capecitabine was eec-
and adjuvant therapy (5-FU-based) versus observation tive (signicantly longer median PFS, 9.1 months vs 5.1
has shown a trend toward improved DFS but not OS months) and well tolerated (treatment-related adverse
with hepatic resection.219–221 This benet comes at risk events o grade 3 or worse, 40% vs 22%) compared with
o increased postoperative complications rom chemo- capecitabine alone.225 Treatment o patients with CRC
therapy-induced steatohepatitis and hepatic sinusoidal should be based on a comprehensive assessment o risk–
injury.219,222 Additionally, although bevacizumab is used, benet encompassing perormance status, comorbidities,
we do not use anti-EGFR mAbs in perioperative setting and consideration o toxicities rather than age alone. Spe-
because o inerior OS and PFS seen with the EPOC cial emphasis should also be placed on dening molecular
study.223 Others challenges are the timing and role o subsets such as dMMR mCRC, wherein targeted thera-
radiotherapy and surgery in patients with metastatic pies can provide clinical benet with lower toxicity com-
disease in the presence o a primary rectal cancer. At pared with conventional cytotoxic chemotherapy.
MDACC, our approach is to perorm liver metastasec-
tomy rst ater a course o neoadjuvant chemotherapy
ollowed by chemoradiation and then primary resection. Malignant Polyps
On occasion, an endoscopically removed polyp may
Follow-up or Patients with Resected demonstrate invasive adenocarcinoma within a vil-
lous or tubular adenoma. Treatment recommenda-
Metastatic Colorectal Cancer tions in this situation should be individualized based
Ater metastasectomy, patients are ollowed closely on eatures, including negative margins, no evidence o
with physician visits, CEA level, and diagnostic imag- invasion beyond the submucosa, well- or moderately
ing every 3 to 4 months or the rst 3 years, every 6 dierentiated adenocarcinoma, and no evidence o
months or the ollowing 2 years, and annually there- lymphatic or vascular invasion. In this setting, the risk
ater. Colonoscopy should continue to be completed o lymph node metastases is low (5%), and ollow-up
every 3 years thereater (or more requently based with periodic colonoscopic examinations is reason-
on endoscopic ndings). CT (or MRI) is the standard able. Unortunately, retrieval o a sessile or bulky polyp
distorts the depth o invasion or margin status. Fur- argon plasma coagulation, may recanalize the lumen.
thermore, i pathology demonstrates poor dierentia- External-beam radiotherapy may then prevent com-
tion, invasion into the muscularis, or lymphovascular plete obstruction while alleviating partial obstruction.
invasion, surgical resection is advised. In particular, T2 Patients with impending bowel obstruction are hospi-
tumors have a 20% likelihood o lymph node metas- talized or bowel rest, nasogastric tube decompression,
tases, so continued endoscopic ollow-up without ur- and intravenous hydration ollowed by multidisci-
ther surgical intervention is not appropriate. plinary evaluation by a gastroenterologist, surgical
A malignant polyp in the distal or midrectum is oten oncologist, medical oncologist, and radiotherapist.
not amenable to urther local staging because endo-
scopic rectal polypectomy leads to unreliable EUS imag-
ing. Denitive surgical resection should be considered
Multidisciplinary Management o Poor
or a resected rectal polyp without clear margins or with Bowel Function Ater Curative Treatment
adverse pathologic eatures. I margins are equivocal Segmental bowel resections leads to permanent altera-
without muscle invasion, transanal excision may be ea- tions in the requency and character o bowel move-
sible. Even when laparotomy is considered, a sphincter- ments. Loss o the rectal vault and radiotherapy lead to
preserving procedure is usually possible. Occasionally, compromised stool storage and stricture ormation at
an adequately inormed patient will reuse surgery, or the anastomotic site, and sphincter unction may not
medical comorbidities preclude surgery as an option. return to baseline, leading to unctional and mechani-
In these special circumstances, nonstandard combined- cal dysunction maniesting as small, requent bowel
ChaptER 32
modality chemoradiation is an alternative to denitive movements, with episodic ecal incontinence.
resection. In general, patients are advised that bowel habits may
improve or up to 1 year rom the time o surgery or up
Nonsurgical Options or Partially to 6 months ater completion o all adjuvant therapy.
For patients with more chronic and severe problems
Obstructing Tumors (innumerable small bowel movements or ecal inconti-
Bowel resection or diverting ostomy may be appro- nence), a multidisciplinary team o surgeons, gastroen-
priate, but in patients with poor perormance status, terologists, and enterostomal nursing sta recommends
nonsurgical management should be considered, which a personalized detailed bowel regimen that, with ade-
includes expandable metal stents, especially in the quate adherence, can improve quality o lie and satis-
rectosigmoid region. Obstructing sites higher in the action with sphincter preservation. On rare occasions,
colon can pose technical barriers to stent insertion. when a sphincter-preserving procedure leads to unbear-
An endoscopically placed colonic decompression tube able dissatisaction with bowel unction, a colostomy or
proximal to the obstruction may provide temporary ileostomy may be recommended to improve unctional
relie. Endoscopic electrosurgical procedures, including status and quality o lie.

J It is difcult to articulate a general treatment algo- J Asymptomatic patients with metastatic disease are
rithm or patients with metastatic disease, but indi- usually ofered systemic therapy. With advent o
vidual consideration o each patient’s case is always newer, more efcacious agents, rontline therapy
considered. Whenever possible, patients with good is better tolerated and more likely to be bene-
perormance status should be oered therapy as cial in asymptomatic patients with good peror-
part o a clinical trial. mance status. An exception to this principle is
J Previous analyses have suggested a survival advan- patients with known metastatic disease that is
tage or patients treated with all three active con- either not evaluable or extremely low volume. In
ventional cytotoxic agents (5-FU, irinotecan, and these cases, close ollow-up with requent imag-
oxaliplatin) during the course o their treatment.226 ing may be an appropriate initial strategy. Ther-
Tumor mutation status has become a core part o apy is then initiated when measurable disease is
treatment decision making and should be perormed evident or, in the oncologist’s judgment, urther
in all patients with metastatic disease. At MDACC, i expectant ollow-up is likely to lead to symptoms.
tumor tissue is unavailable or not amenable or biopsy, Patients with a rising serum CEA level are usually
ctDNA-based proling is done to guide therapy. not recommended to undergo treatment in the
absence o clear clinical or radiographic evidence
J Broad principles have emerged as the oundation
o metastatic disease and are ollowed closely.
or therapeutic decisions at MDACC:

J The initial treatment or patients with metastatic preerence must be considered as well. Thereore, a
disease may depend on the timing and residual chemotherapy treatment holiday may be appro-
toxicities o prior adjuvant therapy. Many patients priate or select patients ater prolonged response
who develop metastatic disease have received or stability o disease.
prior adjuvant therapy consisting o oxaliplatin. J The need or local control should always be con-
When patients relapse, they should be consid- sidered. Recent experience with combination
ered reractory to this combination i ewer than therapies suggested that the primary tumor may
12 months have elapsed since the completion respond well to systemic therapy in some cases,
o adjuvant therapy. Irinotecan oten becomes obviating the need or local therapies. As a rule,
the primary cytotoxic agent in the treatment o however, locally recurrent tumor at a site o pre-
patients with relapsed disease ater recent adju- vious surgery or radiotherapy is not particularly
vant therapy. responsive to systemic therapy. Thereore, oncol-
J Patients should be treated to maximal benet or ogists must continuously reassess whether local
until therapy becomes intolerable. When patients tumor control should take priority over treat-
are receiving systemic therapy or metastatic ment or disseminated disease. Such decisions
disease, we usually continue treatment until pro- are usually made with input rom a multidisci-
ChaptER 32
gression, unacceptable toxicity, or patient’s deer- plinary team.

ment o therapy. Patients receiving oxaliplatin in J Whenever easible a multidisciplinary approach
conjunction with capecitabine or 5-FU, as part o should be considered, including role o surgical
a FOLFOX or CAPOX regimen, may develop unac- resection in metastatic disease: Surgical resection
ceptable peripheral neuropathy. In such cases, appears to coner a signicant survival benet
there is no disadvantage to discontinuation o compared with systemic therapy alone in appro-
oxaliplatin, provided maintenance therapy contin- priately selected patients. When possible, a cura-
ues. Oxaliplatin may be reintroduced as a compo- tive-intent metastasectomy (especially liver and
nent o the regimen when neuropathic symptoms lung) should be incorporated in the treatment
subside or the tumor starts to progress.227 plan with early discussion between surgical and
J The benet o maintenance therapy must be medical oncologists.
weighed against potential toxicity, and patient
22. Meyerhardt JA, Shi Q, Fuchs CS, et al. Celecoxib in addition

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ChaptER 32
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ChaptER 32
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33 Anal Cancer
Emma Holliday
Van Morris
Craig A. Messick
KEY CONCEPTS
 Despite the introduction o a preventive human papillo-  Salvage surgery with abdominoperineal resection remains
mavirus vaccine, both the incidence o anal cancer and the standard o care or patients with nonmetastatic,
the anal cancer–specic mortality rate continue to rise in locoregional anal cancer that recurs ater chemoradiation.
the United States.  Combination chemotherapy is the current treatment rec-
 Concurrent chemoradiation remains the standard o care ommendation in the rontline setting or patients with
or curative-intent therapy or patients with newly diag- inoperable, metastatic anal cancer.
nosed, locoregional anal cancer.  Immune checkpoint blockade therapies, either as mono-
 To date, there are no data to support benet with chemotherapy or as a clinical trial option, should be considered
therapy beore or ater chemoradiation or patients with or patients with treatment-reractory anal cancer.
locoregional anal cancer.
Carcinoma o the anal canal is extremely rare, rep- ANATOMY

resenting approximately 2% to 3% o all gastroin-
testinal (GI) malignancies. It was estimated that in Optimal treatment o patients with SCCA requires
2020, 8590 patients (5900 emale) would be diag- sound understanding o the anatomy o the anus,
nosed with carcinoma o the anal canal in the United which includes the anal canal, anal verge (AV), and
States, resulting in 1350 deaths.1 The incidence o anal margin (AM). The anal canal is variable in length
this disease continues to rise steadily. Over the past and is 2 to 3 cm long in women and 3 to 5 cm in
20 years, increasing rates o advanced (metastatic) men. The AV is the visible portion o the anus seen
stage at initial presentation have been reported in with gentle traction applied to the buttocks, and the
the United States and are linked to a rise in cancer- AM is a region that extends 5 cm radially rom the
specic mortality rates. 2 Still, a practicing oncologist AV around the anal skin (Fig. 33–1). Nomenclature is
will evaluate and treat less than one such patient per vital, and accurate description o the tumor location
year. The majority o anal cancer is squamous cell is critical or optimal management. Although classi-
carcinoma (SCC) and typically arises within the anal cation o these tumors by their histologic denition
mucosa.3 Traditionally, more than 70% o locore- may oer a more consistent approach to guide diag-
gional anal canal caners are cured with the combined nosis and treatment, 3 meaningul data suggest such
modalities o chemoradiation,4 reserving an abdomi- a singular approach to all SCCA may be inadequate,
noperineal resection (APR) or salvage therapy o and a tailored approach to these cancers may be more
patients with persistent or recurrent disease. 5 This important. For example, malignancies o the AM that
chapter ocuses on the multimodality treatment o do not involve the anal sphincter complex and are
SCC o the anus (SCCA) and the emerging role o smaller than 2 cm are oten treated as primary skin
immunotherapy in management o patients with cancers, surgically excised with a wide local excision
this disease. (WLE). This is not to be applied to T2 tumors outright
765
FIGURE 33–2 Nonkeratinized squamous cell carcinoma o

the anal canal.
ChApTER 33
IGURE 33–1 Anatomy o the anal canal.
and especially those in the anal canal, but T2 tumors

that are very small or ar away rom the sphincters
could also conceivably managed with WLE with ade-
quate counseling that T2 tumors may carry up to a
24% risk o positive LN at the time o diagnosis.6,7
The anal canal can be divided into two parts by a
third part, the anal transition zone (ATZ). The proxi-
mal anal canal is composed o rectal mucosa, or colum-
nar epithelium, which transitions to an ill-dened ATZ
made o both cuboidal and columnar epithelium (6–12
mm in length) and extends to the dentate line.8 The
dentate line is a visible anatomic site that represents
FIGURE 33–3 Keratinized squamous cell carcinoma o the
the separation o columnar epithelium (columns o
anal canal.
Morgagni) o the proximal hal o the anal canal and
the squamous epithelium o the distal hal o the anal
canal extending to the AV. The AV is the convergence
o squamous epithelium and the dermis and epidermis RISK FACTORS
o the AM. Importantly, the ATZ mucosa, historically
reerred to as the cloacogenic mucosa, is the location Several risk actors have been previously associated
or approximately 66% o nonkeratinizing SCCAs with the development o SCCA. Some o those relate
(Fig. 33–2),8 whereas tumors distal to the dentate line to sexual activity, including a history o more than 10
are keratinizing SCCAs (Fig. 33–3). sexual partners; anal receptive intercourse (especially
The vascular supply o the anal canal consists o men having sex with men [MSM]); having a prior
the superior, middle, and inerior rectal vessels that sexually transmitted disease, including condyloma
originate rom the inerior mesenteric, internal iliac, acuminata (genital warts, attributed to human papil-
and internal pudendal arteries, respectively. Lymphatic lomavirus [HPV]), gonorrhea, herpes virus, hepatitis,
drainage or tumors located cranially to the dentate line or Chlamydia trachomatis inection; and being human
is identical to rectal carcinomas draining to the peri- immunodeciency virus (HIV) positive.9–11 Another
rectal and paravertebral nodes. Tumors located caudal well-documented risk actor is immune suppression
to the dentate line drain to the inguinal and internal caused by chronic anti–organ rejection medication
iliac and obturator lymph nodes. A complete physical as seen in transplant recipient patients. Patients with
examination should include examination o the lymph these risk actors have been designated “high risk” or
nodes o the groins. HPV-related disease development and are the most
Cater 33 Anal Cancer 767
commonly screened portion o the population or pre- 90% o all SCCA case and develop through a precur-
invasive disease. Recently, patients who have been sor lesion termed high-grade anal squamous cell intraepi-
diagnosed with HPV-related disease at a prior organ thelial lesions (HSIL). However, HSIL is a premalignant
site (cervix, vagina, vulva, penis, scrotum, or oro- condition or which standard anal screening methods
pharyngeal) are considered to be at greater risk that currently have not been universally recommended and
the general population and have been designated “at have been limited to individuals considered high risk.
risk.”12–14 Although benign conditions such as hemor- Two international studies (ANCHOR [NCT02135419]
rhoids, ssures, and anal stulas are oten associated and SPANC [NCT02007421]) are designed to address
with HPV-related disease o the anus, they have not the question that treating HSIL prevents SCCA devel-
been determined to be causative.15 Instead, their asso- opment in high-risk patients.
ciated nonspecic symptoms such as bleeding per To conrm causation o HPV with SCCA devel-
rectum, pain, ullness in the anal canal, or incomplete opment, a cohort o patients with metastatic SCC o
emptying simply overlap with SCCA. the anal canal at the University o Texas MD Ander-
Despite a previous emphasis on HPV being only son Cancer Center (MDACC) revealed the presence
sexually transmitted, it is now understood that HPV o HPV, via detectable HPV DNA or expression o the
can be transmitted outside o sexual activity. Although protein p16, in 68 (95%) o 72 tumor samples ana-
transmission remains predominantly through sexual lyzed.25 Thereore, HPV appears to be ound in the vast
activity and is the most common sexually transmitted majority o SCCA regardless o the initial stage o pre-
inection,16 acquisition o the virus requires only direct sentation, yet some types are not completely associ-
ChApTER 33
contact with either the virus or viral-laden sloughed ated with HPV, including basaloid or verrucous types.
squamous cells. Other documented mechanisms o The presence o HPV also has been reported to
transmission include vertical (maternal–etal)17–19 and be a positive prognostic biomarker or patients with
indirect through omites.20 Indirect transmission may nonmetastatic SCC o the anal canal. In one study
be more important because the anus turns over its cellu- o patients with stages I to III anal cancer, HPV was
larity every 4 days,21 one o the astest in the body, and detected in 120 (88%) o 137 tumors analyzed. In a
the body loses approximately 40,000 squamous cells multivariate analysis, p16 expression was determined
every minute, or roughly 500 million each day, leaving to be associated with an improvement both in overall
substantial potential or patient exposure. Regardless survival (OS) and disease-specic survival relative to
o mode o transmission, the pathogenic changes lead- patients with HPV-negative tumors.26
ing to SCCA are directly related to the chronic inec- In 2006 and 2009, introduction o the prophylactic
tion with high-risk types, most commonly HPV-16 or vaccines Gardasil and Cervarix, respectively, directed
HPV-18. Women with a history o cervical, vaginal, against primary inection by HPV demonstrated e-
or vulvar cancer are three to ve times more likely to cacy in reducing precancerous anogenital lesions
develop anal cancer as opposed to stomach or colon caused by the high-risk subtypes HPV-16 and -18.27–29
cancer.22 Until recently, this relationship was only In late 2014, the U.S. Food and Drug Administration
explained by sexual activity; however, a recent study (FDA) approved the introduction o a nonavalent vac-
in women showed signicant relationship between cine targeting nine HPV subtypes (6, 11, 16, 18, 31,
ront-to-back wiping and HPV local transmission 33, 45, 52, and 58).30 A large, double-blind placebo-
compared with blotting (dabbing) and back-to-ront controlled study in MSM between 16 and 26 years o
wiping.23 Although this does not negate the notion o age demonstrated that use o the quadrivalent vaccine
sexual transmission, it oers additional explanation or against HPV was both sae and well tolerated but also
the large disparity in anal cancer between women and decreased the incidence HSIL.29 These ndings gen-
men or women who deny anal receptive intercourse. erated optimism that this preventive approach may
Human Papillomavirus decrease the incidence o this disease in the uture.
Because HPV is the most common sexually transmit- Originally approved or use in emale adolescents, HPV
ted disease in the United States and strongly associated vaccines have now received extended FDA approval as
with the development o anal carcinoma,16 it is esti- being “gender neutral” (given to both male and emale
mated that 75% o men and women o reproductive age patients) ater their ecacy was shown in both gen-
have been exposed to HPV at some point in their lives. ders, a now very promising primary prevention strat-
A well-cited epidemiological study by Giuliano et al24 egy or SCCA.30
in 2008 revealed that in an international cohort o men,
who were never received the HPV vaccine, had never
practiced anoreceptive intercourse, were HIV-negative,
Human Immunodefciency Virus
and otherwise not recognized as high risk, the HPV Although a direct relationship between HIV and
positivity rate was 65.2%. High-risk HPV subtypes SCCA has not been clearly established, a strong cor-
(16 and 18) are associated with approximately 85% to relation exists between HIV and HPV. Compared with
HIV-negative patients, HIV-positive patients are two may add benet in staging.41–44 Histologic conrmation
to six times more likely to be diagnosed with HPV is required, with a tissue biopsy o the primary site
regardless o sexual practices and are also more likely with ne-needle aspiration o any palpable inguinal
to have a persistent inection.31,32 HIV-positive men and lymph nodes because this may impact the radiation
women exposed to HPV are less likely to “clear” the elds. An HIV test should be considered in all patients,
virus and become HPV-negative.32,33 For HIV-positive and a one-time test or hepatitis C inection may also
patients, the prevalence o SCCA is greater and pres- be considered or patients born beore the year 1965
ents at a younger age o onset than in HIV-negative given the disproportionately high risk o incidence o
patients.34 viral inection or patients in this age range.45
Chronic Immunosuppression STAGING AND pROGNOSIS

Solid organ transplantation has been associated with
a 10-old increased risk o developing SCCA and a The staging classication system or anal cancer was
20-old increased risk or vulvar and vaginal cancers.35 adopted by the American Joint Committee on Cancer
A population-based cohort study conducted using (AJCC). The tumor (T) stage, unlike most GI malig-
the Danish National Patient Registry and the Danish nancies, is not dependent on the degree o tumor tis-
Cancer Registry rom 1978 to 2005 ound that HIV sue penetration but rather on the size o the primary
inection, solid organ transplantation, hematologic tumor site. Tumors 2 cm or smaller are considered T1,
ChApTER 33
malignancies, and a range o specic autoimmune dis- tumors larger than 2 but 5 cm or smaller are considered
eases were strongly associated with increased risk o T2, tumors larger than 5 cm are considered T3, and
SCCA.36 locally invasive tumors invading adjacent organs are
considered T4. The eighth edition o the AJCC staging
guidelines went into eect on January 1, 2018.46 The T
Tobacco Use stage did not change, but the nodal (N) staging system
Prior case-control studies have indicated that chronic changed based on the location o positive nodes. Nodal
tobacco use may result in a two- to veold increased metastases in primary echelon drainage sites such as
likelihood o developing SCCA.37 Moreover, tobacco the inguinal, mesorectal, or internal iliac basins are
smoking appears to be associated with SCCA recur- considered N1a; nodal metastases in the external iliac
rence and increased mortality; thus, smoking cessation basins are considered N1b; and lymph node metastases
should be encouraged when a diagnosis o SCCA is in both N1a and N1b locations are considered N1c.46
conrmed.38 Both T and N stage have been signicantly associ-
ated with response to chemoradiation and OS. Results
rom Radiation Therapy Oncology Group (RTOG)
pRESENTATION AND DIAGNOSIS 8704/Eastern Cooperative Oncology Group (ECOG)
1289 showed patients with tumors 5 cm or larger were
The mean age o diagnosis is approximately 62 years.39 more likely to have a positive biopsy 6 weeks ater
The most common presenting complaint is rectal completing chemoradiation (17%) compared with
bleeding. Other symptoms may include tenesmus, only 7% o patients with a tumor smaller than 5 cm.47
pain, local irritation, discharge, or a change in bowel The RTOG 8314 trial showed a signicant dierence in
habits as mentioned earlier. Clinically enlarged ingui- 3-year local control rates: 84% in patients with tumors
nal lymph nodes are present in 15% to 25% o patients smaller than 3 cm and 62% in patients with tumors
at presentation.40 Extreme and late patient presenta- 3 cm or larger.48 In the EORTC phase 3 trial, tumor
tions may include a ungating perianal mass or a ver- size was not prognostic or survival or local control,
rucous mass. but positive lymph nodes at diagnosis was an inde-
A diagnostic evaluation should consist o a complete pendent poor prognostic actor or both local control
physical examination, including examination o the and OS.49 Subsequent analysis o the long-term results
inguinal lymph nodes, a digital anorectal examination rom RTOG 98-11 showed 5-year locoregional ailure
(DARE), and evaluation o the surrounding mucosa ranged rom 17% or T2N0 disease to 60% or T4N+
o the anus. Diagnostic studies should include proc- disease. OS at 5 years ranged rom 82% or patients
tosigmoidoscopy (rigid or fexible) or anoscopy (side- with T2N0 disease to 42% or patients with T4N+
viewing or fat, on-end anoscope), chest radiography, disease.50 Patients with T1N0 tumors were not eligible
and computed tomography (CT) o the chest, abdo- or enrollment on RTOG 98-11, but small retrospective
men, and pelvis or magnetic resonance imaging (MRI) and population-based studies suggest the local control
o the abdomen and pelvis to rule out distant disease. rates or T1N0 tumors range rom 90% to 100%, and
A transrectal or transvaginal ultrasound examination the 5-year OS ranges rom 80% to 90%.51,52
hISTORY OF ChEMORADIATION: Ongoing studies seek to tailor treatment to patients

ThE NIGRO REGIMEN based on known prognostic actors such as T and N
stage, escalating therapy or those with higher risk o
Beore the work published by Nigro and colleagues recurrence and deescalating therapy or those with
in the 1970s, the preerred treatment or SCCA was high cure rates to reduce toxicities.
radical surgery (APR) with a permanent colostomy.
With this surgical approach alone, the local ailure
rates were unacceptably high. To improve local con- RADIATION VERSUS
trol rates, Nigro and colleagues gave chemoradiation ChEMORADIATION: ThE ROLE OF
to patients in a small pilot study in the preopera-
tive setting. The unexpected result was a complete
MITOMYCIN C
pathologic response in all three patients. This some-
what anecdotal nding led to the pivotal assertion
ACT I Trial
that surgery may not be necessary or curative intent To evaluate or a benet or the addition o cytotoxic
in the treatment o patients with SCCA.53 The ol- chemotherapy to radiation, the phase III Anal Cancer
low-up study published in 1981 by Dr. Nigro’s group Trial (ACT I) randomized patients to radiation alone
outlined the results o 19 urther patients treated (45 Gy) versus continuous inusion 5-FU (1000 mg/
with a regimen consisting o 30 Gy delivered over 15 m2 on days 1–4 or 750 mg/m2 on days 1–5) during the
days. Radiation delivery consisted o a 15- × 15-cm rst and last weeks o radiation (45 Gy) with MMC
ChApTER 33
eld centered at the patient’s midline with the low (12 mg/m2 on day 1).57 Ater a median ollow-up time
edge including the ischial tuberosities. 5-Fluoro- o 42 months, the 3-year local ailure rate was signi-
uracil (5-FU) was given 1000 mg/m 2/24 hours as a cantly reduced in the chemoradiation arm versus the
continuous inusion on days 1 to 4 o radiation and radiation-alone arm (39% vs 61%; P <.0001), suggest-
repeated one month later. Mitomycin C (MMC) ing an oncologic benet with multimodality therapy.
was given as a 15 mg/m2 intravenous bolus on day Here, chemoradiation provided a 46% reduction in
1. Surgery occurred 4 to 6 weeks ater completion local recurrence compared with radiation alone. Nota-
o chemoradiation. Patients were examined preop- bly, the 3-year mortality rate in the radiation-only arm
eratively, and 15 o 19 had no apparent tumor; 12 was greater than that o the chemoradiation arm (39%
o 19 had a pathological complete.54 A subsequent vs 28%). Twenty patients (3%) required a palliative
publication o outcomes or a total o 28 patients colostomy or anorectal excision because o treatment-
treated with Nigro and colleagues’ protocol reported related morbidities. Early morbidity was signicant in
no serious complications resulted rom chemoradia- the chemoradiation arm. Subsequently, dose reduction
tion, though they did experience transient procti- o MMC has been recommended i the patient is 70
tis, leukopenia, and thrombocytopenia. O the 28 years or older or i signicant medical comorbidities
patients, 22 remained tumor ree and alive one to 8 are present.
years ater treatment. 55
The next series o investigations sought to establish
the easibility o treating SCCA with chemoradiation
EORTC Trial
alone as well as to optimize the treatment regimen, A smaller study completed by the European Organiza-
including dose o chemotherapy agent, dose, and tion or Research and Treatment o Cancer (EORTC)
duration o radiotherapy. One such early report evalu- explored the role o chemoradiation and its potential
ated patients treated denitively with 30 to 45 Gy o benet in locoregional control (LRC) and colostomy-
radiation given with two cycles concurrent 5-FU and ree interval.49 A total o 110 patients were random-
MMC. John and colleagues56 reported an 86% com- ized to radiation (45 Gy) with or without continuous
plete response rate to this regimen, with all three local inusion 5-FU (750 mg/m2 on days 1–5 and 29–33) and
ailures being successully salvaged with surgery. The MMC (15 mg/m2 on day 1).
speculations o John et al were (1) the optimal dose o Again, event-ree survival was superior in the
radiation would likely be 41.4 to 50 Gy; (2) radiation combined-modality arm (P = .03). The overall 5-year
was best given continuously, rather than a split course, survival rate was 56% in this patient population. In
which may have radiobiological disadvantages; and (3) contrast to the ACT I study, this clinical trial was lim-
a second dose o MMC may decrease distant ailure ited to patients with more locally advanced anal cancer,
rates. Subsequent prospective trials sought to urther specically, T3 or T4 primary tumors or regional nodal
clariy the added benet o concurrent chemotherapy positivity on initial imaging. Chemoradiation contrib-
to radiation, the optimal concurrent chemotherapy uted 18% actuarial improvement in 5-year LRC and an
agents to give with radiation, and the preerred dose increase in colostomy-ree survival (CFS) (36%). Based
and ractionation schedule or the radiation itsel. on these studies, the phase III UKCCCR and EORTC
studies established combined chemoradiation as supe- completion o chemoradiotherapy reduces recurrence-

rior to radiation alone or LRC and CFS. Most medical ree survival (RFS).58 Using a 2 × 2 actorial design, 940
oncologists in the United States use 5-FU and MMC patients with T1 to T4 node-negative and -positive
as the preerred chemotherapy combination in this disease were randomly assigned to either 5-FU–MMC
setting. or 5-FU–cisplatin administered concurrently with con-
tinuous radiotherapy o 50.4 Gy. The second random-
ization was to two courses o 5-FU–cisplatin (same
ThE INTRODUCTION OF CISpLATIN schedule) consolidation chemotherapy or no urther
treatment. There was a greater incidence o acute grade
Despite the evident benets o MMC in the treatment 3 or 4 hematologic toxicity in the MMC arm (26% vs
o patients with SCCA, potential treatment-related 16%; P <.001) but no statistical dierences in grade 3
toxicities may include leukopenia, thrombocytopenia, or 4 nonhematologic toxicities (Table 33–1).
and, rarely, hemolytic uremic syndrome and leukemia. Results ater a 5-year median ollow-up period dem-
Although a review o prior 5-FU/MMC clinical trials onstrated no statistically signicant dierence or the
in SCCA suggests the potential or superior results endpoint o 6-month CR rate or concurrent chemora-
to radiotherapy alone, these oten come at the cost diation with 5-FU–MMC versus 5-FU–cisplatin (90.5%
o treatment-related morbidity and mortality. There- vs 89.6%, respectively) and no dierence in either RFS
ore, other agents that may reduce treatment-related or CFS, respectively (Table 33–2).
toxicities without compromising ecacy would be Although investigators ailed to ulll the primary
ChApTER 33
preerable. endpoint o superiority or the cisplatin-based regimen,

the results indicate that 5-FU–cisplatin is noninerior to
5-FU–MMC in achieving a CR but is associated with
Mitomycin C Versus Cisplatin in ewer signicant hematologic toxicities. Maintenance
Combination with 5-Fluorouracil 5-FU–cisplatin chemotherapy showed no added ben-
as a Chemosensitizer (ACT II Trial) et or RFS or OS. Thereore, at this time, additional
The UK ACT II trial is the largest phase III trial con- chemotherapy ater denitive chemoradiation, even
ducted in SCC o the anal cancer and is the most direct or patients with higher risk locally advanced SCCA,
analysis o 5-FU–MMC versus 5-FU–cisplatin with is not recommended.
concurrent radiation therapy. The ACT II trial also A retrospective analysis in 197 patients with
evaluated whether maintenance chemotherapy ater TxNxM0 SCC o the anal canal was completed at
TABLE 331 Rates of Grades 3 or 4 Toxicity wit 5-FluorouracilMitomycin C versus 5-Fluorouracil

Cislatin (ACT II)
5-Fluorouracil–Mitomycin C 5-Fluorouracil-Cisplatin
Grades 3/4, Grade 3, Grade 4, Grades
Grade 3, n (%) Grade 4, n (%) n (%) n (%) n (%) 3/4, n (%)
Gastrointestinal 91 (14) 3 (1) 75 (16) 125 (57) 5 (1) 85 (18)
Nausea 10 (2) 0 10 (2) 25 (5) 0 25 (5)
Vomiting 9 (2) 0 9 (2) 20 (4) 1 (<1) 21 (4)
Diarrhea 43 (9) 1 (<1) 44 (9) 42 (9) 3 (1) 45 (10)
Stomatitis 14 (3) 0 14 (3) 19 (4) 1 (<1) 20 (4)
Skin 193 (41) 35 (7) 228 (48) 201 (43) 21 (4) 222 (47)
Pain 114 (24) 8 (2) 122 (26) 120 (26) 15 (3) 135 (29)
Cardiac 7 (1) 7 (1) 7 (1) 2 (<1) 4 (<1) 6 (<1)
Hematologic 107 (23) 17 (4) 124 (26)a 60 (13) 13 (3) 73 (16)a
WBC count 103 (22) 13 (3) 112 (24)a 48 (10) 8 (2) 55 (12)a
Platelets 19 (4) 2 (<1) 21 (4) 2 (<1) 3 (<1) 5 (1)
Hemoglobin 1 (<1) 1 (<1) 2 (<1) 5 (1) 2 (<1) 7 (1)
a
Denotes statistical signicance between two treatment arms.
ACT, Anal Cancer Trial; WBC = white blood cell.
Data rom James RD, Glynne-Jones R, Meadows HM, et al: Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy or treatment o
squamous-cell carcinoma o the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 actorial trial, Lancet Oncol 2013 May;14(6):516-524.
TABLE 332 Rates of Treatment Resonse at Week 26 wit 5-FluorouracilMitomycin C versus

5-FluorouracilCislatin (ACT II)
5-Fluorouracil–Mitomycin C, n (%) 5-Fluorouracil–Cisplatin, n (%)

Complete response 391 (91) 386 (90)
Partial response 14 (3) 24 (6)
Stable disease 5 (1) 6 (1)
Progressive disease 22 (5) 15 (4)
ACT, Anal Cancer Trial.
Reproduced with permission rom James RD, Glynne-Jones R, Meadows HM, et al: Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy
or treatment o squamous-cell carcinoma o the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 actorial trial, Lancet Oncol 2013 May;14(6):516-524.
MDACC.59 Patients received weekly cisplatin (20 mg/ primary tumor or node-positive disease. A total o 306
m2 intravenously) and 5-FU (300 mg/m2/day or 120 patients were allocated to one o our treatment arms:
consecutive hours weekly as a continuous inusion on (1) induction with standard-dose radiation therapy, (2)
days o radiation) or the duration o radiation ther- induction with high-dose radiation therapy, (3) control
apy (55 Gy). The median ollow-up period was 8.6 arm o 5-FU–cisplatin plus standard radiation therapy,
years. Complete responses ater chemoradiation were and (4) control arm o 5-FU–cisplatin plus high-dose
ChApTER 33
observed in 185 patients (94%). The local recurrence radiation therapy. The results were compared in terms
rate was 11% with the use o 5-FU and cisplatin, and o CFS. Ater a median ollow-up period o 43 months,
all patients with a local recurrence underwent salvage no statistically signicant dierence in CFS was noted
APR or diverting colostomies. Only 16 patients (8%) or the induction arm or with the higher dose radia-
developed distant metastases. OS at 5 years was 86%. tion therapy arm versus the control arm. Overall, no
Grade 4 acute toxicities (diarrhea, dehydration, and statistical dierences were noted across all arms or
skin ulceration) were inrequent. Thereore, the use local control, CFS, event-ree survival, or OS. There-
o cisplatin and 5-FU with concurrent radiation is sae ore, induction chemotherapy does not appear to ben-
and eective in patients with locally advanced SCCA et patients with localized anal cancer intended to be
and may be an acceptable alternative to the traditional treated with chemoradiation.
5-FU–MMC regimen. Based on the nding rom the
ACT II trial and MDACC’s institutional experience,
5-FU–cisplatin remains a preerred regimen because o
RTOG 98-11 Trial
its ecacy and decreased myelosuppression relative The RTOG 98-11 trial was a large phase III multi-insti-
to 5-FU–MMC. This combination also allows or saer tutional randomized trial or locally advanced SCC o
treatment o immunocompromised and older patients the anal canal4 that randomized 682 patients with T2 to
who otherwise might not tolerate myelosuppressive T4 tumors and any nodal status to receive 5-FU–MMC
combinations. and concurrent radiation (control arm) or induction
5-FU–cisplatin ollowed by concurrent 5-FU–cisplatin
and radiation. It is important to note the treatment
Neoadjuvant (Induction) Chemotherapy imbalance in the two arms such that whereas patients
Another common question or the management o randomized to the experimental group received induc-
locally advanced anal cancer regards the role o sys- tion chemotherapy, those randomized to the control
temic induction treatment beore chemoradiation arm did not. All patients received 45 to 50 Gy o radia-
decrease the risk o distant disease development and tion, with an additional 10 to 14 Gy in 2-Gy ractions
provide an improvement in OS. given to patients with residual evidence o disease,
tumors larger than 5 cm, or tumor invasion o adjacent
organs. From a recent long-term update, improved out-
Intergroup/ACCORD 03 Trial comes were noted in the group randomized to 5-FU–
The phase III Intergroup/ACCORD 03 trial created a 2 MMC and concurrent radiation. Five-year DFS was
× 2 actorial design to compare standard-dose (45 Gy/25 signicantly better in this group (68% vs 58%) com-
ractions, boost o 15 Gy) versus high-dose radiation pared with those receiving induction 5-FU–cisplatin
therapy (boost o 20–25 Gy) and the potential ben- ollowed by concurrent 5-FU–cisplatin and radiation,
ets o induction chemotherapy with 5-FU (800 mg/ as was 5-year OS (78% vs 71%). Trends in CFS, LRC,
m2 on days 1–4) and cisplatin (80 mg/m2 on day 1) or and colostomy ailure all avored the 5-FU–MMC arm
two cycles in locally advanced SCC o the anal canal.60 as well, although none reached statistical signicance.
Patients were required to have greater than 4-cm Grade 3 or 4 hematologic toxicity was observed more
requently in patients randomized to the 5-FU–MMC angles in which the intensity o each beam is adapted
arm (62% vs 42%; P <.0001). to match the contours o the radiation target and carve
Despite the initial appearance that 5-FU–MMC unnecessary dose out o nearby organs. This technique
treatment is superior or patients with nonmetastatic allows or “dose painting,” also called a simultaneous
SCCA, these ndings must be interpreted with caution. integrated boost technique, which allows dierent
This study has since been critiqued or the inequal- targets within the eld to receive dierent doses o
ity o the two treatment schedules, making a direct radiation per day. IMRT was prospectively testing in a
comparison o MMC and cisplatin, in combination phase 2 study, RTOG 0529. Results showed IMRT was
with 5-FU, dicult because the conounding actor o able to signicantly reduce acute G2+ hematologic and
induction chemotherapy in the investigational arm.58 G3+ dermatologic and GI toxicities compared with
Additionally, administration o induction chemother- historic controls rom RTOG 9811.63 The RTOG 0529
apy delayed the time to initiation o curative chemo- trial established IMRT as the standard o care and it
radiation and thereby prolonged the overall treatment remains today.64 Current investigations are ongoing
time, a metric that, when extended, has been associ- into dierent radiation modalities such as proton beam
ated with worse clinical outcomes in clinical trials or therapy to see i unnecessary dose to normal tissues in
SCCA. Nonetheless, based on these ndings, induction the pelvis can be urther reduced.65
chemotherapy in patients with early-stage SCC o the
anal canal is not routinely administered at MDACC.
Radiation Dose and Fractionation
ChApTER 33
The initial dose and ractionation used in the Nigro

RADIATION TEChNIqUE, DOSE, protocol was 30 Gy in 15 ractions delivered over 3
AND FRACTIONATION weeks.53 Subsequent studies evaluated doses rom 45
to 50.4 Gy delivered over 4 to 5 weeks and showed
Evolution o Radiation Technique local ailure rates o about 25%.47 RTOG 92-08 sought
to decrease local ailure by escalating the radiation dose
The preerred radiation technique has evolved since the to 59.6 Gy delivered split course over 8.5 weeks with
1970s with advances in technology related to imaging, a planned 2-week rest period to allow or recovery o
radiation treatment planning, and radiotherapy deliv- dermal toxicity. Dose escalation in this study did not
ery. Early radiation therapy was delivered using two show improvement in local control and actually had a
simple elds in the anteroposterior and posteroanterior higher colostomy rate at 1 and 2 years posttreatment
directions on a 6-MeV linear accelerator. The intended (23% vs 6% and 30% vs 7%) compared with RTOG
target included the anal canal as well as elective nodal 87-04, which gave 45 to 50.4 Gy without a planned
coverage o the internal iliac, external iliac, perirectal, break.47 The conclusion o that study was that the split
presacral, and obturator lymph nodes. For patients who course schedule may have eroded any potential ben-
had clinical inguinal nodal involvement, the eld was et o dose escalation, and the 2-week break may have
extended laterally to cover the groins, and the surace led to a decrement in tumor control as evidenced by
dose was boosted with supplemental electron beams.56 the higher need or colostomy.66 The RTOG 87-04 and
Limitations to this technique included high rates o G3 RTOG 92-08 studies both used 2D techniques, which
and G4 toxicities, necessitating a treatment break in up limited the ability to conorm the dose away rom nor-
to 50% o patients given the volumes o normal bone mal pelvic organs, so the side eects o radiation pre-
marrow, bowel, and skin exposed.61 As radiation tech- cluded dose escalation in a continuous ashion without
niques moved rom the two-dimensional (2D) to the a treatment break. A French randomized phase III
three-dimensional era, radiation to doses o 50 to 54 study, ACCORD 3, had a 2 × 2 actorial design in
Gy in 1.8-Gy ractions were able to be given continu- which one o the randomizations compared standard-
ously without a planned break and without unplanned dose boost with high-dose boost given 3 weeks ater
breaks because o toxicity. Because o the more con- completion o 45 Gy in 25 ractions. The boost was
ormal dose distribution to the target volume better given with EBRT or brachytherapy with 192-Iridium.
avoids unnecessary dose to nearby organs and tissues. There was also no benet to the higher boost dose in
G3 toxicities or bone marrow, bowel, and skin were this study, but it should be noted that the schedule or
shown to be much improved in a phase II study rom ACCORD 3 was essentially split course with a 3-week
McGill University62 and were used in RTOG 9811, UK break between the end o the initial 45 Gy and the
ACT II, and other contemporary trials. beginning o the boost. It should also be noted that
The next technological improvement in radiation the total dose in the “standard-dose” arm was 60 Gy,
delivery was more conormal technology called inten- and the total dose in the “high-dose” arm was 65 to
sity-modulated radiation therapy (IMRT). It is a tech- 70 Gy.67 The doses delivered on RTOG 0529, which
nique that uses multiple radiation beams rom various used IMRT technique with a continuous radiation
FIGURE 33–4 Representative axial (A), sagittal (B), and coronal (C) slices rom a defnitive chemoradiation plan or a patient
with T2N1a squamous cell carcinoma o the anal canal; 54 Gy in 27 ractions was prescribed to the anal tumor plus margin; 50
Gy in 27 ractions was prescribed to a 1.5-cm presacral lymph node plus margin; and 45 Gy in 27 ractions was prescribed to the
elective nodal volume. Note that a vaginal dilator was inserted or planning and daily treatment to displace the anterior vaginal
wall and urethra away rom the high-dose region.
ChApTER 33
schedule, depended somewhat on tumor size. T2N0 exenteration or total pelvic exenteration, yields a mas-
tumors received a total o 50.4 Gy to the anal tumor sive tissue deect that requires reconstruction, and
with 42 Gy to the elective pelvic lymph nodes in 28 although there are options or tissue rearrangement,
ractions. T3 and T4 tumors received 54 Gy in 30 rac- a vertical rectus abdominus myocutaneous fap oten
tions, and the elective pelvic and inguinal lymph nodes provides the best reconstruction. There is no role or
received 45 Gy.63 Along similar lines, at the MDACC, denitive reirradiation or an in-eld recurrence, but
the current standard uses a moderate dose escalation neoadjuvant chemoradiation (39 Gy in 26 ractions
or T3 and T4 tumors because the analysis o RTOG twice daily with chemotherapy) may be used in cases
98-11 data showed these patients are at highest risk when there are concerns about the radial margin.
or local recurrence.50 In total, 50 Gy in 25 ractions When available, consideration o intraoperative radia-
or T1 tumors, 54 Gy in 27 ractions or T2 tumors, tion may provide an additional option or R1 (tumor 2
and 58 Gy in 29 ractions or T3 and T4 tumors are mm rom margin) disease but has no role i only an R2
delivered. The doses to the elective pelvic and ingui- (gross tumor at margin) resection is achievable.
nal nodes are 43 Gy, 45 Gy, and 47 Gy, respectively, The management o patients with nodal recur-
in those ractionations. Grossly involved lymph nodes rences should be individualized based on the extent o
are similarly dosed based on size, with nodes 2 cm or disease, prior radiation delivered to the area o recur-
smaller receiving 50 Gy, nodes 2 or larger but 5 cm or rence, and perormance status o the patient. When
smaller receiving 54 Gy, and nodes larger than 5 cm patients have been reerred to the MDACC with nodal
receiving 58 Gy (Fig. 33–4). recurrence outside o or at the margin o a prior radia-
With this tailored approach, local recurrence rates tion eld, salvage chemoradiation has been eective
have been only 11% despite a disproportionately provided that a ull dose o reirradiation is possible. For
advanced stage patient population. Furthermore, ret- in-eld nodal recurrences, a preoperative chemoradia-
rospective multivariate analysis did not show T stage tion to 39 Gy in 26 ractions twice daily ollowed by
is a poor prognostic actor, potentially because patients surgical resection is typically considered.
with advanced T-stage tumors are treated appropri-
ately more aggressively.59
METASTATIC ANAL CARCINOMA
RECURRENT DISEASE Chemotherapy or Metastatic Anal Cancer
APR is the only eective, denitive treatment option Although the majority o patients with SCC o the anal
or localized recurrent or residual primary disease ater canal will be cured with chemoradiation, a raction o
chemoradiation or SCC o the anal canal. Although an patients will develop metastatic disease. Median sur-
oten considered aggressive approach to persistence or vival rom the time o metastatic disease has been esti-
recurrent disease, APR provides cure in up to 70% o mated between 18 to 24 months.71 The liver and lymph
patients.68–70 In these patients, a typical APR, posterior nodes are among the most common sites or distant
organ involvement, with bone metastases occurring Rates o grade 3 or higher adverse events with this
in ewer than 10% o cases.71 Because o the rarity o dosing have been reported in single-institution retro-
metastatic SCCA, a universally accepted treatment spective series to be lower than those noted with the
approach or the management had been historically regimens used in the InterAACT trial.74 This biweekly
based on small case series.72 However, results rom schedule or cisplatin–5-FU oers a tolerable and eec-
recently completed prospective studies have generated tive approach or the treatment o patients with meta-
new treatment options or these patients (Table 33–3). static SCCA.
A randomized phase II trial conducted through the Recently, the single-arm HPV-EPITOPES-02 trial
National Cancer Institute (NCI)–sponsored Interna- o docetaxel, cisplatin, and 5-FU or patients with
tional Rare Cancer Initiative (collaboration compared treatment-naïve metastatic anal cancer demonstrated
doublet chemotherapy with cisplatin (60 mg/m2)– impressive survival outcomes.75 Here, the over-
5-FU (1000 mg/m2/day as a continuous inusion or all response rate was reported to be 86% (57 o 66
days 1–4) every 21 days or carboplatin (AUC 5)–pacli- patients), with complete radiographic responses noted
taxel (80 mg/m2 on days 1, 8, and 15) every 28 days in 44% cases. Median PFS or this regimen was 11
in patients with previously untreated, unresectable, months. As expected or concurrent use o three cyto-
locally recurrent or metastatic SCCA.73 In this study toxic agents, rates o grade 3 or higher adverse events
(InterAACT) o 91 patients, the primary objective or exceeded 70% but were less common when modied
detecting a 10% dierence in response rate was not doses were administered every 2 weeks. This regimen
satised. Here, radiographic responses were observed appears very eective in the treatment o patients with
ChApTER 33
in 57% patients receiving cisplatin–5-FU and in 59% metastatic SCCA yet should be reserved or patients
patients receiving carboplatin–paclitaxel. A nonsigni- with a robust perormance status who can withstand
cant trend toward improved progression-ree survival the likelihood o more pronounced treatment-related
(PFS) was observed in patients treated with carbo- toxicity.
platin–paclitaxel (8.1 months vs 5.7 months; P = .38),
with an improvement in OS (20 months vs 12 months;
P = .01). Whereas cisplatin–5-FU had previously been
Immunotherapy or Metastatic Anal
listed as the lone systemic treatment or patients with Cancer
metastatic SCCA, this study was instrumental in estab- Given the paucity o available treatment options or
lishing the role o carboplatin–paclitaxel in this setting. patients with incurable SCCA, the use o immuno-
In the InterAACT trial, rates o grade 3 or higher therapy is an attractive treatment strategy or this
treatment-related adverse events exceeded 70% virally driven malignancy. Here, immune checkpoint
in both arms, although rates o serious grade 3 or blockade therapies have been approved or other HPV-
higher adverse events were more common in patients associated malignancies, given clinical activity noted in
receiving 5-FU–cisplatin every 21 days (62% vs 36%; SCC o the head and neck (with or without concomi-
P = .02). Thereore, oncologists should be mindul o tant chemotherapy)76–78 and o the cervix.79
anticipated toxicities, especially myelosuppression, In the NCI9673 phase II trial o patients with pre-
nausea and vomiting, and atigue, when considering treated, unresectable SCCA, radiographic response to
these regimens. To mitigate the anticipated treatment- the anti–PD-1 (programmed cell death protein 1) anti-
related complications, at our institution, we adminis- body nivolumab was observed in 9 o 37 cases (over-
ter cisplatin (40 mg/m2) and 5-FU (2400 mg/m2/day as all response rate, 24%).80 Including patients with stable
a continuous inusion over 46 hours) every 14 days. disease, the disease control rate with nivolumab was
TABLE 333 Clinical Outcomes of Systemic Teraies in Recent prosective Trials for Metastatic Anal
Cancer
Patients Response Median PFS Median OS

Regimen Trial Name Line o Treatment (n) Rate (%) (months) (months)
Carboplatin–paclitaxel InterAACT Frontline 45 59 8.1 20
Cisplatin–5-uorouracil InterAACT Frontline 46 57 5.7 12
Docetaxel–cisplatin/ HPV-EPITOPES-02 Frontline 69 86 11 NR
5-uorouracil
Nivolumab NCI9673 Reractory 37 24 4.1 12
Pembrolizumab KEYNOTE-158 Reractory 112 11 2.0 12
NR, not reached; OS, overall survival; PFS, progression-ree survival.
72%. Median PFS was 4 months. Nivolumab was well without CR by week 11 ater completion o deni-
tolerated as a monotherapy in this study. Similarly, the tive chemoradiation did achieve a CR by week 26.83
KEYNOTE-158 trial reported an overall response rate o Based on these ndings, in the presence o improving
11% and median PFS o 2 months with single-agent anti– symptoms or continued tumor regression on evalua-
PD-1 antibody pembrolizumab or 112 patients with tion, at the MDACC, patients are allowed 26 weeks
pretreated metastatic anal cancer.81 Here, patients who to achieve a CR beore reerral or APR. I clinical
demonstrated a response to pembrolizumab were able progression becomes apparent beore this point, then
to achieve sustained clinical benet, with PFS exceeding patients are sent promptly or salvage evaluation. Ater
24 months in more than 90% o this subgroup. Based that, routine anal and groin examinations every 3 to
on these collective ndings, nivolumab and pembroli- 6 months by either the medical, radiation, or surgical
zumab are recommended treatment options or patients oncology providers or 2 years. Ater 2 years, routine
with treatment-reractory metastatic SCCA. examinations may be perormed every 6 months or
Although anti–PD-1 therapies benet a raction the remaining 3 years.84 Biopsy o any scar or ques-
o patients with incurable SCCA, establishment o a tionable residual or recurrent disease beore 6 months
biomarker(s) to identiy the subpopulation that derives ater chemoradiation is not suggested unless there is
benet with this approach is needed. Microsatellite clear evidence o residual disease or progression is sus-
instability and high tumor burden are uncharacteris- pected. I clinical CR is achieved but the posttreatment
tic o this disease and may not be drivers or response scar is abnormal yet not suggestive o recurrence, it is
to immune checkpoint blockade.82 Analysis o pre- important that the surgeon ollowing the patient per-
ChApTER 33
treatment biopsies rom the NCI9673 trial ound that orm the routine anal examinations to assess or subtle
higher baseline expression o programmed cell death changes and propose biopsy as necessary. Physical
ligand 1 (PD-L1) on tumor cells and increased numbers examination must include a DARE and assessment or
o activated cytotoxic T-cells within the tumor micro- any palpable inguinal lymph nodes. Vaginal dilators
environment were both associated with an increased may be used three times a week i needed to prevent
likelihood or response to nivolumab. Coexpression vaginal strictures. The critical time or the prevention
o immune biomarkers LAG-3 and TIM-3 with PD-1 o vaginal stenosis is 3 to 6 months ater completion
on activated cytotoxic T-cells were also more common o chemoradiation therapy. Vaginal hormonal creams
or tumors o responding patients. Early results then and suppositories are also useul or treatment o vagi-
suggest that immunologically active tumors at base- nal dryness and dyspareunia. Proctosigmoidoscopy
line may predispose patients with metastatic SCCA to should be perormed biannually ater a CR or 2 years.
increased benet o these immunotherapy agents. Chest radiography and CT o the chest, abdomen, and
Some patients presenting with metastatic disease pelvis or MRI o the abdomen and pelvis should be
do achieve excellent long-term survival. For example, a completed annually or 2 years. Anal cytology collec-
subset o patients at the MDACC with oligometastatic tion via a Dacron anal swab (ormerly anal pap smears)
SCCA underwent denitive therapy to limited site(s) should continue to be perormed annually.
o distant metastases, either with surgical resection or
with (chemo)radiation. For these patients, OS was pro-
longed (53 months vs 17 months; P <.001), which was ADENOCARCINOMA OF ThE ANAL
likely a refection o a lower total burden o disease CANAL
and avorable underlying tumor biology. Consider-
ation o curative-intent surgical resection and/or den- Adenocarcinomas o the anal canal occur less re-
itive chemoradiation o oligometastatic SCCA should quently than SCCs and are not to be conused with
be considered on an individualized basis through mul- extramammary Paget disease o the anus.39 Nonethe-
tidisciplinary discussion, most oten ater demonstra- less, most o the reports overestimate the incidence o
tion o an upront response to systemic therapy. adenocarcinoma o the anal canal because they do not
exclude contamination by the more common distal
rectal cancer. Its true incidence within all anal cancers
SURVEILLANCE is likely less than 10%. The most appropriate manage-
ment remains to be dened, with no large prospective
Although surveillance guidelines are always in fux, studies completed to date given its exquisite rarity. The
current guidelines suggest patients treated with most striking dierence between anal adenocarcinoma
chemoradiation therapy (with curative intent) should and SCCA is the high distant metastasis rate in anal
be initially evaluated by 3 months upon completion adenocarcinoma, which tends to undermine the impact
o therapy with an inguinal lymph node examina- o local tumor control. Retrospective analysis rom the
tion, DARE, and anoscopy i possible. Review o MDACC experience with anal adenocarcinoma has
outcomes rom ACT II revealed that 29% o patients suggested a benet o neoadjuvant chemoradiation
ollowed by APR (in patients without known metasta- is recommended that all patients diagnosed be initially
ses) with the consideration o adjuvant chemotherapy evaluated at a tertiary cancer center or the equivalent
analogous to the treatment o rectal cancer.85 given the rarity o the disease and the potential or
permanent loss o sphincter preservation. It is highly
recommended that a multidisciplinary team discus-
CONCLUSIONS sion with signicant expertise or the most appro-
priate treatment in this rare malignancy is organized
Carcinoma o the anus is an uncommon GI malig- and consulted or management o patients with these
nancy with a rising incidence in the United States diagnoses. Both cytotoxic chemotherapy and immune
despite the introduction o a preventive HPV vaccine. checkpoint blockade therapies have demonstrated e-
Chemoradiation is provided with curative intent or cacy or patients with metastatic disease. It is expected
patients with nonmetastatic disease. Recurrence or that the role o immunotherapy will be expanded ur-
persistent disease ater curative-intent chemoradia- ther in the management o patients with anal cancer in
tion therapy results in the need or an APR. Hence, it the coming years.

Weekly cisplatin and 5-FU is a well-tolerated, clini- Patients presenting with oligometastatic anal can-
ChApTER 33
J J
cally efcacious chemosensitizer associated with cer can be treated successully with curative intent
moderate toxicity or patients with locally advanced through multidisciplinary management o the pri-
anal cancer undergoing chemoradiation. mary tumor and metastatic lesion(s).
J For emale patients, a vaginal dilator should be J Patients with metastatic anal cancer with/without
used during daily radiation treatments to displace coexisting altered immunity (eg, HIV/AIDS, con-
the anterior vaginal wall and urethra rom the current immunosuppressive medications or prior
high-dose region and reduce genitourinary toxici- organ transplantation or autoimmune disorder)
ties rom treatment. For male patients, the scrotum can saely be treated with a modied, every-14-day
should be elevated away rom the perineum during regimen o cisplatin–5-FU with a low likelihood or
treatment to reduce skin and testicular toxicity. For chemotherapy-related myelosuppression.
both men and women, patients should be treated J At present, immune checkpoint blockade thera-
with a ull bladder to displace small bowel rom the pies can saely be administered without consider-
pelvis and reduce the risk o GI toxicity. ation o tumor mutation burden or PD-L1 status
J In the absence o clinical or radiographic progression, or patients with treatment-reractory metastatic
patients with locoregional anal cancer can be ol- anal cancer, although translational studies seek to
lowed or resolution o their disease up to 26 weeks characterize biomarkers associated with response
ater completion o chemoradiation. Salvage surgery to immunotherapy.
with APR is reserved or patients with persistent or
locally recurrent disease ater denitive therapy.
ACKNOWLEDGMENTS
The authors acknowledge Dr. Stanley Hamilton and
the Department o Pathology at the University o
Texas MD Anderson Cancer Center or providing rep-
resentative pathology slides as a contribution to this
chapter.
among children: design, methods and preliminary results o the

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or cancer o the anal canal. Dis Colon Rectum. 1981;24(2):73-75. 72. Eng C, Pathak P. Treatment options in metastatic squamous
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Oncol Biol Phys. 1987;13(3):299-303. taxel (P) in patients (pts) with inoperable locally recurrent (ILR)
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58. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or 75. Kim S, François E, André T, et al. Docetaxel, cisplatin, and
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therapy or treatment o squamous-cell carcinoma o the anus locally recurrent anal squamous cell carcinoma (Epitopes-
(ACT II): a randomised, phase 3, open-label, 2 x 2 actorial trial. HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol.
Lancet Oncol. 2013;14(6):516-524. 2018;19(8):1094-1106.
76. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone a multicentre, single-arm, phase 2 study. Lancet Oncol.
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recurrent or metastatic squamous cell carcinoma o the head and 81. Marabelle A, Cassier PA, Fakih M, et al. Pembrolizumab or
neck (KEYNOTE-048): a randomised, open-label, phase 3 study. advanced anal squamous cell carcinoma (ASCC): results rom
Lancet. 2019;394(10212):1915-1928. the multicohort, phase II KEYNOTE-158 study. J Clin Oncol.
77. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab or 2020;38(4 suppl):1.
recurrent squamous-cell carcinoma o the head and neck. N Engl 82. Salem ME, Puccini A, Grothey A, et al. Landscape o tumor
J Med. 2016;375(19):1856-1867. mutation load, mismatch repair deciency, and pd-l1 expression
78. Chow LQM, Haddad R, Gupta S, et al. Antitumor activity o in a large patient cohort o gastrointestinal cancers. Mol Cancer
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results rom the phase Ib KEYNOTE-012 expansion cohort. J road or neoadjuvant chemoradiotherapy? J Clin Oncol.
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ously treated unresectable metastatic anal cancer (NCI9673): 2009;52(8):1375-1380.
ChApTER 33
34 Neuroendocrine Tumors
Jessica E. Maxwell
James C. Yao
Daniel M. Halperin
KEY CONCEPTS
 Gastroenteropancreatic neuroendocrine tumors (GEP-NETs)  Surgical resection is the standard o care or localized
are increasing in incidence, but delay in diagnosis is com- GEP-NETs. In advanced disease, surgery may be appropriate
mon. Patients may present with specic symptoms related when R0 resection can be achieved, or cytoreduction is
to a unctional tumor or vague gastrointestinal symptoms, perormed or palliation o symptoms.
emphasizing the importance o maintaining a high index o  In cases in which hepatic metastases are unresectable,
suspicion or this disease. hepatic arterial embolotherapies may be used. Peptide
 The majority o GEP-NETs arise sporadically. Multiple receptor radionuclide therapy is ecacious or hepatic
endocrine neoplasia type 1 is the most common inherited and extrahepatic metastases.
syndrome in which nonunctional pancreatic neuroendo-  Systemic therapy or advanced extrapancreatic NETs
crine tumors (PNETs) predominate. includes somatostatin analogues and the targeted ther-
68
 Ga tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3- apy everolimus. In PNETs, FAS (5-uorouracil, doxorubicin,
octreotate (68Ga-DOTATATE) has excellent sensitivity and and streptozocin), capecitabine and temozolomide, and
specicity or GEP-NETs. It is used to detect the location o sunitinib are additional options.
unknown primary tumors and to assess or distant disease.
It is not used or routine surveillance.
Neuroendocrine tumors (NETs) originate rom entero- peptide receptor radionuclide therapy (PRRT), liver-
chroman cells o the diuse endocrine system. A directed therapy, cytotoxic chemotherapy, or targeted
diverse set o tumors, they most commonly arise rom therapies. This chapter discusses current diagnostic
the gastrointestinal (GI) tract, pancreas, lungs, and and management strategies or lung and GEP-NETs.
bronchi. Less common sites include the thyroid, para-
thyroid, pituitary gland, adrenal glands, and thymus.
This chapter ocuses on the low- and intermediate- EPIDEMIOLOGY AND RISK
grade gastroenteropancreatic NETs (GEP-NETs) and ASSESSMENT
lung NETs, leaving small cell carcinomas, medullary
thyroid cancer, neuroblastoma, and Merkel cell carci- The Surveillance Epidemiology End Results (SEER)
nomas (all technically neuroendocrine neoplasms) to database has catalogued a 6.4-old increase in the inci-
other chapters in this text. dence o NETs rom 1973 to 2012. This increase was
NETs may secrete peptides and neuroamines that consistent across anatomic site, grade, and stage. Glob-
cause specic clinical symptoms, although this is ally, NETs remain relatively rare with an age-adjusted
not universally present even among tumors originat- incidence o 6.98 per 100,000 individuals.1 The disease
ing rom the same anatomic site. Localized disease is is slightly more common in women (52.7%) and those
treated surgically or curative intent. Locoregional or 65 years old or older (25.3 per 100,000 persons). Among
metastatic disease not amenable to surgical resection GEP-NETs, the most common site o origin is the small
can be managed with somatostatin analogues (SSAs), intestine ollowed by the rectum and pancreas.1
781
782 Scion VI Gastrointestinal Cancer
The cause o the increased incidence is unknown

but oten attributed to greater disease awareness and
PATHOGENESIS, MOLECULAR
improved diagnostic capabilities. Common behav- CLASSIFICATION, AND GENETIC
ioral risk actors such as smoking, obesity, and exces- PREDISPOSITION
sive alcohol use do not appear to play a role in the
development o these tumors.2 Genetic predisposition Innovation in the eld o molecular biology has
accounts or approximately 20% o GEP-NETs3 and is expanded our knowledge o the drivers o NET
discussed later. pathogenesis. In PNETs, MEN1, DAXX, and ATRX are
requently mutated. MEN1 is a tumor suppressor gene
that predisposes to multiple endocrine neoplasia type
PROGNOSIS 1 (MEN1) when mutated either sporadically or in the
germline. This mutation causes dysregulation o tran-
Prognosis varies by stage, primary site, and grade. scription and cell cycle control. Loss o heterozygosity
Considering the 64,971 patients included in the at this locus on chromosome 11q13 is associated with
SEER database between 1973 and 2012, median the development o duodenal, gastric, and pancreatic
overall survival (OS) ranged rom more than 30 years NETs.4,5 In 2011 Jiao et al. perormed exome sequenc-
in patients with localized NETs to 10 years in those ing on 58 sporadic, resected PNETs. These experi-
with regional disease and 1 year in those with distant ments revealed MEN1 mutations in 44% o tumors.
disease. Examined by grade, low- (G1) and interme- DAXX and ATRX, two components o a histone
Chapter 34
diate- (G2) grade NET had median OSs o 16 and 8 chaperone complex important in chromatin remodel-
years, respectively. High-grade neuroendocrine neo- ing,6 were also requently mutated (43%), though in
plasms (SEER G3 and G4, corresponding to World a mutually exclusive ashion. DAXX/ATRX mutations
Health Organization grade 3 neuroendocrine carci- drive the alternative lengthening o telomeres (ALT)
nomas [NECs] in modern nomenclature) had signi- phenotype,7,8 which contributes to a neoplastic cell’s
cantly worse survival times, with a median o only immortality in a telomerase-independent ashion.9
10 months. Somatic mutations in genes in the mammalian target
Among GEP-NETs, the prognosis is most avor- o rapamycin (mTOR) pathway are ound in approxi-
able or appendiceal (>30-year median OS) and rec- mately 15% o PNETs,10 and loss o heterozygosity o
tal NETs (24.6 years) and worst or pancreatic NETs PHLDA3 (a regulator o the mTOR pathway) at chro-
(PNETs; 3.6 years). Survival patterns vary when mosome 1q31 has been ound in approximately 70%
stage is considered with primary site (Table 34–1). o studied PNETs.11 The mutation status o MEN1,
In localized disease, small intestine NETs have an DAXX/ATRX, and the mTOR pathway in PNETs have
OS o approximately 14 years, and localized appen- an indeterminate impact on prognosis and no clear
diceal NETs are even better with a median OS o relationship with targeted therapy benet.8,10 Thus ar,
more than 30 years. In patients with metastatic dis- tumor mutational analysis has yet to demonstrate ben-
ease, small intestine NETs are best with a median et in the selection o targeted agents.12
OS o 8.6 years. Patients with metastatic colon NETs Fewer pathologic genetic alterations have been
have a median OS o only 14 months.1 ound in small intestine NETs. Hemizygous loss o chro-
mosome 18 and arm-level gains o chromosomes 4, 5,
14, and 20 are relatively requent genomic events.13–15
More recent studies have shown that alterations o
TABLE 341 Median Survival o Distant Stage the gene CDKN1B occur in 7% to 10% o small intes-
G1-G2 Neuroendocrine Tumors1 tine NETs. This gene is a haploinsucient tumor sup-
pressor and plays a role in cell cycle progression.14–17
Organ Site Median Survival (months) Clinical trials are ongoing to investigate the saety and
Appendix NA ecacy o CDK inhibitors in patients with small intes-
Cecum 98 tine NETs (clinical trials.gov; NCT03891784).
MEN1 is the most common inherited cancer syn-
Colon 14
drome in NETs. This autosomal dominant disorder
Lung 24 eatures the development o PNETs (80%–100%),
Pancreas 60 multigland hyperparathyroidism (95%–100%), and
Rectum 33 pituitary adenomas (54%–65%). Hereditary PNETs
Small intestine 103 oten behave less aggressively than sporadic tumors
and are requently small and multiocal. The majority
Stomach 29
o MEN1-related PNETs are nonunctional, although
NA, not available.
Data rom analysis o SEER registry, 2000 to 2012. symptomatic gastrinomas are ound in 54% and
C 34 Neuroendocrine Tumors 783
insulinomas in 18% o patients. Other amilial syn- based on prolieration rate. Poorly-dierentiated
dromes associated with NETs are neurobromatosis NEC is uniormly grade 3. Grade can be determined
type I (NF1), tuberous sclerosis, Cowden syndrome, either by calculating the mitotic rate (mitoses per 10
and von Hippel-Lindau syndrome, though these are high-power elds) or by an IHC method that reports
ar less common than MEN1.18 the percentage o neoplastic cells that stain or the
prolieration antigen Ki-67. Currently, it is most
common or pathologists to dene grade via Ki-67.
PATHOLOGIC CLASSIFICATION Low-grade (G1) GEP-NETs are dened by a Ki-67
index o 2% or less, intermediate grade (G2) 3%
Neuroendocrine neoplasms are categorized as either to 20%, and high grade (G3) greater than 20%.21,22
well- or poorly-dierentiated based on the extent to Regardless o grade, the reproducibility o this test
which the neoplastic cells resemble their non-neoplas- on either biopsy or surgical specimens is greater
tic counterparts. Well-dierentiated NETs are uniorm, than 90%.23
with characteristic “organoid” arrangements o cells in
nesting, trabecular, or gyriorm patterns. These cells
tend to produce large amounts o neurosecretory gran-
ules, which can be detected by immunohistochemical A B
(IHC) staining or common markers such as chromo-
granin A (CgA) and synaptophysin (Table 34–2). In cases
Chapter 34
in which the location o the primary NET is unknown,
IHC can be used on biopsied metastases to oer some
insight into the site o origin.19,20 Poorly-dierentiated
NEC have a more sheetlike or diuse architecture, irreg-
ular nuclei, and less cytoplasmic granularity and can take
on small cell or large cell morphology in many cases.
Expression o common neuroendocrine immunomark-
ers is oten more limited in poorly-dierentiated NEC,
and thus IHC may be less useul during the diagnostic
workup.21 In cases in which the location o the primary
tumor is unknown, IHC can be used on biopsied metas-
tases to elucidate the site o origin.19,20 Figure 34–1 com- FIGURE 34–1 Histologic appearance of neuroendocrine
pares the histologic appearance o a well-dierentiated tumors (NETs). Microscopic appearance of a low-grade NET. A.
NET versus poorly-dierentiated NEC. Standard microscopy showing few mitoses, no necrosis, and a
Neuroendocrine neoplasms are also described by large number of tumor vessels (arrows). B. Immunohistochemi-
their grade, which includes three categories (G1–G3) cal staining for chromogranin A (brown-colored cells).
TABLE 342 Immunohistochemical Markers o Neuroendocrine Tumors19
Marker Signicance
Synaptophysin Presynaptic vesicle membrane glycoprotein, present on normal and neoplastic
neuroendocrine cells
Chromogranin A Universal marker or neuroendocrine tissue
Cytokeratin(s) Lack o cytokeratin expression suggests the tumor is either an anaplastic neoplasm or
may not be a carcinoma
CDX2 (caudal type homeobox 2) Transcription actor expressed by epithelial cells o the bowel distal to the stomach;
expression is highly sensitive or jejunoileal or appendiceal NET origin
TTF-1 (thyroid transcription actor-1) Transcription actor critical in lung, thyroid, and brain development; expressed on type
II pneumocytes; highly specic marker or lung NET
PAX8 (paired box gene 8) Expressed in islets o Langerhans and thus useul or identication o PNET
Islet1 Expressed in mesenchymal cells o the dorsal pancreatic bud, in islet cells, chroman
cells, and in some CNS tissue; positive staining in PNETs and rectal and duodenal
NETs
CNS, central nervous system; NET, neuroendocrine tumor; PNET, pancreatic neuroendocrine tumor.
In general, clinical behavior and management are dic- CgA is a 457–amino acid peptide that is widely dis-
tated by cellular dierentiation and grade. Well-dier- tributed in neuroendocrine tissues, present in normal
entiated tumors are typically low or intermediate grade islet cells, and co-secreted with serotonin. Its sensitiv-
and behave in a more indolent manner. GEP-NETs in this ity and specicity or detection o disease are assay
category are typically slower to metastasize, and even in dependent but range between 67% to 93% and 85-%
advanced stages patients can live or many years. High- to 96%, respectively. Serum levels o CgA can corre-
grade tumors, oten termed NECs, behave aggressively late with tumor burden, and thus this marker is used
with an associated poor prognosis.21,24 Recently, a subset in some centers to determine the success o debulking
o GEP-NETs with a well-dierentiated cellular appear- procedures, disease recurrence, or progression. Levels
ance but high prolieration rate were described. Although can be alsely elevated by SSAs or proton pump inhibi-
series are small, these well-dierentiated tumors seem tors, or in patients with atrophic gastritis or renal,
to have a better prognosis compared with poorly-di- hepatic, or cardiac dysunction.
erentiated NEC. In one series o 31 GEP-NETs, median 5-HIAA is a metabolite o serotonin that is measured
disease-specic survival (DSS) was 55 months, whereas via a 24-hour urine collection or via plasma assays. It
a comparison group o poorly-dierentiated G3 tumors has high sensitivity (>95%) but low specicity (35%)
demonstrated a DSS o 11 months.25 or detection o GEP-NETs. Limitations o the test
Neuroendocrine neoplasms arising in the lung adhere include inconvenience or the patient and alse eleva-
to dierent classication and nomenclature standards tions caused by a number o substances—tryptophan-
than those o the GI tract. Whereas typical carcinoids rich oods (cheese, mockernuts, tomatoes, pineapples,
Chapter 34
approximate grade 1 GEP-NET and are dened by less spinach), wine, caeine, and various medications (acet-
than 1 mitosis/2 mm2 and the absence o necrosis, atyp- aminophen, monoamine oxidase inhibitors, isoniazid,
ical carcinoids approximate grade 2 GEP-NET and are and 5-fuorouracil [5-FU]). Plasma serotonin levels do
dened by 2 to 10 mitoses/2 mm2 or the presence o not correlate with tumor burden and are not relied on
necrosis. Small cell lung cancer and large cell lung can- or diagnosis or surveillance.29
cer, which are classied morphologically, are equivalent Some centers use biomarkers such as pancreastatin
to poorly-dierentiated G3 NEC, but well-dierenti- (a derivative o CgA) and neurokinin A or prognosis,
ated G3 NET currently has no analogous entity.22 especially in patients undergoing surgery or cyto-
reductive or curative intent, but supporting data are
limited.30,31
CLINICAL PRESENTATION, PNETs may produce insulin, gastrin, glucagon,
DIAGNOSTIC WORKUP, AND somatostatin, vasoactive intestinal peptide (VIP), pan-
CLINICAL STAGING creatic polypeptide (PP), or serotonin. Serum mea-
surement o these hormones can aid diagnosis as
NETs are best known or their hormonal syndromes, hypersecretion can produce specic syndromes that
but the pathognomonic triad o diarrhea, wheezing, are discussed in the sections that ollow.
and fushing is ar rom universal. More commonly,
patients are asymptomatic or develop vague GI symp-
toms that can be misinterpreted or years beore a
Imaging
diagnosis o GEP-NET is conrmed.26 Timely diagno- Imaging is essential or the diagnostic workup, stag-
sis and treatment o GEP-NETs requires a high index ing, and surveillance o GEP-NETs. Modalities such
o suspicion and reerral to a high-volume center with as endoscopy, computed tomography (CT), and mag-
specialized multidisciplinary NET teams. netic resonance imaging (MRI) are used to locate the
primary tumor, dene resectability, and monitor or
Laboratory Tests and Biomarkers progression or recurrence. Nuclear medicine studies
(somatostatin-targeted imaging, positron emission
Biochemical testing is used in some centers to monitor tomography [PET]) are used to evaluate tumor unc-
response to therapy, disease progression, and recur- tionality and the presence o distant metastases. Com-
rence. For extrapancreatic GI NETs, both the North plete diagnostic workup typically the requires use o
American Neuroendocrine Tumor Society (NANETS) multiple modalities.
and European Neuroendocrine Tumor Society (ENETS)
recommend considering measurement o CgA and
urine 5-HIAA (u5-HIAA) or these purposes.27,28 How- Endoscopy
ever, the added utility o biomarkers in the era o Endoscopic procedures are used to detect primary
high-quality cross-sectional imaging remains debated. tumors, or local staging, to provide tissue or diag-
Furthermore, these tests lack the sensitivity and speci- nosis, and or treatment. Gastric, duodenal, and
city to be used or diagnosis. proximal jejunal tumors can be visualized with
esophagogastroduodenoscopy. Colonic, rectal, and Somatostatin receptor scintigraphy (SRS) is a nuclear

tumors in the terminal ileum can be seen with colo- medicine imaging modality that uses 111In-labeled
noscopy. Combining an endoscopic procedure with diethylenetriamine penta-acetic acid octreotide (DTPA-
ultrasound (EUS) allows or local staging and tissue D-Phe1-octreotide) to visualize tumors expressing
diagnosis via ne-needle aspiration. In PNETs, EUS somatostatin receptors 2 and 5. It is obtained as a ull-
localizes primary tumors with 93% sensitivity and body scan at 4, 24, and potentially 48 to 72 hours ater
95% specicity. It is less useul or detecting duode- radionuclide injection and is used or detection o dis-
nal NETs with detection rates o 45% to 60%.32 In tant metastases. It has a sensitivity o 85% and specic-
cases in which the location o the primary tumor is ity o 95% or primary GEP-NETs. It has been shown
unknown but the small bowel is suspected, double to detect metastases missed by conventional imaging in
balloon enteroscopy or capsule endoscopy can be 30% o cases, but it may miss 17.5% o hepatic metas-
used to visualize the midportion o the small intes- tases otherwise detected by CT or MRI.40,43
tine. Unortunately, with detection rates less than The development o a positron-emitting 68Ga-
50%, neither modality is very ecient in this task. 33,34 labeled radioligand conjugated to SSAs has enhanced
the sensitivity (97%) o somatostatin imaging. The
PET scan can be used with CT or MRI, enhancing its
Computed Tomography and Magnetic anatomic specicity (Fig. 34–2).44 These studies have
Resonance Imaging improved the detection rate o NETs o the small intes-
CT is excellent or surgical planning and useul or tine, including endoluminal tumors as small as 1 cm.
Chapter 34
disease staging and surveillance. Studies examining False-negative studies are more common with tumors
its utility in detecting primary GEP-NETs report sen- in the head o the pancreas because the uncinate dem-
sitivities ranging rom 43% to 90%.35–37 Regardless o onstrates a moderate amount o physiologic uptake.
primary tumor site, a multiphase study with intrave- As well, subcentimeter multiocal tumors in the small
nous (IV) contrast should be obtained because GEP- intestine, ound in 15% to 30% o patients who are
NETs are most requently hypervascular tumors that surgically explored, may still be below the limit o
are best visualized in the early arterial phase o a triple resolution.
phase scan. A dedicated thin-slice, triphasic (arterial,
late arterial, portal venous phases) “pancreas protocol”
Fluorodeoxyglucose Positron Emission
CT scan can be helpul or locating small, multiocal
PNETs and to clearly dene the relationship o tumors
Tomography
in the head o the pancreas to mesenteric vascular 18-Fluorodeoxyglucose PET (FDG-PET) is used or
structures. Detection o small bowel, colon, or rectal detection o distant metastases in NEC. It has limited
NETs can be enhanced with the use o oral or rectal (or utility or staging well-dierentiated, low- or interme-
both) radiopaque contrast. This modality is also useul diate-grade GEP-NETs because these tumors are meta-
or detecting hepatic and sot tissue metastases with bolically inert and thus ail to take up 18FDG well.45 In
detection rates in this context reported at approxi- high-grade NECs, maximum standardized uptake val-
mately 80%.36,38,39 ues (SUVmax ) exceeding 4.5 are associated with shorter
MRI is the avored modality or detailing hepatic OS and progression-ree survival (PFS) compared with
metastatic tumor burden (sensitivity, 95.2%)40 and GEP-NETs that are not detected.46
the pancreatic ductal system beore surgery. It is also
useul in patients with renal ailure or an allergy to
iodinated contrast. Optimal imaging requires use o IV
Other Nuclear Scintigraphy Techniques
gadolinium contrast because most GEP-NET metasta- Metaiodobenzylguanidine (MIBG) is taken up by some
ses are hyperintense on arterial phases. NET cells. 131Iodine-labeled MIBG (131I-MIBG) has an
overall sensitivity o 55% to 70% in detecting NETs.47
Although 131I-MIBG is less sensitive than SRS, it may be
Somatostatin Receptor Imaging used in patients receiving long-acting octreotide, which
Somatostatin is an endogenous peptide with a hal-lie competitively inhibits uptake o radiolabeled SSAs or
measured in minutes that inhibits the prolierative and or patients whose tumors lack somatostatin receptors.
secretory unctions target cells throughout the body.
There are ve subtypes o somatostatin receptors
(SSTR1–SSTR5) that are the oundation o somatosta-
Clinical Staging
tin-targeted imaging and treatment because more than GEP-NETs are staged using the American Joint Com-
80% o well-dierentiated NETs express a combina- mittee on Cancer (AJCC) tumor, node, metastasis
tion o these receptors.41,42 (TNM) system (Table 34–3 and Table 34-4).48 The
A B C
FIGURE 34–2 Somatostatin receptor imaging. All images are of the same patient. Image in A was obtained in 2015. Images in
Chapter 34
B and C were obtained in 2020. A. Octreoscan demonstrating a large pancreatic primary tumor (arrow) located in the tail of the
pancreas and multiple hepatic lesions. B. 68Ga-DOTATATE planar image. This more sensitive imaging technique demonstrates
an increased number of hepatic metastases, a pulmonary nodule (arrow) and progression of the pancreatic primary tumor.
C. Fused computed tomography and DOTATATE, coronal image. All images show physiologic uptake in the pituitary, thyroid,
uncinate process, spleen, kidneys, and bladder. Note that the patient has a left pelvic kidney.
TABLE 343 TNM Staging System or G1/G2 (and rare G3) Well-Diferentiated Extrapancreatic
Gastrointestinal Neuroendocrine Tumorsa
Duodenum or
Stomach Ampulla Jejunum or Ileum Appendix Colon or Rectum
TX Tumor cannot be evaluated
T0 No evidence o tumor
T1 ≤1 cm and extends ≤1 cm and only ≤1 cm and extends ≤2 cm T1a: <1 cm and
into lamina involves mucosa into lamina invades lamina
propria or or sphincter o propria or propria or
submucosa Oddi submucosa submucosa
T1b: 1–2 cm and
invades lamina
propria or
submucosa
T2 >1 cm or extends >1 cm or extends >1 cm or extends >2 cm but ≤4 cm >2 cm with
T into the into the into the invasion o the
muscularis muscularis muscularis lamina propria
propria propria propria or submucosa
or invades the
muscularis
propria
T3 Invades into but Invades the Invades into but >4 cm or with Invades into but
not through pancreas or not through subserosal not through
subserosa peripancreatic subserosa invasion, or subserosa
adipose tissue involvement o
mesoappendix
T4 Tumor extends beyond serosa or invades nearby organs
TABLE 343 TNM Staging System or G1/G2 (and rare G3) Well-Diferentiated Extrapancreatic
Gastrointestinal Neuroendocrine Tumorsa (Cont.)
Duodenum or
Stomach Ampulla Jejunum or Ileum Appendix Colon or Rectum
N N1 Regional lymph Regional lymph Regional Regional lymph Regional lymph
node metastasis node metastasis lymph node node metastasis node metastasis
metastases <12
lymph nodes
N2 Large mesenteric
masses (>2 cm)
and/or ≥12
nodal deposits,
especially those
that encase
the superior
mesenteric
Chapter 34
vessels
MX Distant metastases cannot be assessed
M M1a Metastases conned to the liver
M1b Metastases in at least one extrahepatic site
M1c Both hepatic and extrahepatic metastases
Stage I Stage II Stage III Stage IV
Stomach
Any T N1 M0
Duodenum or T4 N0 M0
ampulla
Jejunum or T2-3 N0 M0 Any T N1-2 M0 Any T
ileum T1 N0 M0 T4 N0 M0 Any N
Appendix Any T N1 M0 M1
T4 N0 M0
Colon or IIa IIb IIIa IIIb
rectum T2 N0 M0 T3 N0 M0 T4 N0 M0 Any T N1 M0
a
For any T, add (m) or multiple tumors. For multiple tumors with diferent Ts, use the highest. Per World Health Organization/American Joint Committee on Cancer
guidelines, poorly-diferentiated neuroendocrine carcinomas (Ki-67 > 20%) are staged using the staging classications or adenocarcinomas at the individual primary
tumor sites, not as well-diferentiated neuroendocrine tumors.
Data rom Edge SB, Byrd DR, Byrd DR, et al: AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.
system is primary site specic and applies to grade 1 in a single radiation port, based on the staging o the
and 2 NETs. This staging is prognostic but not pre- biologically analogous small cell lung cancer.47
dictive o the benet with any therapy. At least two
staging systems are in use or PNETs. The AJCC TNM
PNET staging system derives rom the exocrine pan- CLINICAL FEATURES OF
creas adenocarcinoma staging system and describes T GASTROINTESTINAL
stage in terms o resectability. In contrast, the ENETS NEUROENDOCRINE TUMORS
staging system denes T stage by size and extent o
invasion. Regardless o the system used, prognosis and
Gastric Neuroendocrine Tumors
stage maintain an inverse association.49 High grade
NEC are described with a TNM stage according to There are three types o gastric NETs. Types I and II
guidelines or carcinomas o the primary site but are arise in response to hypergastrinemia, and type III
summarized as limited-stage or extensive-stage dis- tumors are sporadic.50 Type I NETs are most common
ease, dened by the ability o the cancer to be treated (75%) and are typically located in the gastric body
TABLE 344 Staging System or G1/G2 (and Rare G3) Well-Diferentiated Pancreatic Neuroendocrine
Tumorsa
American Joint TX Tumor Stage Stage Stage

Committee on I II Stage III IV
Cancer Tumor
T1 Limited to the pancreas, <2 cm T1
(T), Node (N),
Metastasis (M) T2 Limited to the pancreas, 2–4 cm T2
Staging System T3 Limited to the pancreas, >4 cm or invading T3
(8th ed, 2017) the duodenum or common bile duct
or G1/G2 (and T4 Invading adjacent organs or the wall o T4 Any T Any T
Rare G3) Well- large vessels
Diferentiated
Pancreatic
Neuroendocrine
Tumorsa T
N N0 No regional lymph node metastasis N0 N0 N0
Any N
N1 Regional lymph node metastasis N1
Chapter 34
MX Distant metastases cannot be assessed

M0 No distant metastases M0 M0 M0
M M1a Metastases conned to the liver
M1b Metastases in at least one extrahepatic site M1
M1c Both hepatic and extrahepatic metastases
a
Limited to the pancreas means there is no invasion o adjacent organs (stomach, spleen, colon, or adrenal gland) or the wall o large vessels (celiac axis or the
superior mesenteric artery). Extension o the tumor into peripancreatic adipose is not a basis or staging. For any T, add (m) or multiple tumors. For multiple tumors
with diferent Ts, use the highest. Per World Health Organization/American Joint Committee on Cancer guidelines, poorly-diferentiated pancreas neuroendocrine
carcinomas (Ki-67 >20%) are staged using the pancreatic adenocarcinoma guidelines, not as well-diferentiated NETs.
Data rom Edge SB, Byrd DR, Byrd DR, et al: AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer; 2017.
or undus. They are associated with chronic atrophic multiple tumors are detected, a diagnosis o MEN1
gastritis or pernicious anemia, are requently subcenti- should be considered.54 Periampullary tumors are typi-
meter and multiocal, and rarely metastasize. The sur- cally more aggressive, and these patients may present
vival rate is estimated at approximately 100% when with obstructive jaundice or cholangitis. Liver metas-
these tumors are discovered as submucosal lesions tases occur in ewer than 10% o patients.51 The most
amenable to endoscopic resection.51 Type II tumors common duodenal NETs are gastrinomas, somatostati-
arise in the context o pathological hypergastrinemia nomas, and nonunctional tumors. Gastrinomas cause
rom Zollinger-Ellison syndrome (ZES; 5%–10%) and symptoms o ZES either sporadically or in the context
are most oten (70%) ound in patients with MEN1.51 o MEN1. These patients develop refux and are at risk
These are more aggressive than type I tumors because or peptic ulcers, GI bleeding, or peroration because o
10% to 30% will metastasize, though usually only to high levels o hydrochloric acid.
locoregional lymph nodes.52 Analyzed together, type I NETs o the jejunum and ileum are colloquially
and II gastric NETs are associated with an approximate reerred to as carcinoid tumors. These tumors are most
80% 5-year OS rate.51 Type III tumors, which arise in oten 1 to 2 cm in size and are located within 100
a eugastrinemic context and are most similar to NETs cm o the ileocecal valve.55 Approximately 41% o
arising elsewhere in the body are the most aggressive patients will have locoregional nodal involvement, and
subtype, with 50% to 100% metastasizing distantly. 30% will have distant metastases.56 In patients who
SEER analysis reveals a median OS o 13 months or undergo surgical exploration, up to 45% are ound to
patients with metastatic gastric NETs. 53 have multiple small-bowel tumors.57 These tumors are
typically subcentimeter and can be missed i patients
undergo a minimally invasive operation because o
Small Intestinal Neuroendocrine Tumors
the lack o haptic eedback. Given their small size,
Sporadic duodenal tumors comprise approximately they may also be missed on SRS imaging. On CT, an
3% o all NETs, according to the SEER registry between endoluminal tumor may not be obvious, but a calci-
1973 and 1999. The vast majority o duodenal tumors ed mesenteric mass is oten seen, which upon sur-
arise in D1 and D2, with approximately 20% occur- gical exploration approximates the location o the
ring in the periampullary region. Sporadic duodenal largest primary within the bowel. Beore developing
tumors are typically small (<2 cm) single lesions. I distant metastases, patients are either asymptomatic
or describe vague GI symptoms unrelated to the pres- insulin, C-peptide, and proinsulin during a monitored
ence or location o the primary tumor. Patients with 72-hour ast conrms the diagnosis. Insulinomas can
distant metastases are more likely to present with be dicult to localize in 40% o cases, but combina-
symptoms related to hormone secretion or rom high tions o MRI, pancreas protocol CT, and EUS have a
tumor burden, such as GI bleeding, jaundice, or bowel sensitivity o 90%. 69Gallium PET imaging may detect
obstruction. Patients who present with a large mes- lesions missed by other modalities.62 Patients with
enteric mass at the takeo o the superior mesenteric lesions that ail to localize on imaging can be discov-
artery may develop chronic mesenteric ischemia. The ered intraoperatively using a combination o careul
median survival time o patients with G1 or G2 small palpation and intraoperative ultrasound to identiy
intestine NETs is 8.5 years. the tumor, though this is becoming less common as
imaging improves. Portal venous sampling and arterial
calcium stimulation are primarily o historical interest.
Appendiceal Neuroendocrine Tumors
Appendiceal NETs are oten discovered incidentally
during an appendectomy. Fity-our percent o patients
Gastrinoma
present with appendicitis, but this is unlikely related to Gastrinomas are located in the duodenum or pancreas
the primary tumor because only one third are located at in an area called the gastrinoma or Passaro’s triangle,
the base o the appendix.58 Median OS is more than 30 which is bound superiorly by the junction o the cys-
years when the disease is localized or locally advanced tic and common bile ducts, ineriorly at the junction
Chapter 34
and 2.3 years with distant disease.53 Still undetermined o D2 and D3, and medially by the neck o the pan-
is whether the disease-specic prognosis is meaning- creas.63 These tumors cause ZES and patients develop
ully dierent between pediatric and adult patients. multiple, recurrent peptic ulcers.64 Twenty percent are
ound in association with MEN1. Approximately 50%
o gastrinomas have distant metastases at diagnosis.65
Rectal Neuroendocrine Tumors Diagnosis requires measurement o asting serum gas-
Rectal NETs are oten ound during an evaluation or trin and basal gastric acid levels. Duodenal gastrino-
symptoms related to a benign condition (ie, bleeding, mas are submucosal and oten dicult to detect with
pain, change in bowel habits). Most tumors are 4 to 8 EGD. 69Gallium SRS PET can detect 68% o gastrino-
cm rom the anal verge, and 80% are localized tumors mas diagnosed biochemically or clinically but missed
less than 1 cm in size.59 Only 4% o patients with recon conventional imaging.66
tal NETs present with distant metastases. These tumors
appear as a yellow-grey submucosal nodule in the rectal
wall. Local excision is adequate or small tumors with-
Glucagonoma
out high-risk eatures. Pathologic characteristics that Glucagonoma is a rare but aggressive PNET that typi-
mandate consideration o more extensive surgical resec- cally arises in the tail o the pancreas. Glucagonoma
tion are perineural or lymphovascular invasion, invasion syndrome eatures necrolytic migratory erythema,
into the muscularis, or size larger than 2 cm. Tumors diabetes mellitus, stomatitis, anemia, neuropsychiat-
with high-risk eatures carry a 60% to 80% risk o dis- ric disturbances, or diarrhea. The majority o patients
tant metastasis.59,60 Localized rectal NETs are associated present with glucose intolerance, necrolytic migratory
with a median OS o 24.2 years, whereas prognosis or erythema, or both. The reddish-brown rash typically
advanced rectal NETs is much poorer at 1.8 years.53 involves the ace, abdomen, perineum, or extremities.
Erythematous areas orm bullae that eventually open
and encrust. The median time between symptom onset
CLINICAL FEATURES OF PANCREATIC and diagnosis is 39 months, and by this time, 80% o
NEUROENDOCRINE TUMORS tumors have metastasized. Diagnosis is supported by
serum glucagon levels exceeding 1000 pg/mL.67
Insulinoma
Insulinoma is the most common type o unctional Somatostatinoma
PNET and is characterized by the “Whipple triad” o Somatostatinoma is an extremely rare (incidence, 1
(1) hypoglycemia; (2) neuroglycopenic symptoms o in 40 million people) solitary tumor that is ound in
shakiness, conusion, or sweating; and (3) resolution the pancreas or periampullary duodenum. Functional
o these symptoms with eating. These tumors are tumors can cause diabetes, cholestasis, or steator-
generally benign (90%), intrapancreatic, solitary, and rhea. Most tumors are malignant (78%), and patients
smaller than 2 cm.61 Approximately 5% are associ- typically present with metastatic disease (70%–92%).
ated with MEN1; thus, a careul amily history must Duodenal somatostatinomas are associated with NF1
be taken at diagnosis. Measurement o plasma glucose, in approximately 50% o cases and are less likely to
have metastasized at presentation. The 5-year OS o “pancreatic carcinoid” have been reported. Com-
or patients with localized disease is 60% to 100%, mon symptoms include fushing, diarrhea, abdominal
whereas the 5-year OS or patients with metastatic cramping, and less requently, wheezing, right-sided
disease is 15% to 60%.68 heart ailure or dysunction, and pellagra. Symptoms
are thought to be caused by circulating serotonin
metabolites, kinins, and prostaglandins.
VIPoma A recent population-based study identied the clini-
VIP-secreting tumors (VIPomas) are rare tumors that copathologic actors associated with the presence o
cause “pancreatic cholera.” Conrmed in human par- carcinoid syndrome at diagnosis. Regionally advanced
ticipants inused with high concentrations o IV VIP (22%) and distant metastatic (24.9%) NETs were asso-
or 10 hours,69 elevated serum concentrations o VIP ciated with carcinoid syndrome more requently than
cause high-volume (>10–20 L/day) watery diarrhea localized NETs (11.9%). Small intestine (32.4%) and
that results in proound dehydration, hypokalemia, cecal (32.2%) NETs were most commonly associated
achlorhydria, and paradoxical acidosis. These tumors with carcinoid syndrome at diagnosis.76
are located in the pancreatic tail and are typically slow
growing with a median OS o 5.9 years. Five percent
are seen in patients with MEN1.70
Carcinoid Heart Disease
Carcinoid heart disease is the result o valvular thicken-
ing and brous plaque ormation on the tricuspid and
Chapter 34
Pancreatic Polypeptide–Secreting Tumor pulmonic valves that results in tricuspid regurgitation

PNETs that hypersecrete PP (PPomas) are exceedingly and pulmonic valve stenosis. Right ventricular dys-
rare (<1% NET), and although considered a unctional unction or ailure suggests long-standing, late-stage
PNET, they do not produce a specic clinical syndrome. disease.77 A result o sustained release o serotonin,
Secretion o PP is associated with increased satiety, tachykinins, histamine, and prostaglandins, carcinoid
delayed gastric emptying, and inhibition o gallblad- heart disease develops in 40% to 70% o patients with
der contraction. Some reports suggest an association carcinoid syndrome.56,78–80 Patients may be asymptom-
between PP hypersecretion and glucose intolerance. In atic but may also present with exercise intolerance.
patients who present with metastatic disease, this may Florid right heart ailure is uncommon. Physical exami-
be the presenting sign.71–73 nation and echocardiography aid in diagnosis. Current
National Comprehensive Cancer Network guidelines
suggest echocardiographic screening or patients with
Nonfunctional Pancreatic Neuroendocrine carcinoid syndrome every 2 to 3 years.81 Screening
Tumors should also be considered in patients preparing or sur-
Whether sporadic or in the context o MEN1, the gical resection or debulking.79
majority o PNETs are nonunctional. These tumors are
asymptomatic at presentation unless tumor size or loca- Carcinoid Crisis
tion creates mass eect within the oregut and biliary
tree. Their asymptomatic nature contributes to a delay Carcinoid crisis is a hemodynamic phenomenon that
in diagnosis, and 60% to 80% present with metas- is the subject o recent controversy. Lacking a consen-
tases.74 Prospective studies o patients with MEN1 sus denition, it is generally described as a prolonged
suggest that at least 50% o patients will develop non- episode o hemodynamic instability occurring during
unctional PNET and that these tumors increase in size or in close proximity to an invasive procedure that
and number over time, albeit very slowly.75 cannot be ascribed to (peri-) procedural actors such as
hypovolemia, medication, hemorrhage, or decreased
venous return. Similar to an episode o carcinoid syn-
CARCINOID SYNDROME, CARCINOID drome, patients may develop cutaneous fushing and
HEART DISEASE, AND CARCINOID diarrhea during an event. In part because o the lack o
denition, the true prevalence o crisis is unknown but
CRISIS reported between 0% and 35% in patients undergoing
surgical resection.82–86 An episode o crisis is thought
Carcinoid Syndrome to be caused by a massive release o bioactive amines
Carcinoid syndrome occurs when metastatic disease, into the systemic circulation, though one recent pro-
primary tumor location, or tumor volume allows spective study did not nd elevated levels o serotonin,
secreted amines to bypass or overwhelm the rst- histamine, kallikrein, or bradykinin during intraopera-
pass eect o the portal circulation. It is most com- tive crises.86 Generally recommended treatment con-
mon in extrapancreatic GI NETs, although some cases sists o bolus injection o 500 to 1000 ug o octreotide
PRRT
Progressive
Cytotoxic
High volume
Cytotoxic
Indolent
Liver directed
Advanced NET
Sunitinib
Progressive
Everolimus
Low volume
SSA
Indolent
Observation
FIGURE 34–3 Approach to therapy for advanced neuroendocrine tumors. Examples of low-volume metastatic disease are
metastases isolated to a single organ or less than 20% liver replacement. PRRT, peptide receptor radionuclide therapy; SSA,
Chapter 34
somatostatin analogue.
or a continuous inusion o 50 to 100 μg/hour in addi- Treatment of Resectable Neuroendocrine

tion to standard management with antihypertensives Tumors
or vasopressors. Patients with high-volume metastatic
disease or a history o carcinoid syndrome undergoing Surgical resection o locoregional disease oers the
invasive procedures may be premedicated with bolus only chance or cure in patients with GEP-NETs.
injections o octreotide. An intraprocedural continuous Appropriate patient selection considers primary site,
inusion o octreotide can be administered as prophy- tumor histology, the extent o detectable disease, and
laxis against periprocedural carcinoid crisis. This inu- clinical presentation.
sion is tapered over the next 8 to 24 hours. The use o Endoscopic resection o types I and II gastric NET is
periprocedural SSAs or these purposes is inconsistent appropriate when tumors are less than 2 cm in size and
among centers and practitioners. Both retrospective relatively ew in number.87 I histopathologic analysis
and prospective studies question the ecacy o SSA in reveals high-risk eatures such as positive resection
this context.83,85 Multi-institutional, prospective stud- margins, invasion into the muscularis or lymphovascu-
ies are required to resolve these issues. lar invasion, partial gastrectomy and regional lymph-
adenectomy must be considered. Tumors larger than
3 cm and type III gastric NETs also necessitate con-
GENERAL APPROACH TO TREATMENT sideration o gastrectomy (partial or total, depending
on location).88–90 Endoscopic resection is not appro-
The dual nature o GEP-NETs—indolent but oten dis- priate or type III gastric NETs o any size because
covered ater metastatic spread—lies at the core o the o their propensity to behave similarly to gastric
challenges that arise during the care o these patients. adenocarcinomas.91
Considered, deliberate ordering o a variety o treat- Treatment o localized PNETs is dictated primarily
ment modalities is oten necessary, which requires by location within the pancreas but also by histology
that patients obtain treatment at centers equipped to because unctional tumors and those diagnosed in the
provide specialized, multidisciplinary care. Primary context o MEN1 are oten multiocal and theoretically
tumor location, stage, and grade dictate management. amenable to repeat surgical treatment with parenchy-
Regardless o primary site, surgical resection is recom- mal-sparing techniques. Sporadic tumors located in the
mended or G1 and G2 GEP-NETs when clearance o head o the pancreas are treated with pancreaticoduo-
all gross disease can be achieved. Regional therapies denectomy (Whipple procedure). Tumors in the body
or G1 and G2 GEP-NETs are also similar across pri- or tail can be resected with a distal pancreatectomy.
mary sites, but systemic therapies diverge or pancre- In sporadic, nonunctional PNETs surgical resection is
atic and extrapancreatic NETs (Fig. 34–3). associated with superior OS (14.3 years vs 3 years),92
although tumors smaller than 1 cm can be observed that o rectal adenocarcinoma, in which low anterior
over time because o their low malignant potential. resection or abdominoperineal resection are options.
Patients with unctional, multiocal tumors present Poorly-dierentiated grade 3 NEC seldom benet
a unique problem because R0 surgical resection may rom surgical resection in isolation because survival
require total pancreatectomy, which is a morbid pro- is poor regardless o the treatment modality selected.
cedure condemning the patient to brittle diabetes and These patients are usually treated with chemother-
exocrine insuciency. Alternatively, patients may be apy, with radiation added or patients with limited-
treated with surgical enucleation. This spares paren- stage disease and surgical consolidation considered in
chyma but increases the risk o pancreatic stula.18 selected cases.
Novel technologies such as irreversible electroporation
are under investigation or these tumors.93
Management o patients with pancreas VIPomas
Treatment of Advanced Neuroendocrine
can be especially challenging because the clinical syn- Tumors
drome is commonly associated with advanced dis- The goal o treatment o patients with advanced GEP-
ease. Typically, management requires a multimodal NETs is improvement o quality o lie and survival.
approach. Surgical resection o the primary tumor and At this stage, treatment is multimodal and can include
all metastases is ideal but rarely achieved. Surgical SSAs, surgery, hepatic metastasis embolization, sys-
cytoreduction is attempted in some centers to decrease temic PRRT, chemotherapy, and systemic targeted
the amount o secreted VIP. Medical therapies may aid therapy. The literature is limited on specic recom-
Chapter 34
in symptom control and in severe cases, inusions o mendations or the order in which these modalities
SSAs or glucocorticoid can be helpul to decrease the should be applied, emphasizing the need or special-
volume o diarrhea. ized, multidisciplinary care.
Duodenal NETs remote rom the ampulla can be
resected endoscopically (<2 cm), via transduodenal Somatostatin Analogues
resection, or with a short-segment resection and anas-
tomosis. Periampullary tumors require a Whipple pro- SSAs such as octreotide and lanreotide control symp-
cedure.54,89,90 Localized NETs o the jejunum and ileum toms o hormonally active NETs and demonstrate anti-
are treated with segmental resection and regional prolierative activity or NETs regardless o secretory
lymphadenectomy.94 Regardless o imaging or gross behavior. These agents are the mainstay o therapy in
inspection o the bowel intraoperatively, careul palpa- carcinoid syndrome. Octreotide is an intermediate-act-
tion o the entire bowel—rom the ligament o Treitz ing SSA that can be sel-administered subcutaneously
to the terminal ileum—is required to ensure identica- every 6 to 12 hours as acute symptoms demand. It
tion and resection o all primary tumors because up to provides complete or partial relie o fushing or diar-
45% o patients have multiocal disease.57 rhea in approximately 85% o patients with carcinoid
For appendiceal NETs, simple appendectomy is syndrome and produces a biochemical response rate
appropriate treatment or tumors 1 cm or smaller, with o up to 72%.95,96 The dose o octreotide varies rom
invasion up to the subserosa or with mesoappendiceal 50 to 500 μg.
invasion 3 mm or less and clear surgical margins. In Long-acting SSAs have eliminated the need or mul-
adult patients, right hemicolectomy is recommended tiple daily injections in most patients. Depot octreotide
or tumors larger than 2 cm, tumors with deep meso- (10, 20, or 30 mg) is administered intramuscularly once
appendiceal invasion or positive margins, and tumors per month. An intermediate-acting SSA can be used
located at the base o the appendix, although studies to supplement long-acting agents until steady state
have not clearly demonstrated a survival benet with is reached. Lanreotide is another SSA in extended-
more extensive surgery.28 release orm, which can be administered subcutane-
Colonic NETs are treated via endoscopic snare or ously monthly in doses o 60, 90, or 120 mg. In 2016,
partial colectomy and regional mesenteric lymphad- the phase III, randomized ELECT trial showed that
enectomy. Small (~1–2 cm) intraluminal tumors that treatment with 120 mg o lanreotide every 4 weeks
do not invade the muscularis can be excised endo- decreased the percentage o days that patients required
scopically. Attempting removal o larger tumors with rescue doses o octreotide97 and improved control o
these procedures risks piecemeal removal, thus com- fushing and diarrhea in these patients.98
plicating pathologic analysis and increasing the risk o SSAs have a avorable side eect prole. These
positive margins. Small, submucosal rectal NETs may drugs can cause sinus bradycardia or cardiac conduc-
be treated with local excision. Tumors that invade the tion abnormalities; thus, caution is advised in patients
muscularis, have high-risk eatures, or are associated with cardiac disease. More commonly, cholestasis and
with locoregional spread are treated with segmental cholelithiasis can result rom long-term use,99 so cho-
resection. Choice o operation in this context parallels lecystectomy should be considered in patients who
undergo resection or their GEP-NETs.94 Hypoglyce- primary in situ.105 Such propensity-matched analyses
mia, or more commonly, hyperglycemia may occur, help minimize selection bias rom the retrospective
especially among patients with brittle diabetes. Steat- analyses but are not denitive evidence o lack o ben-
orrhea may also occur but can be managed with pan- et rom early surgical intervention. For now, consid-
creatic enzymes taken with ood. eration o surgery in patients with low overall tumor
SSAs also have anticancer activity. Interim analysis burdens and good unctional status is reasonable and
o the phase III randomized trial o depot octreotide oered at the majority o high-volume NET centers.
30 mg monthly in untreated metastatic midgut NET Metastasectomy is most oten perormed to treat
(PROMID) demonstrated a signicantly longer time to hepatic metastases and more rarely done or extra-
progression with octreotide compared with placebo hepatic tumor debulking. In the liver, clearance o
(PFS hazard ratio [HR], 0.34; P <.001).100 An interna- all hepatic metastases is ideal, although cytoreduc-
tional double-blind placebo-controlled phase III trial o tion with a goal o clearing a minimum o 70%, and
lanreotide (120 mg every 28 days) in treatment-naïve optimally 90% o disease, is considered reasonable in
patients with nonunctioning GEP-NET (CLARINET) some centers. Anatomic surgical resection or paren-
also demonstrated signicantly improved PFS with chymal-sparing methods such as ablation are accept-
lanreotide compared with placebo (PFS HR, 0.47; able, although recurrence with either strategy is nearly
P <.001).101 universal. Patients undergoing liver-directed surgery
experience superior PFS, OS, symptom control, and
Surgical Resection in the Setting o Advanced have a low postoperative complication rate when care-
Chapter 34
Disease ully selected.94,106–109 Orthotopic liver transplantation
is another investigational surgical approach or treating
Surgical treatment o advanced GEP-NETs is acceptable hepatic metastases and is also associated with OS at 5
either or palliation o symptoms or survival benet. and 10 years that is superior to unselected patients.110
These operations must be considered careully and are The extent to which this represents an eect o the sur-
best perormed at high-volume NET centers by expe- gery as opposed to an eect o the selection o patients
rienced surgeons because achieving an R0 resection is t or these interventions is as yet undetermined.
only possible in a minority o cases.102 The risk o sur-
gery must be careully weighed and expected outcome Hepatic Arterial Embolization and
clearly articulated because surgical complications can
Chemoembolization
impact the survival and quality o lie in a group o
patients who may otherwise survive many years with Liver metastases rom NETs receive more than 80% o
their disease let in situ. their blood supply rom the hepatic arterial circulation,
Palliative resection o the primary GEP-NET is rec- in contrast to normal liver parenchyma, which receives
ommended or patients with unctional tumors caus- approximately 70% o its supply rom the portal
ing debilitating secretory symptoms or in the setting o venous system. Thus, embolizing the hepatic artery
obstruction or bleeding. It is unknown whether resec- targets tumor metastases while leaving normal paren-
tion o a nonunctional tumor is benecial. A meta- chyma relatively unharmed. Three distinct techniques
analysis o six studies examining this issue suggested exist or liver-directed embolotherapy, but all rely on
that patients with advanced jejunal, ileal, or pancreatic selective ischemia o the metastasis or eect. Bland
NETs in the setting o unresectable distant metastatic embolization uses embolic particles (Geloam powder,
disease may have a survival benet with palliative resec- polyvinyl alcohol particles, or microembospheres) to
tion o their primary tumors.103 Studies using propen- cut o the tumor blood supply.111 The addition o an
sity matching are mixed. Daskalakis et al104 compared ethiodized oil emulsion o a chemotherapeutic agent
patients who underwent early “logoregional” surgery to the embolic material, known as transcatheter arte-
or their stage IV small intestinal NETs with those who rial chemoembolization (cTACE), or drugs loaded onto
had surgery at least 6 months ater their initial diagno- embolic microspheres (drug-eluting bead transarterial
sis. They ound no survival dierence between groups, chemoembolization [DEB-TACE]), allows delivery o
but details on the conduct o the operations are not relatively larger doses o agents to the tumor, com-
reported; thus, the extent o surgery is unknown. A bining local cytotoxicity and ischemia. The most re-
single-institution series rom Frankurt, Germany, com- quently used chemotherapeutic agents or cTACE and
pared patients who had surgery as part o their treat- DEB-TACE are doxorubicin, epirubicin, cisplatin, gem-
ment or hepatic metastases with those who had only citabine, 5-FU, and streptozocin.112–116
nonsurgical interventions. This propensity-matched Benets o this treatment include symptom relie,
study showed that there was no survival advantage slowing progression, and reducing tumor burden
to incorporating surgery in the matched analysis. The beore attempting surgical resection or tumor ablation.
10-year mortality rate was associated with leaving the Many retrospective studies in markedly heterogeneous
populations have shown that these three techniques Radioembolization o hepatic metastases has been
control symptoms and are associated with avorable studied retrospectively as well as prospectively. The
PFS and OS. No study has clearly demonstrated one study cohorts are heterogeneous, but 90Y radioemboli-
technique to be superior in patients with GEP-NETs, zation has been shown to improve symptoms, induce
although a randomized trial comparing all three tech- radiographic complete and partial responses, and
niques is currently recruiting patients. It should be decrease tumor marker levels and be associated with
noted that the DEB-TACE arm o this study closed avorable PFS and OS.117,123–125 There are no studies that
early because o reports o unacceptable toxicity.114 show improved survival benet with radioemboliza-
The primary risk o hepatic artery embolization is tion compared with other hepatic arterial embolization
postembolization syndrome, which is typically sel- techniques. This procedure has a avorable saety pro-
limited and characterized by pain, GI distress, ever, le compared with hepatic arterial embolization tech-
leukocytosis, and transaminitis. Major complications niques, with low rates o postembolization syndrome
such as renal ailure, gallbladder peroration, cholangi- and carcinoid crisis, allowing it to be perormed as an
tis, peptic ulcer hemorrhage, and abscess ormation are outpatient procedure.119,126 The risk o hepatic cirrhosis
rare.117 Liver necrosis is also uncommon postprocedur- is low with this technique but has been reported.127
ally but is associated with previous bile duct dilation
and portal vein thrombosis.118 Embolization has been
associated with carcinoid crisis.119 Peptide Receptor Radionuclide Therapy
In patients with extensive liver tumor burden, mul- Radiolabeled SSAs have also been developed, and
Chapter 34
tiple embolization sessions may be required, starting 177

Lu-DOTATATE was approved by the Food and Drug
with the hepatic lobe with the greatest tumor burden. Administration (FDA) in 2018 or use in patients with
Embolization o the whole liver in one session runs metastatic GEP-NETs. DOTATATE is a SSA that can be
the risk o prolonged postembolization syndrome or conjugated to the b- and g-emitter 177lutetium (177Lu).128 In
liver ailure. The timing o subsequent embolizations 2017, the results o the phase 3 trial o 177Lu-DOTATATE
is determined primarily by symptoms, tumor behav- or midgut neuroendocrine tumors (NETTER-1) were
ior, and patient tolerance. reported. The trial included 229 patients with well-di-
The ordering o hepatic arterial embolization with erentiated, metastatic midgut NETs who were random-
other regional and systemic therapies in the disease ized to receive either 177Lu-DOTATATE every 8 weeks
course remains a topic o debate, and specic guide- or high-dose (60-mg) octreotide LAR. PFS was improved
lines rom NANETS on this issue do not exist.18,120 by 79% in the PRRT arm compared with the octreotide
Although some investigators advocate early emboli- arm. The response rate in the 177Lu-DOTATATE group
zation to reduce tumor burden beore initiating sys- was 18% versus 3% in the octreotide group (P <.001). A
temic therapy, late embolization can also be eective. preliminary analysis suggested an OS advantage to PRRT,
In a randomized study, patients with NET treated with 14 deaths in the 177Lu-DOTATATE group compared
with initial liver embolization ollowed by intereron with 26 deaths in the octreotide group (P = .004),129 but
therapy had a higher objective response rate ater 1 more events are required to conrm this early result.
year (86%) than patients who received intereron only Grade 3 and 4 side eects were rare. The most common
(42%), without demonstrating altered survival.121 In in the 177Lu-DOTATATE group were lymphopenia (9%)
contrast, when embolization or chemoembolization and thrombocytopenia (2%). A separate report detailed
are perormed at a median o 37 months ater diagno- the results o patient quality o lie outcomes as assessed
sis, the median survival time ater embolization was with two dierent quality o lie questionnaires admin-
80 months, leading the investigators to conclude that istered at baseline and every 12 weeks until tumor pro-
later embolization is still eective.122 gression. Patients treated on the 177Lu-DOTATATE arm
had signicantly longer time to deterioration or global
Selective Internal Radiation Therapy health status (28.2 months vs 6.1 month) and physical
unctioning (25.2 months vs 11.5 months).
Intra-arterial radioembolization with yttrium-90 (90Y)
microspheres is a technique used to treat unresectable
Chemotherapy
liver metastases.18,120 90Y is a pure b emitter with a mean
sot tissue penetration o 2.5 mm and a maximal depth Selection o chemotherapy regimen depends on grade
o 1.1 cm. Great care must be taken with 90Y radioem- and histology. Well-dierentiated extrapancreatic NETs
bolization to avoid nontarget delivery o radioactive respond poorly to cytotoxic chemotherapy. PNETs
microspheres to organs such as the lungs and stomach, respond better. Early randomized studies o streptozo-
making an angiogram with selective embolization o cin-based chemotherapy regimens demonstrated bio-
all extrahepatic arteries essential beore treatment, as chemical responses and improvements in survival.130,131
well as assessment o lung shunt raction. Building on the progress o Moertel et al, a study rom
MD Anderson Cancer Center noted radiographic months in PNETs and extrapancreatic NETs, respec-
response rates o 39% in a series o 84 patients with tively.139 The subsequent phase III trial in advanced
PNET using a regimen o 5-FU, doxorubicin, and strep- extrapancreatic NETs randomized 198 patients (2:1) to
tozocin (FAS). The median PFS was an estimated 18 300 mg o suruatinib or placebo. This study was termi-
months, with a median OS o 37 months.132 Temozolo- nated at an interim analysis by the data saety monitor-
mide, an alkylating agent, is an alternative to FAS and has ing board because o unequivocal evidence o benet,
the advantage o being an oral ormulation. A random- with suruatinib signicantly prolonging PFS compared
ized trial comparing temozolomide and capecitabine to with best supportive care (HR, 0.334; 95% condence
temozolomide alone in PNET patients demonstrated interval, 0.223–0.499; P <.0001). The most common
improved PFS (22.7 vs 14.4 months) and OS (not reached severe adverse events were proteinuria (19.4%) and
vs 38 months). Poorly-dierentiated high-grade NECs hypertension (36.4%). The disease control rates were
are responsive to platinum-based chemotherapy.133 86.5% in the suruatinib group and 65.6% in the pla-
cebo group (P = .0022). A phase III trial investigating
suruatinib in PNET is ongoing.140
Targeted Therapy
The use o targeted therapies in GEP-NETs has greatly Immunotherapy
expanded in recent years. Building on the observa-
tion that increased vascular endothelial growth ac- Currently, there are no checkpoint or immunothera-
tor (VEGF) portends poor survival in patients with pies approved or use in GEP-NETs. Pembrolizumab,
Chapter 34
NET, the VEGF receptor inhibitor sunitinib was tested a programmed cell death protein 1 (PD-1) checkpoint
in a phase III study o 154 patients with PNET with inhibitor, may have a role in the treatment o patients
advanced and progressive disease. An interim analy- with poorly-dierentiated NEC because one study
sis demonstrated an HR or progression or death o showed expression o PD-1 in 16% o GEP NECs.141
0.42 avoring sunitinib over placebo (P <.001).134 This
resulted in regulatory approval o sunitinib or the
Additional Symptom Control Methods
indication. Simultaneously, the mTOR inhibitor evero-
limus was studied in RADIANT-3. This randomized Carcinoid symptoms can be exacerbated by epi-
phase III trial compared everolimus versus placebo in nephrine, exercise, emotions, eating tryptophan-rich
410 patients with advanced, progressive PNETs. The oods, and ethanol and may be controlled through
HR or progression or death was 0.35 (P <.001) avor- modulating these actors or supplementing dietary
ing everolimus over placebo.135 nicotinamide. Medical management o carcinoid
Less progress has been made with targeted agents symptoms can include a bronchodilator or broncho-
in extrapancreatic GI NETs. The phase II study o spasm and diuretics or fuid overload secondary to
sunitinib showed limited evidence o benet.136 The valvular dysunction. A proton pump inhibitor (but
RADIANT-2 study o everolimus in patients with not an H2 blocker) can manage gastric hypersecre-
extrapancreatic NET, although limited by randomization in gastrinoma patients. Malignant hypoglycemia
tion imbalance and inormative censoring in central in patients with insulinomas can be managed with
radiology review, also ailed to demonstrate statisti- everolimus. 142
cally signicant benet.137 RADIANT-4, a randomized Elevated levels o serotonin are associated with diar-
phase III trial o patients with advanced, progressive, rhea and are not always optimally managed with an SSA.
well-dierentiated, nonunctional NETs o the lung Telotristat ethyl inhibits tryptophan hydroxylase—the
or GI tract were assigned to everolimus or placebo rate-limiting step in serotonin synthesis. As such, it has
in a 2:1 ratio. Everolimus was associated with a 52% been tested prospectively to determine its ecacy in
decrease in the estimated risk o progression or death reducing the requency o NET-associated diarrhea. In
(P <.00001).138 The FDA approved everolimus or well- the phase 3 TELESTAR study, patients had a reduction
dierentiated, nonunctional, advanced NETs in 2016. (-2.1 bowel movements per day compared with base-
Suruatinib is the newest targeted agent to be trialed line but only -0.81 bowel movement per day compared
in NETs. This agent targets the VEGF receptor, bro- with placebo) o the number o bowel movements per
blast growth actor receptor 1, and colony-stimulating day as well as a signicant decrease in their u5-HIAA
actor 1 receptor. In the phase I/IIb trial, 42 patients levels.143 The results o the TELECAST study paralleled
with PNET and 39 patients with extrapancreatic NET those o TELESTAR and showed that telotristat was
were treated with 300 mg o oral suruatinib once daily sae and resulted in a decreased number o bowel move-
until progression. Radiographic objective response rates ments per day, as well as decreased u5-HIAA levels.144
were observed in 19% o PNETs and 15% o extrapan- Telotristat ethyl is FDA approved or use at a dosage o
creatic NETs. Disease control rates were 91% and 92%, 250 mg three times per day in patients with NET-related
with associated median PFS o 21.2 months and 13.4 diarrhea that is inadequately controlled by SSA.
CONCLUSION may all play roles in improving quality and quantity o

lie or the patient. Despite recent advances in targeted
Multidisciplinary diagnosis and management o therapy or GEP-NETs, these tumors remain challeng-
patients with GEP-NETs is essential. For localized ing to treat and remain lie limiting or many patients.
disease, early and clear communication between the Ongoing studies o targeted agents, PRRT, and immu-
surgeon and the pathologist is required or appropriate notherapy will hopeully continue to advance our
prognostication and treatment. Advanced NETs pres- understanding o the biology o these diverse dis-
ent dierent challenges, and surgeons, interventional eases while bringing needed therapies to this growing
radiologists, medical oncologists, and endocrinologists patient population.

J A thin-slice, multiphasic CT scan is required or event, such as 6 to 12 months. It is common or stud-
PNETs being considered or surgical resection. ies read with limited comparison to underestimate
J Jejunal and ileal NETs are resected using an open or overestimate NET growth.
approach to allow or careul palpation o the entire J NEC is undamentally distinct rom NET and requires
small bowel because small, multiocal tumors are very diferent management, principally aggressive
Chapter 34
common. chemotherapy.
J Hepatic metastases are commonly treated with J With the wide variety o systemic and locoregional
resection when all visible tumors can be saely treatment options or patients with advanced dis-
resected. ease, it is always helpul to ask i the intensity o a
J NET growth over time is best gauged with imaging proposed approach is appropriate or the pace,
over longer time intervals since the last progression volume, and biology o disease.
22. Rindi G, Klimstra DS, Abedi-Ardekani B, et al. A common clas-

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Contributors xi 9. aggrssv B-Cll Lyphos 191

Vi GaSTROiNTeSTiNaL 39. Ovrn Cncr 897

29. Blry Trct Cncr 647 ix GeNiTOuRiNaRY

44. Blddr Cncr 1027 55. Cncr Gnocs 1283

45. Prostt Cncr 1049 56. ino-oncology 1297

46. Pnl Cncr 1071 57. Trgtd Thrpy n Cncr 1323

NeuROLOGiC TumORS 59. Fngl inctons n Ptnts wth

61. Oncologc ergncs 1407

62. Oncocrdology 1435

xiV SuPPORTiVe aND PaLLiaTiVe

52. Th acqrd inodfcncy 66. intgrtd Otptnt

53. Crcno o unknown Prry 1253 67. Rhbltton 1529

54. Pdtrc Cncrs 1271 68. Pn mngnt nd Sypto

70. Bg D nd Mhne Lernng

69 . sl Degn fr onlgy clnl 71. Vlue-Bed onlgy 1603

Hind Raei, MD Joseph D. Khoury, MD

Elias J. Jabbour, MD William G. Wierda, MD, PhD

Tapan M. Kadia Koji Sasaki, MD, PhD

Elias Jabbour, MD Srdan Verstovsek, MD, PhD

Prithviraj Bose, MD Raphael Steiner, MD

Lucia Masarova, MD Jason R. Westin, MD

Hesham M. Amin, MD, MSc Sergej N. Konoplev, MD, PhD

Luis E. Fayad, MD Gregory P. Kauman, MD

Preetesh Jain, MBBS, MD, DM, PhD Muzaar H. Qazilbash, MD

Sairah Ahmed Samer A. Srour, MB ChB, MS

Carl M. Gay, MD, PhD Amy Moreno, MD

Marcelo V. Negrao Robert A. Wol, MD

Ruth Sacks, MD Shalini Makawita, MD

Yun Shin Chun, MD, FACS Rony Avritscher

Van Morris, MD Bora Lim, MD

Jessica E. Maxwell, MD, MBA Rachel M. Layman, MD

Daniel M. Halperin, MD Lauren P. Cobb, MD

Mariana Chavez-MacGregor, MD Amir A. Jazaeri, MD

Haven R. Garber, MD, PhD Michaela A. Onstad, MD, MPH

Meghan S. Karuturi, MD Shannon N. Westin, MD, MPH

Karen H. Lu, MD Jose A. Karam, MD, FACS

Pedro T. Ramirez, MD Ashish M. Kamat, MD

Andrew W. Hahn, MD Paul G. Corn, MD

Jad Chahoud, MD, MPH Houssein Saa, MD

John de Groot, MD Ravin Ratan, MD

Vinod Ravi, MD Jason A. Willis, MD

Ha Nguyen, MD Zhijing Zhang

Mouhammed Amir Habra, MD Andy Futreal

Branko Cuglievan, MD James P. Allison, PhD

Wafk Zaky, MD Padmanee Sharma, MD, PhD

Richard Gorlick, MD Rabih Said, MD, MPH

Fareed Khawaja, MD Sai-Ching Jim Yeung

Roy F. Chemaly, MD Ellen F. Manzullo, MD, FACP

Jeena M. Varghese, MD Rony Dev, MD

Shalini Dalal, MD Ahsan Azhar, MD

Abdulrazzak Zaria, MD Eduardo Bruera, MD

Saadia A. Faiz, MD David Hui, MD

Horiana B. Grosu, MD Brian Fricke, MD

Lara Bashora, MD An Ngo-Huang, DO

Vickie R. Shannon, MD Ekta Gupta, MD

Kelly A. Casteel Xuelin Huang, PhD

Michael H. Kroll, MD Wei Qiao, PhD

Liang Zhu, PhD Aileen Chen, MD, MPP

FiGURe 4A. FiGURe 4B.

Additional resources to the No. 1 hospital or cancer

1 Acute Lymphoblastic Leukemia

2 Adult Acute Myeloid Leukemia