The MD Anderson Manual of Medical Oncology 4Th Edition Hagop Kantarjian Full Chapter

The MD Anderson Manual of Medical
Oncology 4th Edition Hagop Kantarjian

Visit to download the full and correct content document:
https://ebookmass.com/product/the-md-anderson-manual-of-medical-oncology-4th-ed
ition-hagop-kantarjian/
The MD Anderson Manual
of Medical Oncology
Notice
Medicine is an ever-changing science. As new research and clinical experi-
ence broaden our knowledge, changes in treatment and drug therapy are
required. The authors and the publisher o this work have checked with
sources believed to be reliable in their eorts to provide inormation that is
complete and generally in accord with the standards accepted at the time o
publication. However, in view o the possibility o human error or changes
in medical sciences, neither the authors nor the publisher nor any other
party who has been involved in the preparation or publication o this work
warrants that the inormation contained herein is in every respect accurate
or complete, and they disclaim all responsibility or any errors or omissions
or or the results obtained rom use o the inormation contained in this
work. Readers are encouraged to conirm the inormation contained herein
with other sources. For example and in particular, readers are advised to
check the product inormation sheet included in the package o each drug
they plan to administer to be certain that the inormation contained in this
work is accurate and that changes have not been made in the recommended
dose or in the contraindications or administration. This recommendation is
o particular importance in connection with new or inrequently used drugs.
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
Copyright © 2022 by McGraw Hill, LLC. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no
part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without
the prior written permission of the publisher.
ISBN: 978-1-26-046765-9
MHID: 1-26-046765-1
The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-046764-2,
MHID: 1-26-046764-3.
eBook conversion by codeMantra

Version 1.0
All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked
name, we use names in an editorial fashion only, and to the benet of the trademark owner, with no intention of infringement of the
trademark. Where such designations appear in this book, they have been printed with initial caps.
McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corpo-
rate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com.
TERMS OF USE
This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject
to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may
not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate,
sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your
own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if
you fail to comply with these terms.
THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WAR-
RANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING
THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR
OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED
TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education
and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its opera-
tion will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any
inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no
responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/
or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or
inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply
to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.
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
This page intentionally left blank
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
Another random document with
no related content on Scribd:
painted in alternate bands of black and white, occasionally red and
white, and resembles a barber’s pole more than anything. The
“Djundagalla” stands in the centre of the cleared space and the rites
are performed around it. In the northern Kimberleys, we find a stone
phallus taking the place of the pole.
It is not every tribe that submits its young men to these mutilations
at the initiation ceremonies. There are some which institute great
graduation-festivals without the infliction of bodily harm to the virile
aspirants. Notably among these are the Larrekiya, Melville Islanders,
and the tribes living along the coast from the King River to the heads
of the Roper and East Alligator Rivers.
As an illustration of a tribe which celebrates the coming of
manhood without resorting to operative measures, the Larrekiya
perhaps serve best. The boy, when definite signs of adolescence
manifest themselves, is decorated with the kapok of the silk cotton-
tree (Bombatt malabaricum) and birds’ down. A straight band passes
below his eyes from ear, and the ends thereof are connected by
means of a horseshoe-shaped figure traversing the cheeks and
having its closed end at the chin. Another horizontal band extends
from shoulder to shoulder, above the nipples, and from this two
symmetrical lines are constructed down the abdomen and on to the
thighs, where each terminates in a circular band around the knee. A
white line is also drawn down the outer surface of each upper arm
and is made to end in the plaited armlets worn above the elbow. His
forehead is decorated with a broad band consisting of a number of
parallel strands of opossum fur thickly besmeared with white
pipeclay; in the middle of this is stuck a plume of emu or heron
feathers, and fur-tassels pend from either side of it. He also wears a
coiled bark belt and, over it, a human hair girdle supporting a large
pubic tassel.
The initiates are made to sit in a row before the old men and are
instructed to keep their eyes closed with their hands. The old men
stamp the ground wildly and brandish their spears poised in the
spear-throwers. Every now and then they utter harsh cries of “Arr-re!
Arr-re!” and “Gora!” Whilst this pandemonium is in full swing, the
boys are ordered to open their eyes and behold their elders
performing; then they are led away into the bush and have to wait on
the men, having especially to collect for them many things that are
good to eat. During this period they are often cowed by being struck
between the shoulder-blades, and threatened with violence if at any
time they talk publicly about anything that has transpired or in any
way betray the trust which the old men have placed in them. Upon
their return to camp, the young men have additional scars cut into
the skin of their chest and are then entitled “Böllier” which signifies
that the first stepping stone to maturity has been passed.
A second ceremony takes place some years later. Each youth is
then under the individual charge of an old man and is decorated
much the same way as the Böllier candidate described above, with
the distinguishing features of four red ochre stripes across the white
forehead band and an extra plume of white cockatoo feathers stuck
into his hair. The proceedings start soon after sundown and last till
about midnight; they include much gesticulation and vociferation. At
the solemn moment when the “conferring” of the maturity-degree
takes place, the youth, still tended by the old man, remains
motionless, with downcast eyes, and listens to the melancholy chant
rendered by the old men in low lagging accents:
“Makolär manga, malolär, ä, är, maklär, immanga.”
No beating of sticks or clapping of hands accompanies this tune,
and no further ceremonial dance follows.
The youth has now been elevated to the status of “Mollinya” which
qualifies him to the full rank and privileges of manhood. Further
cicatrices may now be added to either side of his abdomen. The cuts
are horizontal but do not extend right up to the median line.
During the period intervening between Böllier and Mollinya
festivals, bustard, flying-fox, and yam are forbidden articles of diet,
but after the latter event the fledgelings are invited to eat with the old
men. They honestly believe that if any of the young men, while
undergoing initiation, ate one of the forbidden articles secretly, the
medicine man would be able to detect the food in his stomach; and
having thus disobeyed, the medicine man would be justified in
running a spear through the offender, or at any rate compel him to
swallow certain things which would poison him. These rules are
strictly observed, and, whenever some of the privileged members
have eaten flying-fox or bustard, they take the precaution to collect
the bones and burn them.
The tribes on Nullarbor Plains will tell you that the initiation
ceremonies originated in the following way. Many, many years ago,
the emu and the kangaroo were more or less human in appearance
and possessed of mighty powers. One day the emu caught the
kangaroo with the object of making a man of it. But the great
struthious bird had no hands wherewith it might have performed an
operation; all it possessed was a “finger” on each side of its body. It
might be explained that the emu, because it cannot fly, is not
regarded as a “bird” in the generally recognized sense, and
consequently the wings are looked upon as “fingers.” In most of the
vocabularies, indeed, no distinction is made between “finger” and
“hand,” the south-western tribes of central Australia referring to one
or the other as “marra.” Nothing daunted, however, the emu removed
the præputium from the kangaroo by clutching it between its wings
and pulling it off. Thereupon the emu said to the kangaroo: “Will you
make me a man?” And the kangaroo replied, “Yes.” The kangaroo
had the advantage over the emu because it possessed five “fingers,”
with which it could perform the operation the right way. The animal
caught hold of the bird and circumcised it with a sharp splinter of
flint. But the emu requested to be further operated upon and so it
came about that the kangaroo decided upon a subincision. To the
present day the emu retains the marks of this operation. Some while
after these happenings, the tribal fathers ran across the sacred emu
and noted the change in its anatomy; they forthwith mutilated each
other in a similar way, and only then did they realize that they were
men.
Not boys alone are required to submit to the various initiation
ceremonies here mentioned, but in most tribes young women are
“made” marriageable by having to submit themselves to ordeals
which are quite similar to those of manhood’s approbation.
While discussing the female breast, we noted that when it begins
to develop a girl is taken away by the men and the breast anointed
and sung to, to stimulate its growth. This procedure is the forerunner
of initiation. The girl’s development is forthwith watched with care,
and when the unmistakable signs of ripening are detected the event
is celebrated with dance and song.
Men and women attend, and the items rendered are more or less
of the nature of an ordinary corrobboree, although occasionally some
special feature characterizes the performance. For instance the
Larrekiya and Wogait tribes pass the girl through a “smoking”
ceremony after the following fashion. An old gin places herself
behind the girl and lays her hands upon the latter’s shoulders. Then
all the other women taking part form a continuous chain by standing
in a single row behind each other and “linking up” in a similar way.
They begin to sing “Ya, Ya, Ya,” in a long-drawn melancholy note,
and the old-gin immediately stamps her feet, and, moving forwards,
pushes the girl along in front of her. All the other performers follow
her, stamping in unison and holding on to the shoulders of the
person in front. Quite unexpectedly the monosyllabic “Ya” is changed
to “Yen da min,” and at this the old gin stops short and strikes the
girl’s back thrice with her hand. The same performance is repeated
time after time during the night. Early in the morning of the next day,
the girl is led to the sea, and the whole party wades out to about
hips’ depth. Here a grotesque dance is started during which they
strike their arms, bent in the elbows, against the sides of their bodies
under water, the splash producing a peculiar hollow-sounding note.
The process reminds one of a goose flapping its wings while
enjoying a bath. At this stage, the wording of the song sounds like
“A-lö-lö-lö,” and when its final syllable has resounded, all bathers
duck under the surface of the water.
Next a fire is kindled upon the shore, and, when a good blaze has
been obtained, a heap of grass and leaves previously steeped in
water, is piled upon it. Upon this the old gin seats herself and makes
the girl sit upon her lap facing her and with her legs astride. The
volumes of smoke which are generated completely hide the two from
view. The idea is to allow the smoke to thoroughly play upon the
parts of the novice, the process being facilitated by the manipulation
of the old gin. When the ceremony is concluded, the girl is led into
the bush by the old women and for some time to follow she is not
allowed to partake of certain articles of diet, such as for instance
snake, dugong, and goanna.
Several of the northern and north-eastern coastal tribes mutilate
the hand of a young gin during the period of her initiation by
removing two joints from a finger. The forefinger of either hand is
generally chosen by the former tribes, the latter favouring the small
finger. The Ginmu at the mouth of the Victoria River make the
amputation with a stone knife. In this district a singular case came
under my notice which is of considerable interest from an evolutional
point of view since it suggests a phenomenon usually only met with
in crustations, reptiles, and other creatures whose position is very
much lower in the animal kingdom. A young girl had had two end
phalanges of a finger imperfectly removed, and yet upon the
mutilated stump a horny growth resembling a diminutive finger-nail
had formed anew. The Daly River tribes remove the bones by tying a
ligature of cobweb which they find in the mangroves very tightly
around the joint. The end phalanges of the finger, thus deprived of
the circulation, gradually mortify and drop off. Occasionally the joints
may be bitten off by a parent of the child.
As a general rule, it may be said that wherever mutilations of the
male are undertaken during initiation ceremonies, a corresponding
operation is performed upon the female; and, vice versa, where the
former practice is not indulged in, the latter is also unknown.
Generally speaking, too, the female mutilation ceremonies are much
the same wherever practised in Australia, but the implements or
devices employed for the actual mutilation vary in different localities.
Invitations to the event are sent by special messengers to
adjoining groups and neighbouring friendly tribes. These
messengers are of mixed sexes and are decorated by having their
bodies covered with ochre. The common method is to make the
ground colour of the body a rich red and to draw upon it concentric
circles of white and black. The men carry a “female” tjuringa, whilst
the women, apart from numerous necklaces and armlets which they
wear, are unaccoutred. The latter are near group-relatives of the
young woman concerned. Their mission is readily understood by the
people they look up during their walk-about, and, without much
interchange of words, acceptance is indicated by the recipients of
the message by resorting to an intimacy with the feminine
emissaries. Although considerable liberality is shown during this
indulgence, the privilege is by no means stretched to beyond the
bounds of a tolerable promiscuousness, even though the
messengers may be entertained at the distant camp for two or three
days before they return home.
The celebrating camp in the interim has been busily preparing for
the approaching event. Nightly corrobborees have been held at the
chosen spot by both the men and the women, and the novice has
repeatedly appeared before the performing crowd richly decorated
and besmeared with emu-fat and ochre. At no time, however, even
after the invited guests have arrived, does the excitement become
anywhere near as great as during the initiation ceremonies of the
opposite sex; in fact, at its best, the performance is extremely dull
and monotonous.
When at length it becomes apparent that even the principal actors
themselves are tiring, it seems as though the moment had arrived
when only a desperate decision could revive the enthusiasm. A
number of men, who stand in the same group-relationship to the
novice as her future husband, lead the girl away without any ado,
except perhaps that the remaining members slightly spur their
acting. This stage is mostly reached at daylight, as often as not early
in the morning, after the whole night has been spent in dancing and
singing.
Away from the din of her tribespeople’s celebration in honour of
the occasion of her stepping from girlhood to womanhood, the silent
victim is told to squat on the ground whilst the men surround her. Her
oldest “group-husband” produces a flat, wooden tjuringa, of the
“male” type, with which he several times touches her person, whilst
he mutters incoherent and garbled words. This is done to dispel from
her all possible pain and likely loss of blood during the operation she
is about to be submitted to.
Then she is requested to lie flat on her back, and her head is
placed upon the lap of one of the men who squats to keep it there. It
follows the act which is destined to make her marriageable; her
virginity is doomed to mechanical destruction.
The instruments, if any, which are used for the operation vary
according to locality. In the central areas (Aluridja, Wongapitcha,
Kukata), an ordinary stone-knife with resin haft is used. The Victoria
desert tribes employ cylindro-conical stones from six to eight inches
long, and from one and a half to two inches in diameter. Among the
tribes of the northern Kimberley districts of Western Australia no real
instrument is used at all, but the operator winds the index and middle
fingers of his right hand together with a long piece of fur-string; and
this device answers the same purpose as the above-named
instruments.
The tribes indulging in this practice admit that their action is
prompted by a desire to offer the girl’s pudicity to one of her spirit-
husbands. We might indeed look upon this rite as the equivalent of
sacrificing the jus primae noctis to a mythical or legendary tribal
relative who is supposed to be living in the astral form and who is
likely to come back to earth at any day.
PLATE XXXII
An episode of the great fire ceremony, Kolaia tribe.
“Presently the music starts again, and the spirit known as ‘Ngardaddi’ is seen to be
stealthily creeping towards the fire, his body lying flat upon the ground and his legs
dragging behind.”
CHAPTER XXVII
RELIGIOUS IDEAS
Religious instincts of aboriginal—Nature worship—Fire ceremony—Fire legends—

Mythical fire thief called “Ngardaddi”—Water legends and ceremonial—Sun
worship—Sun myths—The moon man—The mythical serpent—The kobong
and totem—The tjuringa—Tjuringa legend—Ancestor worship—“Knaninja” or
“Totem” deities—The significance of the tjuringa—Sacred tjuringa caves
—“Totemic” diet restrictions—Gradation of sacred ceremonial—Great emu
ceremony—The “Altjerringa”—The sacred yam or “Ladjia” ceremony—The
“Etominja” design—Sex worship—The phallus—Mythical origin of phallus—
Ideas concerning procreation—Grey hairs blackened artificially—A phallic
monolith known as “Knurriga Tjilba Purra”—Foetal elements or “Rattappa”—
The “Tjilba Purra” embodied in the headgear—“Waraka,” a phallic stone on
the Roper River—Similar Kukata legend—Phallic ceremonial on Cambridge
Gulf—Cylindro-conical stones of phallic significance—Matronal chasm of
Killalpaninna—“Arrolmolba,” a sacred stone possessing stimulating principles
—Phallic drawing of “Mongarrapungja”—Evil spirits—Disenchanted
enclosures—Aboriginal belief in Supreme Being—Etymology of His name—
The eternal home of all deities and spirit ancestors.
It has often been written that the Australian aboriginal is without

religious ideas and without religious ceremonies. Such assertions
are grossly incorrect and by no means portray the psychological side
of the primitive man in its true light. He has, on the contrary, religious
institutions and obligations which verge on the basis of all modern
conceptions and recognition of divine supremacy. If we can class
Nature-worship, Ancestor-worship, and Sex-worship as the
beginnings of all religious teachings, then the Australian aboriginal
has certainly inherited by instinct and tradition a very solid foundation
from which we might trace the origin of many, if not most, of our most
sacred beliefs in Christianity. At the same time, it must not be
forgotten that it is really a difficult matter to distinguish clearly
between mythological beliefs and what we class as religion.
Religious thought has fluctuated with the advance of civilization and
science to such a degree that, even within the short space of time
covered by the more reliable records of our history, several
revolutionary modifications have come about. As time advances,
man becomes more sceptical and more exacting in his demand for
proofs, and in his despair over finding nothing tangible to worship, he
resorts to the recognition, by instinct or persuasion, of a God who is
a Spirit. But all the while, as this secular metamorphosis is
proceeding, he keeps his innermost feelings and faith alive by
appealing to his knowledge of the gospel or his belief in salvation, in
the manner it was presented to him by myth, by legend, or by the
Scriptures. His principal guide is his intellect; the less it is trained the
stronger his inherited conviction; the more scientific it becomes, the
greater his desire to probe the truth.
The modern man has so accustomed himself to an artificial
environment that he takes the so-called “elements” of Nature,
especially water and fire, in a strictly matter-of-fact sort of way. But
the primitive man, who realizes that his very existence is dependent
upon these factors, has learned to respect, preserve, and worship
them as legacies he imagines to have been left him by some of his
illustrious forbears who, he supposes, have gone to an unknown
realm where they live in peace and can only return temporarily to
their former haunts in the invisible form or through the medium of
some other object which is related to the individual in some
mysterious way.
The aboriginal looks upon fire as one of the great indispensible
quantities of his social existence; it is the element which dispels the
evil spirits from his camp; it is the means by which comfort and
friendship are made accessible to him; it is his universal companion.
More than this, it is the fire, with its warmth and its light, which draws
individuals, families, groups, and tribes together and through its
agency and influence that social concourse is established which lies
at the bottom of all conviviality, oracular discussion, and ceremony.
How well this sentiment agrees with the knowledge we possess of
the origin of civilization! Indeed the appreciation of fire together with
the knowledge of its preservation is perhaps the mightiest factor
responsible for making our species human. Once man learned to
nurse an original flame he found through accidental cause and kept
it constantly by his side, his progress became an established fact.
His crude camp-fire talks developed into discussions which he
further expanded by means of drawings on the walls of caves he
occupied. The free exchange of thought brought about by
congregation round the cheerful flame could not fail to incite the
intellect; and thus he ascended to the high road of civilization and
gathered the fruits of culture he now enjoys.
The Aluridja, Wongapitcha, and some of the north-western coastal
tribes believe that many years ago, a party of ancestral creatures,
more animal than human, came down from the sky through the
branches of tall gum-trees to confer with the spirits which roam about
at night and conceal themselves in inanimate objects during the day.
These monsters brought a fire-stick with them and when they
reached the earth, they lit a fire to cook some grubs which they had
taken from the bark of the trees during their descent. As they were
feasting, the spirits called them and they went with them to a cave
where the bones of the persons rested, originally occupied by the
spirits themselves. Whilst they were away, the fire which had been
left unguarded, decided to run into the bush and, being in a
mischievous mood, started an enormous blaze which burned down
much of the forest and the tall gum-trees as well. The spirit-
ancestors and the heavenly monsters beheld the disaster with
consternation and called upon the fire to come back. This it did. But
it so happened that some of the tribes’ fathers were hunting in the
area, and when they saw the fire, which was strange to them, they
snatched portion of it away and ran with it to their camp, where they
kept it and fed it with dry grass and sticks. The spirits and their
visitors were very angry and never left the fire out of their sight, lest it
might abscond again; they were compelled to live on earth for a very
long time until the trees grew up again to their lofty domain. The
hunters, on the other hand, zealously guarded their prize fearing that
it might run away from them. Even to the present day, this belief
exists among the older folks, and they always take great care that
the ground is cleared of inflammable matter to stop the fire from
bolting; to be on the safe side, they invariably carry or keep near to
them a fair-sized, glowing fire-stick.
Among the Minning this legend is circulated in a slightly modified
form. Two ancestral spirits had their fires burning in the sky at points
represented by the pointers of the Southern Cross constellation,
when one day they decided to come down to the earth to hunt
opossum. They took their fires with them, but while engaged in the
chase they left them at their camp. When they had obtained a
sufficient number of opossums to make a good meal, they returned
to their camp, where they noticed six young men sitting around the
fires, who immediately made off, and, in doing so, each took a fire-
stick away with him. The spirits gave chase and re-captured five of
the thieves, but the sixth, who was named “Warrupu,” reached the
camp of his tribe and handed the fire-stick to his mother, “Wenoinn.”
The woman ran with it to the white sand hills about Eucla in which
she intended hiding it. But the spirits had noticed her and came
towards her from above with a spear. In her predicament, the woman
threw the fire-stick away, which immediately set the whole of the
country ablaze between Eucla and Israelite Bay. All the tribes were
thus enabled to seize some of the fire which they have carefully
watched over ever since.
PLATE XXXIII
Ceremonial venesection, Arunndta tribe.
1. The median basilic vein is being slit. Note ligature above the biceps.
2. The blood which is spurting from the incision is being collected on a shield.
A similar tradition is perpetuated by the north-western tribes

referred to and affords the motive of one of the most earnest and
sacred fire-ceremonies known in Australia. The performance takes
place during the night. It is introduced by two men; the one
represents a mischievous spirit trying to steal back the sacred fire
which is being carefully guarded by a number of men impersonating
the ancestral tribesmen who originally discovered it; the other is a
warrior who has accidentally come upon the would-be thief and
overpowered him. The spirit crouches at the feet of the warrior,
sitting upon his heels, with his head drooping upon his chest and his
hands hanging loosely between his thighs. The warrior stands erect
behind his supposed captive, with his legs apart, and continues
striking the fellow with small bundles of brushwood, one of which he
holds in either hand. The beating is done regularly, both hands rising
simultaneously, high above the warrior’s head, and falling together
upon the spirit’s head.
Some two chains away, the tribal ancestors are grouped by the
fire-side and are chanting the following lines:
“Wai dang bunnai,

Inna dinna dulla ngai.”
The men sit in a row at the back of the fire, with their thighs asunder
and their legs bent in the knees; their chins are resting upon their
chests whilst they beat the backs of their heads with small bundles of
brushwood, keeping time with their song and with the performance of
the warrior.
When, after a while, the music ceases, the warrior is seen to be
lying asleep beside his captive. The ancestors become restless and
begin to move sideways, first in a body to the left and then to the
right; then they move backwards and forwards. This movement is
peculiarly weird since the performers do it by shuffling over the
ground in the sitting posture, with their arms held erect, but bent in
the elbow.
Presently the music starts again, and the spirit known as
“Ngardaddi” is seen to be stealthily creeping towards the fire, his
body lying flat upon the ground and his legs dragging behind. He
advances very slowly, turning his face towards the ground, in search
of the fire which escaped from heaven. He wears a tall head-dress
quite thirty-two inches long, which consists of a tightly fitting
hemispherical cap carrying a column in its centre, at the top of which
a bundle of split black-cockatoo feathers is attached. The feathers
are from the male bird’s tail, and the brilliant red patches in them are
representative of fire. The whole structure is made of paper-bark and
human hair-string, the outer surface being decorated with ochre,
pipeclay, charcoal, and vegetable-down. Vide Plate XXXII.
All the time the men at the fire-side are beating time with their
hands and simultaneously turn their heads from side to side, to all
intents and purposes quite unconcerned about the Ngardaddi who is
gradually crawling near to them. This is done to entice the thief
nearer and lead him to believe that he is unobserved. All of a
sudden, however, when the spirit is about to touch the fire and is in
the act of snatching it from the tribesmen, one of the group on either
side of the fire throws a handful of dry grass upon the smouldering
heap. The flame responds immediately and casts a bright light all
around.
Alarm is raised by the tribesmen by clapping their hands together
violently. The spirit collapses and lies flat upon the ground at full
length. Two or three of the men nearest by seize some of the burning
grass and hit the prostrate figure over the head. The spirit jumps to
his feet and treads the ground as if endeavouring to make his
escape. Seeing this, the men at the fire rise quickly and treat their
victim most unmercifully with bundles of burning grass and twigs.
Eventually each of them seizes a fire-brand and digs the burning end
deeply into the spirit’s back and the unfortunate fellow eventually
decamps into the darkness amidst the bellowing whoops of his
victors.
The air is fouled for some distance around by the smell of the
burned skin, reminding one of the stench in a smithy when horses
are being shod. The back of the spirit-impersonator is naturally
severely scored by the cruel treatment it is subjected to, but the
fellow takes it all in good faith and without flinching.
The object of the ceremony is twofold. Firstly all members of the
community who are present, men, women, and children, are taught
to appreciate the value of fire, and secondly it is believed that the
exemplification of so harsh and drastic a treatment for attempted
theft will tend to make abortive any schemes of the evil spirits.
The Arunndta are quite convinced in their own minds that in the
days of their tribal fathers there was no water on the surface of the
ground they occupied; their ancestors in those times were compelled
to live on grass and succulent plants, no consideration being given to
the fact, as we have learned, that the vegetation derives its moisture
from outside sources. But it happened one day, when their
forefathers were out hunting, that they met with a number of strange-
looking men who were sitting around a pool of pure water from which
they were drinking. At the sight of the men, the strangers fled,
leaving the water behind. The hunters gave chase but all except one
disappeared and he made for a cave in the hills. The hunters closed
the mouth of the cave with a big stone and went back to the pool of
water to quench their thirst, but when they reached the spot, the
water had turned into a massive, round stone. The men made back
to the cave and removed the obstruction, but imagine their surprise
when they found the cave empty. Upon making a careful search,
however, they discovered a long cylindrical stick which had some
peculiar markings on it. They took the stick and walked once more
towards the petrified pool, and, lo, they beheld the stranger they
were looking for walking in the sky. When he saw the stick in the
hands of the hunters, he took the form of a cloud, and as he bent his
body towards the stick, his long matted hair fell forwards and from it
water poured upon the earth beneath. The hunters drank freely of
the precious fluid and when they looked skywards again the
cloudman had vanished.
From that day onwards the Arunndta medicine men (“Nangarri”)
have kept that spot sacred and taboo to the women and children;
they call the big stone “Imbodna” which means “the hailstone.” The
man who fled to the cave and then escaped from the hunters as a
vapour they call “Nangali,” the name for a cloud. The tribe has never
since been without water because Nangali left his magic wand in the
hands of their ancient sorcerers and whenever the country was
suffering from drought they could call upon him to appear in the sky
and bring forth rain.
Nangali is one of a group of celestial beings who have been
termed “Atoakwatje,” that is Water-Men; they are now looked upon
as Demigods who control all terrestrial supplies of water from their
abode in the clouds. The Atoakwatje are believed to have certain
mysterious connections with some of the tribal sorcerers who in a
sense parade on earth as their disciples and attend to the rain-
making ceremonies through which they are able to commune with
each other.
When the people are in need of water, the rain-makers assemble
around the Imbodna and one or two of them produce the sacred
stick, known to the Arunndta as “kwatje-purra,” literally meaning “the
reproductive organ of water,” and to the Aluridja as “kapi-wiyinna.”
Nowadays these sticks, which strictly speaking are of phallic
significance, are flat and more like a tjuringa in shape, and have a
number of peculiar markings on them. For a time the stick is laid
beside the great water-stone, and the sorcerers kneel while they
chant with a barely audible voice. They rise to their feet and the most
influential individual who is decorated with stripes of yellow
vegetable-down and wears a dog-tail tassel on his belt, lifts the stick
towards the sky and continues mumbling. The other members kneel
again and all present chat together. The man who is standing poises
the stick horizontally between his hands and rocks it one way, then
another; and this performance is frequently repeated.
When at length the principal performer sits down, the other men
leave the spot and run in a single file towards the camp, loudly crying
“kurreke ta ta” in imitation of the call of the spur-winged plover.
In the evening a general corroboree is indulged in; and all grown-
up persons, male and female, are allowed to join in. Several refrains
are forthcoming which are connected with ordinary rain or water
festivals. The principal rainmaker does not attend but joins the camp
again during the night. It appears that in the interim he has visited
the sacred cave, in company of one or two of his brother-sorcerers,
to hide the magic stick and preserve it for future use. Any
representative of the Atoakwatje group inherits the power to fashion
and use the rain-stick, but it is imperative that he learns the art under
the direction of a senior and duly qualified nangarri.
A ceremony directly connected with sun-worship belongs to the
old Arunndta people and is known as “Ilpalinja.” When the weather
has been and continues to be unpleasantly cold, and the mating
season of birds and animals has on that account been long delayed,
the men construct a large colored design upon the selected
ceremonial ground. Radiating from a point upon a cleared space,
many lines are drawn with red and white vegetable-down to
represent the rays of the sun; and these are intersected at different
distances from the central point by a number of concentric circles
which represent the fathers of the tribe. The centre of the design is
occupied by a stick which is supposed to incorporate some mystical
and sacred sun-creature known as “Knaninja Arrerreka.” The same
Ilpalinja-design is occasionally carved as the crest of the Knaninja
upon a sun-tjuringa. Vide Fig. 6.
Fig. 6. Sacred sun-design of the “Ilpalinja” ceremony (× 1/20).
A most impressive function might occasionally be witnessed on

the north coast, which is associated with the setting sun; it is known
to at least two tribes, the one living on the upper reaches of the
Victoria River and the other on the western shores of Carpentaria
Gulf, including some of the islands. It is usually performed in
conjunction with demonstrations calling upon a fabulous being which
lives in the sky to fecundate certain species of plants and animals
necessary for their daily life. The Carpentaria tribes, moreover, keep
their sacred poles, akin to the tjuringas of central Australia, not in
caves but in special huts which they construct upon chosen spots
absolutely taboo to the general public. These slabs of wood are up to
five feet long and are covered with peculiar carvings and markings;
they are of the two sexes. Ordinarily they are kept “asleep” by laying
them on the floor of the hut side by side, and covering them with
sand. When the hour of the ceremony arrives, they are brought out
by the “Sun-Men” and stuck in the ground in the full light of the
sinking sun. Just as the orb is about to touch the horizon, the tenders
of the sacred implements kneel, with their faces turned towards the
sun and, lifting their hands, bend their bodies to the ground much
after the fashion of an Eastern salaam. We have before us a true
form of worship recognizing the supreme powers of the sun, but
aimed primarily at calling upon a demigod or Deity in supplication for
making a needed article of diet, animal or vegetable, fruitful or
prolific.
Mythologically the sun is regarded as a female having human form
and a fiery exterior, who walks daily across the firmament and
returns at night to rest at her sacred haunts on earth. Some of the
central tribes, like the Aluridja, split the sun’s identity into an
indefinite number of such women, a different one of which makes the
journey every day.
The moon on the other hand is thought to be a man who originally
inhabited the earth but was one day chased off it by a gigantic dog
the Aluridja call “Tutrarre.” The man jumped into space and walked
among the clouds until he reached the earth again. His long walk
had made him so hungry and thin that he ravenously ate a great
number of opossums which he found in the trees at night. In
consequence he swelled out, and became fat and round. Then it was
his bad fortune to fall in with the dog again, and this time his obesity
prevented his escape. The dog tore him to pieces and swallowed
him, bone and all. But it so happened that one of his arm-bones flew
from the dog’s jaws and found its way to the sky. There it floated
from east to west as a luminous sickle and gradually swelled until it
was perfectly round. The dog stood looking up at the bone and
howled in anger, but the moon-man reappeared in the sky and
converted the dog into stone.
The Kakatu natives believe in a moon-man who lives in the sky
and controls the clouds. On a certain day, very long ago, this man
was seen by the ancestors of the tribe. It happened thus: Just about
dusk, a cloud was observed descending from the sky which came to
rest upon the summit of a hill; it was glowing red. A big man, a
woman, and two girls stepped upon the earth, and the man took a
fire-stick from the cloud which then became black and ascended
again. It was the moon-man and his family. The party walked down
on to the plain and camped, the old man making a fire with his torch
whereby his feminine escort could warm themselves. The moon-man
left, taking a new fire-stick with him. In a deep, green water-hole
lived a monstrous snake whose colour was much like that of the
slime which covered the surface of the water. A lengthy and secret
interview took place between the moon-man and the snake on the
bank of the lagoon, and the snake produced many tubers of water-
lily, and mussels also, for the moon-man to eat. Then the two heard
a rustling noise. The snake exclaimed: “What is that? Who dares
approach our trysting place?” The moon-man snatched a fire-brand
and held it high in the air; this made it light as day. The moon-man’s
daughters could be seen creeping towards the men to hear the
secret discussion! With a curse upon his mouth, the angry father
hurled the fire-stick at his deceitful daughters. The stick struck the
ground and sent a shower of sparks over the girls. In an instant
everything became dark as night, but every now and again there
came from the spot the girls had last been seen at long-drawn
growls; from the same spot flashes of light shot forth and illumined
the clouds. The snake and the moon-man had disappeared, but the
daughters remained just where they had last been seen, for they had
been turned to stone and had assumed the rigid form of a dog
whose head was directed skywards as if to rebuke the moon-man for
the curse he had brought upon them. For a long time the clouds
remained dark; then the moon-man re-appeared among them and
cast a mournful beam upon the canine image of his daughters. From
then till now he has continued to appear periodically in the sky, and
his repentant daughters gaze at him; but at times, when the sky is
covered with heavy black clouds, the daughters become angry and
growl aloud. At these times, too, bright flashes dart from their eyes

The MD Anderson Manual of Medical Oncology 4Th Edition Hagop Kantarjian Full Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

The MD Anderson Manual of Medical Oncology 4Th Edition Hagop Kantarjian Full Chapter

Uploaded by

Copyright:

Available Formats

The MD Anderson Manual of Medical

Oncology 4th Edition Hagop Kantarjian

eBook conversion by codeMantra

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