12/06/2014

Andrew Wei
Alfred Hospital

ACUTE LEUKAEMIA and MDS

National Cancer Institute. SEER Cancer Statistics Review. 1975-2000

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FBE

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BMAT

Normal

Leukaemia

How is AML distinguished from
ALL?

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12/06/2014 Myeloperoxidase Flow cytometry •Rapid diagnosis of AML •Lineage designation •Monitoring for residual disease 4 .

12/06/2014 Flow cytometry Lymphocytes Monocytes Granulocytes Myeloblasts Lymphoblasts •Rapid diagnosis of AML •Lineage designation •Monitoring for residual disease Is t(15.17) an indicator of favorable or adverse outcome 5 .

t(15. abn(17p). -7.12/06/2014 Cytogenetics 100 Survival (%) Favorable inv(16). N=1130 Acute promyelocytic leukaemia 6 .21).9). t(v.11q23) -5/5q-. all other Intermediate inv(3). t(8. complex Adverse 40 20 0 0 1 2 3 4 5 6 7 8 9 10 Time (years) Age 16-60.17) 80 60 normal karyotype. t(6.

q21) was identified (Rowley) 1985 ATRA efficacy reported in 6 cases (Huang) 1992 Arsenic efficacy reported (Sun) APML therapy in Australia Failure-free survival APML4 100 88 % % surviving 80 Arsenic+ ATRA+Chemo 68 % APML3 ATRA+Chemo 60 40 20 p = 0. ALLG 7 .17)(q22.012 0 0 1 2 3 4 5 years from treatment start 6 Harry Iland.12/06/2014 Progress against APML 1957 APML first described (Hillestad) 1973 Anthracycline efficacy 5y DFS 35% (Bernard) 1977 t(15.

-5 4% -7.21) 6% inv(16) 4% abn(3q) inv(3) 2% 1% add(5q).12/06/2014 The cytogenetic gap t(15.22)4% -17/abn(17p) 1% 3% What molecular factors are useful in classifying cytogenetically normal AML? 8 .17) 11% Favourable risk Normal 33% t(8. del(5q). Intermediate 18% Complex 7% Adverse risk add(7q)/del(7q) 6% t(11q23) t(9.

21) Inv(16) Intermediate (60%) Other Adverse (17%) Abn (3q) Inv (3) Del (5q)/-5 Del (7q)/-7 t(11q23) t(9. 369:1472-1473 Recurrent somatic lesions in AML N Engl J Med 2013.12/06/2014 Genetic architecture of AML Mutation Karyotype FAB De novo (85%) M0 M1 M2 M3 M4 M5 M6 M7 Secondary (15%) MDS MPD Favourable (23%) t(15.17) t(8. Blood 2010 Mutation Freq. 369:1472-1473 9 . in AML (%) DNMT3A NPM1 FLT3 TET2 RUNX1 IDH2 CEBPA IDH1 TP53 NRAS WT1 KIT PTPN11 KRAS U2AF1 SMC3 SMC1A 29 28 27 15 11 10 10 10 9 8 7 5 5 4 4 4 4 N Engl J Med 2013.22) -17/abn(17p) Complex (≥4 abn) Grimwade.

NPM and CEBPA in normal karyotype AML % Overall survival 100 P<0.12/06/2014 Prognostic value of FLT3-ITD.3) AML (megakaryoblastic) with t(1.16) AML / APL with t(15. inv(16) and t(16. 2008 WHO classification in AML • AML with recurrent genetic abnormalities AML with t(8. N Engl J Med.11). AML with inv(3)  and t(3.21). AML with t(6.9).0001 80 CEBPAmut 60 No transplant NPM1mut/FLT3-ITDneg 40 Consider transplant 20 FLT3-ITDpos / triple WT 0 0 1 2 3 4 5 6 7 8 9 10 Time [years] Schlenk .22) AML with NPM1 AML with mutated CEBRA • AML with Myelodysplastic Related Changes AML with multilineage dysplasia AML with poor risk CG • Myeloid Sarcoma • Therapy related AML • Myeloid proliferation related to Down Syndrome • Acute Leukemias of Ambiguous Lineage 10 .17) AML with t(9.

12/06/2014 How is FLT3-ITD detected? FLT3-ITD 11 .

12/06/2014 CEP701 PKC412 Sorafenib AC220 Ligand FLT3 JMD NPMc Frequency in NK‐AML: 35%  Brunangelo Falini. 254 WT MUT 12 . NEJM 2005.

12/06/2014 In which subset is p53 mutation common in AML? p53 mutations associated with adverse risk  karyotype AML Vera Grossmann. Blood 2012 120: 2963-2972 13 .

12/06/2014 How is complete remission (CR) in AML defined? CR < 5% marrow blasts De novo AML (≥20% BM blasts) Myelodysplastic syndrome Myeloproliferative syndrome (ET. PRV. MF. CML) Secondar y AML CMML Previous chemotherapy Previous radiotherapy Therapy related AML I N D U C T I O N C O N S O L I D A T I O N C O N S O L I D A T I O N A L L O G R A R F I T S K I F H I G H 14 .

IVI Daunorubicin 45 mg/m2 x 3 days Complete remission achieved in • 5/8 (untreated AML) • 2/8 (previously treated) J. by cont. 57 (1973) 485–488 15 . Rep. 75 (1967) 951–955 Ellison and Holland. Acute Leukemia Group B J Yates. Cancer Chemother.12/06/2014 What drugs are used for the treatment of AML? Evolution of “modern chemotherapy” for AML Regimen 6-MP and PNL Daunorubicin 45mg/m2 x 3d Ara-C 100 mg/m2 IVI x 7d CR 0% 25% 25% Ref MRC 1966 Bernard 1967 Ellison 1968 7+3 in 1973 Yates and Wallace 16 patients Cytarabine 100 mg/m2 x 7 days. Presse Med. Bernard.

896 Who should receive an allogeneic stem cell transplant in first remission? 16 .5 x4 Mayer RJ.3. 1994.12/06/2014 HiDAC consolidation improves OS in younger AML 7+3 R Ara-C d1-5 200mg/m2 IVI x4 Ara-C (d1. N Engl J Med.3. et al.5) 400mg/m2 bd x4 HiDAC 3g/m2 bd d1.

 –7.9).11) Other CG ADV inv(3)/t(3. ASH 2011. abn(17p). no SCT CR1 INT-II INT-I Krzysztof Mrózek.  t(v. –5 or  del(5q). Blood 2010.q23). t(6.11)(v. 414 Allogeneic stem cell matching 17 . t-AML excluded) ELN (Döhner.12/06/2014 ELN classification in de novo AML (APML. s-AML.  complex karyotype CALGB n=1550.3).  453) FAV CBF NPMc CEBPAm INT‐I FLT3‐ITD+ FLT3‐/NPM‐ INT‐II t(9. <60y.

12/06/2014 Which acute leukemia is most likely? 18 .

12/06/2014 ALL: main subtypes – B‐cell ALL / precursor B lymphoblastic leukemia – T‐cell ALL / precursor T lymphoblastic leukemia  ALL incidence is bimodal 7 Males Females 5 4 3 2 1 0 0–4 5–9 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85+ Age-specific incidence rate 6 Age group at diagnosis Australian Institute of Health and Welfare 19 .

12/06/2014 ALL outcomes for adult regimens Regimen N Age (med) TRM (age) CR OS (age) Ref HyperCVAD 288 15-92 (40) 2% (<60) 15% (>60) 92% 51% 5YS (<40) 30% (40-59) 17% (60+) Kantarjian. Cancer 2004. 930 Minimal residual disease 20 . 2788 HyperCVAD 53 <60 74% 83% 2YS Xu. Leuk Res 2008.

ASH 2012 21 .12/06/2014 Risk assessment in ALL Genetic architecture of ALL Charles Mullighan.

12/06/2014 Advances in ALL therapy • “Paediatric” approaches improve outcome – L-asparaginase – Less cyclophosphamide – Improved compliance – More dexamethasone – Rituximab for CD20+ ALL – MRD guided stem cell transplant decisions What is the management of Ph+ ALL 22 .

Lancet 2000 What are the limitations of TKI therapy for Ph+ ALL? 23 .12/06/2014 Imatinib: molecular‐targeted therapy  for Ph‐positive ALL Imatinib: blocks abl function by interfering with ATP binding Bcr-Abl Substrate P P P ATP P Y = Tyrosine P = Phosphate Goldman et al.

12/06/2014 “Gatekeeper mutation” Are there any new treatments for B-ALL? 24 .

12/06/2014 Blinatumomab What is the diagnosis? 25 .

12/06/2014 MDS • Concepts – Clonal disorder of stem cells – Ineffective hematopoiesis – Transformation to AML WHO classification of MDS 26 .

12/06/2014 IPSS R-IPSS 27 .

Lancet Oncol. 2009 AZA-001 Phase III Study: Azacitidine improves OS compared to CCR (supportive.4 15 months AZA 0.7 0.3 CCR 0.0 Proportion Surviving 0. 7+3.2 0.6 24.1 0.8 0. LDAC or high dose chemo n = 179 Fenaux P et al.5 0. low dose Ara-C) 1.0 0 5 10 15 20 25 30 35 40 Months • Transfusion independence (50%) • Improves quality of life • PBS for int-2 and high risk MDS (Feb 2012) Pierre Fenaux.12/06/2014 Randomised trial of azacitidine for MDS Azacitidine + BSC Int-2/high risk MDS R A N D O M I S E (75 mg/m2/day x 7 days SC q28 days) n = 179 BSC. Lancet 2009 28 .4 months 0.9 0.

12/06/2014 What mutation is linked to RARS? Emerging new MDS mutations Histone modifications DNA methylation mRNA splicing Wahab. ASH 2013 29 .

146) (SETBP1) (PTPN11) (JAK2 V617F) 5q‐ Syndrome The 5q-syndrome is characterized by: •Macrocytosis • Anemia •Thrombocytosis •Erythroblastopenia •Megakaryocyte hyperplasia with nuclear hypolobation •Interstitial deletion of chromosome 5 •Females of advanced age •Low risk of leukemic transformation •Responds to lenalidomide – 60% transfusion independence 30 .12/06/2014 WHO classification of MDS (SF3B1) (RPS-14 and miR-145.

ALL.12/06/2014 Conclusions • AML. MDS morphologic syndromes • Therapy to date empirical • Morphologic entities undergoing transformation by genomic insights • Future goals will be the development of less toxic targetdirected therapies 31 .