Evolving Targeted Management of Acute Myeloid Leukemia

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1 Evolving Targeted Management of Acute Myeloid Leukemia Jessica Altman, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University

2 Learning Objectives Identify which mutations should be assessed in a newly diagnosed patient with AML Describe how specific mutations inform prognosis Discuss how these mutations result in potential targeted therapeutic options

3 AML Introduction Estimated new cases/deaths (US) 2015: 20,830/10,460 ~25% will survive 5 years Median age: years Heterogeneity in genetics, clinical manifestations, and outcome Role of stem cell transplantation continues to be refined New targeted agents promising Improvement in outcome in younger adults has been modest; minimal, if any, in older adults SEER data available at:

4 Approach to Newly Diagnosed Patient History and physical (organomegaly, EMD) CBC with differential, chemistry panel including uric acid Smear review PT, PTT, fibrinogen (DIC panel) Bone marrow aspirate and biopsy Morphology Cytogenetics Flow cytometry Molecular studies Hydration, allopurinol or rasburicase, transfusions as needed Risk assessment and HLA typing Discussion of fertility

5 Overall Survival Adults < 60 years

6 Evolution of Prognostic Factors in AML Prior to 1980s 1980s 1990s 1990s 2000s Age, WBC, antecedent hematologic disorder Cytogenetics Molecular genetics (FLT3, MLL, NPM1, CEBPa, c KIT, IDH, TET2 and growing) and interactions

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8 Acute Myeloid Leukemia Approach to Targeted Therapies AML defined by cytogenetic and molecular interactions Prognosis determined by cytogenetic and molecular abnormalities Incorporation of novel agents in relapsed/refractory AML Use of novel agents in newly diagnosed patients?

9 Randomized Trials of Escalated Daunorubicin (90 vs 45 mg/m2) ECOG trial: CR and OS benefit in <50 years, intermediate risk improvement in OS in FLT3 ITD+ pts HOVON trial: CR and OS benefit in years and corebinding factor KSH Trial: CR and OS benefit in intermediate risk UK NCRI trial: No benefit of 90 over 60 (but everyone got 2 nd cycle induction) Fernandez et al. NEJM, 2009; Lowenberg et al. NEJM, 2009; Lee et al. Blood, 2011; Burnett et al. Blood, 2015

10 Distribution of Cytogenetically and Molecularly Defined AML

11 Mutations of Importance in Practice Today 1 Other studies 15 35% Paschka et al. Blood, 2013; Jourdan et al. Blood, 2013

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13 NPM1 Mutation In ~50% of cytogenetically normal AML Higher blast and platelet counts Frequent extramedullary disease, females Low CD34 and high CD33 expression Rarely associated with MLL or CEBPA Favorable prognostic marker for RFS and OS Frequently associated with FLT3 mutations and negates positive effect of NPM1 Dohner K, et al. Blood. 2005;106(12): ; Falini B, et al. N Engl J Med. 2005;352(3):

14 Relapse Free Survival with or without allosct Schlenk RF, et al. N Engl J Med. 2008; 358(18):

15 Allogeneic Transplantation in NPM1 Mutated AML

16 FLT3 as an AML Target Promotes proliferation and blocks differentiation Over expressed in the majority of AML cases Activating mutations present in 25% 40% of AML (ITD and activation loop) Patients with FLT3/ITD mutations have a worse prognosis increased relapsed rate, lower OS Associated w leukocytosis and high percentage of bone marrow blasts, de novo AML Stirewalt DL, et al. 2003;3: Kottaridis PD, et al. Blood. 2001;98(6): ; Frohiling S, et al. Blood. 2002;100(13): FLT3 inhibitors in development; single agent and combination studies

17 Prior Trials w FLT3 inhibitors Pratz KP and Luger SM, Curr Opin Hematol, 2014

18 Setting of FLT3 Inhibitor Studies Grunwald MR and Levis MJ, Seminars in Hematology, 2015

19 Case Deb, 52 year old female, presented to her PCP with a week of fever of 103 F, generally feeling unwell. Because of the persistent symptoms, a CBC is drawn revealing WBC of 196,000/uL, Hgb of 5.7 g/dl, and PLT count of 80,000/uL. She is instructed to go to the Emergency Room for urgent evaluation. At the ER, her exam is notable only for scattered bruises and mild gingival hyperplasia. She is not toxic in appearance. She undergoes bone marrow evaluation.

20 Morphology peripheral blood smear bone marrow core biopsy

21 Data Acute myeloid leukemia involving >90% of a hypercellular bone marrow Flow cytometric analysis: dim CD34 +, dim CD117 +, CD13+, CD33+, and MPO+. Aberrant staining of CD7, but CD2, CD3, CD5, CD79a and TdT Cytogenetics: 46,XX[20] Molecular genetics: Positive for FLT3 Internal Tandem Duplication Mutation, Negative for FLT3 D835 Mutation, Negative for NPM1 Mutation, Negative for CEBPA mutation

22 Treatment Enrolled on C10603: A Phase III Randomized, Double Blind Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High Dose Cytarabine) Chemotherapy + Midostaurin (PKC412) or Placebo in Newly Diagnosed Patients < 60 Years of Age with FLT3 Mutated AML Attained aplastic marrow at day 14 and then entered CR ~ day 28 Matched sibling donor allogeneic stem cell transplant in CR1

23 Post transplant No major transplant related complications Disease recurrence at ~ day 130 as her immune suppression was being weaned

24 ARS Question

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26 What happened to Deb? Treated with sorafenib + 5 aza and disease in remission, underwent DLI and then maintenance sorafenib (has been 3 years since disease recurrence) 43 adults w relapsed/refractory AML treated with 5 aza + sorafenib: RR of 46%, with 27% CRi, 16% CR, and 3% PR Median time to achieve CR/CRi was 2 cycles Median duration of CR/CRi was 2.3 months (range, months) Ravandi F. Blood 2013

27 CBF Compared with other cytogenetic AML groups, CBF AML considered a favorable AML risk group based on high remission rate and survival probabilities However, ~ one half of patients with CBF AML are still not cured Cytarabine consolidation important but optimal dose still not known Paschka P and Dohner K, Hematology 2013

28 Cooperating mutations in CBF: KIT KIT mutations found in 1/3 CBF leukemias KIT exon 17, encodes the activation loop (A loop), and exon 8, encodes a region in the extracellular part of the receptor are most commonly mutated regions Sufficient cooperating second event in the development of CBF leukemias In several but not all studies in t(8;21) AML, KIT mutations, in particular those affecting the A loop, have been associated with unfavorable outcome, the prognostic impact of KIT mutations in inv(16) AML is less clear Rationale to use TKIs to target both overexpressed and mutated KIT. In vitro studies show inhibited growth of cells that express wild type KIT or various KIT mutants when exposed to TKIs Ongoing trials Paschka P and Dohner K, Hematology 2013

29 Retrospective Studies of kit in inv(16) As reviewed in Paschka P and Dohner K, Hematology 2013

30 CBF AML: FLT3 and RAS Prognostic role of FLT3 mutations is not clear; represents another target RAS: 10 20% t(8;21) and 35 50% inv(16); no impact on prognosis

31 C10801: Phase II Study of Induction and Consolidation + Dasatinib in CBF AML 1) DAS+chemotherapy is tolerable 2) Clinical outcomes for CBF pts receiving DAS+chemotherapy remain at least comparable to those historically observed in CBF pts who received chemotherapy alone Marcucci et al. ASH, 2014 Pts on CALGB continue to be followed for survival Support continued evaluation of inhibitors in CBF AML Rapid screening and protocol allocation are feasible within a cooperative group

32 Mutations of Importance in Practice Tomorrow

33 IDH Mutations Associated With Oncogenic Changes IDHwt: catalyzes oxidative decarboxylation of isocitrate to produce CO 2 and KG 3 isoforms exist: IDH1, IDH2, IDH3 - IDH1: cytoplasm - IDH2: mitochondria IDH mutations have neomorphic activity: - Produce oncometabolite 2 HG (gain of function) - Lead to oncogenic alterations in cellular metabolism Adapted from: Prensner JR, Chinnaiyan AM. Nat Med. 2011;17(3):

34 Acknowledgements: Leukemia Program of Northwestern University Northwestern Medicine Developmental Therapeutics Institute ECOG ACRIN j altman@northwestern.edu

35 NCCN Member Institutions