Disclosures. Acute Myeloid Leukemia: The Past, the Present, the Future 9/17/18

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1 Acute Myeloid Leukemia: The Past, the Present, the Future Disclosures Research Support: ASH, A.P. Giannini Foundation, Stanford Cancer Institute Other Disclosures: None 1

2 Learning Objectives AML: the pre-216 era Genomic revolution in AML lead to reclassification of AML Be aware of the common molecular drivers of AML Understand clonal hematopoiesis (CHIP/ARCH) and increased risk for myeloid malignancies Improve awareness of FDA approved therapies for AML Improve understanding of FDA approved and therapies under development into treatment paradigms of AML treatment What is Acute Myeloid Leukemia? 2

3 AML is a Disease of the Elderly % decline 1x increase Age is an important prognostic marker Accessed from SEER Database on 6/22/218 SEER Survival Rates ~44% ~28% ~24% Accessed from SEER Database on 6/22/218 3

4 A General Model of Hematopoiesis and Relationship to AML FAB classification Morphological classification Initially proposed in 1976 with categories of M1-M6 Later expanded to M-M7 by 1985 ELN/WHO/IWG/NCCN Cytogenetic classification Recurrently mutated genes NEJM (26) 354;234 AML: Diagnosis and Prognosis History and physical Age and performance status Previous treatment history Antecedent marrow disorder Extramedullary disease WBC at presentation Bone marrow aspirate and biopsy Wright s stain Flow cytometry MRD Cytogenetics Molecular genetics Prognosis and treatment Establish prognostic group Favorable Intermediate Unfavorable 4

5 21 European Leukemia Network (ELN) Rollig G et al. J Clin Oncol 29:

6 Past Learning Objectives AML: the pre-216 era Genomic revolution in AML lead to reclassification of AML Be aware of the common molecular drivers of AML Understand clonal hematopoiesis (CHIP/ARCH) and increased risk for myeloid malignancies Improve awareness of FDA approved therapies for AML Improve understanding of FDA approved and therapies under development into treatment paradigms of AML treatment 6

7 DNA Sequencing of a Cytogenetically Normal Acute Myeloid Leukaemia Genome Variant (%) * * Primary tumour Relapse tumour Skin * * * * * * * * * * * * * * * * * * 2 CDH24 SLC15A1 KNDC1 PTPRT GRINL1B GPR123 EB12 PCLKC FLT3 NPM1 BRCA2 TP53 Ley T, Nature 28 TCGA-AML 213 7

8 9/17/18 June 9, 216 established in 1812 vol. 374 no. 23 Genomic Classification and Prognosis in Acute Myeloid Leukemia Elli Papaemmanuil, Ph.D., Moritz Gerstung, Ph.D., Lars Bullinger, M.D., Verena I. Gaidzik, M.D., Peter Paschka, M.D., Nicola D. Roberts, B.Sc., Nicola E. Potter, Ph.D., Michael Heuser, M.D., Felicitas Thol, M.D., Niccolo Bolli, M.D., Ph.D., Gunes Gundem, Ph.D., Peter Van Loo, Ph.D., Inigo Martincorena, Ph.D., Peter Ganly, B.M., B.Ch., Ph.D., Laura Mudie, B.Sc., Stuart McLaren, B.Sc., Sarah O Meara, B.Sc., Keiran Raine, M.Sc., David R. Jones, M.Sc., Jon W. Teague, B.Sc., Adam P. Butler, B.Sc., Mel F. Greaves, Ph.D., Arnold Ganser, M.D., Konstanze Döhner, M.D., Richard F. Schlenk, M.D., Hartmut Döhner, M.D., and Peter J. Campbell, M.B., Ch.B., Ph.D. a bs t r ac t BACKGROUND Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. mecpg OH-meCpG Chromatin Cohesin Splicing RTK RAS signaling Transcription Other Genomic Classif ELN favorable risk number, NCT14612.) CEBPAmonoallelic N Engl J Med 216;374: GATA2 DOI: 1.156/NEJMoa Copyright 216 Massachusetts Medical Society. complex TP n engl j med 374;23 nejm.org June 9, 216 5/5q 17/17p The New England Journal of Medicine 7/7q at Lane Medical Library, Stanford University Med Center on June 26, 218. For personal use only. No other uses without permission. Downloaded from nejm.org 2/2q Copyright 216 Massachusetts Medical Society. All rights reserved. 12/12p +11/11q 18/18q 9q Y abn3q +8/8q RUNX1 MLLPTD SRSF2 U2AF1 SF3B1 BCOR STAG2 EZH2 R14 NRAS FLT3ITD R172 FLT3TKD KIT KRAS NF1 PTPN11 CBL ss dr det ivers ect ed No 172 cla H2 R No ID idy Ch spliroma ceo tin som e elic plo eu M1 BP A biall an 53 TP CE NP ) 7) t ML (8;21 ) Lf usio n inv t(6 (3) ;9) inv(16) t(15;17) t(8;21) t(11q23;x) inv(3) t(6;9) DNMT3A TET2 ASXL1 IDH1 IDH2 IDH2 NPM1 RAD21 MYC CEBPAbiallelic Papaemmanuil E et al. N Engl J Med 216;374: WT1 Figure 2. Identification of Molecular Subgroups in AML. CEBPAmonoallelic The rows in the graph represent individual genomic lesions, and the columns represent patients in the study. Vertical purple lines (some of which appear as blocks because of clustering) indicate the presence of a specified driver GATA2 mutation in a patient. The patients have been ordered by group membership; orange lines demarcate boundaries complex between classes. OH-meCpG denotes hydroxymethyl CpG. TP53 5/5q 2213 n engl j med 374;23 nejm.org June 9, /17p The New England Journal of Medicine Downloaded from nejm.org at Lane Medical Library, Stanford University Med Center on June 26, 218. For personal use only. No other uses without permission. 7/7q Copyright 216 Massachusetts Medical Society. All rights reserved. 2/2q 12/12p (16 Identification of Molecular Subgroups In AML From the Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular METHODS Biology Laboratory (EMBL-EBI) (M.G.), HinxWe enrolled a total of 154 patients in three prospective trials of intensive therapy. ton, the Centre for Evolution and Cancer, InCombining driver mutations in 111 cancer genes with cytogenetic and clinical data, stitute of Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, we defined AML genomic subgroups and their relevance to clinical outcomes. University of Cambridge, Cambridge (N.B.) all in the United Kingdom; the Departments of Genomic Classification and Prognosis in Leukemia RESULTS Epidemiology and Biostatistics and Cancer We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or Biology, the Center for Molecular Oncology more drivers identified in 86% of the patients. Patterns of co-mutation compartmen- and the Center for Hematologic Malignancies, Sloan Kettering Cancer Center, New talized the cohort into 11 classes, each with distinct diagnostic features and clinical Memorial mecpg OH-meCpG York (E.P.); the Department of Internal MediChromatin Cohesin outcomes. In addition to currently defined AML subgroups, three heterogeneous ge- cine III, Ulm University, Ulm (L.B., V.I.G., P.P., Splicing K.D., R.F.S., H.D.), and the Department of nomic categories emerged: AML with mutations in genes encoding chromatin, RNARTK RAS signaling Hematology, Hemostasis, Oncology, and splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromo- Stem Cell Transplantation, Hannover MediTranscription R172 somal aneuploidies,eln orfavorable both (in 13%);ELN and, provisionally, AML with IDH2 mutations cal School, Hannover (M.H., F.T., A.G.) both Other ELN intermediate-ii risk risk intermediate-i risk ELN adverse risk (in 1%). Patients with chromatin spliceosome and TP53 aneuploidy AML had poor in Germany; the Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei outcomes, with the various class-defining mutations contributing independently and Tumori, and Department of Oncology and inv(16) additively to the outcome. In addition to class-defining lesions, other co-occurring Onco-Hematology, University of Milan, Milan t(15;17) the Department of Human Genetics, t(8;21) driver mutations also had a substantial effect on overall survival. The prognostic ef- (N.B.); University of Leuven, Leuven, Belgium (P.V.L.); t(11q23;x) fects of inv(3) individual mutations were often significantly altered by the presence or ab- and the Department of Pathology, University sence oft(6;9) other driver mutations. Such gene gene interactions were especially pro- of Otago, Christchurch, New Zealand (P.G., P.J.C.). Address reprint requests to Dr. CampDNMT3A nouncedtet2 for NPM1-mutated AML, in which patterns of co-mutation identified groups bell at the Cancer Genome Project, Wellcome with a favorable or adverse prognosis. These predictions require validation in prospec- Trust Sanger Institute, Hinxton, CambridgeASXL1 IDH1 shire CB1 1SA, United Kingdom, or at tive clinical trials. IDH2R14 pc8@sanger.ac.uk. IDH2R172 CONCLUSIONS Drs. Papaemmanuil and Gerstung and Drs. H. NPM1 The driver landscape in AML reveals distinct molecular subgroups that reflect dis- Döhner and Campbell contributed equally RAD21 to this article. MYC crete paths in the evolution of AML, informing disease classification and prognosthis article was last updated on July 12, 216, biallelic tic CEBPA stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov at NEJM.org. WT1 5;1 new england journal of medicine The inv 154 patients 3 prospective trials of intensive therapy Cytogenetic Clinical trial data 111 cancer genes 5234 driver mutations across 76 genes or genomic region 11 classes of mutations with distinct outcomes t(1 8

9 Papaemmanuil E et al. N Engl J Med 216;374: Molecular classes of AML and concurrent gene mutations in adult patients up to the age of 65 years. Hartmut Döhner et al. Blood 217;129:

10 Learning Objectives AML: the pre-216 era Genomic revolution in AML lead to reclassification of AML Be aware of the common molecular drivers of AML Understand clonal hematopoiesis (CHIP/ARCH) and increased risk for myeloid malignancies Improve awareness of FDA approved therapies for AML Improve understanding of FDA approved and therapies under development into treatment paradigms of AML treatment CHIP: Clonal Hematopoiesis of Indeterminate Potential Whole exome sequencing in 17,182 healthy individuals Looking for somatic mutations, SNPs, INDELs in 16 recurrently mutated genes found in hematological disorders Genoveses and Jasiwal NEJM 214 DNMT3A ASXL1 TET2 JAK2 PPM1D SF3B1 SRSF2 TP53 CBL MYD88 U2AF1 STAT3 IDH2 ATM No. of Mutations 1

11 ARCH : Age Related Clonal Hematopoiesis <4 y.o <1.% 7-79 y.o. 9.5% 8-89 y.o. 11.7% >9 y.o. 18.4% Percent of Participants Clonal hematopoiesis with candidate drivers Clonal hematopoiesis with unknown drivers Clonal hematopoiesis Age at Sampling (yr) Genoveses and Jasiwal NEJM 214 Clonal hematopoiesis is associated with increased risk of hematologic malignancy Probability HR 25 (95% CI ) No CHIP CHIP /44 TYPE HR (95% CI) Myeloid (AML, MDS, MPN) 115 (19-71) 1/962 Non-Hodgkin Lymphoma Other (HL, MM, CLL) Myeloid > NHL > myeloma, CLL 1 (1.9-53) No events in CHIP group Years Jaiswal S, Unpublished 11

12 A B 3, Clonal Hematopoiesis of Indeterminate Potential Hematopoietic Stem Cells years later years later Driver Mutation Arises No. of Mutations 2, 1, years later Clonal Evolution: Hematological Malignancies Genoveses and Jasiwal NEJM 214 Hematopoietic Clone Develops Hematologic Cancer Develops Figure 1. Clonal Expansion and Allelic Fractions. Panel A shows a model for the expansion of a single hematopoietic ste fluence of a somatic mutation (yellow circle), and the potential convers through subsequent mutation (black circle with red rim). Mutations pre an appreciable allelic fraction (though <5%) in blood-derived genomi lelic fractions observed in sequencing data for high-confidence, ultra-ra participants; the small bump at the left of this distribution represents p David P. Steensma et al. Blood 215;126:

13 Learning Objectives AML: the pre-216 era Genomic revolution in AML lead to reclassification of AML Be aware of the common molecular drivers of AML Understand clonal hematopoiesis (CHIP/ARCH) and increased risk for myeloid malignancies Improve awareness of FDA approved therapies for AML Improve understanding of FDA approved and therapies under development into treatment paradigms of AML treatment Past 13

14 Intensity AML Age FLT-3 wt FLT-3 ITD/TKDm 7+3 Gemtuzumab ozogamicin Sorafenib? 7+3 Midostaurin Quizartinib Gilteritinib Crenolanib CPX-351 Midostaurin TP53m Decitabine IDH1m Ivosidenib Azacitadine Decitabine Venetoclax CR/CRi Favorable unfavorable R/R AML IDH2m Enasidenib Quizartinib Gilteritinib Post-remission therapy Sorafenib? MRD-/+? allohsct TKI maintenance? Gemtuzumab ozogamicin Best Supportive Care Gemtuzumab Ozogamicin: an antibody-drug conjugate MEK inhibitors RAS RAF MEK PI3K ERK PI3K/mToR inhibitors AKT RNA pol TF mtor Transcription Unmethylated CpG Hsp9 inhibitor Thalidomine/ lenalidomine HDAC inhibitors DNA demethylating agents HDAC MBD FLT3 inhibitors Proteosomal degradation FLT3 receptor Bcl-2 inhibitors X-linked inhibitor of apoptosis RNA pol TF Methylated CpG Bax Cytochrome C Apoptosome Bcl-2 SDF-1α CXCR4 CD33 Calicheamycin Plerixafor Gemtuzumab 14

15 Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo AML: A randomized, open-label, phase 3 study CD33 expression on blasts not a requirement Exclusions: secondary AML from MPN/MDS t-aml CNS involvement regimen 3mg/m 2 on d1, d4, d7 8% saturation of CD33 in vivo rapid re-expression of CD33 Control group Gemtuzumab All patients ozogamicin group Patients Age (years) Median (IQR) 61 7 ( ) 62 8 ( ) 62 2 ( ) 6 86 (62%) 1 (72%) 186 (67%) Men 61 (44%) 77 (55%) 138 (5%) ECOG performance status 54 (39%) 5 (36%) 14 (37%) 1 65 (47%) 75 (54%) 14 (5%) 2 17 (12%) 13 (9%) 3 (11%) 3 1 (<1%) 1 (<1%) 2 (<1%) Not available 2 (1%) 2 (<1%) White blood cell count ( 1⁹ per L; median, IQR) 5 ( ) 6 9 ( ) 5 9 ( ) Platelet count ( 1⁹ per L; median, IQR) 67 5 ( ) 66 ( ) 67 ( ) Percentage of CD33-expressing cells (median, IQR) Cytogenetics 88% (57 96) 92% (67 97) 9% (63 97) Favourable 6 (4%) 3 (2%) 9 (3%) Intermediate* 91 (65%) 91 (65%) 182 (65%) Unfavourable 3 (22%) 28 (2%) 58 (21%) Not available 12 (9%) 17 (12%) 29 (1%) NPM1 status Mutated 48 (35%) 45 (32%) 93 (33%) Wild type 9 (65%) 91 (65%) 181 (65%) Not available 1 (<1%) 3 (2%) 4 (1%) FLT3-ITD status Positive 27 (19%) 22 (16%) 49 (18%) Negative 111 (8%) 115 (83%) 226 (81%) Not available 1 (<1%) 2 (1%) 3 (1%) CEBPA status Mutated 8 (6%) 1 (7%) 18 (6%) Wild type 119 (86%) 11 (79%) 229 (82%) Not available 12 (9%) 19 (14%) 31 (11%) Genotype (appendix) Favourable 24 (17%) 24 (17%) 48 (17%) Unfavourable 11 (73%) 95 (68%) 196 (71%) Not available 14 (1%) 2 (14%) 34 (12%) Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo AML: A randomized, open-label, phase 3 study Control group All patients Gemtuzumab ozogamicin group Point estimate (95% CI) CR + CRp 14 (75%) 113 (81%) 1 46* ( ) Induction courses 1 14 (75%) 113 (81%) 2 35 (25%) 25 (18%) Death before induction 1 (<1%) Death during induction 5 (4%) 9 (6%) Resistant disease (no CR or CRp) 29 (21%) 17 (12%) CR 1 (72%) 12 (73%) CRp 4 (3%) 11 (8%) Event-free survival 58 ( 43 78) Death before or during induction 6 (4%) 9 (6%) Resistant disease (no CR or CRp) 29 (21%) 17 (12%) Relapse 61 (44%) 49 (35%) Death in CR or CRp 8 (6%) 2 (1%) Time (months; median, range) 9 7 (8 11 9) 15 6 ( ) Estimated rate at 2 years (95% CI) 17 1% ( ) 4 8% ( ) Overall survival 69 ( 49 98) Death 72 (52%) 59 (42%) Time (months; median, range) 19 2 ( ) 34 (2 5 NR) Estimated rate at 2 years (95% CI) 41 9% ( ) 53 2% ( ) Patients in CR or CRp 14 (75%) 113 (81%) Relapse-free survival 52 ( 36 75) Relapse 61 (44%) 49 (35%) Death before relapse 8 (6%) 2 (1%) Time (months; median, range) 11 4 ( ) 28 1 (15 NR) Estimated rate at 2 years (95% CI) 22 7% ( ) 5 3% ( ) p value Data are number or number (%), unless otherwise indicated. CR=complete remission. CRp=complete remission with incomplete platelet recovery. NR=not reached. *Odds ratio. Hazard ratio. 15

16 Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo AML: A randomized, open-label, phase 3 study Overall survival (%) B % vs. 53.2% Control Gemtuzumab ozogamicin Log-rank p= Number at risk Control Gemtuzumab ozogamicin B Control Gemtuzumab ozogamicin Hazard ratio (CI*) 4 p value Deaths Patients Deaths Patients Age (years) < Cytogenetics Favourable or intermediate Unfavourable Unknown NPM1 status Wild type Mutated FLT3-ITD No Yes Genotype of acute myeloid leukaemia Non-favourable risk Favourable risk Unknown risk Total ( ) 76 ( ) 59 ( ) 1 44 ( ) 51 ( ) 79 ( ) 5 ( ) 82 ( ) 3 ( 1 97) 68( ) 1 23 ( ) 47 ( ) 69 ( 49 98) Improves survival Reduces survival A Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo AML: A randomized, open-label, phase 3 study EFS (%) % vs. 4.8% Control Gemtuzumab ozogamicin Number at risk Control Gemtuzumab ozogamicin Log-rank p= A Control Gemtuzumab ozogamicin Hazard ratio (CI*) p value Events Patients Events Patients Age (years) < Cytogenetics Favourable or intermediate Unfavourable Unknown NPM1 status Wild type Mutated FLT3-ITD No Yes Genotype of acute myeloid leukaemia Non-favourable risk Favourable risk Unknown risk Total ( ) 58 ( 36 92) 5 ( 3 82) 1 3 ( ) 44( ) 64 ( 4 1 3) 47 ( 23 96) 64 ( 4 1 3) 32 ( 23 96) 6 ( 38 93) 65 ( ) 38 ( ) 58( 43 78) Improves survival Reduces survival 16

17 Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo AML: A randomized, open-label, phase 3 study Relapse-free survival (%) C Control Gemtuzumab ozogamicin 22.7% vs. 5.3% Number at risk Control Gemtuzumab ozogamicin Log-rank p= C Control Gemtuzumab ozogamicin Events Patients Events Patients Age (years) < Cytogenetics Favourable or intermediate Unfavourable Unknown NPM1 status Wild type Mutated FLT3-ITD No Yes Genotype of acute myeloid leukaemia Non-favourable risk Favourable risk Unknown risk Total Time (months) Improves survival Reduces survival 3 16 Hazard ratio (CI*) 59 ( ) 47 ( 26 85) 51 ( 29 9) 92 ( ) 23 ( ) 62 ( ) 45 ( ) 6 ( ) 32 ( 11 93) 54 ( 31 94) 6 ( ) 25 ( ) 52( 36 75) p value Effect of Gemtuzumab Ozogamicin on Survival of Adult Patients with De-novo AML: A Randomized, open-label, phase 3 Study Control group (n=139) Duration of treatment-induced cytopenias (days)* Neutropenia (< 5 1⁹ cells per L) Gemtuzumab Point difference ozogamicin (95% CI) group (n=139) p value After induction 22 (18 27) 22 (2 26) 4* ( 2 6 to 1 8) 68 After first consolidation 1 (8 15) 13 (1 18) 2 9* ( 5 4 to 6) 17 After second consolidation 13 (1 16) 15 (12 2) 3 7* ( 6 2 to 1 4) 21 Thrombocytopenia (<5 1⁹ cells per L) After induction 21 (18 25) 25 (2 3) 3 3* ( 5 8 to 8) 6 After first consolidation 9 (6 13) 17 (11 27) 9 5* ( 16 4 to 2 8) < 1 After second consolidation 13 (9 2) 24 (15 35) 9 5* ( 13 5 to 5 4) < 1 Transfusion episodes* Red blood cells After induction 8 (6 12) 8 (6 1) 5* ( 6 to 1 6) 52 After first consolidation 4 (3 6) 4 (3 6) 1 * ( 1 6 to 3) 9 After second consolidation 4 (2 6) 4 (2 6) * ( 8 to 8) 99 Platelets After induction 7 (5 9) 12 (9 17) 5 8* ( 7 6 to 4 ) < 1 After first consolidation 2 (1 3) 6 (4 1) 5 * ( 6 3 to 3 7) < 1 After second consolidation 3 (2 4) 7 (5 1) 4 1* ( 5 2 to 3 ) < 1 Persistent thrombocytopenia (<5 1⁹ cells per L) By day 45 after induction /139 4/139 (3%) ( to 9) 12 By day 45 after first consolidation 2/98 (2%) 9/99 (9%) 2 ( 1 to 9) 582 By day 45 after second consolidation 2/9 (2%) 9/85 (11%) 2 ( 1 to 8) 289 Control group (n=139) Gemtuzumab ozogamicin group (n=139) Relative risk (95% CI) Induction death 5/139 (4%) 9/139 (6%) 56 ( ) 41 Transfer to intensive-care unit 17/139 (12%) 2/139 (14%) 85 ( ) 72 Treatment-related death during CR or CRp Grade 3 and 4 adverse events p value 8/14* (8%) 2/113 (2%) 4 35 ( ) 51 Haemorrhage 4/139 (3%) 12/139 (9%) 33 ( 12 95) 68 Cardiac 9/139 (6%) 11/139 (8%) 82 ( ) 82 Liver 9/139 (6%) 18/139 (13%) 5 ( ) 1 Skin or mucosa 25/139 (18%) 32/139 (23%) 11 ( 3 42) 37 Gastrointestinal 14/139 (1%) 22/139 (16%) 64 ( ) 21 Pulmonary 16/139 (12%) 16/139 (12%) 1 ( ) 1 Grade 3 and 4 infections During induction 5/131 (38%) 59/129 (46%) 83 ( ) 26 During first consolidation 38/95 (4%) 48/97 (49%) 8 ( ) 19 During second consolidation 38/82 (46%) 38/81 (47%) 99 ( ) 99 Data are n/n (%), unless otherwise indicated. CR=complete remission. CRp=complete remission with incomplete platelet recovery. *Includes five deaths after stem-cell transplantation. Table 4: Non-haematological toxicity 17

18 Midostaurin: A multi-receptor tyrosine kinase inhibitor MEK inhibitors RAS RAF MEK PI3K ERK PI3K/mToR inhibitors AKT RNA pol TF mtor Transcription Unmethylated CpG Hsp9 inhibitor Thalidomine/ lenalidomine HDAC inhibitors DNA demethylating agents HDAC MBD FLT3 inhibitors Proteosomal degradation FLT3 receptor Bcl-2 inhibitors X-linked inhibitor of apoptosis RNA pol TF Methylated CpG Bax Cytochrome C Apoptosome Bcl-2 SDF-1α CXCR4 CD33 Calicheamycin Plerixafor Gemtuzumab Study drug is given on Days 8-21 after each course of chemotherapy Days 1-28 of each 28 day maintenance cycle. 18

19 RATIFY CALGB 163 MIDO (N=36) PBO (N=357) Initial CR (within 6 days) Fisher s exact p (2-sided) Rate 59% 53%.15 Time to CR, median (range) 35 days (2-6) 35 days (2-6) Initial CR (at any time) Rate 74% 66%.1 Time to CR, median (range) 38 days (2-553) 38 days (2-215) Stone R et al. ASH, 215 CALGB 163 RATIFY: Outcome The addition of midostaurin to chemotherapy reduced risk of death by 22% compared to placebo The beneficial effect was still seen if patients who underwent allohsct was censored Ihigh transplant rate 57%) The study was not powered for subgroup analysis Efficacy in the elderly population? Stone RM, NEJM Aug 5,

20 CALGB 163 RATIFY Adverse Events: Adverse Event Midostaurin Group (N = 355) Placebo Group (N = 354) P Value * no. of patients (%) Hematologic Thrombocytopenia 346 (97) 342 (97).52 Neutropenia 338 (95) 339 (96).86 Anemia 329 (93) 311 (88).3 Leukopenia 93 (26) 15 (3).32 Lymphopenia 68 (19) 78 (22).35 Other blood or bone marrow event 1 (<1) 4 (1).22 Bone marrow hypocellularity 1 (<1).5 Nonhematologic Febrile neutropenia 29 (82) 292 (82).84 Infection 186 (52) 178 (5).6 Lymphopenia 68 (19) 78 (22).35 Diarrhea 56 (16) 54 (15).92 Hypokalemia 49 (14) 6 (17).25 Pain 47 (13) 44 (12).82 Increased alanine aminotransferase 45 (13) 33 (9).19 Rash or desquamation 5 (14) 27 (8).8 Fatigue 32 (9) 37 (1).53 Pneumonitis or pulmonary infiltrates 28 (8) 29 (8).89 Nausea 2 (6) 34 (1).5 Hyponatremia 31 (9) 23 (6).32 Hyperbilirubinemia 25 (7) 28 (8).67 Mucositis or stomatitis 22 (6) 28 (8).38 Hypophosphatemia 19 (5) 29 (8).14 Hypocalcemia 24 (7) 21 (6).76 v RATIFY: Conclusions Midostaurin + standard chemo in patients with newly diagnosed FLT3-mutated AML Improved OS and EFS vs placebo: Regardless of ITD/TKD stratification AND despite high SCT rate (57%) Reduced risk of death by 23% vs placebo Safety/tolerability similar in midostaurin vs placebo Ratify Investigators suggest: Induction: 7+3+Midostaurin (5 mg BID, days 8-21) Consolidation: HiDAC + Midostaurin (5 mg BID, days 8-21) Maintenance following chemo or BMT with Midostaurin x 12 mos Stone RM et al. ASH 215. Abstract 6. 2

21 Intensity FLT-3 wt FLT-3 ITD/TKDm AML Age 7+3 Gemtuzumab ozogamicin Sorafenib? 7+3 Midostaurin Quizartinib Gilteritinib Crenolanib CPX-351 Midostaurin IDH1m Ivosidenib Azacitadine Decitabine Venetoclax CR/CRi Favorable unfavorable Post-remission therapy MRD-/+? TKI maintenance? allohsct R/R AML IDH2m Enasidenib Sorafenib? Gemtuzumab ozogamicin Quizartinib Gilteritinib TP53m Decitabine Best Supportive Care AML World Health Organization Classification SUBTYPE AML with recurrent genetic abnormalities AML with myelodysplasiarelated changes Therapy-related myeloid neoplasms COMMENTS This category captures balanced chromosomal translocations that produce novel fusion genes. The most common subtypes in this category are shown below along with single gene mutations - AML can be diagnosed in these subtypes with <2% blasts: Acute promyelocytic leukemia (APL) with PML-RARA AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 One of the following criteria must be met: Previous history of myelodysplastic syndrome (MDS) Possession of a myelodysplasia-related cytogenetic abnormality, except for del(9q) Involvement of 1 abnormal myeloid cell type (only in cases in which a mutation of NPM1 or biallelic mutation of CEBPA is lacking) Cytotoxic agents associated with therapy-related hematologic neoplasms include alkylating agents, radiation therapy, and topoisomerase II inhibitors AML, not otherwise specified (NOS) AML cases that do not fit into any of the other subtypes Tumor mass of myeloid blasts Myeloid sarcoma Cases of myeloid sarcoma without marrow disease should be investigated further Myeloid proliferations related NCCN. Clinical to Down practice syndrome guidelines in oncology: acute myeloid leukemia. v

22 CPX-351 Phase III Study of CPX-351 in Newly- Diagnosed Adults With t-aml or AML- MRC (Study 31) 1-3 Induction CPX-351 n=153 Subsequent induction (if needed) Consolidation (1-2 cycles) CPX-351 on Days 1, 3, and 5 CPX-351 on Days 1 and 3 CPX-351 on Days 1 and 3 39 Patients 7+3 n=156 7 days of cytarabine + 3 days of daunorubicin 5 days of cytarabine + 2 days of daunorubicin 5 days of cytarabine + 2 days of daunorubicin Follow-up Key eligibility criteria for Phase 3 study: Previously untreated Aged 6-75 Able to tolerate intensive therapy Performance status -2 Patient Distribution for Phase 3 study (n=39): Therapy-related AML = 2% AML-antecedent heme disorder = 54% De novo AML with MDS cytogenetics = 25% Primary endpoint: Overall survival 1. VYXEOS (CPX-351) [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 2. Data on file. [VYX-217-xxx]. Palo Alto, CA: Jazz Pharmaceuticals. 3. Lancet JE et al. Oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 216; Chicago, IL. 22

23 CPX-351 Phase III Study 31 Patient Characteristics Strata CPX-351 n = 153 (%) 7+3 n = 156 (%) Gender Male 94 (61.4) 96 (61.5) Race Caucasian 128 (83.7) 134 (89.1) Age Group 7 years 57 (37.3) 54 (34.6) Median ECOG PS (9.2) 134 (85.9) Cytogenetic Risk by NCCN PS 2 15 (9.8) 22 (14.1) Favorable 7 (4.6) 5 (3.2) Intermediate 64 (41.8) 58 (37.8) Poor 72 (47.1) 83 (53.2) Unknown 1 (6.5) 1 (6.4) Therapy-related AML 3 (19.6) 33 (21.2) MDS AML with Prior HMA 5 (32.7) 55 (35.3) MDS AML without Prior HMA 21 (13.7) 19 (12.2) CMMoL AML 11 (7.2) 12 (7.7) De novo with MDS Karyotype 41 (26.8) 37 (23.7) AML-MRC CMMoL = chronic myelomonocytic leukemia Response Rate and 6-day Mortality 6 p=.4 p= Patients (%) Patients (%) Odds Ratio (95% CI) CR CR + CRi 1.69 (1.3, 2.78) 1.77 (1.11, 2.81) CPX Deaths 6 Days CPX-351 (n=153) 7+3 (n=156) Deaths 2º to Progressive AML Deaths 2º to Adverse Event Lancet J et al. ASCO,

24 Clinical Results of Phase III Study Lancet J et al. ASCO, Landmark Analysis at Time of Transplant KAPLAN-MEIER CURVE FOR OVERALL SURVIVAL LANDMARKED AT STEM CELL TRANSPLANT ITT ANALYSIS POPULATION Survival (%) CPX Events/N Median Surv. (95% CI) 18/52 Not Reached 26/ (6.21, 16.69) Hazard Ratio =.46 p-value =.46 2 CPX Months from Randomization Lancet J et al. ASCO,

25 CPX-351 Phase III Study 31: Safety Grades 3 to 5 (CTC 3.) CPX-351 (n=153) n (%) 7+3 (n=151) n (%) Hemorrhage 15 (1) 9 (6) Febrile Neutropenia 11 (66) 12 (68) Rash 8 (5) 2 (1) Edema 2 (2) 5 (3) Nausea 1 (1) 1 (1) Diarrhea/Colitis 4 (3) 1 (7) Mucositis 2 (1) 7 (5) Constipation Musculoskeletal pain 5 (3) 4 (3) Abdominal pain 3 (2) 3 (2) Cough 1 (1) Headache 2 (1) 1 (1) Dyspnea 17 (11) 15 (1) Grades 3 to 5 (CTC 3.) CPX-351 (n=153) n (%) 7+3 (n=151) n (%) Fatigue 8 (5) 8 (5) Arrhythmia 1 (7) 7 (5) Decreased appetite 2 (1) 5 (3) Pneumonia (excluding fungal) 3 (2) 26 (17) Sleep disorders 2 (1) 1 (1) Bacteremia (excluding sepsis) 35 (23) 31 (21) Vomiting Chills Hypotension 7 (5) 1 (1) Non-conduction cardiotoxicity 13 (9) 15 (1) CPX-351: Conclusions CPX-351 compared favorably to 7+3 induction for patients with therapy-related AML, AML with MDS-related changes and/or cytogenetics: Improved OS and EFS without increased 3 and 6 day mortality Investigators suggest: Induction: CPX-351 (44 mg/1 mg per m 2 ) as 9 min infusion days 1, 3, 5 2nd Induction (if needed): CPX-351 (44 mg/1 mg per m 2 ) as 9 min infusion days 1, 3 Consolidation: CPX-351 (29/65 mg per m 2 ) as 9 min infusion days 1,3 25

26 Intensity FLT-3 wt FLT-3 ITD/TKDm AML Age 7+3 Gemtuzumab ozogamicin Sorafenib? 7+3 Midostaurin Quizartinib Gilteritinib Crenolanib CPX-351 Midostaurin IDH1m Ivosidenib Azacitadine Decitabine Venetoclax CR/CRi Favorable unfavorable Post-remission therapy R/R AML IDH2m Enasidenib Sorafenib? Quizartinib Gilteritinib TP53m Decitabine MRD-/+? allohsct TKI maintenance? Gemtuzumab ozogamicin Best Supportive Care 26

27 9/17/18 Enasidenib: IDH2m Inhibitor 2-HG m m 2-HG Enasidenib in Mutant IDH2 Relapsed or Refractory Acute Myeloid Leukemia 27

28 9/17/18 From by guest on June 11, 218. For personal use only. 724 STEIN et al BLOOD, 1 AUGUST 217 x VOLUME 13, NUMBER 6 Table 1. Baseline demographic and disease characteristics for patients with relapsed or refractory AML and all patients in the doseescalation and expansion study phases Relapsed or refractory AML Enasidenib 1 mg per day (n 5 19) Characteristic No. Age, median (range), y % 67 (19-1) Sex Representative of R/R AML population All doses (n 5 176) No.!!! % Male Recurrent genetic abnormalities Therapy-related myeloid neoplasms % 7 (19-1) Female 27 No. 67 (19-1) AML classification* Myelodysplasia-related changes All patients (N 5 239) , Not otherwise specified Missing Outcomes of prior AML therapy Refractory to initial induction or re-induction treatment Relapsed/refractory to $2 cycles of first-line lower-intensity therapy Relapsed within 1 y of initial treatment Relapsed posttransplant In second or later relapse Relapsed.1 y after initial treatment Cytogenetic risk status Intermediate Poor Co-occurring mutations NPM CEBPA FLT3-ITD Antecedent history of myelodysplastic syndromes Prior stem cell transplantation ECOG performance status IDH2 mutation location R R ,1 1,1 3 Other{ Bone marrow blasts, median (range), %# 49 (-96) 49 (-98) 1 41 (**-98) Hematology, median (range) WBC, 319/L 3. (.2-88) 2.7 (.2-88) 2.6 (.2-88) Hemoglobin, g/dl 9.3 ( ) 9.2 ( ) 9.1 ( ) Platelets, 319/L 39 (1-372) 44 (1-57) 45 (1-644) ECOG, Eastern Cooperative Oncology Group; WBC, white blood cell count. *Per World Health Organization (WHO) 28 AML classifications of myeloid neoplasms.21 During the study, the protocol was amended to determine AML subtypes according to the WHO classification scheme (AML classification was previously determined by French-American-British criteria). Prior (initial) AML treatment of relapsed/refractory patients. Individual patients may be counted in more than 1 category. ECOG performance status scores of, 1, or 2 (on a scale from to 5, with indicating that the patient is fully active and higher numbers indicating greater disability). {One patient had an IDH2 G145fs mutation, and mutation site was not reported for 2 patients. #Local assessment. **Nine patients had extramedullary disease only at relapse. Enasidenib in Mutant IDH2 Relapsed or Refractory Acute Myeloid Leukemia Figure 1, available on the Blood Web site). Baseline characteristics are Results Between September 2, 213, and April 15, 216, 239 patients (113 in the dose-escalation phase and 126 in the 4-arm expansion phase) received enasidenib and comprised the intention-to-treat population. At data cutoff, 31 patients (13%) continued to receive enasidenib on-study, with median follow-up of 9.7 months (range, months) (supplemental provided in Table 1. Three-fourths of all patients had IDH2-R14 mutations and one-fourth had IDH2-R172 mutations. Of 175 patients with available cytogenetic data, 67% had National Comprehensive Cancer Network defined23 intermediate-risk cytogenetics, including 43% with normal karyotype. The relapsed/refractory AML efficacy cohort comprised 176 patients (74% of all patients). At study entry, 94 patients (53%) had received 2 or more prior AML-directed regimens. Stein EM., et all Blood

29 Enasidenib in Mutant IDH2 Relapsed or Refractory Acute Myeloid Leukemia Stein EM., et all Blood 217 Enasidenib in Mutant IDH2 Relapsed or Refractory Acute Myeloid Leukemia Table 2. Treatment-related TEAEs of grades 3 or 4 occurring in 2% of all patients TEAE Enasidenib 1 mg per day (n 5 153) All patients (N 5 239) No. % No. % Hyperbilirubinemia* IDH differentiation syndrome Anemia Thrombocytopenia Tumor lysis syndrome Decreased appetite Leukocytosis Fatigue Nausea Lipase increased Stein EM., et all Blood

30 Ivosidenib: IDH1m inhibitor 2-HG m m 2-HG Single-arm, open-label, phase 1, multicenter trial study Dose escalation (n=78) Enrollment complete Patients with midh1 advanced hematologic malignancies Oral ivosidenib daily in continuous 28-day cycles Doses included 1 mg BID, 3, 5, 8, 12 mg QD Dose expansion (n=18) Enrollment complete: 5 mg QD in continuous 28-day cycles R/R AML in 2nd+ relapse, relapse after SCT, refractory to induction or reinduction, or relapse within 1 year, n=126 Untreated AML not eligible for SOC, n=25 Other non-aml midh1 R/R advanced hematologic malignancies, n=11 Other R/R AML not eligible for Arm 1, n=18 Durable Remissions with Ivosidenib in RR-AML 3

31 9/17/18 Durable Remissions with Ivosidenib in RR-AML Durable Remissions with Ivosidenib in RR-AML 31

32 Durable Remissions with Ivosidenib in RR-AML Screening Cycle 1 day 15 Cycle 1 day 28 44% blasts 3% blasts 2% blasts Durable Remissions with Ivosidenib in RR-AML 32

33 Durable Remissions with Ivosidenib in RR-AML Durable Remissions with Ivosidenib in RR-AML 33

34 Durable Remissions with Ivosidenib in RR-AML Intensity FLT-3 wt FLT-3 ITD/TKDm AML Age 7+3 Gemtuzumab ozogamicin Sorafenib? 7+3 Midostaurin Quizartinib Gilteritinib Crenolanib CPX-351 Midostaurin IDH1m Ivosidenib Azacitadine Decitabine Venetoclax CR/CRi Favorable unfavorable Post-remission therapy R/R AML IDH2m Enasidenib Sorafenib? Quizartinib Gilteritinib TP53m Decitabine MRD-/+? allohsct TKI maintenance? Gemtuzumab ozogamicin Best Supportive Care 34

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37 Intensity FLT-3 wt FLT-3 ITD/TKDm AML Age 7+3 Gemtuzumab ozogamicin Sorafenib? 7+3 Midostaurin Quizartinib Gilteritinib Crenolanib CPX-351 Midostaurin IDH1m Ivosidenib Azacitadine Decitabine Venetoclax CR/CRi Favorable unfavorable Post-remission therapy R/R AML IDH2m Enasidenib Sorafenib? Quizartinib Gilteritinib TP53m Decitabine MRD-/+? allohsct TKI maintenance? Gemtuzumab ozogamicin Best Supportive Care 37

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43 Class Drug Clinic Trials FLT3 inhibitors Gilteritinib Phase III Post induction maintenance/consolidation in CR1 R/R FLT3+ AML Maintenance post-allohsct in FLT3-ITD+ AML + azacitadine in FLT3+ AML unfit/elderly Quizartinib Phase III R/R AML + standard chemotherapy in induction and maintenance in newly diagnosed FLT3+ AML Crenolanib Pacritinib + decitabine or cytarabine in unfit/elderly AML Midostaurin + decitabine in newly diagnosed unfit/elderly AML BET domain inhibitor FT-111 Phase 1/1b +/- azacitadine in R/R AML Spliceosome inhibitors DNMT3A, TET2, AXL1? TP53 inhibitor R68781/TEN-1 Phase 1 +/- HMA in R/R AML and refractory MDS 43