ESTABLISHED AND EMERGING THERAPIES FOR ACUTE MYELOID LEUKAEMIA. Dr Rob Sellar UCL Cancer Institute, London, UK

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1 ESTABLISHED AND EMERGING THERAPIES FOR ACUTE MYELOID LEUKAEMIA Dr Rob Sellar UCL Cancer Institute, London, UK

2 OVERVIEW Main focus on patients fit for intensive treatment Biological and Clinical Heterogeneity of Acute Myeloid Leukaemia (AML) Importance of heterogeneity to risk stratification and treatment approach Established treatments for AML and the evidence base for these Recent additions to established treatments 4 new drugs regulatory approved in the past 12 months Emerging therapies for AML coming to the clinic soon?

3 DISEASE HETEROGENEITY IMPORTANCE OF CYTOGENETICS Republished with permission of American Society of Hematology from Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials, Grimwade D, et al., Blood 2010;116(3): ; permission conveyed through Copyright Clearance Center, Inc.

4 DISEASE HETEROGENEITY IMPORTANCE OF CYTOGENETICS Risk Group Proportion of patients Refined MRC Favourable 23% t(15;17) APL t(8;21) Inv(16) or t(16;16) Intermediate 67% Normal karyotype or other noncomplex Adverse 10% Inv(3) or t(3;3) Add(5q), del(5q) or -5 Add(7q), del(7q) or -7 t(11q23) excluding t(9;11) and t(11;19) t(9;22) -17 or abn(17p) Complex ( 4 unrelated abn) Grimwade D, et al., Blood 2010;116(3):

5 DISEASE HETEROGENEITY IMPORTANCE OF MOLECULAR DATA From N Engl J Med, The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. 368: , Copyright 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

6 DISEASE HETEROGENEITY IMPORTANCE OF MOLECULAR DATA From N Engl J Med 2015; Döhner H, et al., Acute Myeloid Leukemia, ;373: Copyright 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

7 DISEASE HETEROGENEITY IMPORTANCE OF MOLECULAR DATA From N Engl J Med, Papaemmanuil E, et al., Genomic Classification and Prognosis in Acute Myeloid Leukemia, 2016;374: Copyright 2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

8 DISEASE HETEROGENEITY COMBINING DATA From N Engl J Med, Papaemmanuil E, et al., Genomic Classification and Prognosis in Acute Myeloid Leukemia, 374: Copyright 2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

9 DISEASE HETEROGENEITY IMPORTANCE OF COMBINED DATA Combined prognostic score ELN 2017 Risk category Favourable Intermediate Adverse Genetic abnormality t(8:21)(q22;q22); RUNX1-RUNX1T1 inv(16)(p13.1q22)or t(16;16)(p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD or with FLT3-ITD low Biallelic mutated CEBPA Mutated NPM1 and FLT3-ITD high Wild-type NPM1 and without FLT3-ITD or with FLT3-ITD low (without adverse risk cytogenetics) t(9:11) (p22;q23); MLLT3-KMT2A Cytogenetic abnormalities not classified as favourable or adverse t(6;9) (p23;q34); DEK-NUP214 t(v:11) (v;q23); KMT2A rearranged t(9:22)(q43.1:q11.2); BCR-ABL1 Inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2-MECOM (EVI1) -5 or del(5q); -7; -17/abn(17p) Complex karytoype, monosomal karyotype Wild-type NPM1 and FLT3-ITD high Mutated RUNX1 Mutated ASXL1 Mutated TP53 Döhner H, et al., Blood 2017;129(4):

10 WHY IS THIS RELEVANT TO DISCUSSIONS ABOUT THERAPEUTICS? Risk stratification consolidation chemotherapy Subgroup analysis in clinical trials Rational use of targeted therapies groups that should be targeted on biology groups in which treatments are particularly effective/ineffective

11 WHAT ARE THE CURRENT RECOMMENDATIONS FOR INDUCTION THERAPY AND THE EVIDENCE BASE FOR THIS?

12 RANDOMISED TRIALS OF DAUNORUBICIN DOSE IN AML INDUCTION THERAPY Study Group Age Range (y) No. of patients Doses compared Conclusions ECOG mg/m 2 d1-3 vs. 45 mg/m 2 d1-3 HOVON-SAKK- AMLSG > mg/m 2 d1-3 vs 45 mg/m 2 d1-3 Korean Group mg/m 2 d1-3 vs 45 mg/m 2 d1-3 AML17 (NCRI) mg/m 2 d1/3/5 vs 60 mg/m 2 d1/3/5 Higher RR Longer OS Similar toxicity Higher RR Similar OS Similar toxicity Higher RR Improved EFS/ OS Similar toxicity Similar RR Similar EFS/OS Higher early death rate (60d mortality). Fernandez HF, et al., N Engl J Med 2009;361(13): ; Luskin MR, et al., Blood 2014;123(21):373; Löwenburg B, et al., N Engl J Med 2009;361(13): ; Lee JH, et al., Blood 2011;118(14): ; Burnett AK, et al., Blood 2015;125(25):

15 RANDOMISED TRIALS OF CYTARABINE DOSE IN AML INDUCTION THERAPY Study Group Age Range (y) No. of patients Doses compared Conclusions ALSG mg/m 2 12h d1/3/5/7 vs 100mg/m 2 CIV d1-7 SWOG mg/m 2 12h d1-6 vs 200mg/m 2 CIV d1-7 HOVON-SAKK mg/m 2 12h d1-5 vs 200mg/m 2 CIV d1-7 EORTC-GIMEMA mg/m 2 12h d1/3/5/7 vs 200mg/m 2 CIV d1-10 Similar OS Higher early death (not significant) Similar RR Similar OS Higher early death Similar RR Similar EFS Similar OS Higher RR Longer RFS and OS in younger patients ( 45 y) Similar early death Weick JK, et al., Blood 1996;88(8): , Bishop JF, et al., Blood 1996;87(5): Löwenberg B, et al., N Engl J Med 2011;364(11): , Willemze R, et al., J Clin Oncol 2014;32(3)

16 TRIALS OF PURINE ANALOGUES IN COMBINATION WITH INTENSIVE INDUCTION THERAPY IN PREVIOUSLY UNTREATED PATIENTS NCRI trial Age Range (y) No. of patients Treatment arms Conclusions PALG DAC (Cladribine) vs DAF (Fludarabine) vs DA NCRI AML16 > DA vs Dclo (Clofarabine) NCRI AML DA vs ADE (Etoposide) vs FLAG-Ida (Fludarabine) DAC longer OS DAF same OS Similar OS For FLAG-Ida Higher rate of death in CR, Higher CR after course 1. Longer RFS Similar OS Holowiecki J, et al., J Clin Oncol 2012;30(20): Russell NH, et al., Haematologica 2015;100(s1):514 Burnett AK, et al., J Clin Oncol 2013;31(27):

17 FOR PATIENTS ELIGIBLE FOR INTENSIVE INDUCTION THERAPY Suggested approach for induction therapy days of IV anthracycline + 7 days of continuous infusion cytarabine ( mg/m 2 ) Daunorubicin at least 60 mg/m 2 Alternatives include idarubicin 12 mg/m 2 (noting caveats of recent study Lee et al. J Clin Oncol 2017;35: ) Key additional question Does the addition of targeted agents help?

18 RANDOMISED TRIALS OF GEMTUZUMAB OZOGAMICIN (GO) In combination with intensive induction chemotherapy Study Group Age Range (y) No. of patients GO dosing schedule Conclusions SWOG mg/m 2 d4 cycle 1 ALFA mg/m 2 d1/4/7 cycle 1 d1 consol 1 d1 consol 2 GOELAMS mg/m 2 d4 cycle 1 d4 consol 1 EORTC-GIMEMA mg/m 2 D1/15 before cycle 1 Similar RR Similar RFS Similar OS Higher early death Similar RR Improved RFS Improved EFS Improved OS Similar RR Similar EFS Similar OS Similar RR Similar RFS Similar EFS Similar OS Higher early death Petersdorf SH, et al., Blood 2013:121(24): , Castaigne S, et al., Lancet 2012;379(9825): Delaunay J, et al., Blood 2011;118(21):79, Amadori S, et al., J Clin Oncol 2013;31(35):

19 UK-NCRI RANDOMISED TRIALS OF GEMTUZUMAB OZOGAMICIN (GO) In combination with intensive induction chemotherapy NCRI trial Age Range (y) No. of patients GO dosing schedule Conclusions AML mg/m 2 d1 cycle 1 d1 cycle 3 AML16 > mg/m 2 d1 cycle 1 AML vs 6 mg/m 2 d1 cycle 1 Similar RR Similar RFS Similar OS Improved OS in favourable risk Similar RR Improved RFS Improved OS Similar RR Similar OS Lower early death rate with 3 mg/m 2 Burnett AK, et al., J Clin Oncol 2011;29(4): Burnett AK, et al., J Clin Oncol 2012;30(32): Burnett AK, et al., Blood 2014;124(21):2308.

20 META-ANALYSIS OF GEMTUZUMAB OZOGAMICIN Reprinted from The Lancet Oncol 2014; 15 (9). Hills RK, et al., Copyright 2014, with permission from Elsevier. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials

21 EFS probability RFS probability CAN WE FURTHER STRATIFY WHO RESPONDS TO GEMTUZUMAB? Months Low/int-CD33+, control High-CD33+, control # at risk: Low/int-CD33+, control Low/int-CD33+, GO High-CD33+, control High-CD33+, GO Low/int-CD33+, GO High-CD33+, GO Months # at risk: Low/int-CD33+, control Low/int-CD33+, GO High-CD33+, control High-CD33+, GO Olombel G, et al., Blood 2017;127(17):

24 OTHER WAYS TO TARGET CD33 Other antibody drug conjugates vadastuximab talirine (SGN-CD33A) Encouraging results from early phase trials Ongoing phase 3 trials CASCADE (NCT ) CAR-T

25 ADDITION OF INHIBITORS OF FLT3 UK MRC AML 15 ( ) All patients R ADE DA 3+10 FLAG-Ida If FLT-3 mutant ADE R DA 3+8 FLAG-Ida R Chemo + CEP-701 Chemo MACE ± Mylotarg Ara-C 1.5g/m 2 ± Mylotarg Ara-C 3g/m 2 ± Mylotarg MidAC Ara-C 1.5g/m 2 Ara-C 3g/m 2 R Ara-C 1.5g/m 2 No further treatment UK NCRI AML 17 ( ) Non-APL patients R ADE ADE+GO3 ADE+GO6 DA+GO3 DA+GO6 Knapper S, et al., Blood 2017; 129(9): R IS K A S S E S S M EN T CBF FLT3 +ve Others Poor risk R R R Chemo Chemo+CEP-701 Chemo+placebo Chemo+mTOR Chemo D Clofarabine FLAG-Ida Consolidation chemotherapy 3v4 courses Ara-C 3g/m 2 for 1 or 2 courses Stem cell transplant

26 Estimated percentage still alive Estimated percentage still alive in CR ADDITION OF INHIBITORS OF FLT3 AML15,17 lestaurtinib randomisation overall survival 100 Annual event rates: Years 1-5 Years 6+ Lestaurtinib 20.6% SD % SD 0.0 No lestaurtinib 23.0% SD % SD years AML15,17 lestaurtinib randomisation relapse free survival 100 Annual event rates: Years 1-5 Years 6+ Lestaurtinib 29.1% SD % SD 2.6 No lestaurtinib 32.9% SD % SD years Allocated lestaurtinib (%±s.d.) Allocated no lestaurtinib (%±s.d.) 1 Deaths/person-years: All patients Lestaurtinib 77/263 55/188 17/140 3/93 1/58 0/59 No lestaurtinib 64/177 37/114 8/89 1/62 2/44 0/ % 44.8% 1.3% SD 5.6 (logrank 2P >0.1; NS) % 46.0% 5 6+ years Allocated lestaurtinib (%±s.d.) Allocated no lestaurtinib (%±s.d.) 1 Events/person-years: All patients Lestaurtinib 124/221 28/131 9/102 3/70 1/43 1/39 No lestaurtinib 90/147 24/80 7/63 0/46 1/35 0/ % SD 6.3 (logrank 2P >0.1; NS) % 38.7% 35.7% 35.7% 5 6+ years Knapper S, et al., Blood 2017; 129(9):

27 Alive (%) Alive (%) Relapsing (%) ADDITION OF INHIBITORS OF FLT3 AML15,17: CIR of CEP-701 patients by inhibition to 85% AML15,17: Survival of CEP-701 patients by inhibition to 85% At risk: Years No inhibition Inhibition At risk: Years No inhibition Inhibition No inhibition Inhibition 2 No. pts No. events No inhibition Inhibition No inhibition Inhibition 3 3 2P= No. pts No. events No inhibition Inhibition P= % 43% 60% 33% AML17: Survival by lestaurtinib concomitant GO and azoles 0 0 Lestaurtinib No lestaurtinib 1 No. pts No. events Lestaurtinib No lestaurtinib At risk: Years Lestaurtinib No lestaurtinib P= % 29% Knapper S, et al., Blood 2017; 129(9):

28 CANCER AND LEUKAEMIA GROUP B (CALGB) (RATIFY) TRIAL 1. Trial design Multi-institutional, multinational, randomised, double-blind, placebo controlled trial Patients years with new diagnosis AML without prior antineoplastic therapy (excluding HU) Patients were screened for FLT3 mutations Enrolled if FLT3 mutant Exclusions included APL, taml, bilirubin 2.5x upper limit normal, major coexisting illness Proposed therapy 1. Standard 3+7 plus midostaurin or placebo (1:1 randomisation) days 8 to For patients achieving CR 4 x HiDAC + midostaurin/placebo days 8 to maintenance cycles of midostaurin/placebo Primary Endpoint overall survival Stone RM, et al., N Engl J Med 2017;377:

29 CANCER AND LEUKAEMIA GROUP B (CALGB) (RATIFY) TRIAL 2. Results Patients and AE 3277 preregistered and screened for FLT3 mutation 896 patients had FLT3 mutation 717 enrolled 68.5% had normal karytoype TKD 22.6% ITD with low allelic ration (0.05 to 0.7) 47.6% ITD with high allelic ration (>0.7) 29.8% Placebo and midostaurin groups well matched apart from female sex (59.4% vs. 51.7% (P=0.04) Anaemia and rash higher in midostaurin group Nausea higher in placebo group No difference in count recovery Stone RM, et al., N Engl J Med 2017;377:

30 CANCER AND LEUKAEMIA GROUP B (CALGB) (RATIFY) TRIAL 2. Results Efficacy outcomes Median follow-up of 59 months for the 359 surviving patients CR rates 58.9% midostaurin vs. 53.5% Placebo (P=0.15) From N Engl J Med, Stone RM, et al., Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation, 2017;377: Copyright 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

31 CANCER AND LEUKAEMIA GROUP B (CALGB) (RATIFY) TRIAL 3. Conclusions and further questions Addition of midostaurin to standard intensive chemotherapy in younger patients with FLT3 mutations improves EFS, DFS, and OS Benefit also seen if received allogeneic transplant in CR1 FDA and EMA approved 2017 for treatment of FLT3 mutant AML Further questions Benefit in particular subgroups of FLT3 mutation? Duration of Rx median duration in trial was 3 months? Is there an independent effect of maintenance Rx? Is it only because of FLT3 targeting? Will the same be seen in 60 years? Stone RM, et al., N Engl J Med 2017;377:

32 Event-free survival (%) TP53 MUTANT AND SECONDARY AML AS SPECIAL CASES? Secondary AML De Novo AML Mutated cases, n (%) P value SRSF2 19 (20) 1 (1) < ZRSR2 7 (8) 0 (0) SF3B1 10 (11) 1 (1) ASXL1 30 (32) 5 (3) < BCOR 7 (8) 2 (2) EZH2 8 (9) 3 (2) U2AF1 15 (16) 8 (4) STAG2 13 (14) 3 (2) 0.07 NF1 6 (6) 7 (4) RUNX1 29 (31) 19 (11) < CBL 5 (5) 3 (2) 0.13 NRAS 21 (23) 15 (8) TET2 19 (20) 17 (9) GATA2 2 (2) 2 (1) 0.6 TP53 14 (15) 16 (9) 0.15 KRAS 7 (8) 8 (4) 0.4 PTPN11 5 (5) 9 (5) 1 IDH1 10 (11) 20 (11) 1 IDH2 10 (11) 19 (11) 1 SMC1A 3 (3) 7 (4) 1 RAD21 2 (2) 5 (3) 1 FLT3 18 (19) 50 (28) 0.14 DNMT3A 18 (19) 51 (28) 0.14 SMC3 2 (2) 7 (4) 0.7 CEBPA 3 (3) 13 (7) 0.28 NPM1 5 (5) 54 (30) < q23-rearranged 0 (0) 11 (6) CBF-rearranged 0 (0) 19 (9) < Odds ratio Clinically-defined de novo AML, Age De novo/pan-aml Secondary-type TP53 mutated Months Lindsley RC, et al., Blood 2015;125(9);

33 TP53 MUTANT AND SECONDARY AML AS SPECIAL CASES? From N Engl J Med, Welch JS, et al., TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes, 2016;(21): Copyright 2016 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

34 Overall survival (%) OLDER PATIENTS SECONDARY AML AS SPECIAL CASES? Overall survival saml patients Deaths / N Median in months 7+3:sAML 18 / (1.4, 7.5) CPX-351:sAML 23 / (9.1, 17.5) Log rank P=value = Months from randomisation Lancet JE, et al., Blood 2014;123(21):

35 OLDER PATIENTS SECONDARY AML AS SPECIAL CASES? Phase 3 study of CPX-351 (NCT ) Reported at ASCO 2016 Patients aged with newly diagnosed high risk (secondary) AML CPX-351 treatment resulted in superior outcomes OS (HR=0.69; P=0.005; median OS 9.56 vs months) EFS (HR=0.74; P=0.021) CR+CRi response (47.7% vs. 33.3%; P=0.016) CPX-351 FDA and EMA approved 2017 for treatment of older patients with t-aml or AML-MRC

36 CONSOLIDATION THERAPY YOUNGER PATIENTS Favourable-risk genetics 2-4 cycles of intermediate dose cytarabine Intermediate-risk cytogenetics Allogeneic transplant 2-4 cycles of intermediate dose cytarabine Adverse-risk cytogenetics Allogenic transplant

37 CONSOLIDATION THERAPY OLDER PATIENTS Favourable-risk genetics 2-4 cycles of intermediate dose cytarabine Intermediate/Adverse-risk cytogenetics No established value of consolidation therapy Consider allogeneic transplant or investigational therapy

38 THE RELAPSED REFRACTORY PATIENT For patients fit enough then reinduction followed by allogeneic transplant Multiple reasons why this may not be possible Patients should be considered for novel agents

$THE RELAPSED REFRACTORY PATIENT Enasidenib FDA and EMA approved 2017 for relapsed/refractory IDH2 mutant AML Republished with permission of American Society of Hematology from$

39 THE RELAPSED REFRACTORY PATIENT Enasidenib FDA and EMA approved 2017 for relapsed/refractory IDH2 mutant AML Republished with permission of American Society of Hematology from Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia Stein E, et al., Blood 2017;130(6):722 31; permission conveyed through Copyright Clearance Center, Inc.

40 MULTIPLE NEW AGENTS IN DEVELOPMENT IDH1 inhibitors New inhibitors of FLT3 BET bromodomain inhibitors DOT1L inhibitors HDAC inhibitors BCL-2 inhibitors Inhibitors of splicing factors

41 SUMMARY Treatment for AML is actually changing 4 new treatments regulatory approved in the last 12 months Precedent set Many encouraging signs of further targeted therapies

42 THANK YOU!

Kevin Kelly, MD, Phd Acute Myeloid and Lymphoid Leukemias

Kevin Kelly, MD, Phd Acute Myeloid and Lymphoid Leukemias Relevant financial relationships in the past twelve months by presenter or spouse/partner. Speakers bureau: Novartis, Janssen, Gilead, Bayer The