Acute Leukemia: AML, APL and ALL. Martin S. Tallman, M.D. Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY

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1 Acute Leukemia: AML, APL and ALL Martin S. Tallman, M.D. Memorial Sloan-Kettering Cancer Center Weill Cornell Medical College New York, NY 11 th Annual Indy Hematology Review March, 2015

2 Practice Changing Treatments in AML Allogeneic Transplant Dauno Intensification 7+3 Ara-C Consol Thomas et al. NEJM, 1979; Mayer et al. NEJM, 1994; Fernandez et al. NEJM, 2009

3 Acute Myeloid Leukemia CR: DFS (5 yrs): 60-80% ages % ages >60 40% ages 60 15% ages >60

4 Survival of Newly Diagnosed AML Age Probability ECOG Data (n=2,441) Year Tallman, Gilliland, Rowe Blood, 2005 and update

5 Survival of Newly Diagnosed Age > Probability ECOG Data (n=1,528) Year Tallman, Gilliland, Rowe Blood, 2005 and update

6 Progress in AML in the Last 40 Years Insights into genetic pathogenesis/integrated genetic profiling Drug development Hematopoietic cell transplantation New induction strategies Less intensive treatment for older adults Early biomarkers of MRD

7 Distribution of Cytogenetically and Molecularly Defined Risk Groups in AML 14% Other adverse 5% MLL-PTD 3% inv(3)/t(3;3)/evi-1 ADVERSE 34% 12% FLT-ITD/ NPM1 wt t(15;17)/pml-rara 11% t(8;21)/runx1- RUNX1-T1 8% Inv(16)/t(16;16)/ CBFB-MYH11 5% FAVORABLE 45% NPM1 mut/ FLT3-ITD neg/wt1 wt 18% INTERMEDIATE 21% CEBPα mut (biallelic)/ FLT3-ITD neg 3% Grimwade Hematology Am Soc Hematol Educ Program, 2009 Grimwade Hematology Am Soc Hematol Educ Program, 2009

8 The Company One Keeps Says a Lot We judge a man by the company he keeps The same appears to be true for genetic mutations!

9 Gene Mutations Clinically Important in Everyday Practice Today Gene Incidence Impact FLT3-ITD 25% Unfavorable NPM1 33% Favorable CEBPα (biallelic) 8% Favorable C-KIT (for CBF) 15% Unfavorable

10 Gene Mutations Clinically Important in Everyday Practice Tomorrow Gene Incidence Associations Impact IDH1/2 8%/15% NPM1+/FLT3- Favorable DNMT3A 22% Intermed-risk Unfavorable TET2 10% NPM1 Unfavorable ASXL1 4% Intermed-risk Unfavorable

11 Modified Risk Model For FLT3-ITD-neg, Intermediate Risk AML Group 1 (favorable): IDH2/NPM1 mutant Group 3 (poor-risk): TET2, PHF6, ASXL1, MLL-PTD mutations P<0.001 p-.001 Group 2: all others Patel et al. NEJM, 2012

12 Multivariate Model for FLT3-ITD-pos Intermediate Risk AML Group 1 (favorable): CEBPA P<0.01 CEBPA Group 3 (poor-risk): TET2,trisomy 8, DNMT3A R882, or MLL-PTD Group 2: all others P<.01 TET2, MLL-PTD, tri8, DNMT R882 Others Can discriminate patients with FLT3-mutant disease with much poorer outcome than others Patel et al. NEJM, 2012

13 Areas of Focus at ASH 2014 New insights into outcomes with established agents What is optimal dose of dauno in AML induction? Can we improve on hypomethylating agents? Are peds-inspired protocols standard for AYA in ALL? Combinations of agents with known activity Is ATRA + ATO in low-risk APL new standard? What is best treatment for high-risk APL? Drug development Dasatinib in CBF AML; SGN33A, EPZ-5676, AG-221, ABT-199, Sorafenib in AML; blinatumomab in ALL

14 NCRI AML17 Trial (v. 7.0)

15 AML17: 90mg/m 2 vs 60mg/m 2 OS by Risk Group Burnett et al. ASH, 2014

16 AML17: 90mg/m 2 vs 60mg/m 2 ITD mutant Burnett et al. ASH, 2014

17 Conclusions Randomized data indicate that a 90mg/m 2 dose level is superior to 45mg/m 2 In the AML17 trial, no evidence, overall or in any subgroup, that 90mg/m 2 is superior to 60mg/m 2 90mg/m 2 may give late benefit in FLT3 ITD mutated patients BUT this trial was complicated! Everyone received a second course of induction (dauno 50 x 3) AND there were multiple randomizations in induction (GO, FLT3 inhib, mtor) and consolidation

18 High Dose Daunorubicin Improves Survival in AML up to Age 60, Across All Cytogenetic Risk Groups Including Patients with Unfavorable Cytogenetic Risk, and FLT3-ITD Mutant AML: Updated Analysis from Eastern Cooperative Oncology Trial 1900

19 Update: DNR 90 improves OS in FLT3-ITD+ AML DNR 90: 4-year OS of 28%. DNR 45: 4-year OS of 17%. Probability of Overall Survival n=147 P=0.009 DNR 90 DNR 45 Median OS 15.2 mo 10.1 mo Months Luskin et al. ASH, 2014

20 Benefit of DNR 90 Conclusions of E1900 Update DNR 90 benefits patients age <50 years and intermediate cytogenetic AML. With longer follow-up, DNR 90 now also benefits patients with any cytogenetic risk, and patients with FLT3-ITD, DNMT3A, or NPM1, including patients age DNR 90 (vs 45) necessary for favorable prognostic impact of an NPM1 mutation. DNR 90 should be the standard for all patients up to age 60 who are receiving dauno/cytarabine (3+7) induction. Fernandez et al. N Eng J Med 2009, Patel et al. N Eng J Med 2012; Luskin et al. ASH, 2014

21 APL 0406 Study: Treatment Induction Consolidation ATO arm ATO ATRA ATO ATO ATO ATO 4 weeks on / 4 weeks off R Until CR 2 weeks on / 2 weeks off Induction Consolidation Maintenance Chemo Arm IDA IDA MTZ IDA ATRA ATRA ATRA ATRA Until CR 3 monthly cycles MTX + 6MP ATRA 2 years Lo Coco et al. NEJM, 2013

22 APL 0406 Study (GIMEMA/SAL) Inclusion Criteria Newly diagnosed APL Age years WBC 10 x 10 9 /L WHO performance status 2

23 Event-Free Survival Primary objective Initial series Final series 97.1% 85.6% 98% 84.9% p=0.02 p=<0.001 Lo Coco et al. NEJM, 2013 and Platzbecker et al. ASH, 2014

24 A L L G AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP Final analysis of the APML4 trial All-trans retinoic acid, intravenous arsenic trioxide and idarubicin as initial therapy for acute promyelocytic leukemia Harry J Iland Marnie Collins Mark S Hertzberg Michael Seldon Andrew P Grigg Frank Firkin Shane G Supple Lynda J Campbell Kenneth F Bradstock John F Seymour on behalf of the Australasian Leukaemia and Lymphoma Group

25 A L L G AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP APML3 historical control ATRA IDA ATRA IDA ATRA MTX 6MP Induction Consolidation Maintenance ATRA ATRA APML4 IDA ATRA MTX 6MP ATO ATO

26 APML4 DFS - Sanz risk category % alive and relapse-free Low 100% High 95% Intermediate 93% P [trend] = Years from documented HCR Iland et al. ASH, 2014

27 High-risk APL ATRA + Risk-Adapted Chemo vs APML4 Number Median follow-up (months) IDA equivalent 4 (mg/m 2 ) AraC (g/m 2 ) DFS CIR OS PETHEMA LPA % 14% 79% European APL ( 60 yrs) % 88% GIMEMA AIDA ( 61 yrs) % 9% 83% ALLG 4 APML % 5% 87% 1 Sanz et al. Blood, 2010; 2 Adès et al. Am J Hematol, 2013 ; 3 Lo Coco et al. Blood, Sanz et al. Best Pract Res Clin Haematol, 2003; Iland et al. ASH, 20140

28 Conclusions A L L G AUSTRALASIAN LEUKAEMIA & LYMPHOMA GROUP Mature data indicate the APML4 regimen feasible, tolerable and highly effective, with low early death rate Incorporation of ATO in induction and consolidation allows substantial reduction in total anthracycline exposure, and eliminates need for high-dose cytarabine in patients with high-risk disease Results support inclusion of ATO in both induction and consolidation as standard of care for initial therapy of high-risk as well as standard-risk APL

29 Mechanism-Based Therapeutic Strategies Agent Target Mechanism Comment Status Dasatinib C-KIT Kinase inhibitor Phase II trials encouraging Phase III planned Sorafenib FLT3-ITD Kinase inhibitor CRs as single agent Phase III: EFS benefit, not OS EPZ-5676 DOT1L Histone methyltransferase inhibitor H3K79 methylation by DOT1L responsible for disease phenotype Phase I/II trial accruing AG-221 IDH2 Metabolic enzyme inhibitor First in man Phase I/II trial underway

30 Adding the KIT inhibitor Dasatinib to Chemotherapy Overcomes The Negative Impact of KIT Mutation/overexpression in Core Binding Factor Acute Myeloid Leukemia: Results of the CALGB (Alliance) Guido Marcucci, Susan Geyer, Weiqiang Zhao, Andrew J. Carroll, Donna Bucci, Geoffrey L. Uy, William Blum, Timothy Pardee, Meir Wetzler, Wendy Stock, Ann-Kathrin Eisfeld, Clara D. Bloomfield, Richard M. Stone, Richard A. Larson on behalf of the Alliance for Clinical Trials in Oncology

31 Dose and Schedule Treatment Drug Dose Route Schedule Induction: Cytarabine 200 mg/m2/d IV Days 1-7 Daunorubicin 60 mg/m2/d IV Days 1-3 Dasatinib 100 mg/d PO Days 8-21 Consolidation: Cycles #1, 2, 3, 4 HiDAC* 3000 mg/m2/12h PO Days 1,3,5 Dasatinib 100 mg/d PO Days 6-28 Maintenance: Dasatinib 100 mg/d PO 1 year * 1000 mg/m2/12h for >60 yrs

32 Clinical Outcomes Median Follow-up N= months (range ) 30-day Survival Rate 97% CR Rate 90% 24-month DFS Rate 71% (95%CI: 58-88) 24-month OS Rate 85% (95%CI: 76-94) Marcucci et al. ASH, 2014

33 DFS and OS KIT mutated vs KIT wt Marcucci et al. ASH, 2014

34 Summary Rapid screening for CBF AML feasible within a cooperative group Dasatinib plus chemotherapy tolerable for CBF AML, including older patients. There were no unexpected toxicities Clinical outcomes at least comparable to those historically observed in this patient population. In younger patients, outcomes at 24 months appear somewhat better, but it is too early to draw final conclusions The outcome of patients with KIT mutated treated on CALGB is excellent and not worse than that of patients with KIT wt especially when only younger patients considered Similarly, higher KIT expression levels do not impact negatively on outcome in patients treated on CALGB 10801

35 Sorafenib versus Placebo in Addition to Standard Therapy in Adult Patients 60 Years with Newly Diagnosed Acute Myeloid Leukemia: Results from the Randomized-Controlled SORAML Trial C Röllig, C Müller-Tidow, A Hüttmann, V Kunzmann, CD Baldus, CH Brandts, A Krämer, K Schäfer-Eckart, A Neubauer, SW Krause, A Giagounidis, W Aulitzky, U Krug, T Illmer, M Bornhäuser, M Schaich, S Parmentier, C Thiede, M von Bonin, J Schetelig, M Kramer, H Serve, WE Berdel, and G Ehninger for the SAL Study Group

36 SORAML Design Induction I Induction II Consolidation Maintenance DA I SORA DA II (HAM) SORA 3 x HiDAC SORA SORA 12 months AML Day 16: Response? allo SCT: IR with sibling donor HR with donor DA I PLACEBO DA II (HAM) PLACEBO 3 x HiDAC PLACEBO PLACEBO 12 months

37 Outcome Response and Transplantation Sorafenib (n=134) Placebo (n=133) Complete remission all 81 (60%) 78 (59%) Complete remission FLT3-ITD 13 (57%) 12 (52%) Stem cell transplantation in 1 st CR 42 (31%) 35 (26%) Stem cell transplantation in relapse 39 (29%) 66 (50%)

38 Primary Endpoint Event-Free Survival (ITT, SCT censored) year EFS Placebo vs Sora: 22% vs 40% Probability (%) Sorafenib Median EFS Placebo vs Sora: 9 m vs 21 m p= Placebo 36 Median follow-up 36 months Time (months)

39 100 Overall Survival (ITT, no SCT censoring) 80 Sorafenib 3-year OS Placebo vs Sora: 56% vs 63% Probability (%) Placebo Median OS Placebo vs Sora: not reached 20 p=0.382 Median follow-up 36 months Time (months)

40 Probability (%) Overall Survival FLT3-ITD (explorative analysis) Sorafenib Placebo 1-year OS Placebo vs Sora: 40% vs 56% Median OS Placebo vs Sora: 19 m vs no reached Time (months) Sorafenib Placebo

41 Discussion Sorafenib plus chemotherapy feasible in younger AML patients Significant and relevant EFS and RFS prolongation, no OS benefit (yet?) Higher risk of fever, diarrhea, bleeding events, liver toxicity, handfoot syndrome and rash Potential reasons for efficacy of sorafenib: Kinase inhibition of Raf, VEGFR, PDGFR (and others?) FLT3wt inhibition Deeper molecular remission in the sorafenib arm?

42 Future Directions in FLT3 Inhibition Novel inhibitors: PLX3397 (inhibits FMS, KIT, FLT3), ASP2515 Combinations with chemotherapy Novel agents to overcome resistance Constitutively activating mutations at FLT3 activation loop residue D835 assoc. with resistance to AC220 Development of agents active against D835: Crenolanib Smith et al. ASH 2011 ; Barton et al. ASH, 2011 ; Smith et al. ASH, 2013; Gao et al. ASH, 2013; Randhawa et al. ASH, 2014

43 DOT1L Inhibitor For MLL-Assoc. Leukemias MLL-fusion proteins interact with DOT1L Aberrant recruitment of DOT1L methylation of H3K79 sustained expression of MLL target genes leukemic phenotype Hypothesis that inhibition of DOT1L activity may treat leukemia with MLL translocation Deshpande et al. Trends in Immunology, 2012

44 Translocations Involving MLL Gene Seen in 70% of infant ALL (less than age 1) and has poor prognosis Seen in approx. 10% of de novo adult AML Seen in therapy-related AML More than 60 known fusion partners Most common: t(4;11), t(9:11), t(11;19), t(10;11), t(6;11) Krivtsov and Armstrong Nat Reviews Cancer,

45 First in Human, Phase I-Clinical Activity 9 patients (8/34 MLL-r) had either: marrow response and/or resolution of leukemia cutis and/or leukocytosis or differentiation 45 \ Dose mg/m 2 /day Number of patients (n=42) Marrow Response (n=3) Leukemia cutis resolved (n=2) Leukocytosis or Differentiation (n=8) CR (28 day CIV) 23 1 PR - 2 Stein et al. ASH, 2014

46 Clinical Activity: Marrow Response and Leukemia Cutis Disease MLL-r Dose MPN (CMML) AML AML t(11;19) t(11;19) Other: trisomy mg/m 2 /day 54 mg/m 2 /day 90 mg/m 2 /day Response (weeks on study) Cytogenetic CR (27) Morphologic CR (16*) PR (12) Extramedullary Disease Resolved leukemia cutis NA NA AML t(6;11) 36 mg/m2/day - (6) Resolved leukemia cutis * Off-study for Hematopoietic Cell Transplant Stein et al. ASH, 2014

47 Cycle 1 day 1 Cycle 2 day 1 Cycle 3 day 1 Cycle 4 day 1

48 Conclusions Dose escalation through 90 mg/m 2 /d without reaching protocoldefined MTD Acceptable safety profile Clinical activity, including CRs and clonal differentiation, observed in heavily pre-treated MLL-r patients Currently enrolling up to 20 patients at 54 mg/m 2 /d based on observed clinical responses and clinical activity Molecular characterization of patient samples to identify patient selection and response biomarkers myaml panel 193 commonly mutated genes in AML Whole genome RNA-Seq Pathway analysis

49 Breakdown of IDH Mutations in AML IDH1m (7.5%) in AML IDH2m (15%) in AML R132L 6% R132S 5% R132C 34% R140W <1% R172M <1% R172K 20% R140L 2% R140G <1% R132H 41% R140Q 77% R132G 8%

50 Role of IDH in Malignancy IDH is critical metabolic enzyme in the citric acid cycle IDH1 in cytoplasm and IDH2 in mitochondria Cancer-associated IDHm produces 2- hydroxyglutarate (2-HG) and blocks normal cellular differentiation

51 Best Overall Response by Cumulative Daily Dose* 75 mg 100 mg 150 mg Total (n=9) (n=14) (n=22) (n=45 efficacy evaluable) CR CRp mcr CRi PR SD PD Disease Not Evaluable Overall Response Rate** 4/9 (44%) 9/14 (64%) 12/22 (55%) 25/45 (56%) 95% CI (40%, 70%) * Includes patients with a Day 28 response assessment as of October 1, Excludes 12 on-going patients with Day 28 not yet available and 16 patients off study without a Day 28 assessment. Stein et al. ASH, 2014

52 Conclusions AG-221: safe and well tolerated to date 2-HG inhibited at greater than 90% of baseline in patients with R140Q mutations: - ~50% inhibition in 1 evaluable R172K patient (CRp) Consistent with preclinical models, IDH2 inhibition leads to profound differentiation effect 5 of 7 patients who completed 1 cycle achieved CR or CRp Dose escalation continues; expansion cohorts to begin in late 2014 These data provide early validation of mutant IDH2 as therapeutic target in AML and MDS

53 Novel Drug Development Target NFkB/CD74 BCL-2 Topo II Histone deacetylase PLK-1 PI3/PLK/BRAF/RAS BET Aminopeptidase Agent Bortezomib ABT-199 Vosaroxin Pracinostat Volasertib Rigosertib BET inhibitor Tosedostat

54 Adult ALL Breakthroughs Pediatric or pediatric inspired regimen in AYA patients (Age < 39 years; upper age for safety unclear) Genomic alterations amenable to inhibition with approved tyrosine kinase inhibitors (TKIs) (Ph + and Ph-like ALL) Effective technologies to modify autologous T cells to target and kill and B ALL cells CAR-T cell Blinatumumab

55 Event Free Survival 2 yr EFS = 66% All Patients Stock et al. ASH, 2014

56 Blinatumumab Mechanism V H V L α-cd3 Antibody CD3 T Cell Blinatumomab BiTE V H Target Antigen CD19 Tumor Cell Redirected Lysis VL α-cd19 Antibody Blinatumomab (MT103) is a bispecific T-cell engager antibody designed to direct cytotoxic T-cells to CD19 expressing cancer cells Bargou et al. Science 2008

57 BLAST: Blinatumomab Phase 2 Study in ALL With MRD CR in which Blina was given Baseline, (%) MRD Response (%) First Second Third 2 50 Baseline MRD levels >/=10-1 to < >/=10-2 to > >/=10-3 to Goekbuget et al. ASH, 2014

58 How Can We Get Closer To Curing Acute Leukemias? Carry out mutational profiling on all patients Address high-risk populations Test novel therapies earlier in the natural hx of disease, likely ultimately with chemotherapy Exploit drug discovery and epigenetic/stem cell targeted strategies Make national/international collaborations/registries a priority

59 Acknowledgments Leukemia Service Memorial Sloan Kettering Cancer Center Eytan Stein, Ross Levine, Scott Armstrong Ross levine, M.D. Eytan Stein, M.D. Scott Armstrong, M.D. Ph.D. Colleagues who sent me slides from ASH