Acute Myeloid Leukemia

Transcription

1 Acute Myeloid Leukemia Guido Marcucci, M.D. Director, Gehr Family Center for Leukemia Research Hematologic Malignancies and Stem Cell Transplantation Institute City of Hope

2 Acute Myeloid Leukemia Gene mutations Ç ç

3 In 2015, approximately 20,000 new cases of AML and 10,000 disease-related deaths occurred in the United States alone The median age at diagnosis is 67 years and the incidence of the disease increases with age AML comprises several distinct entities that are molecularly heterogeneous. Molecular heterogeneity is clinically relevant, is associated with outcome and has been used for treatment selection Despite molecular risk-based approaches, however, only approx. 40% of younger (<60 year/old) and 10% of older (>60 years) achieved cure when treated with currently available chemotherapies Allogeneic HCT may improve cure rate, but the long-term success may be somewhat limited by transplant-related toxicity and death

4 Age, Survival, and Treatment Era in AML 1. Kantarjian H et al. Cancer. 2010;21:

5 Principle of AML Treatment for Younger Patients Remission consolidation D i a g n o s i s Remission induction 7+3 x 1-2 courses CR Favorable Clinical Trials Intermediate Adverse High-dose Ara-C Allo HCT Relapse No CR Salvage chemotherapy

6 Principle of AML Treatment for Older Patients Remission consolidation D i a g n o s i s Low intensity 7+3 x 1-2 courses CR Low intensity Clinical Trials Modified HiDAC RIC Allo HCT Relapse No CR Clinical Trials Best Supportive Care

7 Treatment questions Is a high risk AML? Chemotherapy dosage? MRD status? Type of HCT? Molecular targeting therapeutics What? How? When?

8 Current Approaches to AML Based on prognostic and predictive factors: Age Chemotherapy Antecedent hematologic disorder Risk Factors in AML Comorbid conditions Cytogenetics Molecular markers Minimal residual disease 1. NCCN Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. Version Grimwade D, Hills RK. Hematology Am Soc Hematol Educ Program. 2009: Estey EH. Am J Hematol. 2013;88:

9 Frequency Distribution of Major Chromosome Abnormalities among 4246 Adults with AML not Therapy-related 42% - normal karyotype 20% - other aberrations 5% - t(8;21) 12% - complex karyotype CALGB 8461, % - inv(3)/t(3;3) 0.5% - t(6;9) 1.7% - t(9;11) 2.4% - t(11q23) 9% - t(15;17) 6% - inv(16)

10 Impact of cytogenetics F I A David Grimwade et al. Blood 2010;116: by American Society of Hematology

11 *Reported in order of discovery as prognostic (separately for mutations and expression) Green ( ) ** First molecular prognostic marker in CN-AML *** Recommended for study in CN-AML by WHO 2008, ELN 2009, NCCN 2011 Prognostic Single-gene Markers in Primary Adult CN-AML Gene Symbol Gene Location Prognostic Impact Frequency MLL-PTD** (1998) 11q23 Adverse Neutral 5-10% FLT3-ITD*** (1999) 13q12 Adverse 30-35% FLT3-TKD (2002) 13q12? Adverse ~10% CEBPA mutations*** (2002) 19q13.1 Favorable 10-20% NPM1 mutations*** (2005) 5q35 +/-Favorable 55-65% WT1 mutations (2007) 11p13 Adverse 6-12% IDH mutations (IDH1 & IDH2) (2009) 2q33.3 & 15q26.1 +/- Adverse 25-35% RUNX1 mutations (2009) 21q22.12 Adverse 8-16% TET2 mutations (2010) 4q24 +/- Adverse 18-30% ASXL1 mutations (2010) 20q11.21 Adverse 4-16% DNMT3A mutations (2011) 2p23.3 Adverse ~35%

12 ELN Clinical Practice Guidelines: New Recommended Standardized Reporting for Correlation of Cytogenetic & Molecular Genetic Data with Clinical Data in AML* Genetic Group Subsets Favorable Intermediate-I Intermediate-II Adverse 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 (normal karyotype) Mutated CEBPA (normal karyotype) Mutated NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 without FLT3-ITD (normal karyotype) t(9;11)(p22;q23); MLLT3-MLL; Cytogenetic abnormalities not classified as favorable or adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 t(6;9)(p23;q34); DEK-NUP214 t(v;11q23); MLL rearranged 5 or del(5q); 7; abn(17p); complex karyotype ( 3) 2 *International expert panel recommendations on behalf of ELN (Blood 115:453-74, Epub 2009 Oct 30)

13 Overall Survival ELN Genetic Groups Associate with Overall Survival among Younger and Older Patients 1.0 P <.001 < 60 yrs 1.0 P < yrs 0.8 Favorable (n=339) 0.8 Favorable (n=145) Intermediate-II (n=156) Intermediate-I (n=144) Intermediate-II (n=222) Intermediate-I (n=136) Adverse (n=179) Years Adverse (n=229) Years

14 Morphology Molecular characterization Next Generation Sequencing Cytogenetics Immunophenotype

15 The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:

16 Döhner H et al. N Engl J Med 2015;373: Mutations Themes in AML

17 Unsupervised RNA and mirna Expression Patterns The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:

18 Unsupervised Analysis of DNA Methylation The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:

19 Integrated Genetic-Epigenetic Molecular (GEM) Score Mutational Analysis Methylome Analysis Gene Expression Analysis Identification of unique Differentially Methylated Regions (DMRs) associated with each prognostic gene mutation Identification of the DMRs whose methylation levels impact on outcome Identification of genes whose both promoter DMRs and expression impact on outcome CALGB 8525,8923,9420,9720,10201 Marcucci, et al, JCO 2013

20 OS of Older Patients With CN AML: Impact of Seven Genes GEM Score 1 Gene a CD34 Chromosome Location 1q32 RHOC 1p13.1 SCRN1 F2RL1 7p14.3-p14.1 5q13 FAM92A1 8q22.1 MIR155HG 21q12.3 VWA8 13q14.11 Outcome P-value No. 0-1 of 2-3 genes CR < % 80% 54% 25% a Genes are ordered according to decreasing gene expression HRs. 1. Marcucci G et al. J Clin Oncol. 2014;32:

21 Chemotherapy : What is the best dose? The standard combination is the 7+3, continuous infusion of cytarabine at the dosage of 100 or 200 mg/m 2 per day on days 1 to 7 Anthracycline ( daunorubicin or idarubicin on days 1 to 3) CR is expected in 60-85% younger and 40-60% older High-dose cytarabine-based regimens achieve high CR rates, but it remains to be determined if higher than standard dose cytarabine without worsening toxicity

22 Randomized Trials of Escalated Daunorubicin E1900 trial: 90mg/m 2 vs 45mg/m 2 in adults <60 years (n=657) Fernandez HF et al. NEJM, 2009;361: CR 70% vs 57%/ OS 38% vs 23% -benefit in <50 s, intermediate cytogenetics HOVON trial: 90mg/m 2 vs 45/m 2 in adults >60 years (n=813) Lowenberg B et al. NEJM, 2009;361: CR: 64% vs 54%/ OS: no difference - benefit in yrs/ trend in CBF subgroup (35% vs 23%) Korean Trial: 90mg/m 2 vs 45mg/m 2 in adults <60 years (n=383) Lee J-H et al. Blood, 2011;118: OS: 51% vs 34% - benefit due to intermediate risk

23 AML17: DA60 vs DA90 Censored at Transplant

24 Probability of DFS According to Age and Consolidation Dosage of Cytarabine All Younger Older Mayer RJ et al. N Engl J Med 1994;331:

25 Tyrosine Kinase Inhibitors

26 CALGB 10603: Prospective Phase III, double-blinded randomized study of induction and consolidation +/- Midostaurin (PKC412) in newly diagnosed patients < 60 years old with FLT3 mutated AML 26 R E G I S T E R FLT3 ITD or TKD R A N D O M I Z E DNR ARA-C PKC412 DNR ARA-C PLACEBO CR CR HiDAC PKC412 HiDAC PLACEBO X 4 X 4 PKC412 MAINTENANCE 12 months PLACEBO MAINTENANCE 12 months Not on STUDY: FLT3 WILD TYPE Study drug is given on Days 8-21 after each course of chemotherapy, and Days 1-28 of each 28 day Maintenance cycle.

27 27 Overall Survival without transplant censoring (p=0.0076) censored at the time of transplant (p=0.05)

28 Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial CR 59%vs 60% (P=.7) median EFS 9.2 vs 20.5 months (p=0.013) 3-year EFS 22% vs 40% median RFS 23 months vs not reached after corresponding to a 3-year RFS of 38% vs 56%, (p=0.017) median OS not reached in either arm; 3-year OS 56% vs 63% (p=0.382). In FLT3-ITD positive patients, no difference in EFS.

29 Rationale for Using TKI in CBF AML CBF AML: a favorable cytogenetic subset with t(8;21) [RUNX1/RUNX1T1] or inv(16)[cbfb/myh11] KIT mutations, which result in aberrant tyrosine kinase activity and leukemia growth, are present in ~ 25-30% of CBF AML and associate with worse outcomes Higher expression of wild-type KIT is found in CBF AML and may associate with worse outcome Therefore, novel therapeutic approaches targeting aberrantly activated KIT are being tested

30 CALGB A Phase II Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy Plus Dasatinib in Newly Diagnosed CBF AML P R E - R E G I S T R A T I O N S C R E E N I N G R E G I S T R A T I O N Ara-C Daunorubicin + Dasatinib X 1-2 courses Remission induction CR High-dose Ara-C + Dasatinib X 4 cycles Remission consolidation Dasatinib X 12 months Maintenance

31 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)

32 C10801vs C9621 & C19808 CALGB CALGB 9621 & (YOUNGER ONLY) Younger C1980-Younger Older C9621-Younger Younger C1980-Younger Older C9621-Younger

33 CD33 Antibodies

34 Gemtuzumab Ozogomycin (Mylotarg) ALFA Newly-diagnosed Age ± GO GO dose 3 mg/m 2 Median OS improved MRC AML16 2 Untreated, older AML Chemo ± GO GO dose 3 mg/m 2 OS improved Meta-analysis 3 Five RCTs (3,325 patients) No improvement in CR rate OS rate improved Best results in CBF AML Favorable-Risk AML 1. Castaigne S et al. Lancet. 2012;379: Burnett AK et al. Br J Haematol. 2012;158: Hills RK et al. Lancet Oncol. 2014;15:

35 Targeting CD33 Antibody-drug conjugate SGN-CD33A AML Byte CAR-T cells Clinical trials: single agents with 7+3 with hypomethylating with allohct

36 Hypomethylating Agents

37 Hypomethylating agents in older patients with AML OS in Patients With AML-MRC: AZA vs CCR 1 Decitabine vs Total TC in AML 65 Years 2 1. Dombret H et al. Blood. 2015;126: Kantarjian HM et al. J Clin Oncol. 2012;30:

38 DNMT3A Mutations As Response Predictors for Hypomethylating Agents in AML 46 mostly older AML patients (median age, 74 years) treated with 20 mg/m 2 decitabine on a 10-day schedule in phase I/II trials. CR rate of entire cohort: 41% DNMT3A mutations found in 17% of patients DNMT3A mutations were associated with P=.05 a better response to decitabine (P=.05) CR rate 100% 80% 60% 40% 20% 0% DNMT3Amutated n=8 CR rate P=.05 75% 34% DNMT3Awild-type n=38 DNMT3Awild-type n=38 Metzeler et al. Leukemia, 2012

39 Approaches to Relapsed or Primary Refractory AML 20-30% of AML patients may be refractory to initial remission induction chemotherapy Disease relapse occurs within 3 years after diagnosis for most patients with AML A short duration of remission (i.e., <6 months), adverse genetic factors, prior allosct, older age, and poor general health status are the main negative determinants of outcome after relapse There have been few controlled trials providing data regarding the best salvage regimen for AML patients with refractory or relapsed disease Commonly used intensive salvage regimens are designed to achieve a CR and proceed to allohsct in order to maximize the chances of durable remission

40 Minimal Residual Disease Method Target Sensitivity Strengths and Weaknesses Flow cytometry Leukemia-associated aberrant immunophenotype 1/10,000 (0.01%) Applicable to most AML cases RQ-PCR Fusion transcripts, gene mutations, overexpressed genes 1/1,000,000 (0.0001%) Highly sensitive A B C D (A) after induction cycle 1, (B) after cycle 2, (C) after consolidation (D) after cycle 2, good risk; (E) after cycle 2, intermediate risk; (F) after cycle 2, poor risk. Flow 1. Ravandi F, Jorgensen JL. J Natl Compr Canc Netw. 2012;10: Terwijn M et al. J Clin Oncol. 2013;31: Krönke J et al. J Clin Oncol. 2011;29: E F

41 All pts Minimal Residual Disease in Blood after the Second Cycle of Chemotherapy and Clinical Outcomes in NPM1 positive patients Ivey A et al. N Engl J Med 2016;374: w/o FLT3-ITD w FLT3-ITD w/o DNMT3A w DNMT3A

42 AML:New Drugs Agent Mechanism of action Comments Clinical trials Multicenter randomized phase III trial in combination with cytarabine did not Vosaroxin meet primary end NCT ; Cytotoxic; DNAintercalating agent point, but NCT ; demonstrated NCT improved outcomes in older patients. Lower intensity trials ongoing. CPX-351 Cytotoxic; liposomal formulation of cytarabine and daunorubicin in 5:1 molar ratio Cytotoxic; orally Sapacitabine bioavailable novel nucleoside analog SGI-110 Volasertib Cytotoxic; longer acting hypomethylating agent Randomized trial of CPX-351 versus demonstrated NCT ; improved outcomes in NCT patients with secondary AML. Single-agent sapacitabine had outcomes similar to LDAC, but sequential combination study with NCT decitabine showed promising results. A randomized study of this approach is ongoing. Single-agent activity in AML and myelodysplastic syndrome seems promising. A randomized study versus conventional care is ongoing, as are combination studies. A phase II study of volasertib combined Small-molecule inhibitor with LDAC of Polo-like kinase demonstrated improved outcomes over LDAC. A NCT ; NCT ; NCT NCT ; NCT AG-221 AG-120 ABT-199 Sorafenib Small-molecule inhibitor of isocitrate dehydrogenase (IDH)-2 enzyme Small-molecule inhibitor of IDH-1 enzyme Small-molecule BH3 mimetic, inhibitor of BCL-2 Small-molecule multikinase inhibitor with activity against mutant FLT3 (FLT3-ITD) in AML Midostaurin Small-molecule multikinase inhibitor Single-agent studies have reported significant activity in patients with IDH2- mutated AML. Combination studies with conventional chemotherapy have been planned. Single-agent study has demonstrated activity in patients with IDH1- mutated AML. Combination studies are planned. NCT ; NCT NCT Single-agent ABT-199 demonstrated a signal of response in patients with AML, particularly in NCT ; patients with IDH NCT mutations. Combination studies are now underway. Following several single-arm studies, a phase III randomized study of with or without sorafenib demonstrated improved outcomes (but not improved OS) with sorafenib in younger patients with AML. A randomized study in older patients did not show a benefit. Lower intensity therapy such as hypomethylating agents are being studied in combination with sorafenib. Results from a large phase III randomized NCT ; NCT NCT Small-molecule multikinase inhibitor with Quizartinib potent activity against FLT3-ITD Small-molecule kinase inhibitor with activity Crenolanib against mutant FLT3 (both FLT3-ITD and FLT3-D835) ASP2215 FLX925 SGN-33a AMG-330 Small molecule both FLT3 and AXL kinases Small-molecule inhibitor of both FLT3 kinase and CDK4/6 Monoclonal antibodydrug conjugate directed at CD33, carrying a pyrrolobenzodiazepine dimer (toxin) Monoclonal bispecific antibody directed at CD33 and CD3 Single-agent dosefinding studies have demonstrated efficacy, but DLT is QT prolongation. Lower doses of quizartinib have demonstrated similar activity but less toxicity. These are now being studied in combination studies. Single-agent studies have demonstrated activity in heavily pretreated patients; combination studies are now being conducted Single-agent studies are just underway, with preliminary data anticipated. Single-agent studies are just underway, with preliminary data anticipated. Single-agent and combination studies are underway in several clinical settings. Preliminary experience is positive, demonstrating good safety profile and efficacy in clearing bone marrow blasts. Single-agent studies are just getting underway. NCT ; NCT ; NCT ; NCT ; NCT NCT ; NCT ; NCT NCT NCT ; NCT NCT

43 IDH Mutations As a Target in AML IDH is a critical enzyme of the citric acid cycle IDH mutations occur in a spectrum of solid and hematologic tumors IDH2 mutations: 9-13% of AML and 3-6% of MDS IDH1 mutations: 6-10% of AML and 3% of MDS IDH1/2 mutations confer a gain-of-function Increased DNA methylation Impaired cellular differentiation

44 Normal and Aberrant IDH Activities

45 Clinical Impact of Distinct IDH Mutations in AML 1,2 Cytogenic Classification Mutations Overall Risk Profile Favorable Any FLT3/ITD negative Mutant NPM1 and IDH1 or IDH2 Favorable FLT3/ITD negative Wild-type ASXL1, MLL- PTD, PHF6, and TET2 Normal karyotype or intermediaterisk cytogenetic lesions FLT3/ITD negative or positive FLT3/ITD positive FLT3/ITD negative Mutant CEBPA Wild-type MLL-PTD, TET2, and DNMT3A and trisomy 8 negative Mutant TET2, MLL-PTD, ASXL1, or PHF6 Intermediate FLT3/ITD positive Mutant TET2, MLL-PTD, DNMT3A, or trisomy 8, without mutant CEBPA Unfavorable Unfavorable Any 1. Marcucci et al. J Clin Oncol. 2010;28: Patel JP et al. N Engl J Med. 2012;366:

46 Best Overall Response of AG221 by Cumulative Daily Dose 1,a 75 mg (n = 9) 100 mg (n = 14) 150 mg (n = 22) Total (n = 45 efficacy evaluable) CR CRp Marrow CR CRi 1 1 ORR 4/9 6/14 5/22 15/45 (33%) Marrow CR = 5% blasts in BM; no hematological recovery. a Includes patients with a day-28 response assessment as of October 1, Excludes 12 ongoing patients with day 28 not yet available and 16 patients off study without a day-28 assessment. 1. Stein EH et al. ASH Abstract 115.

47 Ongoing Trials and Future Directions AG-120 (orally administered): phase 1 evaluation in subjects with advanced hematologic malignancies with an IDH mutation AG-221 and AG120 tested in combination with chemotherapy AG-221 and AG120 tested in combination with hypomethylating agents

48 Targeting Anti-Apoptotic Mechanisms

49 Background: MOA of Venetoclax (ABT-199/GDC-0199) 1 Pro-apoptotic Proteins (BAX, BAK) An Increase in Bcl-2 Expression Allows the Cancer Cell to Survive Anti-apoptotic Proteins (Bcl-2) 2 Venetoclax Binds to and Inhibits Overexpressed Bcl-2 Venetoclax BH3-only BAK BAX Bcl-2 Bcl-2 3 Apoptosome APAF-1 Cytochrome C Apoptosis is Initiated Active Caspase Procaspase Mitochondria Mitochondria Mitochondria 1. Konopleva M et al. ASH Abstract 118.

50 Overall Activity 1 Response N = 32 (%) Objective response (CR + CRi) 6 (19) CR 2 (6) CRi 4 (13) Response in Patients With IDH Mutations N = 11 (%) Objective response (CR + CRi) 4 (36) CR 2 (18) CRi 2 (18) 1. Konopleva M et al. ASH Abstract 118.

51 Venetoclax/Bcl-2 Inhibition: Ongoing Trials and Future Directions Combination with hypomethylating agents Combination with chemotherapy Combination with IDH inhibitors

52 Younger AML Patients CBF ELN Favorable ELN Intermediate I &II ELN Adverse KIT mutations IDH mutations FLT3 mutations 7+3 Clinical Trials (e.g., 7+3/ molecular therapeutics) 7+3 Clinical Trials (e.g., 7+3/ molecular therapeutics) 7+3 CR CR CR CR CR MRD MRD Clinical Trials (e.g., HiDAC and/or molecular therapeutics) Clinical Trials (e.g., HiDAC and/or molecular therapeutics) Neg Neg HiDAC allohsct allohsct Clinical Trials allohsct

53 Older Fit AML Patients CBF ELN Favorable ELN Intermediate I &II ELN Adverse KIT mutations IDH mutations FLT3 mutations 7+3 Clinical Trials (e.g., 7+3/ molecular therapeutics) 7+3 Clinical Trials 7+3 CR CR CR CR CR MRD MRD Modified HiDAC Clinical Trials (e.g., molecular therapeutics) allohsct Clinical Trials (e.g., IDAC and/or molecular therapeutics) Neg allohsct Clinical Trials allohsct

54 Older AML Patients Unfit or Unwilling to undergo intensive chemotherapy ELN Favorable (not CBF) ELN Intermediate I &II ELN Adverse IDH mutations FLT3 mutations Clinical Trials with (molecularly targeted therapeutics) OR HMAs BSC LDAC

55 Conclusions Exciting time in the treatment of AML because of novel molecular targets and new drugs and new transplant modalities that may lead to implementation of truly personalized therapies Challenge is how to best incorporate into clinical practice: Novel predictive biomarkers New drugs Treatment for MRD Prognostic risk assessment given the emrging predictive biomarkers and molecularly targeting agents