How the Treatment of Acute Myeloid Leukemia is Changing in 2019
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1 How the Treatment of Acute Myeloid Leukemia is Changing in 2019 Guido Marcucci, M.D. Director, Gehr Family Center for Leukemia Research Chair, Dept. Hematologic Malignancies Translational Science City of Hope
2 AML Gene mutations Ç ç
3 In 2018, approximately 19,520 new cases of AML and 10,670 disease-related deaths occurred in the United States alone. Survival for the last 5 years in US 27.4% ( ) Median Age at Diagnosis Median Age at Death
4 Survival has improved in younger, but not in older AML patients 1. Kantarjian H et al. Cancer. 2010;21:
5 Current Approaches to AML is based on prognostic and predictive factors: Clinical Age Chemotherapy Antecedent hematologic disorder Risk Factors in AML Comorbid conditions Cytogenetics Molecular markers Genomic Minimal residual disease
6 Impact of cytogenetics Favorable Intermediate Adverse David Grimwade et al. Blood 2010;116: by American Society of Hematology
7 The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:
8 Nucleophosmin Activated Signaling Mutations Themes in AML Tumor Suppressors DNA Methylation Transcription deregulation Döhner H et al. N Engl J Med 2015;373: Cohesin Chromatin Modification Splicesome
9 Mutations are not mutually exclusive in AML Chen S-J et al Nature Genetics 45, (2013)
10 Cytogenetic/Molecular classes of AML Döhner et al. Blood 2017;129: by American Society of Hematology
11 2017 ELN risk stratification by genetics
12 Validation of the ELN 2017 Classification for AML with Intermediate Risk Cytogenetics with or without NPM1-Mutations and High or Low Ratio FLT3-ITDs Schetelig et al ASH 2017 low ratio (LR) and high allelic ratio (HR) mutations using a cut-off of 0.5
13 Morphology Diagnostic work-up for AML Immunophenotype Cytogenetics Molecular characterization Next Generation Sequencing HLA typing Human leukocyte antigen (HLA) typing for patient with potential hematopoietic cell transplantation (HCT) KIT, FLT3 [ITD and TKD], NPM1, CEBPA, IDH1, IDH2, TP53,
14 Until 2016 FDA approved drugs for AML Year Cytarabine (ara-c) 1969 Daunorubicin 1979 Mitoxantrone 1987 Idarubicin 1990
15 Seven new drugs approved for AML Vyxeos (CPX-351)- liposomal cytarabine and daunorubicin at a fixed 5:1 molar ratio Gemtuzumab ozogamicin (Mylotarg)- humanized antibody against CD33 and conjugated to calicheamicin Midostaurin - a multikinase inhibitory activity against FLT3, PDGFR, CDK1, KIT and VEGF Gilteritinib, a selective inhibitor of FLT3 Enasidenib (AG221)- IDH2 inhibitor Ivosidenib (AG120)- IDH1 inhibitor; (FDA) has granted orphan drug and fast track designations Venetoclax - a BCL-2 inhibitor Glasdegib- inhibitor of the Sonic hedgehog pathway
16 Principle of AML Treatment for Younger AML Patients Remission consolidation D i a g n o s i s Remission induction 7+3 x 1-2 courses CR Favorable Intermediate Adverse High-dose Ara-C Molecular Targeting Therapeutics Allo HCT Relapse No CR Salvage chemotherapy
17 Principle of AML Treatment for Fit Older Patients Remission consolidation D i a g n o s i s Low intensity 7+3 x 1-2 courses CR Low intensity RIC Allo HCT Molecular Targeting Therapeutics Modified HiDAC CR Relapse No CR Clinical Trials Best Supportive Care
18 Principle of AML Treatment for UnFit Older Patients D i a g n o s i s Best Supportive Care Low intensity: HMA or low dose cytarabine CR/CRi Molecular Targeting Therapeutics CR Relapse No CR Clinical Trials Best Supportive Care
19 Molecular Targeting : what, when, where?
20 Genomics AML Patients BM sample Bioinformatics Biostatistics Biologic Subtype AML Tumor Board: Target Prioritization and Treatment Selection Integrated biomarker Available drugs Probability of success FDA approved drugs Investigational drugs Conventional Chemotherapy or HMA
21 Gemtuzumab ozogamicin CD33-directed monoclonal antibody Linker N-Acetyl Calicheamicin
22 Gemtuzumab Ozogomycin (Mylotarg) ALFA Newly-diagnosed Age /consolidation ± GO GO dose 3 mg/m 2 EFS and 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 improved Best results in Favorable/Intermediate risk 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:
23 Challenges/Opportunities related to Myelotarg Risk of VOD, especially among patients who receive HCT within 3 months ALFA-0701 study, GO was combined with DA, which differs from higher-dose cytarabine-based consolidation utilized in USA Combinations with other molecular targeting therapeutics need to be explored
24 24 Ratify (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 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.
25 Kaplan-Meier analysis of OS not censored for transplant in RATIFY showed a 22% reduction in risk of death with midostaurin plus chemotherapy vs placebo + chemotherapy. acox model stratified on FLT3 subtype; 1-sided, log-rank P value. Richard M. Stone et al. Blood Adv 2018;2: by The American Society of Hematology
26 In RATIFY, OS not censored for transplant showed improvement across all FLT3 subgroups. ap value is 1 sided for the overall (stratified) analysis; P values are 2 sided for the analyses by FLT3 subgroup. Richard M. Stone et al. Blood Adv 2018;2: by The American Society of Hematology
27 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
28 Pharmacologic Inhibition of IDH mutations
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31 Overall survival by American Society of Hematology Eytan M. Stein et al. Blood 2017;130:
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35 Challenges/Opportunities related to IDH inhibitors Differentiation syndrome 14% Prolonged periods of time for a clinical response Preliminary results suggest a low likelihood of response when mutant NRAS is present Post-transplant use Combination with other chemotherapeutics or molecular targeting therapeutics including other TKIs Combination with hypomethylating agents
36 Targeting Anti-Apoptotic Mechanisms
37 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.
38 Venetoclax Increased expression of the pro-survival protein BCL-2 relative to the pro-apoptotic protein BAX is associated with reduced CR rates, earlier relapse and inferior OS in patients receiving intensive chemotherapy for AML Venetoclax was only modestly effective as monotherapy in relapsed/refractory AML (19% CR/CRi) Phase II studies in elderly patients unfit for intensive chemotherapy have combined venetoclax with either HMAs or LDAC, producing CR/CRi rates of 54 68% and 12- month survival outcomes of 50 70%
39 Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia Di Nardo et al Blood 2019
40
41 Survival of refractory/relapsed AML after hypomethylating agent and venetoclax therapy. Patients n=33 Median age of patients was 62 years (range 19-81). Sixty-one percent (n=20) of patients had failed HMA therapy previously and 39% (n=13) had had prior allogeneic hematopoietic cell transplantation (HCT). Overall response rate (ORR) was 64% (n=21); 10 (30%) patients achieved CR, 7 (21%) CRi, 4 (12%) morphological leukemia-free state (MLFS). Ibrahim Aldoss et al. Haematologica 2018;103:e404-e by Ferrata Storti Foundation
42 Hypomethylating agents in combination with venetoclax for acute myeloid leukemia: Update on clinical trial data and practical considerations for use decitabine 20 mg/m 2 for 5 days or 5 azacytidine 75 mg/m 2 for 7 days decitabine and 5 azacytidine be started concurrently with the VEN. VEN dosing 400 mg daily as this appears to be the optimal dose from the initial phase Ib study. Initial cycle duration of 28 days with daily dosing of VEN. After achievement of maximal response, VEN treatment duration may need to be modified for cytopenia Mei et al. AJH 2018
43 Mei et al. AJH 2018
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52 MRD the bottom line! Studies in AML have demonstrated the correlation between MRD and risks for relapse A negative MRD after induction predicts a lower incidence of relapse. A persisting positive MRD after induction is associated with an increased risk of relapse. After completion of therapy, Molecular relapses predict hematologic relapses within a 3- to 6-month timeframe There is no evidence that modifying clinical management based on a positive MRD (persisting after induction, or relapsing during or after therapy) modifies the outcome. There is no evidence supporting MRD assessment during the post treatment monitoring phase. The ELN still recommends monitoring CBF AML and APL for 2 years after completion of therapy. Timing of MRD assessment: Upon completion of initial induction. Before allogeneic transplantation Additional time points should be guided by the regimen used.
53 Future Directions Antiapoptotics Mcl-1 inhibitors Antibodies Naked (CD47, CD123) Bite (CD33, CD123) Conjugated (CD33) CAR-T Drs Forman and Budde) FLT3 CD33 NKG2DL CD38, CD56, CD117 (outside US) HCT new transplant modalities (TMLI plus intensification condition)
54 Conclusions Exciting time in the treatment of AML because of new genomic classification, novel molecular targets and immunotherapeutics novel transplant modalities implementation of personalized approaches Challenge is how to best incorporate into clinical practice: Prioritization of novel predictive biomarkers Non-mutation biomarkers (epigenetics, ncrnas, transcriptome, proteomics, signaling pathways) Minimal Residual Disease Combinatory or sequential use of novel molecularly targeting drugs with Allogeneic Hematopoietic Stem Cell Transplantation
55 Guido Marcucci, MD at City of Hope Please contact 24/7 Cell phone:
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