Outcomes of Adult Patients with Newly Diagnosed IDH-Mutated Acute Myeloid Leukemia Receiving Intensive Chemotherapy Plus Venetoclax

Background: Isocitrate dehydrogenase (IDH) 1 or 2 mutations are present in ~20% of patients with acute myeloid leukemia (AML). The availability of new agents, including venetoclax and the targeted IDH1 and IDH2 inhibitors, have improved the outcomes of patients with IDH-mutated AML, especially in the relapsed/refractory (R/R) setting, and for newly diagnosed intensive chemotherapy (IC)-ineligible patients. However, the optimal induction regimen for IDH-mutated patients who are eligible for IC is not established. Ivosidenib and enasidenib, potent IDH1 and IDH2 inhibitors, have been evaluated in combination with standard 7+3 chemotherapy (Stein EM, Blood 2021), and have led to robust remission rates leading to an ongoing randomized phase 3 clinical trial. Similarly, venetoclax (VEN)-containing regimens have demonstrated improved remission rates in newly diagnosed AML patients eligible for IC (Lachowiez CA, Lancet Haematol 2022), including IDH-mutated AML. However, limited data exists regarding outcomes of AML patients with IDH1 and IDH2 mutations receiving IC regimens including VEN.

Methods: We performed a retrospective single-center study of patients with newly diagnosed IDH1- and IDH2-mutated AML treated between January 11, 2019, and February 18, 2023. Eligible patients aged 18-70 were treated with IC+VEN during the study period. Regimens used were cladribine, idarubicin, and cytarabine + VEN (CLIA+VEN) and fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + VEN (FLAG-IDA+VEN), as part of ongoing prospective clinical trials (NCT02115295, NCT03214562). Key endpoints included overall response rate (ORR), rate of complete remission (CR), and rate of complete remission with incomplete hematologic recovery (CRi) after induction therapy, as well as overall survival (OS). Survival analysis was performed using the Kaplan-Meier method and differences between groups were assessed using the log-rank test.

Results: Median follow-up was 37.3 months. During the study period, 124 patients with AML were treated with frontline IC+VEN. Of these, 99 (80%) were IDH wild type, 10 (8%) were IDH1-mutated, and 15 (12%) were IDH2-mutated. Ages of these cohorts were 46 years (range 19-67), 56 years (45-65), and 54 years (29-64), respectively. The majority of IDH1- and IDH2-mutated patients had de novo AML (96%), and most were adverse risk (44%) per ELN 2022 classification. Seventy-three (59%) patients were treated with CLIA+VEN: 58 (59%) IDH wild type, 6 (60%) IDH1-mutated, and 9 (60%) IDH2-mutated, and 51 (41%) received FLAG-IDA+VEN: 41 (41%) IDH wild type, 4 (40%) IDH1-mutated, and 6 (40%) IDH2-mutated. No patient received targeted IDH inhibition as part of their induction.

After IC+VEN induction, the ORR was 96% (95/99) in IDH wild type, 80% (8/10) in IDH1-mutated, and 100% (15/15) in IDH2-mutated (p=0.134). CR/CRi was achieved in 92 (92%) of IDH wild type, 8 (80%) of IDH1-mutated (including 7 of 8 MRD negative), and 15 (100%) of IDH2-mutated patients (12 of 15 MRD negative) (p=0.173). Of these patients, 3 (38%) IDH1-mutated and 4 (27%) IDH2-mutated transitioned to HSCT in CR1. OS at 3 years for IDH wild type, IDH1-mutated, and IDH2-mutated patients was 76% (95% CI 67-85%), 60% (95% CI 36-84%), and 61% (95% CI 36-86%), respectively.

Conclusions: Venetoclax combined with intensive induction chemotherapy results in a high rate of MRD-negative remissions and impressive 3-year OS in newly diagnosed, IDH-mutated AML. Further study and randomized trials are needed to determine the optimal induction regimen for patients with IDH-mutated AML.

Konopleva:Allogene: Research Funding; Cellectis: Other: Clinical Trials; Redona: Consultancy; Immune Oncology: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: clinical trials; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Research Funding; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-LaRoche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Sellas: Consultancy; Sanofi Aventis: Consultancy, Other: clinical trials, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding; Janssen: Consultancy, Other: clinical trials; Reata Pharmaceutical: Other: IP; Rafael Pharmaceutical: Research Funding; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; AstraZeneca: Consultancy, Other: clinical trials, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Vincerx: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; MEI Pharma: Consultancy, Research Funding; Legend Biotech: Consultancy. Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Daver:Celgene: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Syndax: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Menarini Group: Consultancy; KITE: Research Funding; Jazz: Consultancy; Astellas: Consultancy, Research Funding; Arog: Consultancy; Trillium: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Hanmi: Research Funding; Trovagene: Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Shattuck Labs: Consultancy; Agios: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding. Abbas:Illumina: Honoraria, Other: Inkind Support, Research Funding; Alamar Biosciences: Honoraria; Enzyme By Design: Research Funding; Ascentage: Research Funding; Molecular Partners: Consultancy; Blueprint Medicines Corporation: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding. Sasaki:Enliven: Research Funding; Chugai: Other: Lecture fees; Otsuka: Other: Lecture fees; Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy, Research Funding. Garcia-Manero:Onconova: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Genentech: Research Funding; H3 Biomedicine: Research Funding; Genentech: Other: Personal fees; Janssen: Research Funding; Curis: Research Funding; Merck: Research Funding; Amphivena: Research Funding; Helsinn: Research Funding; Aprea: Research Funding; Astex: Other: Personal fees; Astex: Research Funding; Helsinn: Other: Personal fees; Bristol Myers Squibb: Other: Personal fees, Research Funding; AbbVie: Research Funding. Jain:MingSight: Honoraria, Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Servier: Research Funding; Takeda: Research Funding; TransThera Sciences: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Research Funding; NovalGen: Research Funding; Aprea Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Newave: Research Funding; Medisix: Research Funding; Fate Therapeutics: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; Ipsen: Consultancy, Honoraria, Other: Travel Support; BeiGene: Consultancy, Honoraria, Other: Travel Support; Incyte: Research Funding; Loxo Oncology: Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; Dialectic Therapeutics: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Pemmaraju:Celgene: Honoraria, Other: Travel Expenses; Neopharm: Honoraria; CareDx: Honoraria; Bristol-Myers Squibb: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Incyte: Honoraria; Plexxikon: Research Funding; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; Pacylex: Consultancy; Springer Science + Business Media: Honoraria; LFB Biotechnologies: Honoraria; ClearView Healthcare Partners: Consultancy; Roche Molecular Diagnostics: Honoraria; DAVA Oncology: Honoraria, Other: Travel Expenses; Blueprint Medicines: Consultancy, Honoraria; Triptych Health Partners: Consultancy; Protagonist Therapeutics: Consultancy; Affymetrix/Thermo Fisher Scientific: Research Funding; Immunogen: Consultancy; CTI BioPharma: Consultancy; Samus Therapeutics: Research Funding; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Short:Amgen: Honoraria; Pfizer Inc.: Honoraria; BeiGene: Honoraria; Xencor: Research Funding; Novartis: Honoraria; Stemline Therapeutics: Research Funding; NextCure: Research Funding; Sanofi: Honoraria; Autolus: Honoraria; GSK: Consultancy, Research Funding; Adaptive Biotechnologies: Honoraria; Takeda Oncology: Honoraria, Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding; AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy. Masarova:PharmaEssentia: Other: Advisory Board Participant; Cogent: Other: Advisory Board Participant; GSK: Consultancy, Other: Travel support; MorphoSys: Other: Advisory Board Participant. Chien:Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Issa:Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding. Montalban-Bravo:Rigel: Research Funding; Takeda: Research Funding. Yilmaz:daiichi sankyo: Honoraria, Research Funding. Maiti:Chimeric Therapeutics: Research Funding; Hibercell Inc.: Research Funding; Lin Biosciences: Research Funding; Inspirna: Research Funding; CytoMed Therapeutics: Research Funding; Indapta Therapeutics: Research Funding. Ravandi:Amgen: Research Funding; Astyex/Taiho: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Xencor: Research Funding; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria. 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DiNardo:Astex: Research Funding; ImmuneOnc: Research Funding; Amgen: Consultancy; Foghorn: Research Funding; Loxo: Research Funding; Riegel: Honoraria; Cleave: Research Funding; Rigel: Research Funding; Schrodinger: Consultancy, Honoraria; Notable Labs: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Astellas: Consultancy, Honoraria; Immunogen: Honoraria; GSK: Consultancy, Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Genetech: Honoraria; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Gilead: Consultancy; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy.