Session: 617. Acute Myeloid Leukemias: Commercially Available Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Combination therapy, Adult, Elderly, Clinical Research, Diseases, Treatment Considerations, Myeloid Malignancies, Study Population, Human
Methods: This was a single center phase 2 study that enrolled patients with newly diagnosed AML ≥ 18 years and ineligible for intensive chemotherapy, defined as at least one of the following: age ≥ 75 years, ECOG performance status of 2-3, clinical congestive heart failure, LVEF ≤ 50%, DLCO ≤ 65%, or FEV1 ≤ 65%. Patients with acute promyelocytic leukemia (APL) and those with central nervous system leukemia were excluded. This study also included a relapsed/refractory cohort which is not presented here. The treatment regimen consisted of ASTX727 35/100 mg on days 1-5 plus venetoclax 400 mg (azole adjusted) on days 1-28, every 28 days. Venetoclax was stopped on day 21 if bone marrow examination showed blasts < 5%. Dose reductions of both ASTX727 and venetoclax were permitted in consolidation cycles (cycles 2 and onwards). Treatment continued until progression or limiting toxicity for up to 24 cycles. The primary objective was overall response rate (ORR). Secondary objectives were overall survival (OS), relapse-free survival (RFS), and safety/tolerability. This study is registered on ClinicalTrials.gov (NCT04746235).
Results: 60 patients have been enrolled in the frontline cohort. The median age was 80 years (range 50-92) and 21/60 (35%) were female. By ELN 2022 risk, 8 (13%) patients were favorable, 4 (7%) were intermediate, and 48 (80%) were adverse. 15 (25%) patients had complex cytogenetics, 9 (15%) had TP53 mutations, 9 (15%) had therapy-related AML, and 25 (42%) had AML arising from antecedent MDS/MPN, including 11 (18%) with prior hypomethylating agent (HMA) exposure for MDS.
The median number of cycles given was 3 (range 1-21). The median follow-up time was 20 months. The ORR was 40/60 (67%), including 24 (40%) complete remission (CR), 13 (22%) CR with incomplete count recovery (CRi), and 3 (5%) morphologic leukemia-free state (MLFS). Of 37 responding patients with adequate samples, measurable residual disease (MRD) was negative in 19/37 (51%). The median OS was 10.2 months for the full frontline cohort and the median RFS in patients achieving CR/CRi (n=37) was 9.8 months. When excluding patients with prior HMA exposure (n=11), the median OS was 12.7 months and the median RFS was 9.9 months. We next stratified patients into 3 categories of benefit as described by Döhner and colleagues (ASH 2022). Patient with high predicted benefit were those without TP53, FLT3-ITD or N/KRAS mutations. Patients with FLT3-ITD or N/KRAS were intermediate benefit, and those with TP53 mutations were low benefit. The median OS was 16.2, 9.1, and 2.2 months in patients with high (n=34), intermediate (n=17), or low (n=9) predicted benefit, respectively (p<0.01). The median RFS was 12.6, 6.1, and 8.6 months in patients with high (n=23), intermediate (n=11), or low (n=3) predicted benefit, respectively (p=0.03). Only 3 (5%) patients went off study to receive stem cell transplantation. The most common grade 3/4 treatment-emergent adverse events were neutropenic fever (10%), pneumonia (8%), neutropenia (8%), bacteremia (7%), thrombocytopenia (7%), and respiratory failure (7%). Grade 3/4 infections of any type occurred in 27% of patients. 3 deaths occurred on study treatment in patients in remission and were potentially treatment-related (1 from bleeding and 2 from infections).
Conclusions: ASTX727 plus venetoclax allows for effective fully oral therapy in chemotherapy-ineligible older patients with newly diagnosed AML. OS is comparable to that obtained with parenteral azacitidine plus venetoclax (VIALE-A) in HMA-naïve patients. No new clinically relevant safety signals were observed.
Disclosures: Garcia-Manero: Onconova: Research Funding; Astex: Research Funding; Amphivena: Research Funding; Helsinn: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Curis: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Aprea: Research Funding; Astex: Other: Personal fees; Helsinn: Other: Personal fees; Genentech: Other: Personal fees. Yilmaz: daiichi sankyo: Honoraria, Research Funding. Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Montalban-Bravo: Rigel: Research Funding; Takeda: Research Funding. Pemmaraju: Neopharm: Honoraria; ClearView Healthcare Partners: Consultancy; LFB Biotechnologies: Honoraria; Springer Science + Business Media: Honoraria; Bristol-Myers Squibb: Consultancy; Aptitude Health: Honoraria; Celgene: Honoraria, Other: Travel Expenses; Roche Molecular Diagnostics: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Incyte: Honoraria; Protagonist Therapeutics: Consultancy; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Pacylex: Consultancy; CareDx: Honoraria; Blueprint Medicines: Consultancy, Honoraria; CTI BioPharma: Consultancy; Immunogen: Consultancy; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Triptych Health Partners: Consultancy; Affymetrix/Thermo Fisher Scientific: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; 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. Issa: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Celgene: Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Merck: Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding. Short: Sanofi: Honoraria; NextCure: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; Novartis: Honoraria; Autolus: Honoraria; Stemline Therapeutics: Research Funding; Xencor: Research Funding; Amgen: Honoraria; BeiGene: Honoraria; Pfizer Inc.: Honoraria; Adaptive Biotechnologies: Honoraria; GSK: Consultancy, Research Funding; Takeda Oncology: Honoraria, Research Funding. Kadia: JAZZ: Research Funding; Novartis: Honoraria; Sellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Cellenkos: Research Funding; Rigel: Honoraria; Regeneron: Research Funding; BMS: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding; Incyte: Research Funding; ASTEX: Research Funding; Amgen: Research Funding; Abbvie: Consultancy, Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; Pfizer: Research Funding; Servier: Consultancy. Jain: AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Dialectic Therapeutics: Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Medisix: Research Funding; Aprea Therapeutics: Research Funding; NovalGen: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; TransThera Sciences: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; MingSight: Honoraria, Research Funding; Servier: Research Funding; Fate Therapeutics: Research Funding; Newave: Research Funding; Pfizer: Research Funding; Loxo Oncology: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Masarova: PharmaEssentia: Other: Advisory Board Participant; GSK: Consultancy, Other: Travel support; Cogent: Other: Advisory Board Participant; MorphoSys: Other: Advisory Board Participant. Daver: Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Trovagene: Research Funding; Jazz: Consultancy; Syndax: Consultancy; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Menarini Group: Consultancy; Agios: Consultancy; KITE: Research Funding; Arog: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Hanmi: Research Funding; Shattuck Labs: Consultancy; Trillium: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding. Borthakur: Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Maiti: Inspirna: Research Funding; Indapta Therapeutics: Research Funding; CytoMed Therapeutics: Research Funding; Hibercell Inc.: Research Funding; Chimeric Therapeutics: Research Funding; Lin Biosciences: Research Funding. Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Abbas: Blueprint Medicines Corporation: Research Funding; Enzyme By Design: Research Funding; GlaxoSmithKline: Research Funding; Ascentage: Research Funding; Molecular Partners: Consultancy; Genentech: Research Funding; Illumina: Honoraria, Other: Inkind Support, Research Funding; Alamar Biosciences: Honoraria. Ohanian: Bio-Path Holdings, Inc.: Consultancy. DiNardo: Rigel: Research Funding; Jazz: Consultancy, Honoraria; Notable Labs: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Immunogen: Honoraria; Schrodinger: Consultancy, Honoraria; Foghorn: Research Funding; Gilead: Consultancy; Cleave: Research Funding; ImmuneOnc: Research Funding; Riegel: Honoraria; Loxo: Research Funding; Astellas: Consultancy, Honoraria; Astex: Research Funding; Amgen: Consultancy; GSK: Consultancy, Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Genetech: Honoraria; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Ravandi: Syros: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Syndax: Honoraria; Amgen: Research Funding; Xencor: Research Funding; Abbvie: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astyex/Taiho: Research Funding.
OffLabel Disclosure: ASTX727 is not currently approved for AML by the FDA
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