Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies
Methods: Patients ≥ 18 years with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) not currently eligible for stem cell transplantation (SCT) and unable/unwilling to complete standard therapy were eligible. Patients having received either intensive induction (at least 2 cycles of therapy based on intermediate to high dose cytarabine) or low-intensity induction (at least 3 cycles based on low-dose cytarabine or a hypomethylating agent) were permitted. Other inclusion criteria were ECOG ≤ 3, adequate hepatic/renal function, absolute neutrophil count > 0.5 x 109/L, and platelets > 50 x 109/L. Patients were enrolled in one of five arms per physician choice based on molecular profile. Arm A consisted of ASTX727 35/100 mg PO on D1-3. All other arms combined this ASTX727 backbone with either venetoclax 400 mg (adjusted for azoles) PO on D1-5 (arm B), gilteritinib 120 mg PO on D1-28 (arm C), enasidenib 100 mg PO on D1-28 (arm D), or ivosidenib 500 mg PO on D1-28 (arm E). Treatment was administered in 4-week cycles, up to 24 cycles. Each arm initially consisted of a safety lead-in cohort with predetermined dose reductions for dose-limiting toxicity (DLT) per a 3+3 dose de-escalation design. Prophylactic antibiotics, antifungals, and antivirals were encouraged. The primary objective was safety and tolerability. Secondary objectives included relapse-free survival (RFS) and OS. Patients becoming eligible for SCT were taken off study and censored at the time of SCT for time-to-event endpoints.
Results: 23 patients, with a median age of 68 years (range 33-83), have been enrolled (3 on arm A, 19 on arm B, and 1 on arm C). 12 (52%) were enrolled following intensive induction and 11 (48%) after low-intensity induction. 16 (70%) had prior venetoclax. Best response at enrollment was CR in 22 (96%) patients and CRi in 1 (4%). 6/22 (27%) patients with available testing were measurable residual disease (MRD)-positive. 2 (9%) patients had antecedent myelodysplastic/myeloproliferative neoplasms and 1 (4%) had therapy-related AML. ELN 2022 risk was favorable in 10 (43%), intermediate in 3 (13%), and adverse in 10 (43%) patients.
The most common grade 3/4 adverse events were neutropenia (96%), thrombocytopenia (74%), anemia (39%), lung infection (22%), hypertension (17%), and neutropenic fever (17%). Cycle 2 dose reductions due to myelosuppression occurred in 5/23 (22%) patients. No DLTs were observed. No deaths occurred on protocol. Two patients died in remission from SCT-related complications after going off maintenance.
The current median follow-up time is 5.3 months (m). The median number of cycles given is 3 (1-15). Three relapses have occurred to date (1 in arm A, 2 in arm B). The median RFS for the full cohort is not reached (NR, 1-year 71%). The median OS for the full cohort (figure 1A) is NR (1-year 100%). The median RFS for arms A, B, and C are NR (1-year 67%), NR (1-year 84%), and NR, respectively (figure 1B). The median RFS is 14.5 m (1-year 50%) for patients who received intensive induction and NR (1-year 75%) for those who received low-intensity induction. The median RFS for patients who were MRD-negative and MRD-positive at enrollment were NR (6-month 93%) and NR (6-month 75%), respectively (p=0.50). Of the 6 MRD-positive patients, 2 (33%) cleared their MRD while on maintenance (both patients in arm B).
Conclusions: A fully oral, targeted maintenance regimen is feasible in AML. Early results show encouraging RFS and OS. Further enrollment and follow-up are required to better assess the safety and efficacy of these regimens.
Disclosures: Kantarjian: Pfizer: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Orsinex: Honoraria; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Actinium: Honoraria; Astex: Research Funding; Immunogen: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria. Ravandi: Biomea fusion: Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Xencor: Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Short: Stemline therapeutics: Research Funding; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Honoraria; Novartis: Consultancy; Pfizer: Consultancy. Daver: Glycomimetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Kronos Bio: Research Funding; ImmunoGen: Consultancy, Research Funding; Celgene: Consultancy; FATE: Research Funding; Amgen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Shattuck Labs: Consultancy; AROG: Consultancy; Trillium: Consultancy, Research Funding; Syndax: Consultancy; Servier: Consultancy, Research Funding; Novimmune: Research Funding; Hanmi: Research Funding; Jazz: Consultancy; Trovagene: Research Funding; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Agios: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Maiti: Celgene: Research Funding; Lin BioScience: Research Funding. DiNardo: ImmuniOnc: Honoraria; Fogham: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Schrödinger: Consultancy; AbbVie/Genentech: Honoraria; Servier: Honoraria; Astellas: Honoraria; Notable Labs: Honoraria; BMS: Honoraria. Masarova: MorphoSys US: Membership on an entity's Board of Directors or advisory committees. 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. Jabbour: Adaptive Biotech: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astex: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Garcia-Manero: Genentech: Research Funding; Bristol Myers Squibb: Other: Medical writing support, Research Funding; AbbVie: Research Funding. Kadia: Hikma Pharmaceuticals: Speakers Bureau; Amgen, Inc.: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Iterion: Research Funding; Pinotb-Bio: Consultancy; Astellas Pharma Global Development: Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Agios: Consultancy; Ascentage Pharma Group: Research Funding; Genzyme: Honoraria; Celgene: Research Funding; Janssen Research and Development: Research Funding; GenFleet Therapeutics: Research Funding; Cure: Speakers Bureau; Cellenkos Inc.: Research Funding; Cyclacel: Research Funding; Astex: Honoraria; AstraZeneca: Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; BMS: Consultancy, Research Funding; Servier: Consultancy; Genentech: Consultancy, Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Glycomimetics: Research Funding; Pfizer: Consultancy, Research Funding; Liberum: Consultancy; Novartis: Consultancy; Pulmotect, Inc.: Consultancy, Research Funding; Regeneron Pharmaceuticals: Research Funding; Sanofi-Aventis: Consultancy; SELLAS Life Sciences Group: Research Funding.
OffLabel Disclosure: ASTX727 is not currently approved for AML.