AUTHORS
Eric Huselton, MD, Othus Megan, PhD2, Uma Borate, MBBS, MSc3, John Reagan, MD4, Richard F. Little, MD5, Steven Gore, MD6, Anna Moseley, MS7, Lorraine Pelosof, MD, PhD8, Manu Pandey, MBBS9, Xin Wang, MD, MSCE10, James Thompson, M.D., M.S.11, Anand Ashwin Patel, MD12, Lindsay Wilde, MD13, Min Fang, MD, PhD, FACMG14, Jerald Radich, MD15, Cecilia CS Yeung, MD, Professor Pathology16, Shahanawaz Jiwani, MBBS, PhD17, Laura C Michaelis, MD18, Geoffrey L. Uy, MD19, Anjali Sunder Advani, MD20, Harry Erba, MD, PhD21
AFFILIATIONS
1 University of Rochester, Rochester, New York, United States
2 SWOG Statistics and Data Management Center, Seattle, Washington, United States
3 The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States
4 Brown University Health Cancer Institute, Providence, Rhode Island, United States
5 National Cancer Institute, Washingon, District of Columbia, United States
6 National Cancer Institute, Washingon, District of Columbia, United States
7 SWOG Statistics and Data Management Center, Seattle, Washington, United States
8 National Cancer Institute, Washingon, District of Columbia, United States
9 University of Oklahoma Stephenson Cancer Center, Oklahoma City, Oklahoma, United States
10 Memorial Sloan Kettering Center Center, New York, New York, United States
11 Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States
12 University of Chicago Comprehensive Cancer Center, Chicago, Illinois, United States
13 Sidney Kimmel Comprehensive Cancer Center at Jefferson Health, Philadelphia, Pennsylvania, United States
14 Fred Hutchinson Cancer Center, Seattle, Washington, United States
15 Fred Hutchinson Cancer Center, Seattle, Washington, United States
16 Fred Hutchinson Cancer Center, Seattle, Washington, United States
17 Frederick National Laboratory for Cancer Research/National Cancer Institute, Frederick, Maryland, United States
18 Medical College of Wisconsin, Milwaukee, Wisconsin, United States
19 Washington University School Of Medicine, St Louis, Missouri, United States
20 Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, United States
21 Duke University School of Medicine, Durham, North Carolina, United States
ABSTRACT
Background:
Hypomethylating agents (HMA) and venetoclax (ven) are the standard of care for older or unfit patients with newly diagnosed AML. Approximately 15% of AML cases harbor an IDH2 mutation, a biologically distinct subtype that demonstrates high response rates to ven-based therapy. Despite these favorable responses, many remain molecular measurable residual disease (MRD) positive. Enasidenib, an oral IDH2 inhibitor approved for relapsed/refractory IDH2 mutant AML, has the potential to deepen remissions when incorporated into frontline therapy with HMA/ven.
Methods
MM1OA-S03 is a tier 1 MyeloMATCH substudy, and an open-label, randomized phase II trial enrolling adults with newly diagnosed IDH2-mutated AML who are either ≥60 years of age or ≥18 years and considered unfit for intensive chemotherapy (NCT06672146). Patients are randomized to oral decitabine/cedazuridine (ASTX727) and ven or ASTX727, ven, and enasidenib. The study includes a safety run-in evaluating the triplet regimen in 6 evaluable patients. Toxicities of interest (TOI) were predefined as severe cytopenias persisting beyond D42 or clinically relevant grade ≥3 nonhematologic adverse events (AEs) attributed to study therapy that did not resolve within 7 days during the first 2 treatment cycles.
Results
Between May to October 2025, 8 patients were enrolled in the safety run-in. The median age of patients was 69 (range 67-83), 63% were female, and median ECOG performance status was 1 (range 1-2). Two patients received cytoreduction with hydroxyurea and/or cytarabine prior to enrollment. Median bone marrow blast percentage at enrollment was 64% (range, 23-83%), with a median white blood cell count of 1.4 × 10?/L (range, 0-15.1) and circulating blasts of 24.4% (range, 0-57%). Median baseline absolute neutrophil count was 0.25 × 10?/L (range, 0.02-3.2) and median platelet count was 53 × 10?/L (range, 7-265).
Two patients discontinued treatment during C1. Discontinuations were due to grade 3 rhabdomyolysis with acute kidney injury and weakness in one patient and grade 3 ileus, sepsis, and dysphagia in the second; neither event was considered treatment related. The 6 evaluable patients received a median of 4 cycles (range, 2-7 [ongoing]). Seven of 8 patients received posaconazole for antifungal prophylaxis with dose reduction in ven to 70 mg daily as per protocol.
All patients underwent a marrow biopsy between days 15 and 21 of C1 and were allowed to stop ven as early as D21 if marrow blasts were <5%. Patients received a median of 25.5 days of ven during C1 (range, 21-28). The median C1 duration was 30.5 days (range, 29-48). Before starting C2, only 1 patient recovered an ANC of ≥1.0 and 4 recovered platelet counts ≥50. During C2, ven was dose reduced in 4/6 patients to a median of 22.5 days (range, 15-24), and the median cycle length was 34 days (range, 28-56). After C2, 5/6 evaluable patients recovered an ANC ≥0.5 and platelets ≥50 at a median time of 36 and 19 days, respectively.
Consistent with known pharmacology of enasidenib, 5 of 8 patients developed asymptomatic indirect hyperbilirubinemia during C1 (grade 2, n=2; grade 3, n=3). Enasidenib was dose reduced to 50 mg in 2 patients in C2. No patients were suspected of having Gilbert’s syndrome at enrollment. Other grade 3 events that occurred during the first 2 cycles of treatment included non-cardiac chest pain, pleural effusion, nausea, and anorectal infection.
Conclusions
The safety run-in of this fully oral triplet regimen of ASTX727, ven, and enasidenib demonstrated an acceptable safety profile, with only 2 predefined TOI events: both grade 4 thrombocytopenia persisting beyond D42. No unexpected safety signals were identified, and all treatment related grade ≥3 nonhematologic AEs resolved within 7 days. As anticipated with ven based therapy, hematologic toxicity was common, with all patients experiencing grade 4 neutropenia and 3 experiencing grade 4 thrombocytopenia. Early bone marrow assessment with response adapted shorting of ven may facilitate hematologic recovery. Based on these findings, the study advanced to the randomized portion in February 2026. MM1OA-S03 will enroll an additional 96 patients to determine whether the addition of enasidenib increases the rate of MRD negative complete remission after 2 cycles of therapy.
Funding: NIH/NCI grants U10CA180888, U10CA180819
DISCLOSURES
Eric Huselton, MD: No relevant conflicts of interest to declare.