MM1OA-EA02 – A Randomized Phase II Study of Venetoclax and HMA-based Therapies for the Treatment of Older and Unfit Adults with Newly Diagnosed FLT3-mutated Acute Myeloid Leukemia (AML): A myeloMATCH Substudy

By Jessica Altman, MD

@jaltmanmd

And Alexander Perl, MD, MS

The FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 20% of older adults with acute myeloid leukemia (AML) and is associated with high leukemic burden and increased risk of relapse. Often, these patients have very aggressive disease, characterized by rapid tumor doubling times and high white blood cell counts.

MD Anderson Cancer Center conducted a single-institution study of a triplet combination of azacitidine, venetoclax, and gilteritinib in both newly diagnosed and relapsed/refractory FLT3-mutated AML. The study showed a complete remission rate with full white blood cell count recovery of approximately 93% for the regimen in the frontline setting with no early deaths observed. A multi-center study evaluating the same regimen found similar results.

Based on these and other data, researchers with the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) opened MM1OA-EA02, a randomized phase 2 study under the National Cancer Institute and SWOG Cancer Research Network's myeloMATCH precision medicine initiative. It is testing two variations of the triplet combination of azacitidine, venetoclax, and gilteritinib compared to a control regimen of azacitidine and venetoclax in older adults with FLT3-mutated AML. The study’s primary objective is to compare the achievement rates of MRD-negative complete remission within four cycles of therapy across the three groups.

Amendment #3 (v.06/01/26) activated on August 4, 2026, and includes numerous important changes to the substudy, outlined below.

 Eligibility Criteria

• Confirmed diagnosis of AML determined by the team at the site where the patient is enrolled and confirmed by the treatment verification team (previously, diagnosis had been per WHO 2016 classifications)
• Patient must not have had prior therapy for AML with the exception of hydroxyurea, all-trans retinoic acid (ATRA), cytarabine-based emergency therapy, or leukapheresis to ensure WBC <25,000/mm³ prior to starting venetoclax treatment
• Patients with the I836del mutation are now eligible
• An electrocardiogram (ECG) is required if clinically indicated by risk factors listed in the protocol

Study Plan/Treatment Plan

• Both the induction and consolidation schemas have been revised (see the schemas for complete details)
• The induction phase will continue for up to two treatment cycles or until bone marrow assessment shows at least a morphologic leukemia-free state (MLFS) response or better
• Treatment must begin within 10 calendar days after randomization (previously 7 working days)
• Dosing schedules, guidelines/requirements, and adjustments have been updated for all study treatment agents, including adverse event and toxicity management dose modifications
  • Venetoclax dose adjustment required if taken concomitantly with CYP3A4 inhibitor
  • Safety labs for venetoclax now required 1 day after reaching final dose to monitor for tumor lysis syndrome
• Duration of Follow-Up: Follow up will occur every 3 months if patient is < 2 years from randomization, every 6 months if patient is 2-5 years from randomization, and every year if patient is 5-10 years from randomization

Specimen Collection/Bone Marrow Assessment

• Amendment #3 includes updates to biospecimen collection and revisions to the bone marrow assessment
  • All myeloMATCH trials are now using the SWOG Specimen Tracking System (STS). Paper-based forms will no longer be accepted. For further details, see “Specimen Tracking System Updates” located under Supplemental Documents on the MM1OA-EA02 protocol page at cancer.gov

 This is not a complete list of all changes to the protocol. Please review the updated protocol carefully for complete details (posted at CTSU.cancer.gov). Study resources have been updated to reflect Amendment #3 and are available for download at CTSU.cancer.gov.

myeloMATCH

MM1OA-EA02 is part of myeloid Malignancies Molecular Analysis for Therapy Choice (myeloMATCH; [NCT05564390]), a precision medicine initiative for people with myeloid malignancies. The screening protocol is led by the SWOG Cancer Research Network (SWOG), and treatment substudies are led by the Alliance for Clinical Trials in Oncology, Canadian Cancer Trials Group, ECOG-ACRIN, and SWOG. The entire initiative is sponsored by the National Cancer Institute through its National Clinical Trials Network.

To take part, patients with newly diagnosed AML must enroll in the myeloMATCH Screening or Reassessment Protocol (MSRP), led by SWOG. Patients may then be matched to a treatment substudy based on clinical, cytogenetic, and molecular features. If no appropriate treatment substudy is available, myeloMATCH participants will receive standard-of-care treatment as recommended by their physician, while remaining in the MSRP to maintain access to later tiers of treatment substudies.

 Dr. Altman (Northwestern University) is the study chair for this trial. Alexander Perl, MD (University of Pennsylvania), PhD, is the study co-chair.