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 Treatment Trial

The study chair for this treatment trial is Jessica K. Altman, MD (Northwestern University/Robert H. Lurie Comprehensive Cancer Center), and the study co-chair is Alexander E. Perl, MD (University of Pennsylvania/Abramson Cancer Center).

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.

In older AML patients ineligible for intensive chemotherapy, the most common treatment is a combination of the hypomethylating chemotherapy agent (HMA) azacitidine plus the BCL-2 inhibitor venetoclax, since receiving FDA approval in 2020. However, some patients do not benefit from this frontline treatment, and for them, outcomes are dismal. Also, mutations in FLT3 tyrosine kinase have been implicated as a factor in resistance to venetoclax. Patients with relapsed/refractory FLT3-mutated AML receive monotherapy with gilteritinib, an FLT3 inhibitor.

Preliminary findings emerged recently from a single-institution study at MD Anderson Cancer Center 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.

Based on these and other preclinical data, researchers with the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) are opening MM1OA-EA02, a randomized phase 2 study. It will test 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.

Patients who enroll in the MM1OA-EA02 study will be randomly assigned to one of three treatment groups*. For each group, the induction phase will last for two treatment cycles, or until the patient reaches remission (whichever comes first). The consolidation phase can last for up to 2 years from the start of consolidation therapy. Each cycle = 28 days:

• Group 1: Azacitidine plus venetoclax (control)
• Group 2: Azacitidine plus venetoclax plus concurrent gilteritinib
• Group 3: Azacitidine plus venetoclax plus sequential gilteritinib

The accrual goal for MM1OA-EA02 is 147 participants to be randomized equally among the three groups. Key eligibility criteria include: newly diagnosed FLT3-ITD or TKD-mutated AML and no prior treatment with an HMA or FLT3 inhibitor; ≥ 60 years of age or patients < 60 years who, in the assessment of their treating physician, are better served by azacitidine-based chemotherapy rather than intensive cytarabine-based chemotherapy.

*For complete details on the treatment administration schedule, see section 5.1 of the MM1OA-EA02 protocol.

Learn more about MM1OA-EA02 at ecog-acrin.org.

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.