Bleximenib or placebo in combination with standard induction and consolidation therapy followed by maintenance for the treatment of patients with newly diagnosed KMT2A-rearranged or NPM1-mutant Acute Myeloid Leukemia eligible for intensive chemotherapy: A double-blind Phase 3 study (HOVON 181 AML / AMLSG 37-25)

Abstract Background and Significance Newly diagnosed (ND) acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar) is associated with poor treatment outcomes. While NPM1 mutated (NPM1m) AML is generally associated with favorable risk, patients aged ≥65 years with NPM1m have worse outcomes. Intensive chemotherapy (IC), comprising '7+3' with cytarabine consolidation remains the standard-of-care (SoC) therapy in those 'fit' enough to undergo such therapy. Bleximenib is a menin inhibitor designed to target KMT2Ar and NPM1m AML. By potently and selectively disrupting the KMT2A from binding to menin, bleximenib induces leukemia cell differentiation and cell death. No menin inhibitors are currently approved for ND KMT2Ar or NPM1m AML patients eligible for IC. Investigational use of bleximenib in combination with SoC anti-leukemic treatments as well as monotherapy is supported by preclinical evidence and preliminary clinical data. In the Phase 1 ALE1002 study (NCT05453903), high rates of response were observed with bleximenib in combination with '7+3' in participants with ND KMT2Ar or NPM1m AML. The safety profile of bleximenib and '7+3' was consistent with the '7+3' backbone, with no drug-drug interactions observed. HOVON 181 AML / AMLSG 37-25 is a Phase 3, randomized, double-blind, placebo-controlled, global multicenter study evaluating the efficacy and safety of bleximenib vs. placebo in combination with SoC remission induction and consolidation chemotherapy followed by maintenance therapy in adults with ND KMT2Ar or NPM1m AML (EU CT number 2025-52276715). Study Design and Method Eligible participants are ≥18 years with ND KMT2Ar or NPM1m AML (≥10% blasts per 2022 International Consensus Classification criteria) and considered eligible for IC. Other inclusion criteria include Eastern Cooperative Oncology Group performance status ≤2 and adequate hepatic and renal function. Exclusion criteria include prior chemotherapy for AML, including hypomethylating agents; known active leukemic involvement of the central nervous system; prior solid organ transplant; any significant cardiac disorder ≤6 months prior to randomization; chronic respiratory disease requiring supplemental oxygen; and uncontrolled active infections including hepatitis B/C and HIV. 875 participants will be randomized to one of three study arms. In Arm 1, participants will receive induction therapy with bleximenib in combination with cytarabine plus daunorubicin or idarubicin. Those achieving complete remission (CR), CR with partial hematologic recovery (CRh), CR with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) after completing induction therapy are eligible to receive either up to three cycles of consolidation with cytarabine plus bleximenib or allogeneic stem cell transplantation, depending on risk category, followed by up to 24 cycles of bleximenib maintenance. Participants in Arm 2 will receive the same induction and consolidation treatment as Arm 1, and placebo during maintenance. In Arm 3, participants will receive placebo instead of bleximenib throughout, with the same chemotherapy schedule as Arms 1 and 2. The primary endpoint is event-free survival (EFS). Secondary endpoints include OS, rate of CR without measurable residual disease (CRMRD-), duration of CR, and incidence of adverse events. Enrollment is planned to begin in late 2025.