Bleximenib in combination with intensive chemotherapy: A phase 1b study in newly diagnosed Acute Myeloid Leukemia with KMT2A or NPM1 alterations

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Abstract Objective Bleximenib is a potent, selective menin inhibitor with activity in NPM1-mutated (NPM1m)or KMT2A-rearranged (KMT2Ar) acute myeloid leukemia (AML), now in Phase 3 development in combination with AML-directed therapies. Previous data have shown an acceptable safety and efficacy profile in participants (pts) with newly diagnosed (ND) NPM1m or KMT2Ar AML treated with bleximenib in combination with intensive chemotherapy (IC) (Recher C, ASH 2024). We now report updated safety and efficacy data (clinical cut-off: July 2025) from this combination treatment in IC-eligible ND AML pts (Cohort C1). Methods In the ALE1002 Phase 1b, multicenter, dose-finding study (NCT05453903), pts in Cohort C1 received a standard '7+3' regimen of cytarabine 200 mg/m2/day and daunorubicin 60 mg/m2/day intravenous (IV) or idarubicin 12 mg/m2/day IV in combination with bleximenib. Bleximenib was administered by mouth at 30–100 mg twice daily (BID) continuously starting on Day 4 of induction, including during count recovery. Pts who achieved a complete remission (CR) received consolidation therapy with up to 4 cycles of intermediate-dose cytarabine plus bleximenib. Those not proceeding to allogeneic hematopoietic stem cell transplant could receive bleximenib in continuation for up to 12 months. The safety dataset includes all dosed pts receiving bleximenib 30–100 mg BID in combination with '7+3'. Relative dose intensity (RDI) is the total bleximenib dose received divided by total planned doses of bleximenib for a 28-day cycle. The intention-to-treat efficacy dataset comprises pts with NPM1m or KMT2Ar who received bleximenib 100 mg BID in combination with '7+3', including those who discontinued prior to first disease evaluation. Response criteria was assessed by each investigator according to European LeukemiaNet (ELN) recommendations. Results The safety analysis set included 44 ND AML pts (median age, 57.0 years [range, 19–71]; 52.3% female; 56.8% NPM1m, 43.2% KMT2A; 15.9% FLT3 co-mutations; ELN risk classification: 44.2% favorable, 27.9% intermediate, 27.9% adverse). The median duration of follow-up was 6.3 months (range, 1.31–22.51). All 44 pts had ≥1treatment-emergent adverse event (TEAE, all grades), with the most common being thrombocytopenia (35/44; 79.5%), neutropenia (32/44; 72.7%), diarrhea (31/44; 70.5%), nausea (30/44; 68.2%), anemia, and febrile neutropenia (both 28/44; 63.6%). The majority of cytopenia TEAEs were Grade 3/4, consistent with an IC backbone. Of the 44 pts dosed, the 30- and 60-day mortality was 0/44 (0%) and 1/44 (2.3%), respectively. There was no differentiation syndrome (DS) observed. Three TEAEs of QT prolongation were reported, all of which were Grade 1/2 and resolved without bleximenib interruption. Among 37 pts achieving composite CR (cCR=CR + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]), the median time from Day 1 of induction to platelet count recovery (50x109/L) was 32.0 days (range, 22.0–82.0), and the median time to neutrophil count recovery (0.5x109/L) was 30.0 days (range, 21.0–71.0). During induction, the median RDI of bleximenib was 100% (range, 16–100), with no required dose reductions of co-agents. Of 24 pts (NPM1m, n=15; KMT2Ar, n=9) in the intention-to-treat efficacy dataset receiving bleximenib 100 mg BID in combination with '7+3', overall response rate (ORR; ≥partial response) was 95.8%, cCR was 87.5%, and CR/CRh was 75%. Responses were similar across mutational subtypes. Median time to CR in the 100 mg BID group was 28 days (range, 21–36) and this was similar to the median time to first response. Median duration of response was not reached. Four pts receiving bleximenib 100 mg BID in combination with '7+3' proceeded to allogenic transplant. ConclusionsIn ND NPM1m or KMT2Ar AML, the safety profile of bleximenib + '7+3', including count recovery, was consistent with a '7+3' IC backbone, with no DS adverse events and no QTc prolongation signal observed. Combined with early efficacy, the clinical data are supportive of a planned Phase 3 study of bleximenib + '7+3' in IC-eligible ND AML pts harboring KMT2Ar or NPM1m.

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