Phase 1b study of bleximenib in combination with venetoclax in Acute Myeloid Leukemia with KMT2A or NPM1 alterations

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. Phase 1 data with bleximenib 100 mg twice daily (BID) dose in combination AML-directed therapies in participants (pts) with relapsed/refractory (R/R) or newly diagnosed (ND) AML were previously reported (Wei, EHA 2025). We now report the evaluation of safety and efficacy data for the all-oral combination of the bleximenib + venetoclax (VEN) doublet in pts with R/R AML harboring KMT2A or NPM1 alterations (Cohort A1). Methods ALE1002 (NCT05453903) is an ongoing Phase 1b, multicenter, dose-finding study exploring bleximenib in combination with AML-directed therapies. In Cohort A1, pts with R/R AML received VEN in combination with oral bleximenib at 15–100 mg twice daily (BID) continuously. VEN dosing was guided by the label, with ramp-up followed by a plateau dose of 400 mg daily in 28-day cycles. Bleximenib started on Day 4, after VEN ramp-up. Safety analysis includes all dosed pts. Relative dose intensity (RDI) is the total bleximenib dose received divided by total planned doses of bleximenib for a 28-day cycle. Intention-to-treat efficacy analysis includes NPM1m or KMT2Ar AML pts receiving bleximenib 50 mg or 100 mg BID in combination with VEN, including pts who discontinued prior to first disease evaluation. Results As of July 2025, 15 pts received bleximenib in combination with VEN. Median age was 69.0 years (range, 36–81), 8 (53.3%) were female, 4 (26.7%) had KMT2A, and 11 (73.3%) had NPM1. Five (33.3%) pts had a FLT3 co-mutation. Pts had received a median of 2 (range, 1–4) prior lines of therapy; 40% (n=6) had prior VEN exposure, 20% (n=3) had received a prior allogenic transplant, and 6.7% (n=1) had prior menin exposure. In the all-dosed safety dataset (N=15), the median duration of follow-up was 8.9 months (range, 0.95–11.20); the median number of cycles was 3 (range, 1–11) and the median duration of Cycle 1 was 35 days (range, 27–71). The most common all-grade (G) treatment-emergent adverse events (TEAEs) were neutropenia (53.3%), thrombocytopenia and anemia (both 46.7%). The most common ≥G3 TEAEs were anemia and neutropenia (both 46.7%), and thrombocytopenia (40.0%). No events of differentiation syndrome (DS) were observed in Cohort A1. One TEAE of unrelated G2 QTc prolongation was reported, with no bleximenib dose modification required. One dose-limiting toxicity of G4 neutropenia and thrombocytopenia was reported; this pt continues on reduced dose bleximenib and reduced duration of VEN with a best response of complete remission with partial hematologic recovery (CRh). The median RDI of bleximenib in Cycle 1 was 100% (range, 76–100). Fatal TEAEs occurred in 2 pts, 1 due to COVID-19 lung infection and 1 due to cardiac arrest. These events occurred in the first 60 days and were the only pts that discontinued treatment due to TEAEs. The efficacy population included 13 R/R KMT2Ar (n=3) or NPM1m (n=10) pts treated with bleximenib 50 mg BID or 100 mg BID in combination with VEN. Overall response rate (ORR; ≥partial response [PR]) was 69.2%, composite CR (cCR = CR + CRh + CR with incomplete hematologic recovery [CRi]) was 38.5%, and CR/CRh was 23.1%. Additionally, one pt not in the efficacy population due to prior menin inhibitor therapy had a best response of CRi with bleximenib + VEN. In 6 pts with prior VEN exposure, ORR and cCR were 66.7%, and 16.7%, respectively. In 7 pts that were VEN naïve, ORR and cCR were 71.4%, and 57.1%, respectively. Among responders in the efficacy population (n=9), median time to first response was 22 days (range, 19–56). Four of 13 (30.8%) pts proceeded to transplant. Conclusions In this Phase 1b trial, this all-oral doublet regimen had a tolerable safety profile with no DS observed and limited discontinuations due to TEAEs. Bleximenib in combination with VEN demonstrated preliminary clinical activity in pts with R/R AML harboring KMT2A or NPM1 alterations, including those with prior exposure to VEN and other menin inhibitors, and prior allogeneic transplant.