Phase 1b Study of Menin-KMT2A Inhibitor Bleximenib in Combination with Intensive Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with KMT2Ar or NPM1 Alterations
Authors: Recher Christian , O'Nions Jenny , Aldoss Ibrahim , Pierola Ana Alfonso , Allred Alicia , Alonso-Dominguez Juan Manuel , Barreyro Laura , Bories Pierre , Curtis Martin , Daskalakis Nikki , Della Porta Matteo Giovanni , Döhner Hartmut , D'Souza Amber , Dugan James P. , Esteve Reyner Jordi , Exum Matthew , Fathi Amir T. , Fedele Pasquale L. , Ferrante Lucille , Gaj Stan , Garciaz Sylvain , Garrido Ana , Garrido Paniagua Sara , Guttke Christina , Gyan Emmanuel , Hiebert Brett , Jabbour Elias , Jentzsch Madlen , Kantarjian Hagop M. , Konopleva Marina , Krönke Jan , Kwon Min Chul , Loefgren Christina , Lomas Oliver , Mancini Valentina , Mantzaris Ioannis , Martinelli Giovanni , Morillo Giles Daniel , Murphy Joseph , Packman Kathryn , Papayannidis Cristina , Philippar Ulrike , Platzbecker Uwe , Rangaraju Sravanti , Röllig Christoph , Salamero Olga , Sanga Madhu , Sauer Tim , Searle Emma , Tovar Natalia , Tucker Trevor , Vallet Nicolas , Vaughan Lachlin , Vega Gala , Vyas Paresh , Wei Andrew 
Published: December 2024

Background: Newly diagnosed (ND) acute myeloid leukemia (AML) is a genetically heterogeneous disease with a median 5-year overall survival of approximately 30%. Combining standard intensive chemotherapy (IC) approaches with targeted therapies may further improve outcomes. Bleximenib is a potent, selective menin-KMT2A complex inhibitor with activity in NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) AML when given either as monotherapy or in combination for relapsed/refractory disease (Jabbour et al., ASH 2023; Wei et al., EHA 2024). The focus of this study has been to explore the safety and preliminary efficacy of combining bleximenib with IC for ND AML.

Aims: To determine the safety and preliminary efficacy of bleximenib in combination with intensive cytarabine + daunorubicin/idarubicin, followed by cytarabine consolidation for ND NPM1m or KMT2Ar AML participants (pts) eligible for IC.

Methods: NCT05453903 is an ongoing Phase 1b, multicenter, dose-finding study. In dose escalation, pts received a standard '7+3' regimen of cytarabine 200mg/m2/day and daunorubicin 60mg/m2/day IV or idarubicin 12mg/m2/day IV. Bleximenib was administered orally, twice daily (BID), and dosed continuously. 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 continuation for up to 12 months. As of July 16th 2024, bleximenib doses ≥30 mg BID have been explored in combination with '7+3' IC. The safety dataset includes all dosed pts, with adverse events (AEs) reported per CTCAE v5. The efficacy dataset, as assessed by investigators (per modified ELN 2017), comprises ND pts with NPM1m or KMT2Ar who received ≥50 mg bleximenib BID in combination with '7+3' IC and completed at least 1 disease evaluation.

Results: In the safety dataset, 22 ND AML pts (median age: 58 [27-70] years; 54.5% female, 45.5% male; 11 NPM1, 11 KMT2A altered) received bleximenib across dose levels explored in combination with IC. 95% (21/22) of pts had ≥1 treatment-emergent AE (TEAE, all grades): diarrhea (17/22; 77%), thrombocytopenia (15/22; 68%), febrile neutropenia (14/22; 64%), pyrexia (13/22; 59%), anemia and nausea (11/22; 50% each) were the most common. Grade ≥3 TEAEs also occurred in 95% (21/22) of pts; the most frequent events were febrile neutropenia (14/22; 64%), thrombocytopenia (15/22; 68%), anemia, neutropenia (9/22; 41% each) and leukopenia (6/22; 27%). TRAEs (all grades) attributed to bleximenib alone occurred in 18% (4/22) of pts, including thrombocytopenia and neutropenia (2/22; 9% each) and single cases (5% each) of anemia, diarrhea, cerebrovascular accident, dysesthesia and upper abdominal pain. Grade ≥3 TRAEs attributed to bleximenib alone occurred in 14% (3/22) of pts, including thrombocytopenia (2/22; 9%) and single cases (5% each) of anemia and neutropenia. No differentiation syndrome (DS) or dose-limiting toxicities (DLTs) were observed. Two episodes of Grade 1 QTcF prolongation were recorded but not attributed to bleximenib. In pts who achieved initial blast clearance, the median time from Day 1 of induction to platelet count recovery (50x109/L) was 32 days (range, 22-45), and the median time to neutrophil count recovery (0.5x109/L) was 32 days (range, 25-45). The efficacy dataset includes 14 pts (8 NPM1m, 6 KMT2Ar). In this population, overall response rate (ORR: ≥PR) was 93% (79% CR; 86% CR/CRh) and median time to CR was 30 days (range, 22-41). By genotype, the ORR was 83% in pts with KMT2Ar AML (83% CR/CRh) and 100% in pts with NPM1m (88% CR/CRh). Of those pts who have completed consolidation therapy, five have proceeded to allogeneic hematopoietic stem cell transplantation.

Summary/Conclusion: Dose escalation is ongoing in this Phase 1b study. Preliminary results demonstrate that bleximenib in combination with ‘7+3‘ IC regimen in ND AML pts eligible for such therapy has an acceptable safety profile with no DS or DLTs observed. There is no consistent delay in neutrophil or platelet count recovery after induction. In addition, preliminary antileukemic activity is observed in pts with ND NPM1m or KMT2Ar AML treated with bleximenib in combination with IC.