Phase 1b study of bleximenib in combination with venetoclax in Acute Myeloid Leukemia with KMT2A or NPM1 alterations
Abstract
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.
Article Details
Authors (49)
Jenny O'Nions
13Department of Hematology, University College London Hospital NHS Foundation Trust, London, United Kingdom
Andrew Wei
3Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Jordi Esteve
13Hematology Department, Institute of Cancer & Blood Diseases (ICAMS), Hospital Clinic, Barcelona, Spain
Ibrahim Aldoss
Ana Alfonso-Pierola
7Department of Oncology-Hematology, CIMA Universidad de Navarra-IDISNA-CCUN. Centro de Investigación Biomédica en Red de Cáncer, CIBERONC. Clínica Universidad de Navarra, Pamplona, Spain
Alicia Allred
6Johnson & Johnson Innovative Medicine, Spring House, United States
Juan Manuel Alonso-Domínguez
Princess Margaret Cancer Centre, Toronto, Ma, Canada
Laura Barreyro
6Johnson & Johnson Innovative Medicine, Spring House, United States
Pierre Bories
8Institut Universitaire du Cancer de Toulouse – Oncopole, Toulouse, France
Nikki Daskalakis
1Johnson & Johnson, Spring House, United States
Matteo Della Porta
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Hartmut Döhner
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
Amber D'Souza
1Johnson & Johnson, Spring House, United States
James Dugan
12Novant Health Cancer Institute, Winston-Salem, United States
Amir Fathi
1Massachusetts General Hospital, Medical Oncology, Boston, United States
Pasquale Fedele
13Monash Health, Clayton, Australia
Lucille Ferrante
3Johnson & Johnson Innovative Medicine, Spring House, United States
Rachel Kobos
Johnson & Johnson, Raritan, NJ
Ana Garrido
12Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Sara Garrido Paniagua
1Vall d'Hebron Hospital, Department of Hematology, BARCELONA, Spain
Christina Drenberg Guttke
3Johnson & Johnson Innovative Medicine, Spring House, United States
Emmanuel Gyan
2CHU Tours, Tours, France
Brett Hiebert
6Johnson & Johnson Innovative Medicine, Spring House, United States
Elias Jabbour
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Danielle Trancucci
3Johnson & Johnson Innovative Medicine, Spring House, United States
Naa Sackey
6Johnson & Johnson Innovative Medicine, Spring House, United States
Madlen Jentzsch
19Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Disease, University of Leipzig Medical Center, Leipzig, Germany
Hagop Kantarjian
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Marina Konopleva
Jan Krönke
Marie Luise Hütter-Krönke
5Charité - Universitätsmedizin, Department of Hematology, Oncology and Tumor Immunology, Berlin, Germany
Christina Loefgren
3Johnson & Johnson Innovative Medicine, Spring House, United States
Oliver Lomas
6Johnson & Johnson Innovative Medicine, Spring House, United States
Valentina Mancini
7ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
Daniel Morillo
From Tel Aviv Sourasky Medical Center (Y.C.C., I.A.), and the Faculty of Medical and Health Sciences, Tel Aviv University (Y.C.C., H.M., I.A.), Tel Aviv, Chaim Sheba Medical Center, Ramat Gan (H.M.), and Hadassah Hebrew University Medical Center, Jerusalem (M.G.) — all in Israel; McGill University and McGill University Health Centre, Montreal (M.S.), and Alberta Health Services, Edmonton (M.P.C.) — all in Canada; Samsung Medical Center, Sungkyunkwan University School of Medicine (K.K.), Seoul St. Mary’s Hospital, Catholic University of Korea (C.-K.M.), and Seoul National University College of Medicine (S.-S.Y.) — all in Seoul, South Korea; Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla, Universidad de Cantabria, Santander (E.M.O.), Cancer Center Clínica Universidad de Navarra, Center for Applied Medical Research, Pamplona (P.R.-O.), Institut Català d’Oncologia, Josep Carreras Leukemia Research Institute, and the Hospital Germans Trias i Pujol, Barcelona (A.O.)...
Kathryn Packman
1Johnson & Johnson, Spring House, PA
Cristina Papayannidis
2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
Christian Récher
Christoph Röllig
22Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany
Olga Salamero
13Hospital U. Vall D'Hebron, Barcelona, Spain
Prathap Nagaraja Shastri
3Johnson & Johnson Innovative Medicine, Spring House, United States
Tim Sauer
3Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Dr. Emma Searle
1The Christie NHS Foundation Trust University of Manchester, Manchester, United Kingdom
Natalia Tovar
1Hospital Clinic of Barcelona, Barcelona, Spain
Nicolas Vallet
33Centre Hospitalo-universitaire Tours University Hospital, Service d'hématologieHematology and Cell Therapy Department, Tours, France
Lachlin Vaughan
Paresh Vyas
Uwe Platzbecker
Sylvain Garciaz
5Institut Paoli-Calmettes, Marseille, France