Bleximenib in combination with intensive chemotherapy: A phase 1b study in newly diagnosed 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. 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.
Article Details
Authors (51)
Hartmut Döhner
1Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
Andre Schuh
1Princess Margaret Cancer Centre, Department of Medical Oncology and Hematology, Toronto, Canada
Christian Récher
Jenny O'Nions
13Department of Hematology, University College London Hospital NHS Foundation Trust, London, United Kingdom
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
Amber D'Souza
1Johnson & Johnson, Spring House, United States
James Dugan
12Novant Health Cancer Institute, Winston-Salem, United States
Jordi Esteve
13Hematology Department, Institute of Cancer & Blood Diseases (ICAMS), Hospital Clinic, Barcelona, Spain
Amir Fathi
1Massachusetts General Hospital, Medical Oncology, Boston, United States
Lucille Ferrante
3Johnson & Johnson Innovative Medicine, Spring House, United States
Stan Gaj
7Johnson & Johnson Innovative Medicine, Cambridge, United States
Sylvain Garciaz
5Institut Paoli-Calmettes, Marseille, France
Ana Garrido
12Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Olga Salamero
13Hospital U. Vall D'Hebron, 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
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
Ioannis Mantzaris
1Montefiore Medical Center, Bronx, United States
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
Ulrike Philippar
2Johnson & Johnson, Beerse, Belgium
Uwe Platzbecker
Sara Garrido Paniagua
1Vall d'Hebron Hospital, Department of Hematology, BARCELONA, Spain
Naa Sackey
6Johnson & 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
Prathap Nagaraja Shastri
3Johnson & Johnson Innovative Medicine, Spring House, United States
Danielle Trancucci
3Johnson & Johnson Innovative Medicine, Spring House, United States
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
Andrew Wei
3Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Christoph Röllig
22Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany