bleximenib (JNJ-6617)

Currently, several small-molecule menin inhibitors are being tested in combination with conventional therapies. This publication reviews the recent progress in investigating the clinical evidence of menin inhibitors (revumenib, ziftomenib, bleximenib, enzomenib, BMF-219, emilumenib) toward aggressive leukemias, guides future study and optimal treatment for patients with this type of leukemia.

P1/2, N=420, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jun 2026 --> Feb 2027

P3, N=875, Recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | N=423 --> 875

P1/2, N=420, Recruiting, Janssen Research & Development, LLC | Trial completion date: May 2028 --> Sep 2030 | Trial primary completion date: Feb 2026 --> Jun 2026

P3, N=875, Recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Not yet recruiting --> Recruiting | N=328 --> 875

This manuscript reviews the molecular rationale of menin inhibition for aberrant homeobox/myeloid ectopic insertion site 1 (HOX/MEIS1)-driven gene expression and leukemogenesis, clinical trial outcomes, and safety data for menin inhibitors, with a focus on recently FDA-approved revumenib and several other agents in development, ziftomenib (KO-539), bleximenib (JNJ-75276617), and icovamenib (BMF-219). We also focused our discussion on future directions to include resistance mechanisms, biomarker identification and monitoring strategies, and combination therapies. Menin inhibition is now being clinically integrated into relapsed/refractory and frontline treatment settings.

While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents...IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30-94% in AML with DS in 10-19%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33-88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10-25% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1-5%...Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL.

Revumenib received approval in 2024-2025 for relapsed or refractory KMT2A-rearranged acute leukemia and NPM1-mutated AML...Several menin inhibitors, including ziftomenib, bleximenib, and enzomenib, are in clinical development...Combination therapies with azacitidine and venetoclax or intensive chemotherapy have achieved high response rates in newly diagnosed patients, supporting their potential use in frontline treatment...Approximately 30-40% of responders in relapsed or refractory trials proceeded to allogeneic transplantation, which remains a key pathway to potential cure. This review examines the molecular mechanisms of the menin-KMT2A interaction, and summarizes clinical trial data on the efficacy and safety of menin inhibitors as monotherapy and in combination.

P2/3, N=271, Recruiting, Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

P1, N=196, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

Menin inhibitor approval/use is expanding into other HOX-driven subtypes (e.g. NPM1, NUP98r), as frontline option and in combination settings. Monitoring for differentiation syndrome, QT interval prolongation, recognizing pseudo-progression, and supportive care needs remains essential to maximize patient benefit.

P1, N=10, Recruiting, Janssen Research & Development, LLC