Menin inhibitors in acute leukemia: Advances and future directions

Acute leukemias with KMT2A rearrangements (KMT2Ar) or mutant NPM1 (NPM1m) have historically poor outcomes despite intensive therapy. Menin, a scaffold protein encoded by MEN1, is a critical cofactor for the leukemic transcriptional program in these subsets. Targeting the menin-KMT2A interaction emerged as an effective strategy, leading to the first approvals of menin inhibitors (revumenib and ziftomenib) for relapsed/refractory disease. This review assesses the current evidence and future directions for menin inhibition in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

We systematically searched PubMed, clinical trial registries, and conference proceedings (2015-2025) for studies on menin inhibitors in AML/ALL. Both peer-reviewed articles and pivotal trial data, including FDA labels and regulatory documents, were included. Key trials were appraised for bias using the Cochrane criteria, which indicated a high risk of bias due to single-arm designs and short follow-up.

Menin inhibitors achieve CR or CRh in ∼20%-25% of heavily pretreated KMT2Ar or NPM1m leukemia patients. Median remission duration is ∼5-6 months, with over half of responders attaining minimal residual disease (MRD) negativity. Differentiation syndrome (DS) occurs in ∼15% of patients and is generally reversible with corticosteroids. Menin inhibitors' class-specific toxicities include QTc prolongation (notable with revumenib) and require careful electrocardiographic monitoring. Acquired resistance arises in ∼40% of relapsed cases via MEN1 point mutations (especially M327I and T349M) that interfere with drug binding. Next-generation menin inhibitors (e.g., bleximenib) retain activity against some resistant variants. In newly diagnosed older adults with NPM1m or KMT2Ar AML, triplet therapy with revumenib, venetoclax, and azacitidine yielded composite CR rates >80% and MRD-negative remissions in nearly all responders. Early integration of menin inhibitors into frontline regimens and maintenance therapy is feasible, including use in pediatric patients ≥1 year old. Emerging AI-driven models (e.g., multimodal drug response predictors and optimal-transport embedding of flow cytometry data) show promise in guiding combination strategies and MRD assessment.

Menin inhibitors represent a significant advance for genetically defined acute leukemias, safely delivering clinically meaningful responses in KMT2Ar and NPM1m cases. Ongoing phase 3 studies will clarify if there is a survival benefit and the optimal use. Integrating menin inhibitors with existing therapies, from low-intensity combinations in older adults to intensive chemotherapy backbones in fit patients, is driving unprecedented response rates. Continued research into resistance mechanisms and innovative AI-guided treatment personalization will be essential to extend remission durability. As menin inhibitors move into frontline and pediatric settings, and as maintenance therapy posttransplant, they are positioned to become a new pillar of precision hematology, potentially improving cure rates for high-risk acute leukemia subgroups.