Menin Inhibitors in Acute Myeloid Leukemia: From Molecular Rationale to Clinical Practice

Background: Acute Myeloid Leukemia (AML) harboring KMT2A rearrangements (KMT2Ar) or NPM1 mutations (mNPM1) constitutes a substantial and molecularly coherent subset of AML characterized by aberrant activation of homeobox (HOX) gene programs driven by the menin–MLL transcriptional complex. Disruption of this interaction through small-molecule menin inhibitors represents a compelling therapeutic strategy. Methods: We conducted a narrative (non-systematic) review of the clinical literature on four menin inhibitors—revumenib, ziftomenib, bleximenib, and enzomenib—as monotherapy and in combination regimens, identified through PubMed/MEDLINE and conference abstract searches (ASH, EHA) without a pre-specified systematic search protocol, as detailed in the Introduction. Results: Revumenib received FDA approval in November 2024 for relapsed/refractory (R/R) acute leukemia with a KMT2A translocation (an indication not restricted by lineage; the pivotal cohort included AML, ALL and MPAL), demonstrating a CR + CRh rate of 21.2% in the pivotal AUGMENT-101 trial, and a second FDA approval followed in October 2025 for R/R mNPM1 AML. In R/R mNPM1 AML (cohort 2C), an overall response rate (ORR) of 46.9% was observed. Ziftomenib achieved its primary phase II endpoint in R/R mNPM1 AML (CR/CRh 23%, p = 0.0058 vs. historical control) and received FDA approval (as Komzifti) in November 2025 for the same indication. Combination strategies with venetoclax/azacitidine have shown high response rates in small, non-randomized newly diagnosed cohorts (ORR approximately 88–94%), although the contribution of the menin inhibitor cannot be established without randomized data. Bleximenib and enzomenib show similarly encouraging early-phase signals. Resistance via acquired MEN1 mutations (M327I/V, G331R/D, T349M) has been identified in approximately 38.7% of revumenib-treated patients who progress after two or more cycles. Differentiation syndrome remains the most characteristic class-specific toxicity, occurring in approximately 11–28% of patients across agents (rates vary by cohort, data cut and prophylaxis strategy). Conclusions: Menin inhibitors represent a clinically important addition to the treatment of KMT2A- and mNPM1-driven AML, following the precedent set by FLT3 and IDH inhibitors. Combination approaches with hypomethylating agents and BCL-2 inhibition show particular promise, although no randomized controlled trial has yet demonstrated a survival benefit and current evidence derives predominantly from single-arm, early-phase studies. Ongoing randomized trials will define the definitive role of these agents across disease settings.