Menin inhibitors in acute myeloid leukaemia: Mechanisms, clinical pharmacology, and emerging therapeutic strategies.

Acute myeloid leukaemia (AML) remains associated with poor outcomes in relapsed or refractory disease and in molecularly defined high-risk subgroups. AML with KMT2A rearrangements (KMT2Ar) or NPM1 mutations (NPM1m) shares a dependence on the menin-KMT2A interaction, which sustains HOXA/MEIS1-driven transcription required for leukaemic maintenance. This dependence has provided the rationale for developing menin inhibitors as a targeted approach in selected AML subsets. This review summarises the mechanistic basis, clinical pharmacology, and current clinical role of menin inhibitors in AML. Revumenib, ziftomenib, bleximenib, and enzomenib are orally administered small molecules that disrupt menin-dependent transcription, induce myeloid differentiation, and have shown clinical activity in KMT2Ar and NPM1m AML. Monotherapy has produced clinically relevant remission rates in relapsed or refractory disease, and early-phase combinations with venetoclax-based therapy, hypomethylating agents, intensive chemotherapy, or FLT3 inhibitors have shown higher response rates in selected settings. Despite sharing a common target, these agents differ in dosing schedule, pharmacokinetic profile, CYP3A4-mediated drug-drug interaction potential, sensitivity to food or gastric pH, and safety profile. Differentiation syndrome and QTc prolongation are the principal toxicities requiring monitoring, although QT liability appears to vary across compounds. Acquired resistance-mediated by MEN1 binding-pocket mutations, co-occurring genomic alterations, and adaptive transcriptional or epigenetic programmes-remains a clinical limitation. Current evidence supports menin inhibition as a targeted strategy for molecularly selected AML. Ongoing studies will be important for defining optimal sequencing, combination regimens, approaches to resistance, and the role of pharmacologically informed dose optimisation in routine practice.