Menin inhibitors as targeted therapy in KMT2A-Rearranged acute leukemia: A comprehensive review of current advances and therapeutic implications.

Acute leukemias harboring KMT2A rearrangements (KMT2A-r) or NPM1 mutations (NPM1-m) are aggressive subtypes with limited therapeutic options and high relapse rates. Their biology is sustained by aberrant HOXA9/MEIS1 transcription, critically dependent on the interaction between menin and the KMT2A complex. This insight has established menin as a tractable therapeutic target, leading to the development of selective small-molecule inhibitors. By disrupting the menin KMT2A interaction, these agents collapse leukemogenic transcriptional programs and promote blast differentiation. Among them, revumenib and ziftomenib have advanced furthest in clinical testing. Early-phase trials demonstrated meaningful responses in relapsed or refractory KMT2A-r and NPM1-m leukemias, and the recent FDA approval of revumenib represents the first clinical validation of menin inhibition in genetically defined disease. Nonetheless, resistance most often mediated by MEN1 pocket mutations limits durability, while treatment requires vigilance for differentiation syndrome and QTc prolongation. Ongoing trials are now evaluating menin inhibitors in rational combinations, frontline regimens, and maintenance therapy. Collectively, these advances highlight menin inhibition as a transformative strategy in acute leukemia, reshaping therapy through precision-targeted epigenetic intervention.