Menin inhibitors as a treatment for acute leukemia: from bench to the clinic.

Menin inhibitors exploit the key biological mechanism behind KMT2A-rearranged (KMT2A-r) and nucleophosmin 1-mutated (NPM1-mut) leukemias by targeting the menin-KMT2A interaction and disrupting KMT2A/KMT2A fusion complexes binding to chromatin, thereby preventing transcriptional activation of fundamental leukemogenic programs (HOXA9/MEIS1). A series of remarkable discoveries, from the cloning and identification of the MLL1 (KMT2A) gene in 1991, to the first discovery of menin's role in leukemia in 2005, to the development of the first small-molecule menin inhibitor in 2012, and to the initiation of the first-in-human clinical trials in 2019, led to the US Food and Drug Administration (FDA) approval of the first menin inhibitor (revumenib) in 2024 for in the treatment of relapsed or refractory (R/R) KMT2A-r acute leukemia, representing a significant scientific achievement for the rapid clinical translation of molecularly targeted therapy. The menin inhibitors revumenib and ziftomenib have subsequently been FDA approved for R/R NPM1-mut acute myeloid leukemia (AML) in 2025, and at least 5 other menin inhibitors are in clinical development for leukemia. Here, we review the discovery, preclinical and clinical development, and safety and efficacy of menin inhibitors through 2025. Menin inhibitors hold promise as one of the most powerful single-agent targeted therapies in acute leukemia, with response rates of ∼50% or higher in R/R AML with KMT2A-r or NPM1-mut disease. Despite this notable clinical activity, response duration to menin inhibitors remains short-lived for most patients, which has resulted in an explosion of combination therapy trials in both R/R and newly diagnosed AML, including intensive chemotherapy and nonintensive (venetoclax-based) approaches, as well as combinations with targeted therapies and novel differentiation therapies.