Targeting menin dependency in acute leukemias: the role of revumenib in NPM1-mutated and KMT2A/NUP98-rearranged disease

Rearrangements of the lysine methyltransferase 2A gene (KMT2Ar) occur in up to 10% of acute leukemias in children and adults and are associated with adverse outcomes in the relapsed setting. Although nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is traditionally classified as a favorable-risk disease, more than half of patients ultimately relapse. The leukemogenesis of both KMT2Ar and NPM1m leukemias is dependent on the interaction between menin and KMT2A, making menin an attractive therapeutic target. Revumenib, a first in class menin inhibitor, was approved by the US Food and Drug Administration in November 2024, for relapsed or refractory (R/R) KMT2Ar acute leukemias and subsequently, in October 2025, for patients with R/R NPM1m AML who have no satisfactory alternative treatment. Beyond its single-agent activity, investigational studies have shown successful incorporation into a variety of backbone regimens. Furthermore, there is growing interest in exploring revumenib in earlier treatment settings, including frontline therapy, post-transplant maintenance and in other molecularly defined leukemias characterized by HOX gene upregulation (e.g. NUP98 rearrangements). Herein, we summarize the landmark trials that established revumenib as an effective therapy option for patients with KMT2Ar acute leukemia and NPM1m AML.