Menin inhibitors in KMT2A-rearranged and NPM1-mutated acute leukemia: A scoping review of safety and efficacy

Abstract

Background: Menin inhibitors represent a novel therapeutic approach targeting the Menin-KMT2A interaction in acute leukemias with KMT2A rearrangements or NPM1 mutations. This scoping review synthesizes current clinical evidence for emerging Menin inhibitors in development.

Methods: We systematically analyzed clinical trials, conference proceedings, and regulatory documents regarding Menin inhibitors in clinical development through December 2024. Primary outcomes included response rates, minimal residual disease (MRD) status, and safety profiles.

Results: Thirteen clinical trials investigating six Menin inhibitors (Revumenib, Ziftomenib, Bleximenib, BMF-219, DS-1594, and Enzomenib) were identified. Revumenib demonstrated consistent efficacy across five pivotal trials, achieving MRD-negative rates of 70-90 % in both KMT2A-rearranged and NPM1-mutated leukemias, leading to FDA approval in November 2024. Ziftomenib showed particular efficacy in NPM1-mutated cases but exhibited a higher incidence of differentiation syndrome (30 %) in KMT2A-rearranged patients. Bleximenib reported a 93 % overall response rate, pending MRD validation. Early resistance emergence, primarily through MEN1 mutations, was observed across trials, emerging as early as two treatment cycles.

Conclusions: Menin inhibitors demonstrate promising clinical activity in molecularly defined leukemias, with Revumenib establishing proof-of-concept for this therapeutic approach. However, challenges remain, including resistance development, optimal timing of therapy initiation, and determination of effective combination strategies. Larger randomized trials with extended follow-up are needed to establish long-term efficacy and safety profiles. The rapid clinical development of multiple agents in this class suggests an expanding role for Menin inhibitors in leukemia treatment paradigms.

Keywords: Acute leukemia; Clinical trials; KMT2A rearrangement; Menin inhibitors; NPM1 mutation; Targeted therapy.