Authors
Claudia Simio, Alessandra Vatteroni
Published in
Clinical lymphoma, myeloma & leukemia. Aug 01, 2026. Epub Aug 01, 2026.
Abstract
Menin inhibitors (MIs) represent a novel class of targeted agents that disrupt the interaction between the nuclear protein menin and the KMT2A (MLL) complex, thereby interrupting a crucial oncogenic transcriptional program in acute myeloid leukemias (AML) with KMT2A rearrangements and NPM1 mutations. Robust preclinical data have shown that menin inhibition suppresses HOXA/MEIS1 expression, induces differentiation, and reduces the fitness of leukemic cells, including the stem-like compartment. These findings rapidly led to phase I/II clinical trials with oral MIs such as revumenib and ziftomenib, which demonstrated CR+CRh rates of 22% to 23% in refractory/relapsed patients, with conversion to measurable residual disease (MRD) negativity in 61% to 68% of responders and early use as a bridge to allogeneic transplantation. However, the median duration of response remains limited (approximately 4-5 months), suggesting that menin inhibition as monotherapy may be insufficient to ensure durable disease control. Key emerging clinical issues include specific adverse events (QTc prolongation in 12%-44%, differentiation syndrome in 10%-29%), drug-drug interactions mediated by CYP3A4 metabolism, resistance dynamics (on-target mutations in 39% of cases), and the definition of the optimal role in combination with venetoclax, hypomethylating agents, and intensive chemotherapy. This review synthesizes molecular mechanisms, preclinical and clinical data, discusses use within MRD-guided and transplant pathways, and proposes translational priorities for integrating MIs into future therapeutic paradigms, pending confirmation from randomized studies.
PMID:
42637611
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.
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