Targeting the Menin-KMT2A Axis in AML: Translating Molecular Insights into Therapeutic Success

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.