The role of menin inhibitors in acute myeloid leukemia

Purpose of reviewAcute myeloid leukemia (AML) characterized by NPM1 mutations or KMT2A rearrangements depends on abnormal epigenetic programs mediated by menin, a critical scaffold protein for sustaining the expression of oncogenic HOX/MEIS1 genes. Therefore, menin inhibitors have become a promising class of AML treatments.Recent findingsEarly-phase trials have shown that agents such as revumenib, ziftomenib, bleximenib, and enzomenib are active, particularly in relapsed/refractory disease, with 23-48% of patients achieving composite complete remission. However, the durability of single-agent treatment remains limited, and resistance mechanisms, such as MEN1 mutations or transcriptional reprogramming, have been identified. Consequently, combination approaches involving venetoclax, hypomethylating agents, or chemotherapy are being investigated to improve response depth and duration. Recent SAVE, KOMET-007, and cAMeLot-2 trials have demonstrated high overall response rates (68%-100%) and encouraging MRD-negative complete remissions when combining menin inhibitors with venetoclax-based regimens. This has been observed even in patients who have previously received venetoclax. Combinations with intensive chemotherapy (e.g., 7 + 3) in the frontline setting have also yielded high CRc rates (up to 94% in NPM1-mutated AML) without exacerbating toxicity.SummaryThese findings justify the integration of menin inhibitors into the AML therapeutic landscape, and support ongoing randomized trials to confirm their benefit in both frontline and relapse or refractory settings.