Therapeutic Implications of Menin Inhibitors in the Treatment of Acute Leukemia: A Critical Review.

Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with mutations m) and rearrangements (r) represent the primary targets of this emerging drug class. Acute myeloid leukemia (AML) with m-which accounts for approximately 30% of AML cases and AML or acute lymphoblastic leukemia (ALL) with r-and is present in 5-10% of cases, shares a common pathogenetic mechanism: the aberrant activation of the axis. These leukemic subsets are associated with poor prognosis, particularly in the relapsed/refractory (R/R) setting. For r AML, the prognosis is especially dismal, with a median overall survival (OS) of 2.4 months and a complete remission (CR) rate of only 5%. In m AML, intensive chemotherapy achieves remission in approximately 80% of cases, but relapse remains a major challenge, occurring in nearly 50% of patients. Relapsed m AML is linked to a poor prognosis, with a median OS of 6.1 months (12-month OS: 30%) and a median relapse-free survival (RFS) of 5.5 months (12-month RFS: 34%). Menin inhibitors directly target the leukemogenic transcriptional program driven by and , disrupting oncogenic signaling and offering a promising therapeutic approach for these high-risk patients. This class of agents has rapidly progressed through clinical development, showing promising antileukemic activity in both treatment-naïve and R/R AML. Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. In this review, we critically analyze the clinical development and therapeutic potential of the four most extensively studied menin inhibitors-revumenib, ziftomenib, bleximenib, and enzomenib. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for m and r AML and other acute leukemia with the aberrant axis, offering new hope for patients with limited therapeutic options.