Multicenter phase 1 trial of the menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukemia

The interaction of menin with the epigenetic regulator KMT2A is a dependence in acute leukemia caused by either rearrangement of KMT2A or mutation of NPM1. KMT2A rearrangements occur in up to 10% of acute leukemias and have an adverse prognosis, whereas NMP1 mutations occur in up to 30%. A phase 1 trial at nine US centers evaluated menin, a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukemia. The study found a low frequency of grade 3 or higher treatment-related adverse events and an overall response rate of 53%, with complete remission or complete remission with partial hematologic recovery in 30% the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was the only dose-limiting toxicity. The authors conclude that menin inhibition may be a therapeutic strategy for susceptible acute leukemia subtypes.