Menin Inhibitors in Acute Myeloid Leukemia: Clinical Integration, Resistance, and the Path Beyond Monotherapy
TL;DR
Looking ahead, menin inhibitors may increasingly be incorporated into earlier lines of therapy, used as maintenance following allogeneic stem cell transplantation, and integrated into treatment approaches guided by measurable residual disease and evolving patterns of drug resistance.
Abstract
Simple Summary Treatment of acute myeloid leukemia (AML) has evolved rapidly with the development of novel targeted therapies. Menin inhibitors represent a new class of targeted agents with particular activity in AML harboring KMT2A rearrangements or NPM1 mutations, genetic alterations that promote leukemia development and survival through menin-dependent transcriptional programs. Recent clinical trials have demonstrated meaningful activity of menin inhibitors in patients with relapsed or refractory AML. This review summarizes the biological rationale and mechanism of action of menin inhibition, the clinical trial data supporting their use, and their emerging role in combination with upfront AML therapies. We also discuss mechanisms of primary and acquired resistance and strategies being investigated to overcome resistance. Looking ahead, menin inhibitors may increasingly be incorporated into earlier lines of therapy, used as maintenance following allogeneic stem cell transplantation, and integrated into treatment approaches guided by measurable residual disease and evolving patterns of drug resistance.