Resistance mechanisms and therapeutic strategies after menin inhibitor failure in acute myeloid leukemia.

INTRODUCTION: Menin inhibitors, including the FDA-approved agents revumenib and ziftomenib, have emerged as transformative targeted therapies in acute myeloid leukemia (AML), particularly in KMT2A-rearranged (KMT2Ar) and NPM1-mutated (NPM1m) disease. Despite high initial response rates, durability remains limited, and most patients relapse within months, defining a critical unmet clinical need. AREAS COVERED: This review synthesizes current evidence on the biological and clinical landscape of menin inhibitor resistance in AML. We address on-target MEN1mutations, off-target clonal evolution, epigenetic and transcriptional reprogramming, and microenvironment-mediated adaptive signals. We also review clinical outcomes after treatment failure and emerging therapeutic strategies. A literature search was conducted in PubMed and ClinicalTrials.gov through June 2026, supplemented by recent international congress abstracts. EXPERT OPINION: No clinical tests are currently available to reliably predict emerging resistance or early therapeutic failure, and treatment options after menin inhibitor failure remain limited and largely empiric, including, if not previously used, venetoclax-based regimens, mutation-directed therapies, and intensive chemotherapy as a bridge to allogeneic HSCT. Emerging preclinical data identify key vulnerabilities, including bypass signaling, apoptotic dependence, and epigenetic escape, providing a rationale for next-generation combination strategies, ideally in the frontline setting to maximize the chance of success and minimize the risk of clonal escape.