Revumenib + AZA/VEN Hits 88% ORR and Universal MRD-Negativity in Older NPM1m/KMT2Ar AML

Revumenib, an oral menin inhibitor that disrupts the menin-KMT2A/NPM1 transcriptional axis, was added to frontline azacitidine + venetoclax in a phase I dose-escalation/expansion study (NCT03013998) enrolling 43 intensive-chemo-ineligible adults ≥60 years with newly diagnosed NPM1-mutated or KMT2A-rearranged AML; NPM1 mutations are present in about 30% of AML patients, while KMT2A rearrangements occur in approximately 5–10% and are mutually exclusive (non-overlapping) for a total of about 35-40% of AML patients. After a median follow-up of 27 mo, the triplet delivered an 88% overall response rate and 81% composite CR (CR/CRh/CRi), with 84% of responders achieving remission by cycle 1 and 100% (37/37) attaining flow-MRD negativity. One early death (2%) occurred; grade ≥3 QTcF prolongation (44%) and differentiation syndrome (19%) were manageable without permanent drug discontinuation. For context, the VIALE-A doublet (azacitidine + venetoclax) posts a 66% CRc and 14.7-mo median OS in unselected IC-ineligible AML, while AGILE’s azacitidine + ivosidenib shows 47% CR and 24-mo OS in IDH1-mut cases—making the menin-based triplet the current efficacy frontrunner in genetically defined, older AML