AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation
Blocking menin, a scaffold protein the leukaemia depends on, produced remissions in heavily pretreated patients with KMT2A-rearranged or NPM1-mutated acute leukaemia.
The phase 1 portion of AUGMENT-101 treated 68 adults and children with relapsed or refractory acute leukaemia carrying a KMT2A rearrangement or NPM1 mutation with oral revumenib (SNDX-5613), a small molecule that disrupts the menin-KMT2A interaction. Among 60 efficacy-evaluable patients the overall response rate was 53% and the rate of complete remission or remission with partial haematological recovery 30%, with most responders MRD-negative. QT prolongation was dose limiting and differentiation syndrome occurred in 16%. Resistance through MEN1 mutations was subsequently described. The phase 2 KMT2A-rearranged cohort met its primary endpoint and revumenib was approved in 2024 for KMT2A-rearranged acute leukaemia and in 2025 for NPM1-mutated AML, the first drugs in a new class.
- 68 patients treated (60 efficacy-evaluable) with relapsed/refractory KMT2A-rearranged or NPM1-mutated acute leukaemia.
- Overall response 53%; CR/CRh 30%; most remissions MRD-negative.
- Dose-limiting toxicity was QT prolongation; differentiation syndrome in 16%.
- Responses in both KMT2A-rearranged and NPM1-mutated disease and in children and adults.
- Phase 2 KMT2A-rearranged cohort: CR/CRh in roughly a fifth of patients, sufficient for regulatory approval; acquired MEN1 mutations identified as a resistance mechanism.
Revumenib proved that a transcriptional dependency, rather than a kinase, can be drugged in leukaemia, opening treatment for two genetic subgroups that together cover roughly a third of AML plus most infant ALL. It is now approved and is being combined with venetoclax-azacitidine and intensive chemotherapy in front-line trials. Single-agent remissions are often short without transplant.
- Single-arm phase 1/2 in end-stage patients; no randomised data yet.
- Modest CR/CRh rates as monotherapy; benefit likely to come from combinations and as a bridge to transplant.
- QT prolongation and drug interactions with azoles require dose adjustment.
- Resistance via MEN1 mutations emerges within months in some patients.