Revumenib in KMT2A-Rearranged Leukaemia: MRD Clearance Validates Menin Inhibition
This first-in-human phase 1 trial of revumenib, an oral menin-KMT2A interaction inhibitor, achieved a 30% complete remission rate in heavily pretreated acute leukaemia patients with KMT2A rearrangements or NPM1 mutations. Critically, the study demonstrated clearance of measurable residual disease using sensitive clinical assays, validating MRD monitoring as a response biomarker for this drug class. For molecular laboratories, this trial underscores the importance of KMT2A FISH/sequencing for patient identification and MRD assays for treatment response assessment.
The original study
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia.
- Authors
- Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, et al.
- Journal
- Nature
- Type
- Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural
- PMID
- 36922593
Original abstract
Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.