The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia Journal Article
| Authors: | Issa, G. C.; Aldoss, I.; DiPersio, J.; Cuglievan, B.; Stone, R.; Arellano, M.; Thirman, M. J.; Patel, M. R.; Dickens, D. S.; Shenoy, S.; Shukla, N.; Kantarjian, H.; Armstrong, S. A.; Perner, F.; Perry, J. A.; Rosen, G.; Bagley, R. G.; Meyers, M. L.; Ordentlich, P.; Gu, Y.; Kumar, V.; Smith, S.; McGeehan, G. M.; Stein, E. M. |
| Article Title: | The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia |
| 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. © 2023, The Author(s). |
| Keywords: | adolescent; adult; child; aged; major clinical study; genetics; mutation; leukemia, myeloid, acute; fatigue; cancer recurrence; diarrhea; drug efficacy; side effect; antineoplastic agents; chemotherapy; antineoplastic agent; gene; nuclear protein; nausea; thrombocytopenia; vomiting; qt prolongation; inhibitor; nuclear proteins; alanine aminotransferase blood level; febrile neutropenia; hypokalemia; hyponatremia; cancer regression; acute leukemia; gene rearrangement; infant; multicenter study; bioassay; peripheral edema; remission; remission induction; open study; headache; phase 1 clinical trial; epistaxis; electrocardiography; differentiation; dysgeusia; inhibition; recovery; decreased appetite; acute myeloid leukemia; hyperphosphatemia; npm1 gene; cancer; humans; prognosis; human; article; differentiation syndrome; kmt2a gene; revumenib |
| Journal Title: | Nature |
| Volume: | 615 |
| Issue: | 7954 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-03-30 |
| Start Page: | 920 |
| End Page: | 924 |
| Language: | English |
| DOI: | 10.1038/s41586-023-05812-3 |
| PUBMED: | 36922593 |
| PROVIDER: | scopus |
| PMCID: | PMC10060155 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Export Date: 1 May 2023 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work