The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia

Ghayas C. Issa (), Ibrahim Aldoss, John DiPersio, Branko Cuglievan, Richard Stone, Martha Arellano, Michael J. Thirman, Manish R. Patel, David S. Dickens, Shalini Shenoy, Neerav Shukla, Hagop Kantarjian, Scott A. Armstrong, Florian Perner, Jennifer A. Perry, Galit Rosen, Rebecca G. Bagley, Michael L. Meyers, Peter Ordentlich, Yu Gu, Vinit Kumar, Steven Smith, Gerard M. McGeehan and Eytan M. Stein ()
Additional contact information
Ghayas C. Issa: The University of Texas MD Anderson Cancer Center
Ibrahim Aldoss: City of Hope
John DiPersio: Washington University School of Medicine in St. Louis
Branko Cuglievan: The University of Texas MD Anderson Cancer Center
Richard Stone: Dana-Farber Cancer Institute
Martha Arellano: Emory University School of Medicine
Michael J. Thirman: University of Chicago
Manish R. Patel: Florida Cancer Specialists/Sarah Cannon Research Institute
David S. Dickens: University of Iowa
Shalini Shenoy: Washington University School of Medicine in St. Louis
Neerav Shukla: Memorial Sloan Kettering Cancer Center
Hagop Kantarjian: The University of Texas MD Anderson Cancer Center
Scott A. Armstrong: Dana-Farber Cancer Institute
Florian Perner: Dana-Farber Cancer Institute
Jennifer A. Perry: Dana-Farber Cancer Institute
Galit Rosen: Syndax Pharmaceuticals
Rebecca G. Bagley: Syndax Pharmaceuticals
Michael L. Meyers: Syndax Pharmaceuticals
Peter Ordentlich: Syndax Pharmaceuticals
Yu Gu: Syndax Pharmaceuticals
Vinit Kumar: Syndax Pharmaceuticals
Steven Smith: Syndax Pharmaceuticals
Gerard M. McGeehan: Syndax Pharmaceuticals
Eytan M. Stein: Memorial Sloan Kettering Cancer Center

Nature, 2023, vol. 615, issue 7954, 920-924

Abstract: 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.

Date: 2023
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-023-05812-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:615:y:2023:i:7954:d:10.1038_s41586-023-05812-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-023-05812-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().