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; Eytan M Stein

doi:10.1038/s41586-023-05812-3

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

Journal article

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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, …

Nature (London), Vol.615(7954), pp.920-924

2023

DOI: 10.1038/s41586-023-05812-3

PMCID: PMC10060155

PMID: 36922593

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Abstract

Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function . 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) . 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 leukaemia . 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.

Antineoplastic Agents - pharmacology

Humans

Leukemia, Myeloid, Acute - drug therapy

Leukemia, Myeloid, Acute - genetics

Nuclear Proteins - genetics

Prognosis

Remission Induction

Details

Title: Subtitle: The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
Creators: Ghayas C Issa - The University of Texas MD Anderson Cancer Center
Ibrahim Aldoss - City Of Hope National Medical Center
John DiPersio - Washington University School of Medicine in St. Louis, St. Louis, MO, USA
Branko Cuglievan - The University of Texas MD Anderson Cancer Center
Richard Stone - Dana-Farber Cancer Institute, Boston, MA, USA
Martha Arellano - Emory University School of Medicine
Michael J Thirman - University of Chicago
Manish R Patel - Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA
David S Dickens - University of Iowa
Shalini Shenoy - Washington University School of Medicine in St. Louis, St. Louis, MO, USA
Neerav Shukla - Memorial Sloan Kettering Cancer Center
Hagop Kantarjian - The University of Texas MD Anderson Cancer Center
Scott A Armstrong - Dana-Farber Cancer Institute, Boston, MA, USA
Florian Perner - Greifswald University Medical Center, Greifswald, Germany
Jennifer A Perry - Dana-Farber Cancer Institute, Boston, MA, USA
Galit Rosen - Syndax Pharmaceuticals, Waltham, MA, USA
Rebecca G Bagley - Syndax Pharmaceuticals, Waltham, MA, USA
Michael L Meyers - Syndax Pharmaceuticals, Waltham, MA, USA
Peter Ordentlich - Syndax Pharmaceuticals, Waltham, MA, USA
Yu Gu - Syndax Pharmaceuticals, Waltham, MA, USA
Vinit Kumar - Syndax Pharmaceuticals, Waltham, MA, USA
Steven Smith - Syndax Pharmaceuticals, Waltham, MA, USA
Gerard M McGeehan - Syndax Pharmaceuticals, Waltham, MA, USA
Eytan M Stein - Memorial Sloan Kettering Cancer Center
Resource Type: Journal article
Publication Details: Nature (London), Vol.615(7954), pp.920-924
DOI: 10.1038/s41586-023-05812-3
PMID: 36922593
PMCID: PMC10060155
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Grant note: P30 CA086862 / NCI NIH HHS
Language: English
Date published: 2023
Academic Unit: Stead Family Department of Pediatrics; Hematology/Oncology
Record Identifier: 9984381024302771

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