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

Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function(1–3). 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...

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Autores principales: Issa, Ghayas C., Aldoss, Ibrahim, DiPersio, John, Cuglievan, Branko, Stone, Richard, Arellano, Martha, Thirman, Michael J., Patel, Manish R., Dickens, David S., Shenoy, Shalini, Shukla, Neerav, Kantarjian, Hagop, Armstrong, Scott A., Perner, Florian, Perry, Jennifer A., Rosen, Galit, Bagley, Rebecca G., Meyers, Michael L., Ordentlich, Peter, Gu, Yu, Kumar, Vinit, Smith, Steven, McGeehan, Gerard M., Stein, Eytan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10060155/
https://www.ncbi.nlm.nih.gov/pubmed/36922593
http://dx.doi.org/10.1038/s41586-023-05812-3
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author Issa, Ghayas C.
Aldoss, Ibrahim
DiPersio, John
Cuglievan, Branko
Stone, Richard
Arellano, Martha
Thirman, Michael J.
Patel, Manish R.
Dickens, David S.
Shenoy, Shalini
Shukla, Neerav
Kantarjian, Hagop
Armstrong, Scott A.
Perner, Florian
Perry, Jennifer A.
Rosen, Galit
Bagley, Rebecca G.
Meyers, Michael L.
Ordentlich, Peter
Gu, Yu
Kumar, Vinit
Smith, Steven
McGeehan, Gerard M.
Stein, Eytan M.
author_facet Issa, Ghayas C.
Aldoss, Ibrahim
DiPersio, John
Cuglievan, Branko
Stone, Richard
Arellano, Martha
Thirman, Michael J.
Patel, Manish R.
Dickens, David S.
Shenoy, Shalini
Shukla, Neerav
Kantarjian, Hagop
Armstrong, Scott A.
Perner, Florian
Perry, Jennifer A.
Rosen, Galit
Bagley, Rebecca G.
Meyers, Michael L.
Ordentlich, Peter
Gu, Yu
Kumar, Vinit
Smith, Steven
McGeehan, Gerard M.
Stein, Eytan M.
author_sort Issa, Ghayas C.
collection PubMed
description Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function(1–3). 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 leukaemia(7,8). 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.
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spelling pubmed-100601552023-03-31 The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia Issa, Ghayas C. Aldoss, Ibrahim DiPersio, John Cuglievan, Branko Stone, Richard Arellano, Martha Thirman, Michael J. Patel, Manish R. Dickens, David S. Shenoy, Shalini Shukla, Neerav Kantarjian, Hagop Armstrong, Scott A. Perner, Florian Perry, Jennifer A. Rosen, Galit Bagley, Rebecca G. Meyers, Michael L. Ordentlich, Peter Gu, Yu Kumar, Vinit Smith, Steven McGeehan, Gerard M. Stein, Eytan M. Nature Article Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function(1–3). 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 leukaemia(7,8). 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. Nature Publishing Group UK 2023-03-15 2023 /pmc/articles/PMC10060155/ /pubmed/36922593 http://dx.doi.org/10.1038/s41586-023-05812-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Issa, Ghayas C.
Aldoss, Ibrahim
DiPersio, John
Cuglievan, Branko
Stone, Richard
Arellano, Martha
Thirman, Michael J.
Patel, Manish R.
Dickens, David S.
Shenoy, Shalini
Shukla, Neerav
Kantarjian, Hagop
Armstrong, Scott A.
Perner, Florian
Perry, Jennifer A.
Rosen, Galit
Bagley, Rebecca G.
Meyers, Michael L.
Ordentlich, Peter
Gu, Yu
Kumar, Vinit
Smith, Steven
McGeehan, Gerard M.
Stein, Eytan M.
The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
title The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
title_full The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
title_fullStr The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
title_full_unstemmed The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
title_short The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
title_sort menin inhibitor revumenib in kmt2a-rearranged or npm1-mutant leukaemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10060155/
https://www.ncbi.nlm.nih.gov/pubmed/36922593
http://dx.doi.org/10.1038/s41586-023-05812-3
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