Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: A study by ERIC in HARMONY

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  • dc.contributor.author Mansouri, Larry
  • dc.contributor.author Espinet Solà, Blanca
  • dc.contributor.author Rosenquist, Richard
  • dc.date.accessioned 2023-04-18T06:25:45Z
  • dc.date.available 2023-04-18T06:25:45Z
  • dc.date.issued 2022
  • dc.description.abstract Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.
  • dc.description.sponsorship The European Research Initiative on CLL (ERIC) is a partner in the HARMONY Alliance, the EHA Scientific Working group on CLL and the ELN Workpackage 7 on CLL. This work was in part supported by; Associazione Italiana per la Ricerca sul Cancro—AIRC, Milano, Italy (Investigator Grant #20246 and Special Program on Metastatic Disease—5 per mille #21198); ERA NET TRANSCAN-2 Joint Transnational Call for Proposals: JTC 2014 (project #143 GCH-CLL) and JTC 2016 (project #179 NOVEL), project code (MIS) 5041673; Bando della Ricerca Finalizzata 2018, Ministero della Salute, Roma, Italy (progetto RF-2018–12368231); “la Caixa” Foundation (Health Research 2017 Program HR17-00221); the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223); the Hellenic Precision Medicine Network in Oncology; project ODYSSEAS (Intelligent and Automated Systems for enabling the Design, Simulation and Development of Integrated Processes and Products) implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014-2020) and co-financed by Greece and the European Union, with grant agreement no: MIS 5002462”; MH CZ—DRO (FNBr, 65269705), NV19-03-00091 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next-Generation EU; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; the EU’s Horizon 2020 research and innovation program under grant agreement No. 739593, by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the K21_137948, FK20_134253, TKP2021-EGA-24 and TKP2021-NVA-15 funding schemes, and Elixir Hungary; Instituto de Salud Carlos III (ISCIII), “PI21/00983”, co-funded by the European Union; Fondo di Ateneo per la Ricerca (FAR) 2019, 2020 and 2021 of the University of Ferrara (GMR; AC), Associazione Italiana contro le Leucemie-Linfomi e Mieloma ONLUS Ferrara (AC; GMR), BEAT Leukemia Foundation Milan Italy (AC); the Danish Cancer Society and the CLL-CLUE project under the frame of ERA PerMed; Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/A18087, and programme C2750/A23669); the Swedish Cancer Society (19 0425 Pj 01 H), the Swedish Research Council (2020-01750), the Knut and Alice Wallenberg Foundation (2016.0373), Region Stockholm (ALF/FoUI-962423), and Radiumhemmets Forskningsfonder (194133), Stockholm; and Lion’s Cancer Research Foundation, Uppsala.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, et al. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: A study by ERIC in HARMONY. Leukemia. 2023 Feb;37(2):339-47. DOI: 10.1038/s41375-022-01802-y
  • dc.identifier.doi http://dx.doi.org/10.1038/s41375-022-01802-y
  • dc.identifier.issn 0887-6924
  • dc.identifier.uri http://hdl.handle.net/10230/56483
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Leukemia. 2023 Feb;37(2):339-47
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/739593
  • dc.rights © The Author(s) 2022. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer genetics
  • dc.subject.keyword Genetics research
  • dc.title Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: A study by ERIC in HARMONY
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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