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

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
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.
0887-6924
339-347
Mansouri, Larry
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Mansouri, Larry, Thorvaldsdottir, Birna, Sutton, Lesley-Ann, Karakatsoulis, Georgios, Meggendorfer, Manja, Parker, Helen, Nadeu, Ferran, Brieghel, Christian, Laidou, Stamatia, Moia, Riccardo, Rossi, Davide, Kotaskova, Jana, Catherwood, Mark, Delgado, Julio, Rodriguez-Vicente, Ana E., Benito, Rocio, Rigolin, Gian Matteo, Bonfiglio, Silvia, Scarfo, Lydia, Mattsson, Mattias, Davis, Zadie, Gogia, Ajay, Rani, Lata, Baliakas, Panagiotis, Foroughi-Asl, Hassan, Jylhä, Cecilia, Skaftason, Aron, Rapado, Inmaculada, Miras, Fatima, Martinez-Lopez, Joaquín, de la Serna, Javier, Hernández Rivas, Jesús María, Thornton, Patrick, José Larráyoz, María, José Calasanz, María, Fésüs, Viktória, Mátrai, Zoltán, Bödör, Csaba, Smedby, Karin E., Espinet, Blanca, Puiggros, Anna, Gupta, Ritu, Bullinger, Lars, Tazón-Vega, Bárbara, Baran-Marszak, Fanny, Oscier, David, Nguyen-Khac, Florence, Zenz, Thorsten, Jose Terol, Maria, Cuneo, Antonio, Hernández-Sánchez, María, Pospisilova, Sarka, Mills, Ken, Gaidano, Gianluca, Niemann, Carsten U., Campo, Elias, Strefford, Jonathan C., Ghia, Paolo, Stamatopoulos, Kostas and Rosenquist, Richard (2023) 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, 37 (2), 339-347. (doi:10.1038/s41375-022-01802-y).

Record type: Article

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.

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Accepted/In Press date: 15 December 2022
e-pub ahead of print date: 24 December 2022
Published date: 1 February 2023
Additional Information: Funding Information: 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. Publisher Copyright: © 2022, The Author(s).

Identifiers

Local EPrints ID: 474037
URI: http://eprints.soton.ac.uk/id/eprint/474037
ISSN: 0887-6924
PURE UUID: 467149cd-381e-4202-a567-e4d6d741a1db
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 09 Feb 2023 17:49
Last modified: 17 Mar 2024 02:59

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Contributors

Author: Larry Mansouri
Author: Birna Thorvaldsdottir
Author: Lesley-Ann Sutton
Author: Georgios Karakatsoulis
Author: Manja Meggendorfer
Author: Helen Parker ORCID iD
Author: Ferran Nadeu
Author: Christian Brieghel
Author: Stamatia Laidou
Author: Riccardo Moia
Author: Davide Rossi
Author: Jana Kotaskova
Author: Mark Catherwood
Author: Julio Delgado
Author: Ana E. Rodriguez-Vicente
Author: Rocio Benito
Author: Gian Matteo Rigolin
Author: Silvia Bonfiglio
Author: Lydia Scarfo
Author: Mattias Mattsson
Author: Zadie Davis
Author: Ajay Gogia
Author: Lata Rani
Author: Panagiotis Baliakas
Author: Hassan Foroughi-Asl
Author: Cecilia Jylhä
Author: Aron Skaftason
Author: Inmaculada Rapado
Author: Fatima Miras
Author: Joaquín Martinez-Lopez
Author: Javier de la Serna
Author: Jesús María Hernández Rivas
Author: Patrick Thornton
Author: María José Larráyoz
Author: María José Calasanz
Author: Viktória Fésüs
Author: Zoltán Mátrai
Author: Csaba Bödör
Author: Karin E. Smedby
Author: Blanca Espinet
Author: Anna Puiggros
Author: Ritu Gupta
Author: Lars Bullinger
Author: Bárbara Tazón-Vega
Author: Fanny Baran-Marszak
Author: David Oscier
Author: Florence Nguyen-Khac
Author: Thorsten Zenz
Author: Maria Jose Terol
Author: Antonio Cuneo
Author: María Hernández-Sánchez
Author: Sarka Pospisilova
Author: Ken Mills
Author: Gianluca Gaidano
Author: Carsten U. Niemann
Author: Elias Campo
Author: Paolo Ghia
Author: Kostas Stamatopoulos
Author: Richard Rosenquist

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