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. 2023 Feb;37(2):339-347.
doi: 10.1038/s41375-022-01802-y. Epub 2022 Dec 24.

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

Larry Mansouri #  1 , Birna Thorvaldsdottir #  1 , Lesley-Ann Sutton #  1 , Georgios Karakatsoulis  2   3 , Manja Meggendorfer  4 , Helen Parker  5 , Ferran Nadeu  6   7 , Christian Brieghel  8 , Stamatia Laidou  2 , Riccardo Moia  9 , Davide Rossi  10   11 , Mark Catherwood  12 , Jana Kotaskova  13   14   15 , Julio Delgado  6   7   16   17 , Ana E Rodríguez-Vicente  18   19   20 , Rocío Benito  18   19   20 , Gian Matteo Rigolin  21 , Silvia Bonfiglio  22 , Lydia Scarfo  22 , Mattias Mattsson  23 , Zadie Davis  24 , Ajay Gogia  25 , Lata Rani  25 , Panagiotis Baliakas  23 , Hassan Foroughi-Asl  1 , Cecilia Jylhä  1 , Aron Skaftason  1 , Inmaculada Rapado  26   27 , Fatima Miras  26 , Joaquín Martinez-Lopez  26   27 , Javier de la Serna  26   27 , Jesús María Hernández Rivas  18   19   20 , Patrick Thornton  28 , María José Larráyoz  29   30 , María José Calasanz  29   30 , Viktória Fésüs  31 , Zoltán Mátrai  32 , Csaba Bödör  31 , Karin E Smedby  33 , Blanca Espinet  34 , Anna Puiggros  34 , Ritu Gupta  25 , Lars Bullinger  35 , Francesc Bosch  36 , Bárbara Tazón-Vega  36 , Fanny Baran-Marszak  37 , David Oscier  24 , Florence Nguyen-Khac  38 , Thorsten Zenz  39 , Maria Jose Terol  40 , Antonio Cuneo  21 , María Hernández-Sánchez  18   19   20 , Sarka Pospisilova  13   14   15 , Ken Mills  12 , Gianluca Gaidano  9 , Carsten U Niemann  8 , Elias Campo  6   7   16   17 , Jonathan C Strefford  5 , Paolo Ghia  22 , Kostas Stamatopoulos  1   2 , Richard Rosenquist  41   42
Affiliations

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

Larry Mansouri et al. Leukemia. 2023 Feb.

Erratum in

  • Correction: Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY.
    Mansouri L, Thorvaldsdottir B, Sutton LA, Karakatsoulis G, Meggendorfer M, Parker H, Nadeu F, Brieghel C, Laidou S, Moia R, Rossi D, Catherwood M, Kotaskova J, Delgado J, Rodríguez-Vicente AE, Benito R, Rigolin GM, Bonfiglio S, Scarfo L, Mattsson M, Davis Z, Gogia A, Rani L, Baliakas P, Foroughi-Asl H, Jylhä C, Skaftason A, Rapado I, Miras F, Martinez-Lopez J, de la Serna J, Rivas JMH, Thornton P, Larráyoz MJ, Calasanz MJ, Fésüs V, Mátrai Z, Bödör C, Smedby KE, Espinet B, Puiggros A, Gupta R, Bullinger L, Bosch F, Tazón-Vega B, Baran-Marszak F, Oscier D, Nguyen-Khac F, Zenz T, Terol MJ, Cuneo A, Hernández-Sánchez M, Pospisilova S, Mills K, Gaidano G, Niemann CU, Campo E, Strefford JC, Ghia P, Stamatopoulos K, Rosenquist R. Mansouri L, et al. Leukemia. 2023 Feb;37(2):504. doi: 10.1038/s41375-023-01813-3. Leukemia. 2023. PMID: 36635392 Free PMC article. No abstract available.

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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Conflict of interest statement

PG: Honoraria/advisory board: AbbVie, Acerta/AstraZeneca, Adaptive, ArQule/MSD, BeiGene, CelGene/Juno, Gilead, Janssen, Loxo/Lilly, Sunesis. Research funding: AbbVie, Gilead, Janssen, Novartis, Sunesis; LS: advisory board AbbVie, AstraZeneca, Janssen; RR: honoraria/advisory board: Abbvie, AstraZeneca, Janssen, Illumina and Roche; KS: honoraria/advisory board: AbbVie, Acerta/AstraZeneca, Gilead, Janssen. Research funding: AbbVie, Gilead, Janssen; PB: honoraria from Abbvie, Gilead and Janssen. Research funding from Gilead; GG: Advisory Board/Speaker’s bureau: Janssen, Abbvie, AstraZeneca, Beigene; LB: honoraria/advisory board: Abbvie, Amgen, Astellas, BMS/Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, Seattle Genetics. Research funding: Bayer, Jazz Pharmaceuticals; GMR: honoraria from Abbvie, AstraZeneca, Gilead and Janssen. Research funding from Gilead: CB: Honoraria/advisory board: AbbVie, Janssen. The other authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1. Overview of 1588 CLL cases carrying mutations in recurrently mutated genes.
A Oncoplot of detected gene mutations (in order of frequency), IGHV gene somatic hypermutation (SHM) status and chromosomal aberrations. B Relative distribution of recurrent gene mutations stratified by IGHV gene SHM status, ** denotes a p value <0.01, while *** represents a p value <0.001. C Co-occurence of recurrently mutated genes and chromosomal aberrations.
Fig. 2
Fig. 2. Time-to-first-treatment (TTFT) in Binet A CLL patients carrying recurrent gene mutations stratified based on IGHV gene SHM status.
Pairwise comparisons were performed using the Cox–Mantel log-rank test. U-CLL, CLL with unmutated IGHV genes, M-CLL, CLL with mutated IGHV genes.
Fig. 3
Fig. 3. Clinical impact of hotspot versus non-hotspot mutations in recurrently mutated genes assessed using time-to-first-treatment (TTFT) as clinical endpoint.
Pairwise comparisons were performed using the Cox–Mantel log-rank test.
Fig. 4
Fig. 4. Multivariate analysis in Binet stage A CLL patients with unmutated IGHV genes (U-CLL) and mutated IGHV genes (M-CLL).
CI95, 95% confidence interval; * indicates a p value <0.05, ** denotes a p value <0.01, while *** represents a p value <0.001.
See this image and copyright information in PMC

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