Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
Author:
Mansouri Larry, Thorvaldsdottir BirnaORCID, Sutton Lesley-Ann, Karakatsoulis Georgios, Meggendorfer Manja, Parker Helen, Nadeu FerranORCID, Brieghel ChristianORCID, Laidou StamatiaORCID, Moia RiccardoORCID, Rossi Davide, Catherwood Mark, Kotaskova JanaORCID, Delgado Julio, Rodríguez-Vicente Ana E.ORCID, Benito RocíoORCID, Rigolin Gian Matteo, Bonfiglio Silvia, Scarfo Lydia, Mattsson Mattias, Davis ZadieORCID, Gogia Ajay, Rani Lata, Baliakas PanagiotisORCID, Foroughi-Asl HassanORCID, Jylhä Cecilia, Skaftason Aron, Rapado Inmaculada, Miras Fatima, Martinez-Lopez Joaquín, de la Serna JavierORCID, Rivas Jesús María Hernández, Thornton Patrick, Larráyoz María José, Calasanz María José, Fésüs Viktória, Mátrai Zoltán, Bödör CsabaORCID, Smedby Karin E., Espinet BlancaORCID, Puiggros Anna, Gupta RituORCID, Bullinger Lars, Bosch Francesc, Tazón-Vega Bárbara, Baran-Marszak FannyORCID, Oscier David, Nguyen-Khac Florence, Zenz ThorstenORCID, Terol Maria Jose, Cuneo Antonio, Hernández-Sánchez MaríaORCID, Pospisilova Sarka, Mills KenORCID, Gaidano Gianluca, Niemann Carsten U.ORCID, Campo EliasORCID, Strefford Jonathan C.ORCID, Ghia PaoloORCID, Stamatopoulos KostasORCID, Rosenquist RichardORCID
Abstract
AbstractRecent 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.
Publisher
Springer Science and Business Media LLC
Subject
Oncology,Cancer Research,Hematology
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