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, Birna Þorvaldsdóttir, Lesley‐Ann Sutton, Georgios Karakatsoulis, Manja Meggendorfer, Helen Parker, Ferran Nadeu, Christian Brieghel, Stamatia Laidou, Riccardo Moia, Davide Rossi, Mark Catherwood, Jana Kotašková, Julio Delgado, Ana E. Rodríguez‐Vicente, Rocío Benito, Gian Matteo Rigolin, Silvia Bonfiglio, Lydia Scarfò, Mattias Mattsson, Zadie Davis, Ajay Gogia, Lata Rani, Panagiotis Baliakas, Hassan Foroughi Asl, Cecilia Jylhä, Aron Skaftason, Inmaculada Rapado, Fátima Mirás, Joaquín Martínez‐López, Javier de la Serna, Jesús María Hernández‐Rivas, Patrick Thornton, María José Larráyoz, Marı́a José Calasanz, Viktória Fésüs, Zoltán Mátrai, Csaba Bödör, Karin E. Smedby, Blanca Espinet, Anna Puiggros, Ritu Gupta, Lars Bullinger, Francesc Bosch, Bárbara Tazón‐Vega, Fanny Baran‐Marszak, David Oscier, Florence Nguyen‐Khac, Thorsten Zenz, María José Terol, Antonio Cuneo, María Hernández‐Sánchez, Šárka Pospı́šilová, Ken Mills, Gianluca Gaïdano, Carsten Utoft Niemann, Elı́as Campo, Jonathan C. Strefford, Paolo Ghia, Κώστας Σταματόπουλος, Richard Rosenquist
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.