TY - JOUR
T1 - Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY
AU - Mansouri, Larry
AU - Thorvaldsdottir, Birna
AU - Sutton, Lesley-Ann
AU - Karakatsoulis, Georgios
AU - Meggendorfer, Manja
AU - Parker, Helen
AU - Nadeu, Ferran
AU - Brieghel, Christian
AU - Laidou, Stamatia
AU - Moia, Riccardo
AU - Rossi, Davide
AU - Catherwood, Mark
AU - Kotaskova, Jana
AU - Delgado, Julio
AU - Rodríguez-Vicente, Ana E
AU - Benito, Rocío
AU - Rigolin, Gian Matteo
AU - Bonfiglio, Silvia
AU - Scarfo, Lydia
AU - Mattsson, Mattias
AU - Davis, Zadie
AU - Gogia, Ajay
AU - Rani, Lata
AU - Baliakas, Panagiotis
AU - Foroughi-Asl, Hassan
AU - Jylhä, Cecilia
AU - Skaftason, Aron
AU - Rapado, Inmaculada
AU - Miras, Fatima
AU - Martinez-Lopez, Joaquín
AU - de la Serna, Javier
AU - Rivas, Jesús María Hernández
AU - Thornton, Patrick
AU - Larráyoz, María José
AU - Calasanz, María José
AU - Fésüs, Viktória
AU - Mátrai, Zoltán
AU - Bödör, Csaba
AU - Smedby, Karin E
AU - Espinet, Blanca
AU - Puiggros, Anna
AU - Gupta, Ritu
AU - Bullinger, Lars
AU - Bosch, Francesc
AU - Tazón-Vega, Bárbara
AU - Baran-Marszak, Fanny
AU - Oscier, David
AU - Nguyen-Khac, Florence
AU - Zenz, Thorsten
AU - Terol, Maria Jose
AU - Cuneo, Antonio
AU - Hernández-Sánchez, María
AU - Pospisilova, Sarka
AU - Mills, Ken
AU - Gaidano, Gianluca
AU - Niemann, Carsten U
AU - Campo, Elias
AU - Strefford, Jonathan C
AU - Ghia, Paolo
AU - Stamatopoulos, Kostas
AU - Rosenquist, Richard
N1 - © 2022. The Author(s).
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
U2 - 10.1038/s41375-022-01802-y
DO - 10.1038/s41375-022-01802-y
M3 - Article
C2 - 36566271
SN - 0887-6924
VL - 37
SP - 339
EP - 347
JO - Leukemia
JF - Leukemia
ER -