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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

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Authors

MANSOURI Larry THORVALDSDOTTIR Birna SUTTON Lesley-Ann KARAKATSOULIS Georgios MEGGENDORFER Manja PARKER Helen NADEU Ferran BRIEGHEL Christian LAIDOU Stamatia MOIA Riccardo ROSSI Davide CATHERWOOD Mark KOTAŠKOVÁ Jana 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 JYLHA Cecilia SKAFTASON Aron RAPADO Inmaculada MIRAS Fatima MARTINEZ-LOPEZ Joaquin JAVIER de la Serna RIVAS Jesus Maria Hernandez THORNTON Patrick LARRAYOZ Maria Jose CALASANZ Maria Jose FESUS Viktoria MATRAI Zoltan BODOR Csaba SMEDBY Karin E ESPINET Blanca PUIGGROS Anna GUPTA Ritu BULLINGER Lars BOSCH Francesc TAZON-VEGA Barbara BARAN-MARSZAK Fanny OSCIER David GUYEN-KHAC Florence ZENZ Thorsten TEROL Maria Jose CUNEO Antonio HERNANDEZ-SANCHEZ Maria POSPÍŠILOVÁ Šárka MILLS Ken GAIDANO Gianluca NIEMANN Carsten U CAMPO Elias STREFFORD Jonathan C GHIA Paolo STAMATOPOULOS Kostas ROSENQUIST Richard

Year of publication 2023
Type Article in Periodical
Magazine / Source Leukemia
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.nature.com/articles/s41375-022-01802-y
Doi http://dx.doi.org/10.1038/s41375-022-01802-y
Keywords chronic lymphocytic leukemia; immunoglobulin heavy variable gene; somatic mutations; gene mutations
Attached files
Description 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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