Biological and clinical implications of mutations in chronic lymphocytic leukemia.

is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of mutations are largely unexplored. Furthermore, little is known about the prognostic impact of mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in -mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, -mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, <0.001) similar to cases harboring mutations (median progression-free survival: 2.6 years, <0.0001). mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, =0.004) in multivariate analysis adjusted for mutation, 17p deletion and mutation status. If validated, mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.