Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

The current shift of therapy of chronic lymphocytic leukemia (CLL) towards novel targeted agents mandates the identification of molecular predictors to inform on who can still benefit from chemoimmunotherapy and who can be instead early considered for novel targeted agents. Fludarabine, cyclophosphamide, and rituximab (FCR) is the most effective chemoimmunotherapy regimen for the management of CLL and represents the current standard of care for young and fit patients devoid of TP53 disruption. 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 BIRC3 mutations identify a poor prognostic subgroup of patients failing FCR (median progression free survival: 2.2 years, p < 0.001) similar to cases harboring TP53 mutations (median progression free survival: 2.6 years, p < 0.0001). BIRC3 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, p = 0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. The functional implications of BIRC3 mutations are largely unexplored and little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first line FCR. By immunoblotting analysis, we showed that the non-canonical NF-kB pathway is active in BIRC3 mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3 mutated primary CLL cells are less sensitive to fludarabine. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.