Mutations of NOTCH1are an independent predictor of survival in chronic lymphocytic leukemia

Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P< .001). Multivariate analysis selected NOTCH1mutations as an independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1mutated patients were devoid of TP53disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1mutations was similar to that of TP53mutated/deleted CLL. NOTCH1mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53abnormalities, and identify cases with a dismal prognosis.