mutation is associated with increased age and adverse outcome in adult T-cell acute lymphoblastic leukemia.

The prognostic implications of genotype in T-cell acute lymphoblastic leukemia are incompletely understood. We performed comprehensive genetic and clinico-biological analyses of T-cell acute lymphoblastic leukemia patients with mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had alterations. Two patients also had mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-cell acute lymphoblastic leukemia. mutation was associated with older age (median 43.9 years 29.4 years, <0.001), immature T-cell receptor genotype (53.3% 24.4%, =0.016) and lower remission rates (72.2% mutated 94.4% non-mutated, =0.006). alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (HR 2.33, 95% CI: 1.05-5.16, =0.037) and markedly poorer event-free survival (HR 3.22, 95% CI: 1.81-5.72, <0.001) and overall survival (HR 2.91, 95% CI: 1.56-5.43, =0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of -mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, mutation was significantly associated with shorter event-free survival (HR 2.33, 95% CI: 1.06 - 4.04, =0.02). Altogether, these results identify genotype as a predictor of aggressive T-cell acute lymphoblastic leukemia biology. The GRAALL-2003 and -2005 studies were registered at as and , respectively.