Abstract
The prognostic implications of DNMT3A genotype in T-ALL are incompletely understood. We performed comprehensive genetic and clinicobiological analyses of T-ALL patients with DNMT3A mutations treated during the GRAALL-2003 and -2005 studies. Eighteen of 198 cases (9.1%) had DNMT3A alterations. Two patients also had DNMT3A mutations in non-leukemic cell DNA, providing the first potential evidence of age-related clonal hematopoiesis in T-ALL. DNMT3A mutation was associated with older age (median 43.9 years v 29.4 years, p < 0.001), immature T-receptor genotype (53.3% v 24.4%, p = 0.016) and lower remission rates (72.2% mutated v 94.4% non-mutated, p = 0.006). DNMT3A alterations were significantly associated with worse clinical outcome, with higher cumulative incidence of relapse (CIR, HR 2.33, 95% CI 1.05-5.16, p = 0.037) and markedly poorer event-free survival (EFS, HR 3.22, 95% CI 1.81-5.72, p < 0.001) and overall survival (OS, HR 2.91, 95% CI 1.56-5.43, p = 0.001). Adjusting for age as a covariate, or restricting the analysis to patients over 40 years, who account for almost 90% of DNMT3A-mutated cases, did not modify these observations. In multivariate analysis using the risk factors that were used to stratify treatment during the GRAALL studies, DNMT3A mutation was significantly associated with shorter EFS (HR 2.33, 95% CI 1.06 - 4.04, p = 0.02). Altogether, these results identify DNMT3A genotype as a predictor of aggressive T-ALL biology. The GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.