Clinical features of De Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

BACKGROUND De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML DNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically. METHODS We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AML DNMT3A/FLT3/NPM1 patients. RESULTS Patients with AML DNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AML DNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation. CONCLUSIONS DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.