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.

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.

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.

DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.