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Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

Sanam Loghavi, Zhuang Zuo, Farhad Ravandi, Hagop M Kantarjian, Carlos Bueso-Ramos, Liping Zhang, Rajesh R Singh, Keyur P Patel, L Jeffrey Medeiros, Francesco Stingo, Mark Routbort, Jorge Cortes, Rajyalakshmi Luthra, Joseph D Khoury
Journal of Hematology & Oncology 2014 October 4, 7: 74

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.


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