The impact of DNMT3A variant allele frequency and two different comutations on patients with de novo cytogenetically normal acute myeloid leukemia.

To refine the biological and prognostic significance of DNMT3A mutations in acute myeloid leukemia (AML), we assessed the impact of DNMT3A variant allele frequency (VAF) and its comutations in this study. Using targeted next-generation sequencing, we analyzed 171 adult patients with de novo cytogenetically normal AML for DNMT3A mutations and associated comutations. DNMT3A was detected in 35 patients. DNMT3A patients were divided into DNMT3A and DNMT3A using a cut-off VAF value of 42%. We observed that DNMT3A patients at diagnosis had increasing white blood cell (WBC) counts (p < 0.001) and a higher lactate dehydrogenase (LDH) level (p = 0.027), and were associated with lower complete remission (CR) rate (p = 0.015) and shorter overall survival (OS) (p = 0.032) than DNMT3A patients. We classified two different comutated genetypes, including DNMT3A NPM1 FLT3-ITD and DNMT3A IDH1/IDH2 . Patients with DNMT3A NPM1 FLT3-ITD showed worse OS (p = 0.026) and relapse-free survival (RFS) (p = 0.003) than those with DNMT3A IDH1/IDH2 , and showed a shorter OS (p = 0.027) than those with DNMT3A NPM1 FLT3-ITD . We also observed that patients with DNMT3A IDH1/IDH2 had higher platelet counts (p = 0.009) and a lower BM blast percentage (p = 0.040) than those with DNMT3A IDH1/IDH2 . In multivariate analyses, DNMT3A was independently associated with a lower CR rate (OR = 5.883; p = 0.004) and shorter OS (HR = 3.768; p < 0.001). DNMT3A NPM1 FLT3-ITD independently affected worse OS (HR = 6.030; p < 0.001) and RFS (HR = 8.939; p < 0.001). Our findings might be potentially useful for predicting clinical outcomes.