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

Abstract

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. DNMT3Amut was detected in 35 patients. DNMT3Amut patients were divided into DNMT3AHigh and DNMT3ALow using a cut-off VAF value of 42%. We observed that DNMT3AHigh 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 DNMT3ALow patients. We classified two different comutated genetypes, including DNMT3Amut NPM1mut FLT3-ITDmut and DNMT3Amut IDH1/IDH2mut . Patients with DNMT3Amut NPM1mut FLT3-ITDmut showed worse OS (p=0.026) and relapse-free survival (RFS) (p=0.003) than those with DNMT3Amut IDH1/IDH2mut , and showed a shorter OS (p=0.027) than those with DNMT3Awt NPM1mut FLT3-ITDmut . We also observed that patients with DNMT3Amut IDH1/IDH2mut had higher platelet counts (p=0.009) and a lower BM blast percentage (p=0.040) than those with DNMT3Awt IDH1/IDH2mut . In multivariate analyses, DNMT3AHigh was independently associated with a lower CR rate (OR = 5.883; p=0.004) and shorter OS (HR=3.768; p <0.001). DNMT3Amut NPM1mut FLT3-ITDmut 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.