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. DNMT3A^mut was detected in 35 patients. DNMT3A^mut patients were divided into DNMT3A^High and DNMT3A^Low using a cut-off VAF value of 42%. We observed that DNMT3A^High 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^Low patients. We classified two different comutated genetypes, including DNMT3A^mut NPM1^mut FLT3-ITD^mut and DNMT3A^mut IDH1/IDH2^mut . Patients with DNMT3A^mut NPM1^mut FLT3-ITD^mut showed worse OS (p = 0.026) and relapse-free survival (RFS) (p = 0.003) than those with DNMT3A^mut IDH1/IDH2^mut , and showed a shorter OS (p = 0.027) than those with DNMT3A^wt NPM1^mut FLT3-ITD^mut . We also observed that patients with DNMT3A^mut IDH1/IDH2^mut had higher platelet counts (p = 0.009) and a lower BM blast percentage (p = 0.040) than those with DNMT3A^wt IDH1/IDH2^mut . In multivariate analyses, DNMT3A^High was independently associated with a lower CR rate (OR = 5.883; p = 0.004) and shorter OS (HR = 3.768; p < 0.001). DNMT3A^mut NPM1^mut FLT3-ITD^mut 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.

Keywords: DNMT3A mutations; acute myeloid leukemia; variant allele frequency.