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(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-ITDmut and DNMT3A(mut)IDH1/IDH2(mut). Patients with DNMT3A(mut)NPM1(mut)FLT3-ITDmut 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-ITDmut. 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-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.