DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation

• DNMT3A R882 mutation, particularly when accompanied by FLT3-ITD positivity, had a significant prognostic impact on survival and relapse rates in patients with NK-AML after allogeneic hematopoietic cell transplantation.
• In contrast, non–R882 DNMT3A mutations did not influence transplantation outcome.
• No differences in overall survival, event-free survival, or relapse incidence were observed in patients with TET2 mutation or IDH1/2 mutation after allogeneic hematopoietic cell transplantation.

The prognostic relevance of epigenetic modifying genes (DNMT3A, TET2, and IDH1/2) in patients with acute myeloid leukemia (AML) has been investigated extensively. However, the prognostic implications of these mutations after allogeneic hematopoietic cell transplantation (HCT) have not been evaluated comprehensively in patients with normal-karyotype (NK)-AML. A total of 115 patients who received allogeneic HCT for NK-AML were retrospectively evaluated for the FLT3-ITD, NPM1, CEBPA, DNMT3A, TET2, IDH1/2, WT1, NRAS, ASXL2, FAT1, DNAH11, and GATA2 mutations in diagnostic samples and analyzed for long-term outcomes after allogeneic HCT. The prevalence rates for the mutations were as follows: FLT3-ITD positivity (FLT3-ITDpos) (32.2%), NPM1 mutation (43.5%), CEBPA mutation (double) (24.6%), DNMT3A mutation (DNMT3Amut) (31.3%), DNMT3A R882mut (18.3%), TET2 mutation (8.7%), and IDH1/2 mutation (16.5%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57.3% and 58.1%, respectively. A multivariate analysis revealed that FLT3-ITDpos (hazard ratio, [HR], 2.23; P = .006) and DNMT3A R882mut (HR, 2.74; P = .002) were unfavorable prognostic factors for OS. In addition, both mutations were significant risk factors for EFS and relapse. People with DNMT3A R882mut accompanied by FLT3-ITDpos had worse OS and EFS, and higher relapse rates than those with the other mutations, which were confirmed in a propensity score 1:2 matching analysis. These results suggest that DNMT3A R882mut, particularly when accompanied by FLT3-ITDpos, is a significant prognostic factor for inferior transplantation survival outcome by increasing relapse risk, even after allogeneic HCT.