Prognostic impact of DNMT3A mutation in acute myeloid leukemia with mutated NPM1

Abstract

The negative prognostic impact of internal tandem duplication of FLT3 (FLT3-ITD) in patients with acute myeloid leukemia with mutated NPM1 (AML-NPM1) is restricted to those with a higher FLT3-ITD allelic ratio (FLT3high; $0.5) and considered negligible in those with a wild-type (FLT3WT)/low ITD ratio (FLT3low). Because the comutation of DNMT3A (DNMT3Amut) has been suggested to negatively influence prognosis in AMLNPM1, we analyzed the impact of DNMT3Amut in FLT3-ITD subsets (absent, low, and high ratios). A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Overall, DNMT3Amut status did not have a prognostic impact, with comparable overall survival (P 5 .2). Prognostic stratification established by FLT3-ITD (FLT3WT 5 FLT3low . FLT3high) was independent of DNMT3Amut status. Measurable residual disease (MRD) based on NPM1 quantitative polymerase chain reaction was available for 94 patients. DNMT3Amut was associated with a higher number of mutated NPM1 transcripts after induction (P 5 .012) and first consolidation (C1; P, .001). All DNMT3Amut patients were MRD1 after C1 (P, .001) and exhibited significant MRD persistence after C2 and C3 (MRD1 vs MRD2; P 5 .027 and P 5 .001, respectively). Finally, DNMT3Amut patients exhibited a trend toward greater risk of molecular relapse (P 5 .054). In conclusion, DNMT3Amut did not modify the overall prognosis exerted by FLT3-ITD in AML-NPM1 despite delayed MRD clearance, possibly because of MRD-driven preemptive intervention.