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

The negative prognostic impact of FLT3-ITD in patients with acute myeloid leukemia with mutated NPM1 (AML-NPM1) is restricted to patients with a higher FLT3-ITD allelic ratio (≥0.5; FLT3high) and considered negligible in wild-type (FLT3wt)/low ITD ratio (FLT3low) patients. Since the co-mutation of DNMT3A (DNMT3Amut) has been suggested to negatively influence the prognosis of AML-NPM1, we analyzed DNMT3Amut impact in FLT3-ITD subsets (absent, low and high ratio). A total of 164 patients diagnosed with AML-NPM1 who received intensive chemotherapy according to two consecutive protocols (AML-03 and AML-12) were selected: 76 harboring FLT3-ITD (46%), 79 DNMT3Amut (48%), and 39 (24%) showing both mutations. Overall, DNMT3A mutational status did not show prognostic impact with comparable OS (mut vs. wt 62±6% vs. 56±6%; p=0.2), RR (22±11% vs. 31±11%; p=0.2) and LFS (65±6 vs. 54±6, p=0.1). Prognostic stratification established by FLT3-ITD (FLT3wt= FLT3low> FLT3high) was independent of DNMT3A mutational status. Measurable residual disease (MRD) based on NPM1 quantitative-PCR kinetics was available in 94 patients. DNMT3Amut was associated with a higher number of mutated NPM1 transcripts following induction (p=0.012) and first consolidation (C1; p<0.001). All DNMT3Amut patients were MRD positive following C1 (p<0.001) and exhibit significant MRD persistence after second and third consolidations (MRD positive vs. negative p=0.027 and p=0.001). Finally, DNMT3Amut patients presented a trend to greater risk of molecular relapse (p=0.054). When molecular failure was proven, patients underwent an allogeneic transplant. In conclusion, DNMT3Amut did not modify overall prognosis exerted by FLT3-ITD in AML-NPM1 despite delayed MRD clearance, possibly due to MRD-driven pre-emptive intervention.