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. 2022 Feb 8;6(3):882-890.
doi: 10.1182/bloodadvances.2020004136.

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

Guadalupe Oñate  1 , Alex Bataller  2 , Ana Garrido  1 , Montserrat Hoyos  1 , Montserrat Arnan  3 , Susana Vives  4 , Rosa Coll  5 , Mar Tormo  6 , Antònia Sampol  7 , Lourdes Escoda  8 , Olga Salamero  9 , Antoni Garcia  10 , Joan Bargay  11 , Alba Aljarilla  1 , Josep F Nomdedeu  1 , Jordi Esteve  2 , Jorge Sierra  1 , Marta Pratcorona  1
Affiliations

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

Guadalupe Oñate et al. Blood Adv. .

Erratum in

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 AML-NPM1, 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 = .2). Prognostic stratification established by FLT3-ITD (FLT3WT = 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 = .012) and first consolidation (C1; P < .001). All DNMT3Amut patients were MRD+ after C1 (P < .001) and exhibited significant MRD persistence after C2 and C3 (MRD+ vs MRD-; P = .027 and P = .001, respectively). Finally, DNMT3Amut patients exhibited a trend toward greater risk of molecular relapse (P = .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.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Overall impact of DNMT3Amut on AML-NPM1. OS (A) and LFS (B) of patients according to DNMT3Amut status.
Figure 2.
Figure 2.
DNMT3A influence over FLT3-ITD allelic ratio subgroups. OS of DNMT3AWT (A,C) and DNMT3Amut (B,D) patients in different FLT3 subsets.
Figure 3.
Figure 3.
Cumulative incidence of relapse in AML-NPM1 patients based on DNMT3Amut status. DNMT3AWT (A) and DNMT3Amut (B) patients according to FLT3-ITD subgroup.
Figure 4.
Figure 4.
NPM1 MRD distribution at relevant clinical time points according to DNMT3Amut status. (A) NPM1 absolute transcript distribution in logarithmic scale. (B-G) MRD response, with MRD+ and MRD− rates (B-D) and corresponding equivalent log10 reductions (E-G) at postinduction (B,E), post-C1 (C,F), and post-C2 (D,G).
Figure 5.
Figure 5.
DNMT3A influence in the favorable FLT3-ITD subgroup. Distribution of patients with FLT3WT or FLT3low according to OS (A) and molLFS (B).
See this image and copyright information in PMC

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