Molecular, Clinical, and Therapeutic Factors in NPM1-Mutated AML
26. September 2024
New Horizons in Leukemia Research:
Focus on Selected Papers
In the journal Blood, Othman et al. report on the genetic profile of 1357 intensively treated acute myeloid leukemia (AML) patients harboring an NPM1 mutation. This data set, the largest to date for this entity, provides important insights into the prognostic value of recurrent co-mutations in NPM1-mutated AML.
NPM1 mutations are found in approximately 30% of adults with acute myeloid leukemia (AML), defining a disease subtype with unique clinicopathologic features. Although the prognosis is generally favorable, there is considerable heterogeneity in disease outcome.
To further investigate the influence of basic molecular and clinical characteristics, measurable residual disease (MRD) status after induction therapy, and treatment intensity, Othman et al. performed DNA sequencing and molecular MRD monitoring in AML patients with NPM1 mutation. A total of 1357 patients from two consecutive prospective randomized trials (AML 17 and 19) were analyzed.
Detailed results of the study:
The most frequently mutated genes were FLT3 with 57% (ITD 40%, TKD 16% and other mutations 9%), DNMT3A (52%), PTPN11 (19%), NRAS (18%), TET2 (16%), IDH2 (16%), IDH1 (14%) and WT1 (12%).
Using multivariable analysis (Figure 1), Othman et al. identified factors associated with the achievement of MRD negativity. NPM1 non-ABD, FLT3-ITD, DNMT3A and WT1 were significantly associated with increased odds of MRD positivity, while FLAG-Ida was associated with decreased MRD positivity.
FLT3-ITD (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.01-1.63), DNMT3A (HR, 1.65; 95% CI, 1.32-2.05), WT1 (HR, 1.74; 95% CI, 1.27-2.38), and non-ABD NPM1 mutations (HR, 1.64; 95% CI, 1.22-2.21) were also independently associated with worse overall survival (OS). Among patients who achieved MRD-negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse and poorer OS.
The study provides important insights into the prognostic factors of NPM1-mutated AML. Othman et al. were able to identify several variables that negatively influence the treatment outcome of patients with NPM1-mutated AML. However, the authors conclude that molecular MRD negativity in peripheral blood remains the strongest independent prognostic factor for survival after two cycles of treatment.
Our comprehensive range of genetic tests, which you can find on our request form, covers all the relevant genes from the Othman et al. study, enabling individualized therapy planning and targeted treatments.
Figure 1: Visual Abstract
Othman J et al. Molecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AML. Blood. 2024;144(7):714-728.
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Dr. rer. nat. Katharina Hörst
Medical Writer