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Mutation testing in AML:
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Prognostic factors in patients with NPM1-mutated AML: Analysis from the AML17 and AML19 trials
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The phase III AML17 and AML19 trials evaluated intensive chemotherapy in newly diagnosed, younger adult patients with AML or high-risk MDS.1 An analysis of patients from these trials with NPM1-mutated AML (n = 1,357) assessed the impact of baseline molecular and clinical features, postinduction MRD status, and treatment intensity on outcomes. Results from this analysis were published in Blood by Othman et al.1 |
| Key learnings |
| Multivariable analysis revealed that age (HR, 1.26; 95% CI, 1.13–1.39), WBC (HR, 1.08; 95% CI, 1.02–1.15), adverse cytogenetics (HR, 2.06; 95% CI, 1.00-4.24), NPM1 non-ABD (HR, 1.64; 95% CI, 1.22–2.21), FLT3-ITD (HR, 1.28; 95% CI, 1.01–1.63), DNMT3A (HR, 1.65; 95% CI, 1.32–2.05), and WT1 (HR, 1.74; 95% CI, 1.27–2.38) were associated with worse OS, while treatment with FLAG-Ida (HR, 0.58; 95% CI, 0.42–0.81) and GO (HR, 0.80; 95% CI, 0.64–1.00) were associated with improved OS. |
| FLT3-ITD (HR, 2.62; 95% CI, 1.60–4.34), DNMT3A (HR, 2.55; 95% CI, 1.56–4.26), WT1 (HR, 2.16; 95% CI, 1.15–3.99), and NPM1 non-ABD (HR, 1.98; 95% CI, 1.01–3.83) mutations were associated with higher rates of MRD positivity. Among patients who achieved MRD negativity, DNMT3A (HR, 2.01; 95% CI, 1.40–2.89), WT1 (HR, 1.88; 95% CI,1.11–3.18), NPM1 non-ABD (HR, 2.54; 95% CI, 1.57–4.11), IDH1 (HR, 2.00, 95% CI, 1.32–3.03), and IDH2 (HR, 1.81; 95% CI, 1.19–2.76) mutations were associated with higher relapse rates. |
| Achieving MRD negativity in the PB after Cycle 2 was associated with improved outcomes; MRD-negative patients had a 3-year OS rate of 79% vs 40% for MRD-positive patients, and a CIR of 29% vs 65%. In the multivariable analysis, MRD negativity was strongly associated with OS (HR, 0.31; 95% CI, 0.23–0.43). |
| When compared with all other regimens, FLAG-Ida was associated with increased MRD negativity (87% vs 79%; p = 0.009), reduced relapse rates both overall (21% vs 40%; p < 0.001) and in MRD-negative patients (16% vs 34%; p < 0.001), and improved 3-year OS rates overall (79% vs 63%; p < 0.001) and in MRD negative patients (88% vs 76%; p = 0.003). These benefits were observed across all subgroups, particularly in patients with adverse features. |
| This analysis identified several factors associated with outcomes in patients with NPM1-mutated AML. MRD negativity in the PB after Cycle 2 was a strong independent prognostic factor, suggesting that routine MRD monitoring could guide clinical decisions. |
Abbreviations: AML, acute myeloid leukemia; CI, confidence interval; CIR, cumulative incidence of relapse; FLAG-Ida, fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin; GO, gemtuzumab ozogamicin; HR hazard ratio; ITD, internal tandem duplication; MDS, myelodysplastic syndromes; MRD, measurable residual disease; OS, overall survival; PB, peripheral blood; WBC, white blood cell count.
- Othman J, Potter N, Ivey A, et al. Molecular, clinical, and therapeutic determinants of outcome in NPM1-mutated AML. Blood. 2024;144(7):714-728. DOI: 1182/blood.2024024310
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