NPM1-mutated acute myeloid leukaemia (AML) risk stratification has been significantly refined using a new genetic classification that integrates key co-mutations, according to a large international analysis of intensively treated adults. The findings demonstrate that combining mutational profiles can meaningfully reclassify prognosis and inform allogeneic haematopoietic stem cell transplantation decisions in first complete remission.
Background and Study Design
NPM1-mutated acute myeloid leukemia is typically associated with a favourable prognosis, although outcomes vary widely depending on accompanying genetic alterations. Investigators analysed adult patients with NPM1-mutated AML treated with intensive therapy using data from the HARMONY Alliance database. A newly developed risk classification incorporating combinations of co-mutations in FLT3 internal tandem duplication, DNMT3A, IDH1 or IDH2, and TET2 was applied across three cohorts. These included a training cohort of 1,001 patients enrolled in clinical trials, an internal validation cohort of 762 patients reflecting real-world practice, and an external validation cohort of 585 patients from UK-NCRI trials.
Refined Risk Groups and Survival Outcomes
Using the HARMONY classification, 51.8% of patients in the training cohort were categorised as favourable risk, 24.8% as intermediate risk, and 23.4% as adverse risk. Median overall survival differed markedly across groups: 14.4 years in the favourable group; 2.2 years in the intermediate group; and 0.9 years in the adverse group; p<0.001. Notably, this approach reassigned 42.7% of patients with NPM1-mutated AML to a different European LeukemiaNet 2022 risk category, highlighting substantial prognostic heterogeneity within this molecular subgroup.
Validation and Transplant Implications
The prognostic performance of the HARMONY classification was confirmed in both the internal and external validation cohorts, supporting its robustness across trial-based and real-world populations. Importantly, analysis of treatment outcomes showed that allogeneic haematopoietic stem cell transplantation in first complete remission provided the greatest survival benefit in the adverse-risk NPM1-mutated AML subgroup. This suggests that refined genetic risk assessment could play a critical role in identifying patients most likely to benefit from early transplant strategies.
Overall, the HARMONY classification offers a more nuanced framework for NPM1-mutated AML risk stratification and has potential clinical impact with regard to personalised treatment planning and transplant decision-making.
Reference
Hernández-Sánchez A et al. Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study. Leukaemia. 2026; https://doi.org/10.1038/s41375-025-02851-9.
