Preliminary evidence for the integration of CNAs, CN‑LOH and mutational profiles into the prognostic stratification of elderly patients with NPM1‑mutated acute myeloid leukemia

Acute myeloid leukemia (AML) exhibits substantial genetic heterogeneity in elderly patients. Although validated genomic alterations have improved precision prognostication, incomplete integration of genetic profiles, particularly the underutilization of copy number alterations (CNAs) and copy‑neutral loss of heterozygosity (CN‑LOH), contributes to prognostic uncertainty in elderly patients with nucleophosmin 1 (NPM1)‑mutated AML. To address this gap, the present exploratory single‑center study evaluated 61 elderly patients with NPM1‑mutated AML. Shallow whole‑genome sequencing was used to detect CNAs and CN‑LOH, and targeted next‑generation sequencing was performed to assess mutations in myeloid‑associated genes. Genomic data were integrated with clinical and laboratory parameters to evaluate their prognostic significance. NPM1 subtype A was the predominant variant, and most patients harbored 4 or 5 concurrent somatic mutations, frequently involving fms‑related receptor tyrosine kinase 3 (FLT3), DNA methyltransferase 3 (DNMT3A), tet methylcytosine dioxygenase 2 (TET2), and isocitrate dehydrogenase 2 (IDH2). Overall, 65.57% of patients harbored CNAs and/or CN‑LOH events, with recurrent genomic aberrations including dup(4)(q11q35) in 4 cases. No significant differences in clinical parameters, complete remission rates or overall survival (OS) were observed between CNA/CN‑LOH‑positive and ‑negative groups. However, univariate survival analysis demonstrated that the OS of patients with ≥5 total mutations or ≥3 CNA/CN‑LOH events was significantly shorter compared with that of other patients. Integrative analysis revealed a trend toward shorter OS in patients with FLT3 internal tandem duplication‑positive AML and ≥2 CNA/CN‑LOH events, and longer OS in patients with IDH2‑mutated AML without CNA/CN‑LOH. Multivariate Cox regression analysis tentatively identified ≥3 CNA/CN‑LOH events and ≥5 total mutations as potential independent predictors of a poor prognosis. These findings provide preliminary evidence that integrating CNA/CN‑LOH burden with mutational profiles may improve risk stratification in elderly patients with NPM1‑mutated AML. However, given the small sample size, single‑center design and lack of external validation, larger multi‑center studies are warranted to assess the robustness of these findings.