382 Acute Myeloid Leukemia with Concurrent NPM1 and TP53 mutations: A Classification Dilemma

Introduction/Objective The current ICC and WHO classifications emphasize the importance of genetic alterations in the diagnosis of acute myeloid leukemia (AML). Mutations in NPM1 and TP53 are considered disease-defining, with cases classified as AML with NPM1 mutation and AML with TP53 mutation, respectively. Methods/Case Report We report two cases of AML with concurrent NPM1 and TP53 mutations, describing their clinicopathologic features and discussing the appropriate diagnostic classification. Results The bone marrow biopsies from both cases showed markedly increased blasts. In both cases, conventional karyotyping revealed complex karyotypes, and FISH analysis demonstrated loss of one TP53 allele. Next-generation sequencing identified somatic mutations in both NPM1 and TP53, with high variant allele frequencies. Immunohistochemistry showed diffuse cytoplasmic NPM1 staining and strong p53 expression in all blasts, confirming co-existence of both mutations. Both patients were resistant to treatment and died 7.1 and 0.6 months after diagnosis, respectively. Conclusion Concurrent NPM1 and TP53 mutations in AML are exceedingly rare, posing a challenge in disease classification. In such cases, both mutations are dominant and should be incorporated into the diagnostic classification. We propose that these cases be designated as AML with concurrent NPM1 and TP53 mutations to reflect their distinct genetic profile and dismal prognosis.