Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study

Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.3%) NPM1 mutations, and 30 (10.2%) CEBPA biallelic mutations. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. The results suggest that analyzing these gene mutations at diagnosis can inform selection of the optimal intensity of therapy for patients with CN-AML.