Background: According to the recent National Comprehensive Cancer Network (NCCN) guidelines, the risk level in acute myeloid leukemia (AML) patients with FLT3-ITD  and NPM1  double mutation (AML^{FLT3-ITD+/NPM1+} ) depends on the allelic ratio of FLT3-ITD . But despite a low or high allelic ratio of FLT3-ITD , AML^{FLT3-ITD+/NPM1+}  patients belong to the favorable or intermediate risk, for whom allogeneic stem cell transplantation is not obligated. However, some latest studies pointing out that NPM1  and FLT3-ITD  double mutation patients showed an inferior prognosis, which have raised concern about the risk categorization and more effective treatment of AML^{FLT3-ITD+/NPM1+}  patients.
Methods: A total of 76 patients were selected for coexisting FLT3  and NPM1  mutations with normal cytogenetics. The prognostic risk factors were analyzed, and treatment strategies including allogeneic stem cell transplantati1on and chemotherapy were compared.
Results: In 76 AML^{FLT3-ITD+/NPM1+}  patients, 36.8% of patients had hyperleukocytosis (HL) and DNMT3A R882  mutation was the most common concomitant gene (23.7%). For 53 patients in the complete remission (CR), 22 had received allogeneic hematopoietic stem cell transplantation (allo-HSCT) on first complete remission (CR1). Patients in transplantation group had better overall survival (OS) and disease-free survival (DFS) than chemotherapy only (P =0.002 and 0.001, respectively). In multivariable Cox model analyses, HL and DNMT3A R882  mutation were independent adverse prognostic factors (all P <0.05) for AML^{FLT3-ITD+/NPM1+}  patients. Nevertheless, allo-HSCT was an independent good factor of OS and DFS (P =0.001 and 0.000; HR =0.173 and 0.138; 95% CI were 0.062–0.483 and 0.049–0.389). And allo-HSCT could moderately improve the poor prognosis of AML^{FLT3-ITD+/NPM1+/DNMT3A R882+} .
Conclusion: Although, AML^{FLT3-ITD+/NPM1+}  patients are categorized as favorable or intermediate risk levels according to recent NCCN and ELN guidelines, these patients should receive allo-HSCT in CR1 for a longer survival. AML^{FLT3-ITD+/NPM1+}  patients with DNMT3A R882  mutation had a very poor prognosis, and allo-HSCT could moderately improve their survival.
Keywords: FLT3-ITD , NPM1 , DNMT3A R882 , allo-HSCT