Prognostic Impact of Distinct Combinations of Molecular Mutations in AML Patients. Results of Two-Center International Cooperation Study

To analyze the prognostic impact of distinct combinations of molecular aberrations, a retrospective analysis of 620 acute myeloid leukemia (AML) was performed. The mean patient's age was 57 (16-85) years. 47% of patients were characterized by abnormal karyotype: favorable (11%), intermediate (67%), and adverse (22%) risk. We analyzed NPM1, FLT3, DNMT3A, IDH1/2, and c-KIT mutations in diagnostic samples. Molecular genetics and cytogenetics considered adverse risk for 28% of patients, favorable for 26%, and intermediate in 46% of patients. More common mutations in whole cohort of patients and in patients with normal karyotype (NK) were NPM1 (22% and 36%), FLT3- ITD (23% and 31%). In addition, DNMT3A and IDH1 mutations were found in 18% and 17% of NK-AML patients, respectively. IDH2 mutations were associated with older patients age (p=.0001). DNMT3A and NPM1 mutations were more frequently detected in patients with monocyte/myelomonocytic differentiation of leukemic blasts (p=.0001). C-kit mutations were more common in Core Binding Factor AML.

The presence of NPM1 mutations were associated with low relapse rate (p=.02) and significant better disease free (DFS) and overall survival (OS), particularly in cases of single mutation (p=.05). NPM1^mut AML patients with additional FLT3 -ITD mutations were characterized by the inferior DFS as compared with others combination of mutations (p=.01). Patients with DNMT3A^mut / FLT3^mut / NPM1^wt have demonstrated more inferior DFS than DNMT3^mut / FLT3^wt / NPM1^mut (p=.01). Moreover, in patients after allogeneic stem cell transplantations, combinations of DNMT3A^mut and FLT3 -ITD^mut was a significant adverse prognostic factor (p=.01). Among FLT^wt patients, the favorable DFS was seen in patients with NPM1 mutation and poor outcome was estimated in those with DNMT3A mutation (p=.03). Among FLT3^mut / NPM1^mut patients, more favorable outcome was found in cases with additional IDH1 and IDH2 mutations. The data suggest that favorable prognosis of NPM1 mutation dominates in cases of DNMT3A but not in FLT3 mutations, but poor prognosis of FLT3 mutation prevails all others. We conclude that mutations status is important factor for risk stratifications of AML patients.