Prognostic Significance of FLT3/ITD Mutation in AML1/ETO-Associated Acute Myeloid Leukemia.

Background: AML1-ETO fusion gene in acute myeloid leukemia (AML) usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. An internal tandem duplication of the FLT3 gene (FLT3/ITDs) is known to be associated with poor outcome after standard induction chemotherapy in AML patients with normal cytogenetics. However, this mutation is reported to be rarely found in cases with AML1/ETO positive and it remains a matter of debate as to whether these mutations play an independent role in the prognosis of AML patients with AML1/ETO fusion gene.

Aims: To determine the prevalence and the prognostic role of FLT3/ITD in patients with AML1/ETO positive AML.

Methods: FLT3/ITD and NPM1 mutation status was evaluated by performing DNA polymerase chain reaction assays on 39 bone marrow samples obtained at initial diagnosis from the patients with AML1/ETO fusion gene positive AML. GeneScan analysis was performed to confirm the FLT3/ITD mutation and to measure mutant levels.

Results: Of total 39 patients, 11 patients (28.2%) demonstrated the aberrant FLT3/ITD mutations. The median age of patients was 40 years (range, 17–75 years). There were 24 males (61.5%) and 15 females (38.5%). There was no statistically significant difference in age, gender, leukocyte count, hemoglobin level, platelet count and percentage of peripheral or bone marrow blasts between the patients with or without FLT3/ITD. No NPM1 mutation was found in these AML Patients. To analyze the response to or outcome of therapy, we evaluated 34 patients who received intensive induction chemotherapy containing cytarabine. In univariate analysis, there was no significant difference in complete response rate (FLT3/ITD+: 100% vs. FLT3/ITD−: 95.6%, p = 0.48). However, the presence of FLT3/ITD was associated with higher relapse rate in these patients (FLT3/ITD+: 72.7% vs. FLT3/ITD−: 27.3%, p = 0.01).Significant shorter leukemic-free survival (LFS) was observed in patients with FLT3/ITD compared with those without FLT3/ITD (6.9±1.0 ms vs. 18.9±10.9 ms, p = 0.01), but there was no statistical significance in overall survival (OS) (10.6±0.6 ms vs. 16.5± NA ms, p = 0.56).

Conclusions: This study demonstrates that the presence of FLT3/ITD mutations is a significantly higher relapse rate and shorter LFS in AML1/ETO positive patients. Therefore, a stratified treatment plan such as stem cell transplantation may be warranted for the AML1/ETO positive AML harvoring FLT3/ITD mutation.