The High Prevalence of FLT3-ITD Mutations Is Associated with the Poor Outcome in Adult Patients with t(6;9)(p23;q34) Positive AML - Results of an International Metaanalysis.
Authors: Thiede Christian , Bloomfield Clara D. , Coco Francesco Lo , Fröhling Stefan , Hiddemann Wolfgang , Krauter Jürgen , Schaich Markus , Whitman Susan P. , Saglio Guiseppe , Döhner Konstanze , Spiekermann Karsten , Schnittger Susanne , Ganser Arnold , Heil Gerhard , Büchner Thomas , Döhner Hartmut , Larson Richard A. , Ehninger Gerhard 
Published: October 2019

FLT3 is one of the most frequently mutated genes in acute myeloid leukemia (AML). Two types of mutations are predominantly found, internal tandem duplications (ITDs) and point mutations in the second tyrosine kinase domain (TKD). Both mutations are mostly observed in AML patients with a normal karyotype, but certain karyotype abnormalities are also found associated with FLT3-mutations, e.g. the t(15;17) and the t(6;9). The t(6;9) is found in about 0.5–1% of adult patients with AML; the presence of this abnormality has been associated with a high risk of treatment failure. However, in patients with t(6;9) up to 90% FLT3-ITD positivity has been reported. The importance of FLT3 mutations for the poor prognosis in patients with t(6;9) has not been previously evaluated. In an attempt to study this question, we performed a metaanalysis based on primary clinical and molecular data of patients with AML and t(6;9). Information was collected for 55 patients (aged 17–78 years) with DEK-CAN positive AML (n=50) and MDS (n=5) recruited by six cooperative AML study groups (AML-CG, AML-SG, AML-SHG, CALGB, DSIL, GIMEMA). All included patients had been analyzed for FLT3-ITD mutations.

Results: The prevalence of FLT3-ITD among patients with t(6;9) was 42/55 (76.4%). No FLT3-TKD mutations were found in the 51 analyzed patients. There was no significant difference in age or sex distribution, but patients with FLT3-ITD had significantly higher white blood cell counts (median: 23.0 vs.: 6.3 GPT/l; P=.019) and higher bone marrow blast percentages (median: 79.5% vs. 50%; P=.041). Patients with FLT3-ITD mutations had a significantly lower probability of achieving a complete remission (CR-rate: 36% vs. 75%; P=.042). In addition, the estimated probability of survival for patients lacking FLT3-ITD mutations was significantly better (median not reached) compared to the ITD positive patients (median 8.2; range: 5.9–10.5 mo; P = .006). This was also true for the probability of disease free survival (median 26.1 vs. 6.7 mo.; P=.043). Although not significant there was a trend for a higher rate of transplantation (6/13 vs 8/42) performed in FLT3-ITD negative patients, which may be due to the higher CR rate in these patients.

Conclusions: These data confirm the very high rate of FLT3-ITD mutations in a large cohort of patients with t(6;9). In addition, these data are the first to suggest that in patients with t(6;9) the high prevalence of FLT3-ITD mutations, not the DEK-CAN fusion itself, may be responsible for the dismal outcome. These results support further molecular testing in these patients and the potential use of molecularly targeted therapy (e.g. Tyrosine Kinase Inhibitors).