Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia

Abstract

Background: Recently, an internal tandem duplication of the FLT3 gene (FLT3/ITD) was found in approximately 20% of adult acute myeloid leukemia (AML) cases and associated with a poor outcome. However, there are few studies on FLT3/ITD in childhood AML, and the clinical significance of FLT3/ITD is thus unclear.

Methods: FLT3/ITD was analyzed in 80 children with de novo AML. The genomic DNA polymerase chain reaction (PCR) assay was performed to identify FLT3/ITD. Genescan analysis to determine the allelic distribution was then performed for those PCR products with aberrant bands. Direct sequencing of PCR products was also carried out in each sample with FLT3/ITD.

Results: The incidence of FLT3/ITD was 11.3% (9 out of 80 patients) in AML, with 25% (3 out of 12 patients) in acute promyelocytic leukemia (APL) and 8.8% (6 out of 68 patients) in non-M3 AML. The size of duplicated fragments varied from 21 base pairs (bp) to 75 bp, and the mutant to wild type ratio of FLT3 ranged from 0.28 to 16.60 in the nine patients with FLT3/ITD. The incidence of FLT3/ITD in childhood AML in patients > 10 years of age was 24%, compared to 5% of those patients <or= 10 years of age (P = 0.011). The six non-M3 AML patients with FLT3/ITD were all older than 10 years of age. In APL, FLT3/ITD was found in 2 of 2 patients with S-form PML/RARalpha, compared with 1 in 10 patients with non-S form PML/RARalpha(P = 0.045). There were no cytogenetic abnormalities or fusion transcripts derived from common specific translocations found in non-M3 AML patients with FLT3/ITD. There was no significant difference in treatment outcome between APL patients with FLT3/ITD and those without FLT3/ITD. The authors failed to find a correlation between the treatment outcome and the presence of FLT3/ITD in non-M3 AML patients. Instead, the authors found that all three patients with a mutant FLT3 to wild type ratio of greater than 2.0 died within eight months after diagnosis; two of them failed to achieve complete remission.

Conclusions: The current study shows that the mutant FLT3 to wild type ratio, but not the presence of FLT3/ITD itself, may serve as a potential marker to improve risk-assessment in childhood AML.