|Tumor Type||Primary Site|
FLT3 is a receptor tyrosine kinase important in hematopoietic cell proliferation and differentiation. In-frame, FLT3 internal tandem duplications (ITD), which show a wide range of number of nucleotides duplicated and/or inserted (eg, 18-204 bp), affect exons 14 and 15 in the FLT3 juxtamembrane/tyrosine kinase domain and have been reported in 20-30% of patients with acute myeloid leukemia. FLT3 ITDs usually occur in cases of AML with a normal karyotype and but may also occur in cases with chromosome abnormalities including t(15;17) or other cytogenetic groups. Individuals with FLT3 mutations are more likely to have AML than MDS and FLT3 mutations in MDS are associated with a poor prognosis. Functional studies have shown that FLT3 ITDs are ligand-independent, gain-of-function mutations. In addition, activating mutations at codon D835 in exon 20 (A-loop of the tyrosine kinase domain, TKD) of FLT3 have been reported in approximately 7-10% of AML. The FLT3 D835 mutations are also ligand-independent, gain-of-function mutations. FLT3 ITD and D835 mutations tend to occur in a mutually exclusive manner; however, the FLT3 D835 mutation or other mutations in the A-loop(eg, D839, Y842) may occur as an acquired resistance mutation in the setting of patients with FLT3 ITD mutations being treated with targeted therapy. In addition, variants at codon N676 and in exon 17 F691, G697 have been associated with resistance to FLT3 targeted therapy. The presence of FLT3 ITD mutation in young patients with AML and normal cytogenetics is thought to be associated with a poor prognosis. On the other hand, the prognostic significance of the FLT3 D835 and TKD mutations appears less clear. More recently, therapeutic targeting of FLT3 in combination with other chemotherapy is available in certain settings for acute myeloid leukemia with FLT3 ITD or TKD mutations. Lastly, in T cell acute lymphoblastic leukemia, up to 20% of cases have been reported to show a FLT3 mutation (TKD or ITD) and are often associated with an ETP(early T cell precursor) phenotype. In addition, FLT3 mutations have also been reported in up to 15% of B-ALL cases ("Ph-like phenotype") and may also be associated with hyperdiploidy and MLL rearrangement. Targetting FLT3 in acute lymphoblastic leukemia therapy may also be possible in some settings.