Implications of FLT3 mutations in the therapy of acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that is expressed on the surface of hematopoietic stem cells and plays an important role in normal hematopoiesis. FLT3 is mutated in approximately one-third of cases of acute myeloid leukemia (AML) with normal karyotype. The mutations are most commonly internal tandem duplications found in the juxtamembrane domain of the FLT3 receptor. There are also cases of point mutations within the tyrosine kinase domain. The presence of a FLT3 mutation confers a poorer prognosis in disease-free survival and overall survival. Patients with an FLT3 mutation have poorer outcomes even with a concomitant nucleophosmin1 (NMP1) mutation, which is normally a good prognostic factor. These observations raise the question about how best to treat patients with AML who have FLT3 mutations. There are some retrospective data that allogeneic stem cell transplantation should be offered to patients with FLT3 mutations who have achieved a first remission, but prospective trials are lacking. There are a number of FLT3 inhibitors that are in various stages of clinical testing. It is hoped that this new class of drugs will be combined with traditional cytotoxic therapies to treat AML and improve outcomes in this difficult-to-treat patient population.