Targeting FLT3 for the Treatment of Leukemia

FLT3 is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. It is frequently overexpressed in acute leukemias and is frequently mutated in acute myeloid leukemia (AML). FLT3 internal tandem duplication (ITD) mutations in AML portend poor prognosis in both adult and pediatric patients. A number of small molecule tyrosine kinase inhibitors (TKIs) with activity against FLT3 have been discovered. Many of these are still in preclinical development, but several have entered clinical phase I and II trials as monotherapy in patients with relapsed AML. These trials have resulted in frequent but short-lived responses of peripheral blasts and less frequent responses of bone marrow blasts. This led to clinical testing of FLT3 TKIs in combination with conventional chemotherapy. Several combination trials are ongoing or planned in both relapsed and newly diagnosed FLT3-mutant AML patients. Anti-FLT3 antibodies may also prove to be an excellent way of targeting FLT3 in AML and acute lymphocytic leukemia (ALL) by inhibiting signaling and through antibody-dependent cell-mediated cytotoxicity.