FLT3 inhibitors for the treatment of acute myeloid leukemia.

The fms-like receptor tyrosine kinase-3 (FLT3), which is important for the normal development of hematopoietic stem cells and cells of the immune system, is frequently mutated in patients with acute myeloid leukemia (AML). FLT3 is, therefore, a potential therapeutic target in AML. Recently, FLT3 inhibitors have shown therapeutic activity in AML patients with FLT3 mutations. Sorafenib and sunitinib were the first FLT3 inhibitors to be studied in the clinic and have the most clinically relevant data. Limited data are available for midostaurin (PKC412), lestaurtinib (CEP-701), tandutinib (MLN518), AC220, and KW-2449. It is likely that optimal application of these agents will involve combinations of inhibitors and combinations of inhibitors and chemotherapy, potentially with a mammalian target of rapamycin inhibitor such as everolimus or temsirolimus. This review discusses the theoretical rationale for the use of these agents and summarizes the relevant clinical data.