Incorporating FLT3 inhibitors into acute myeloid leukemia treatment regimens.
FMS-Like-Tyrosine kinase-3 (FLT3) mutations are found in about 30% of cases of acute myeloid leukemia and confer an increased relapse rate and reduced overall survival. Targeting of this tyrosine kinase by direction inhibition is the focus of both preclinical and clinical research in AML. Several molecules in clinical development inhibit FLT3 with varying degrees of specificity. Preclinical models suggest that these compounds enhance the cytotoxicity of conventional chemotherapeutics against FLT3 mutant leukemia cells. The pharmacodynamic interactions between FLT3 inhibitors and chemotherapy appear to be sequence dependent. When the FLT3 inhibitor is used prior to chemotherapy, antagonism is displayed, while if FLT3 inhibition is instituted after to exposure to chemotherapy, synergistic cytotoxicity is seen. The combination of FLT3 inhibitors with chemotherapy is also complicated by potential pharmacokinetic obstacles, such as plasma protein binding and p-glycoprotein interactions. Ongoing and future studies are aimed at incorporating FLT3 inhibitors into conventional induction and consolidation therapy specifically for patients with FLT3 mutant AML.
Pratz
Keith
K
Division of Hematologic Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Levis
Mark
M
D000970:Antineoplastic Agents / Q000627:therapeutic use; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051941:fms-Like Tyrosine Kinase 3