Progress in Hematology Efficacy and resistance of molecularly targeted therapy for myeloid malignancies

International Journal of Hematology

, Volume 97, Issue 6, pp 683-694

FLT3 inhibitors for acute myeloid leukemia: a review of their efficacy and mechanisms of resistance

  • Michael R. GrunwaldAffiliated withDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • , Mark J. LevisAffiliated withDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Email author 

Abstract

Since the Food and Drug Administration approval of imatinib for treatment of chronic myeloid leukemia in 2001, tyrosine kinase inhibitors (TKIs) have become a mainstay in the care of many malignancies. In acute myeloid leukemia (AML), activating mutations in the FMS-like tyrosine kinase 3 (FLT3) gene result in survival and proliferation of leukemic blasts and are associated with adverse prognosis. Therefore, the FLT3 receptor is an appealing target for inhibition. Multiple small molecule TKIs are currently in development for FLT3-mutated AML, and agents are beginning to show promising efficacy. In other malignancies, the development of resistance to TKIs during the course of therapy has proven to be a challenge, and thus far, in clinical trials of FLT3 TKIs, resistance to inhibition represents a significant barrier to successful FLT3 inhibition. Understanding the mechanisms of resistance and overcoming these obstacles to target inhibition will be central to the success of these agents.

Keywords

Acute myeloid leukemia (AML) FLT3 Tyrosine kinase inhibitor (TKI)