Will FLT3 inhibitors fulfill their promise in acute meyloid leukemia?
OBJECTIVE
'FMS'-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) have been brought from discovery in the early 1990s to clinical targeting in the past 10 years. Despite several promising leads in preclinical models, no agent has yet been approved for clinical use. Here we will review the development of novel therapies for AML with FLT3 mutations.


RESULTS
Initial clinical development focused on broad kinase inhibitors which were found to have limited clinical activity due to insufficient kinase inhibitory activity and high toxicity. Subsequent development has brought forth narrow-spectrum inhibitors with potent in-vivo activity and reasonable clinical tolerance, but many patients still progress with prolonged use.


CONCLUSIONS
The optimal role for targeting FLT3 may depend on multimodality therapy and will likely require hematopoietic transplant. The incorporation of ABL kinase inhibitors into acute lymphoblastic leukemia management should serve as a model for incorporation of FLT3-targeted agents into clinical care. Strategies incorporating FLT3-targeted agents into AML therapy are ongoing, but challenges in trial design, clinical heterogeneity and need for long-term follow-up make these investigations complicated in design and implementation.
aDepartment of Oncology, Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland bAbramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Keith W
KW
Pratz
Selina M
SM
Luger
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020440:Gene Duplication; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012307:Risk Factors; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051941:fms-Like Tyrosine Kinase 3