The role of FLT3 in Acute Leukemia
Approximately one third of AML patients harbor a constitutively activating internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase 3 (FLT3), which is associated with poor prognosis. Additional point mutations occur in FLT3, commonly in the activation loop residue D835 and the “gatekeeper” residue F691, which can result in drug resistance to existing therapies and disease relapse. As demonstrated by the success of FLT3 inhibitors approved by the FDA or in late-stage development, the inhibition of FLT3 is a validated strategy in this patient populations. Yet, the clinical benefit of dirty agents is limited due to the challenges of titration due to their toxicity, while the clinical benefit of more selective agents is not overarchingly durable due to the emergence of resistance.