Title:FLT3 Inhibition in Acute Myeloid Leukaemia – Current Knowledge and Future Prospects
VOLUME: 20 ISSUE: 7
Author(s):Francesca L. Hogan, Victoria Williams and Steven Knapper*
Affiliation:Department of Haematology, University Hospital of Wales, Cardiff, Department of Haematology, University Hospital of Wales, Cardiff, School of Medicine, Cardiff University, Cardiff
Keywords:Acute myeloid leukaemia (AML), FLT3 inhibitor, midostaurin, quizartinib, gilteritinib main text, chemotherapy.
Abstract:Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in 30% of acute
myeloid leukaemia (AML) patients at diagnosis and confer an adverse clinical prognosis. Mutated
FLT3 has emerged as a viable therapeutic target and a number of FLT3-directed tyrosine kinase inhibitors
have progressed through clinical development over the last 10-15 years. The last two years
have seen United States Food and Drug Administration (US FDA) approvals of the multi-kinase inhibitor
midostaurin for newly-diagnosed FLT3-mutated patients, when used in combination with intensive
chemotherapy, and of the more FLT3-selective agent gilteritinib, used as monotherapy, for
patients with relapsed or treatment-refractory FLT3-mutated AML. The ‘second generation’ agents,
quizartinib and crenolanib, are also at advanced stages of clinical development. Significant challenges
remain in negotiating a variety of potential acquired drug resistance mechanisms and in optimizing
sequencing of FLT3 inhibitory drugs with existing and novel treatment approaches in different
clinical settings, including frontline therapy, relapsed/refractory disease, and maintenance treatment.
In this review, the biology of FLT3, the clinical challenge posed by FLT3-mutated AML, the
developmental history of the key FLT3-inhibitory compounds, mechanisms of disease resistance,
and the future outlook for this group of agents, including current and planned clinical trials, is discussed.
