FLT3 Inhibition in Acute Myeloid Leukaemia – Current Knowledge and Future Prospects

Author(s): Francesca L. Hogan, Victoria Williams, Steven Knapper*

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 7 , 2020

DOI : 10.2174/1570163817666200518075820

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Graphical Abstract:


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.

Keywords: Acute myeloid leukaemia (AML), FLT3 inhibitor, midostaurin, quizartinib, gilteritinib main text, chemotherapy.

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VOLUME: 20
ISSUE: 7
Year: 2020
Page: [513 - 531]
Pages: 19
DOI: 10.2174/1570163817666200518075820
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