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FLT3 Inhibition in Acute Myeloid Leukaemia - Current Knowledge and Future Prospects
Francesca L Hogan1, Victoria Williams1, Steven Knapper2
1Department of Haematology, University Hospital of Wales, Cardiff, United Kingdom.
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.
Insights
Activating mutations in FMS-like tyrosine kinase 3 (FLT3) drive acute myeloid leukemia (AML). FLT3 inhibitors like midostaurin and gilteritinib show promise, but overcoming resistance is key for future treatments.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are found in 30% of acute myeloid leukemia (AML) patients, associated with poor prognosis.
- Mutated FLT3 is a validated therapeutic target, leading to the development of several FLT3-directed tyrosine kinase inhibitors (TKIs).
- Recent US FDA approvals include midostaurin for newly-diagnosed FLT3-mutated AML and gilteritinib for relapsed/refractory FLT3-mutated AML.
Purpose of the Study:
- To review the biology of FLT3 mutations in AML.
- To discuss the clinical development and efficacy of FLT3 inhibitors.
- To explore challenges in overcoming drug resistance and optimizing treatment strategies.
Main Methods:
- Review of scientific literature on FLT3 biology, AML, and FLT3 inhibitors.
- Analysis of clinical trial data for approved and investigational FLT3-targeted therapies.
- Discussion of mechanisms of acquired resistance to FLT3 inhibitors.
Main Results:
- FLT3 inhibitors have demonstrated clinical activity in FLT3-mutated AML.
- Midostaurin and gilteritinib are approved treatments for specific AML settings.
- Second-generation FLT3 inhibitors like quizartinib and crenolanib are in advanced development.
Conclusions:
- FLT3 inhibitors represent a significant advancement in AML treatment.
- Addressing acquired resistance mechanisms is crucial for improving long-term outcomes.
- Optimizing the sequencing and combination of FLT3 inhibitors with other therapies is essential for different clinical scenarios.
