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Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Leukemia volume 26, pages 2176–2185 (2012)Cite this article

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Abstract

Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/pharmacodynamic profile. Novel combination regimens are also discussed.

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Acknowledgements

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Erinn Goldman, PhD, for medical editorial assistance with this manuscript.

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Authors and Affiliations

  1. Sylvester Comprehensive Cancer Center, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA

    R Swords

  2. Barts and The London NHS Trust, St Bartholomew’s Hospital, London, UK

    C Freeman

  3. HRB Clinical Research Facilities, National University of Ireland Galway and Trinity College Dublin, Dublin, Ireland

    F Giles

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  1. R Swords
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  2. C Freeman
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Correspondence to F Giles.

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Dr Giles has received research support and has served as a consultant for Novartis Pharmaceuticals.

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Swords, R., Freeman, C. & Giles, F. Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. Leukemia 26, 2176–2185 (2012). https://doi.org/10.1038/leu.2012.114

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