Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions

Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attract...

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Main Authors:	Engen, Caroline Benedicte Nitter, Wergeland, Line, Skavland, Jørn, Gjertsen, Bjørn Tore
Format:	Online
Language:	English
Published:	MDPI 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470194/

id	pubmed-4470194
recordtype	oai_dc
spelling	pubmed-44701942015-07-28 Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions Engen, Caroline Benedicte Nitter Wergeland, Line Skavland, Jørn Gjertsen, Bjørn Tore Review Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML. MDPI 2014-12-15 /pmc/articles/PMC4470194/ /pubmed/26237612 http://dx.doi.org/10.3390/jcm3041466 Text en © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Engen, Caroline Benedicte Nitter Wergeland, Line Skavland, Jørn Gjertsen, Bjørn Tore
spellingShingle	Engen, Caroline Benedicte Nitter Wergeland, Line Skavland, Jørn Gjertsen, Bjørn Tore Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
author_facet	Engen, Caroline Benedicte Nitter Wergeland, Line Skavland, Jørn Gjertsen, Bjørn Tore
author_sort	Engen, Caroline Benedicte Nitter
title	Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
title_short	Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
title_full	Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
title_fullStr	Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
title_full_unstemmed	Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions
title_sort	targeted therapy of flt3 in treatment of aml—current status and future directions
description	Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML.
publisher	MDPI
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470194/
_version_	1613236602271694848

Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions

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