Abstract
Internal tandem duplications (ITD) and tyrosine-kinase domain (TKD) mutations of the FMS-like tyrosine-kinase 3 (FLT3) can be found in up to one third of patients with acute myeloid leukemia (AML) and confer a poor prognosis. First discovered 20 years ago, these mutations were identified as viable therapeutic targets, and FLT3 tyrosine-kinase inhibitors (TKIs) have been in development for the last decade with steadily increasing potency. However, FLT3-mutated AML often acquires resistance to the growing armamentarium of FLT3 inhibitors through a variety of mechanisms. In this review, we discuss the distinct clinical phenotype of FLT3-mutated AML, historically and currently available therapeutics, mechanisms of resistance, ongoing trials, and future outlook at treatment strategies.
Keywords:
Acute myeloid leukemia (AML); FLT3; Tyrosine-kinase inhibitor (TKI).
MeSH terms
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Clinical Trials as Topic
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Combined Modality Therapy
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Drug Resistance, Neoplasm
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Molecular Targeted Therapy*
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Mutation
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Signal Transduction / drug effects
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Tandem Repeat Sequences
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Treatment Outcome
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fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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fms-Like Tyrosine Kinase 3