title: Targeted Therapy of FLT3 in Treatment of AML-Current Status and Future Directions.
abstract: 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.
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen N-5020, Norway. caroline.engen@k2.uib.no.
authors.forename: Caroline Benedicte Nitter
authors.initials: CB
authors.lastname: Engen
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen N-5020, Norway. line@wergeland.jacobsen.net.
authors.forename: Line
authors.initials: L
authors.lastname: Wergeland
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen N-5020, Norway. jorn.skavland@k2.uib.no.
authors.forename: Jørn
authors.initials: J
authors.lastname: Skavland
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen N-5020, Norway. bjorn.gjertsen@uib.no.|Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen N-5021, Norway. bjorn.gjertsen@uib.no.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
keywords: FLT3; acute myeloid leukemia; clinical trials; tyrosine kinase inhibitors