title: Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412.
abstract: Leukemic cells from 30% of patients with acute myeloid leukemia (AML) have an activating mutation in the FLT3 (fms-like tyrosine kinase) gene, which represents a target for drug therapy. We treated 20 patients, each with mutant FLT3 relapsed/refractory AML or high-grade myelodysplastic syndrome and not believed to be candidates for chemotherapy, with an FLT3 tyrosine kinase inhibitor, PKC412 (N-benzoylstaurosporine), at a dose of 75 mg 3 times daily by mouth. The drug was generally well tolerated, although 2 patients developed fatal pulmonary events of unclear etiology. The peripheral blast count decreased by 50% in 14 patients (70%). Seven patients (35%) experienced a greater than 2-log reduction in peripheral blast count for at least 4 weeks (median response duration, 13 weeks; range, 9-47 weeks); PKC412 reduced bone marrow blast counts by 50% in 6 patients (2 of these to < 5%). FLT3 autophosphorylation was inhibited in most of the Corresponding patients, indicating in vivo target inhibition at the dose schedule used in this study. PKC412 is an oral tyrosine kinase inhibitor with clinical activity in patients with AML whose blasts have an activating mutation of FLT3, suggesting potential use in combination with active agents, such as chemotherapy.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA 02115, USA. rstone@partners.org
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Virginia
authors.initials: V
authors.lastname: Klimek
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Eli
authors.initials: E
authors.lastname: Estey
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.forename: Wilson
authors.initials: W
authors.lastname: Grandin
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Pamela
authors.initials: P
authors.lastname: Cohen
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fox
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clark
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000328:Adult; D000368:Aged; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D019000:Phosphotyrosine / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D019311:Staurosporine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D011518:Proto-Oncogene Proteins; D019000:Phosphotyrosine; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin