title: Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia.
abstract: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately 30% of patients with de novo acute myeloid leukemia (AML) and are associated with lower cure rates from standard chemotherapy-based treatment. Targeting the mutation by inhibiting the tyrosine kinase activity of FLT3 is cytotoxic to cell lines and primary AML cells harboring FLT3 mutations. Successful FLT3 inhibition can also improve survival in mouse models of FLT3-activated leukemia. CEP-701 is an orally available, novel, receptor tyrosine kinase inhibitor that selectively inhibits FLT3 autophosphorylation. We undertook a phase 1/2 trial to determine the in vivo hematologic effects of single-agent CEP-701 as salvage treatment for patients with refractory, relapsed, or poor-risk AML expressing FLT3-activating mutations. Fourteen heavily pretreated AML patients were treated with CEP-701 at an initial dose of 60 mg orally twice daily. CEP-701-related toxicities were minimal. Five patients had clinical evidence of biologic activity and measurable clinical response, including significant reductions in bone marrow and peripheral blood blasts. Laboratory data confirmed that clinical responses correlated with sustained FLT3 inhibition to CEP-701. Our results show that FLT3 inhibition is associated with clinical activity in AML patients harboring FLT3-activating mutations and indicate that CEP-701 holds promise as a novel, molecularly targeted therapy for this disease.
authors.affiliation: Departments of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. smithdo@jhmi.edu
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
authors.forename: Miloslav
authors.initials: M
authors.lastname: Beran
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Karin
authors.initials: K
authors.lastname: Berg
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Tianna
authors.initials: T
authors.lastname: Dauses
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Allebach
authors.forename: Donald
authors.initials: D
authors.lastname: Small
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D002227:Carbazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004252:DNA Mutational Analysis; D016903:Drug Monitoring; D005260:Female; D005663:Furans; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D016879:Salvage Therapy / Q000379:methods*; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D002227:Carbazoles; D005663:Furans; D007211:Indoles; D011518:Proto-Oncogene Proteins; C119379:lestaurtinib; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3