title: A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia.
abstract: Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.
authors.affiliation: Department of Oncology/Hematology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. fiedler@uke.uni-hamburg.de
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Rolf
authors.initials: R
authors.lastname: Mesters
authors.forename: Heike
authors.initials: H
authors.lastname: Tinnefeld
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.forename: Peter
authors.initials: P
authors.lastname: Staib
authors.forename: Ulrich
authors.initials: U
authors.lastname: Duhrsen
authors.forename: Michael
authors.initials: M
authors.lastname: Flasshove
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jung
authors.forename: Franco
authors.initials: F
authors.lastname: Cavalli
authors.forename: Rolf
authors.initials: R
authors.lastname: Kuse
authors.forename: Joerg
authors.initials: J
authors.lastname: Thomalla
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Anne M
authors.initials: AM
authors.lastname: O'Farrell
authors.forename: Mark
authors.initials: M
authors.lastname: Jacobs
authors.forename: Nicoletta M
authors.initials: NM
authors.lastname: Brega
authors.forename: Paul
authors.initials: P
authors.lastname: Scigalla
authors.forename: Dieter K
authors.initials: DK
authors.lastname: Hossfeld
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001853:Bone Marrow / Q000378:metabolism; D002469:Cell Separation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008833:Microcirculation; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011758:Pyrroles / Q000627:therapeutic use*; D012008:Recurrence; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008565:Membrane Proteins; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C084881:flt3 ligand protein; C116890:Semaxinib