title: SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes.
abstract: Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.
authors.affiliation: Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030, USA. frankgiles@aol.com
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Silverman
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Cooper
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cherrington
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: O'Farrell
authors.forename: Helene A
authors.initials: HA
authors.lastname: Yuen
authors.forename: Sharianne G
authors.initials: SG
authors.lastname: Louie
authors.forename: Weiru
authors.initials: W
authors.lastname: Hong
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: Susan M
authors.initials: SM
authors.lastname: O'Brien
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D001856:Bone Marrow Examination; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007951:Leukemia, Myeloid / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D009336:Necrosis; D010599:Pharmacokinetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D012074:Remission Induction / Q000379:methods; D016879:Salvage Therapy
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases