SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes.
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.
Giles
Francis J
FJ
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030, USA. frankgiles@aol.com
Stopeck
Alison T
AT
Silverman
Lewis R
LR
Lancet
Jeffrey E
JE
Cooper
Maureen A
MA
Hannah
Alison L
AL
Cherrington
Julie M
JM
O'Farrell
Anne-Marie
AM
Yuen
Helene A
HA
Louie
Sharianne G
SG
Hong
Weiru
W
Cortes
Jorge E
JE
Verstovsek
Srdan
S
Albitar
Maher
M
O'Brien
Susan M
SM
Kantarjian
Hagop M
HM
Karp
Judith E
JE
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
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases