title: A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance).
abstract: BACKGROUND
  Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death.
  
  
  METHODS
  Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750-1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity.
  
  
  RESULTS
  The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥ 2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib.
  
  
  CONCLUSIONS
  Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.
authors.affiliation: University of Minnesota, Minneapolis, MN, USA, gupta013@umn.edu.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.forename: Flora
authors.initials: F
authors.lastname: Mulkey
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hasserjian
authors.forename: Ben L
authors.initials: BL
authors.lastname: Sanford
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.forename: David D
authors.initials: DD
authors.lastname: Hurd
authors.forename: Olatoyosi M
authors.initials: OM
authors.lastname: Odenike
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D010793:Phthalazines / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor