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.

Conflict of interest statement

Conflict of Intersest: The authors declare that they have no conflict of interest.

Figures

Figure 1. Progression-free survival and overall survival

Progression-free survival (A) and overall survival (B) for patients in dose cohorts 1 and 2 combined were estimated from the start of vatalanib treatment, according to the Kaplan-Meier method. Significance of differences between patients in the International Prognostic Scoring System (IPSS) low risk (Low or Intermediate {Int}-1; score 0–1) and high risk (IPSS Int-2 or High; score ≥1.5) groups was determined using the log-rank test (p

Figure 2. Cumulative incidence of transformation to acute myeloid leukemia or death

The cumulative incidence of acute myeloid leukemia (AML) or death for patients in dose cohorts 1 and 2 combined was estimated from the start of vatalanib treatment using a competing risk model as described in Methods. A: Cumulative incidence of transformation to AML or death for all patients. B: Cumulative incidence of transformation to AML or death by International Prognostic Scoring System (IPSS) low risk (Low or Intermediate {Int}-1; score 0–1) and high risk (IPSS Int-2 or High; score ≥1.5) groups.