title: Association Between BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia and Cardiovascular Events, Major Molecular Response, and Overall Survival: A Systematic Review and Meta-analysis.
abstract: OBJECTIVE
  A phase 3 trial with ponatinib in patients with chronic myeloid leukemia (CML) was interrupted due to an important increase of vascular occlusive events. A similar risk was also suspected with nilotinib, another BCR-ABL tyrosine kinase inhibitor (TKI) used in patients with CML.
  
  
  OBJECTIVE
  To assess the risk of vascular occlusive events in patients with CML treated by new generations of TKIs and provide an overall assessment of the clinical benefit.
  
  
  METHODS
  Two independent reviewers selected studies from PubMed, Scopus, and the Cochrane library database from their inception to October 21, 2014. Abstracts published during the past 3 years at international congresses and a trial register were also searched.
  
  
  METHODS
  Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO 2014 protocol: CRD42014014147. Among the 249 abstracts identified, 10 studies fulfilled the established criteria.
  
  
  METHODS
  Two investigators independently extracted data using a standard form.
  
  
  METHODS
  Information extracted included study and patients characteristics, type of intervention and data on vascular occlusive events, overall survival, and major molecular response (MMR). The meta-analysis was performed using a fixed-effects model. Odds ratios (ORs) with 95% CIs were computed using the Peto method.
  
  
  RESULTS
  Ten randomized clinical trials (3043 patients) were analyzed. Risk of vascular occlusive events was increased with dasatinib (OR, 3.86; 95% CI, 1.33-11.18), nilotinib (OR, 3.42; 95% CI, 2.07-5.63), and ponatinib (OR, 3.47; 95% CI, 1.23-9.78) compared with imatinib in patients with CML. No significant difference was found with bosutinib (OR, 2.77; 95% CI, 0.39-19.77). New-generation TKIs increased the rate of MMR at 1 year compared with imatinib (overall OR, 2.22; 95% CI, 1.87 to 2.63). No statistical difference in overall survival at 1 year was found (overall OR, 1.20; 95% CI, 0.63-2.29). Inaccessibility to individual data and time-to-event data and differences in evaluation criteria between studies could have introduced bias.
  
  
  CONCLUSIONS
  Dasatinib, nilotinib, and ponatinib increase vascular occlusive events. New-generation TKIs improve MMR but not the overall survival at 1 year in patients with CML.
authors: Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium.
authors: Jonathan
authors: J
authors: Douxfils
authors: Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium.
authors: Hélène
authors: H
authors: Haguet
authors: Hematology Laboratory, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, CHU UCL Namur, Belgium.
authors: François
authors: F
authors: Mullier
authors: Department of Hematology, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, CHU UCL Namur, Belgium.
authors: Christian
authors: C
authors: Chatelain
authors: Department of Hematology, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, CHU UCL Namur, Belgium.
authors: Carlos
authors: C
authors: Graux
authors: Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium.
authors: Jean-Michel
authors: JM
authors: Dogné