Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis

Expert Opin Drug Saf. 2017 Jan;16(1):5-12. doi: 10.1080/14740338.2017.1261824. Epub 2016 Nov 28.

Abstract

Background: A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events in patients with Ph+ chronic myeloid leukemia compared with imatinib. This meta-analysis of randomized controlled trials aims at assessing these risks separately.

Methods: The literature search was performed by two independent reviewers following the previous protocol (PROSPERO 2014:CRD42014014147). A random-effects model and a fixed-effect model were used according to the characteristics of the included studies. Peto odds ratios with 95%CI were computed.

Results: Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib. Ponatinib (ORPETO:3.26; 95%CI:1.12 to 9.50), nilotinib (ORPETO: 3.69; 95%CI:2.29 to 5.95) and dasatinib (ORPETO:3.32; 95%CI:1.37 to 8.01) are all associated with a higher risk of arterial occlusive events than imatinib. Venous occlusive events occur in 0.72% of patients treated with new generation TKIs and in 0.27% of imatinib-treated patients. Overall, a trend toward an increase of the rate of venous occlusive events with new-generation TKIs (ORPETO:2.17; 95%CI:0.90 to 5.25) was highlighted but stratifications by treatment gave nonsignificant results.

Conclusions: Vascular occlusive events associated with new-generation BCR-ABL TKIs are driven by arterial occlusive events.

Keywords: Arterial occlusive disease; BCR-ABL positive; chronic; leukemia; meta-analysis; myelogenous; protein kinase inhibitors; venous thrombosis.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Dasatinib / adverse effects
  • Dasatinib / therapeutic use
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Humans
  • Imatinib Mesylate / adverse effects
  • Imatinib Mesylate / therapeutic use
  • Imidazoles / adverse effects
  • Imidazoles / therapeutic use
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Protein Kinase Inhibitors / adverse effects*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridazines / adverse effects
  • Pyridazines / therapeutic use
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use
  • Randomized Controlled Trials as Topic
  • Vascular Diseases / chemically induced
  • Vascular Diseases / epidemiology

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridazines
  • Pyrimidines
  • ponatinib
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • nilotinib
  • Dasatinib