BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

Hélène Haguet; Jonathan Douxfils; Christian Chatelain; Carlos Graux; François Mullier; Jean-Michel Dogné

doi:10.1055/s-0038-1624566

TH Open, Table of Contents

CC-BY 4.0 · TH Open 2018; 02(01): e68-e88
DOI: 10.1055/s-0038-1624566

Review Article

Georg Thieme Verlag KG Stuttgart · New York

BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

Hélène Haguet

¹University of Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Namur, Belgium

²Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Hematology Laboratory, Yvoir, Belgium

,

Jonathan Douxfils

¹University of Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Namur, Belgium

⁴QUALIblood s.a., Namur, Belgium

,

Christian Chatelain

¹University of Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Namur, Belgium

,

Carlos Graux

³Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Department of Hematology, Yvoir, Belgium

,

François Mullier

²Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center, Hematology Laboratory, Yvoir, Belgium

,

Jean-Michel Dogné

¹University of Namur, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Department of Pharmacy, Namur, Belgium

› Author Affiliations

Abstract

Imatinib, the first-in-class BCR-ABL tyrosine kinase inhibitor (TKI), had been a revolution for the treatment of chronic myeloid leukemia (CML) and had greatly enhanced patient survival. Second- (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKIs have been developed to be effective against BCR-ABL mutations making imatinib less effective. However, these treatments have been associated with arterial occlusive events. This review gathers clinical data and experiments about the pathophysiology of these arterial occlusive events with BCR-ABL TKIs. Imatinib is associated with very low rates of thrombosis, suggesting a potentially protecting cardiovascular effect of this treatment in patients with BCR-ABL CML. This protective effect might be mediated by decreased platelet secretion and activation, decreased leukocyte recruitment, and anti-inflammatory or antifibrotic effects. Clinical data have guided mechanistic studies toward alteration of platelet functions and atherosclerosis development, which might be secondary to metabolism impairment. Dasatinib, nilotinib, and ponatinib affect endothelial cells and might induce atherogenesis through increased vascular permeability. Nilotinib also impairs platelet functions and induces hyperglycemia and dyslipidemia that might contribute to atherosclerosis development. Description of the pathophysiology of arterial thrombotic events is necessary to implement risk minimization strategies.

Keywords

BCR-ABL - arterial thrombotic events - tyrosine kinase inhibitors - chronic myeloid leukemia

Full Text

References

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