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.
Highlights
In 2001, the approval of imatinib, the first-in-class tyrosine kinase inhibitor (TKI) targeting BCR-ABL, transformed the prognosis of patients with chronic-phase (CP) chronic myeloid leukemia (CML) from a life-threatening condition to a manageable and chronic disease.[1]
This lack of antifibrotic effect at higher doses might be explained by inhibition of additional offtargets by nilotinib that affect the benefit of low-dose nilotinib against fibrosis
Arterial thrombosis occurring with dasatinib and nilotinib are probably not the consequence of vascular smooth muscle cell (VSMC) impairment, but investigations should be performed on VSMCs rather than on fibroblasts
Summary
In 2001, the approval of imatinib, the first-in-class tyrosine kinase inhibitor (TKI) targeting BCR-ABL, transformed the prognosis of patients with chronic-phase (CP) chronic myeloid leukemia (CML) from a life-threatening condition to a manageable and chronic disease.[1] Yet, despite satisfactory outcomes, 33% of patients did not achieved optimal response because of treatment resistance or intolerance.[1] The identification of the predominant resistance mechanism (i.e., point mutations in the kinase domain of Bcr-Abl) led to the development of second-generation BCR-ABL TKIs (dasatinib, nilotinib, and bosutinib, respectively, approved in 2006, 2007, and 2012) active against most of the BCR-ABL mutated forms.[2,3] Second-generation TKIs demonstrated no or little improvement of the overall survival compared with imatinib,[4,5,6] but two of these (i.e., dasatinib and nilotinib) improve received September 13, 2017 accepted after revision November 27, 2017. Ponatinib is currently the only treatment active against the T315I mutation and is reserved for patients with this mutation or for patients resistant to frontline treatments.[11]
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