Tyrosine Kinase Inhibitors as Risk Factors for Cerebral Vascular Disease: Report of Two Cases and Literature Review

Treatment for chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs), especially nilotinib and ponatinib, has been associated with atheromatic vascular adverse events including cerebrovascular disease. Herein, we present two patients with CML and long-term nilotinib treatment, who developed severe carotid atherosclerotic stenoses, both extra- and intracranial, resulting in ischemic stroke. The clinical and radiological findings as well as the possible pathophysiological mechanisms of these clinically significant complications are discussed. It seems that new-generation TKIs such as nilotinib, ponatinib, and, to a far lesser extent, bosutinib increase the incidence of vascular occlusive events compared to imatinib, in a dose- and duration-dependent manner. The mechanisms leading to vasculopathy are various and comprise promoting a prothrombotic platelet state, the dysregulation of glucose and lipid metabolism, increase of inflammatory cytokines, and affecting vessel wall endothelial cells. Regarding the outcome of cerebrovascular events, it seems that the discontinuation of TKIs alone or switching to a safer one is insufficient to resolve the stenoses of the cerebral arteries, even under dual antiplatelet treatment, anticoagulation, or high-potency statin therapy. Thus, revascularization strategies such as extracranial to intracranial bypass surgery or stenting should be considered, especially when there is no improvement with medical treatment. These observations expand our knowledge on the association between TKIs and cerebral vascular disease, as well as provide more insights into the underlying pathogenesis. TKIs should not only be selected based on disease-related variables but also based on patient-related factors such as cardiovascular comorbidities.