Pathogenesis of Tyrosine Kinase Inhibitor–Associated Vascular Toxicity in Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs) have revolutionized the outcomes of chronic myeloid leukemia (CML). However, over the past years, evidence has emerged demonstrating an association between treatment with the TKIs nilotinib, ponatinib and dasatinib (but not imatinib or bosutinib) and vascular adverse events (VAEs) in CML. This is of concern as the duration of TKI therapy is potentially life-long.

Our in-vitro studies showed that both endothelial cell functionality (viability, apoptosis, migration, tube formation) and gene expression are widely influenced by ponatinib, nilotinib and dasatinib but not by imatinib and bosutinib thus corresponding with the VAE profiles of these inhibitors and supporting a direct effect on vascular cells. In our in-vivo model, femoral artery excision was performed to induce ischemia and stimulate new blood vessel formation in mice treated with clinically relevant doses of TKIs. Dasatinib-treated mice showed a significantly delayed recovery as assessed via Doppler imager and a significant increase in toe necrosis. Imatinib- and bosutinib-treated mice showed a similar recovery pattern to that of control-treated mice. The recovery with ponatinib treatment was also similar to that of control, differing from the anti-angiogenic effect observed in-vitro. Therefore, ponatinibs effect on endothelial toxicity requires further investigation. The dasatinib in-vivo and in-vitro results are in-line with its clinical VAE profile, implicating endothelial toxicity related to dasatinib and supporting a direct effect of dasatinib on vascular pathogenesis. Further elucidation of the molecular mechanism governing this endothelial toxicity could contribute to the future development of safer next-generation TKIs and to mitigating cardiovascular risk.