ABSTRACT
Ponatinib (Iclusig, ARIAD Pharmaceuticals-Incyte Co.) is a third-generation structure-guided tyrosine kinase inhibitor that is approved for treatment of Philadelphia chromosome-positive leukaemias resistant or intolerant to other inhibitors. The clinical use of ponatinib is complicated by the possible development of cardiovascular events, primarily hypertension and arterial or venous thrombotic events. The US Food and Drug Administration and the European Medicine Agency recommend that the cardiovascular profile of patients candidate for ponatinib should be carefully evaluated. For patients deemed to carry a high risk of cardiovascular events, other life-saving therapeutic options should be considered. When alternative options are not available, treatment with ponatinib is indicated but requires that haematologists and cardiologists collaborate and identify modalities of surveillance and risk mitigation in the best interest of the patient. This article reports on the expert opinion provided by a panel of Italian haematologists, cardiologists and clinical pharmacologists. It summarises suggestions that may help to improve the therapeutic index of ponatinib, primarily in the settings of chronic-phase chronic myeloid leukaemia.
Subject(s)
Antineoplastic Agents/therapeutic use , Cardiovascular Diseases/prevention & control , Disease Management , Expert Testimony , Imidazoles/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Pyridazines/therapeutic use , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Clinical Trials as Topic/methods , Expert Testimony/methods , Follow-Up Studies , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Risk FactorsABSTRACT
An unexpectedly high incidence of thrombosis in patients that received the polylactic acid bioresorbable vascular scaffold (BVS) suggests a delayed/incomplete endothelial repair with this stent. The anti-platelet agent tirofiban stimulates endothelial cell migration and proliferation, mediated by VEGF production. We investigated the tirofiban effect on the migration and adhesion of endothelial cells to BVS, in vitro. We performed human umbilical endothelial cell (HUVEC) cultures in the presence of BVS. Tirofiban, similarly to VEGF, increased the ability of HUVEC to grow on the vascular scaffold, compared to unstimulated or abciximab-treated cells. Tirofiban increased HUVEC expression of ß1 and ß3 integrins along with collagen and fibronectin. A role for ß1 integrin in the "pro-adhesive and -migratory" signals elicited by tirofiban was suggested by use of an anti-ß1-blocking antibody that prevented poly-levo-lactic acid vascular scaffold colonization. Our study suggests that tirofiban may improve the outcomes of patients receiving BVS by accelerating stent endothelization.