C. Chatelain Archives

O2 In Vitro Effects of BCR-ABL Tyrosine Kinase Inhibitors on Endothelial Cells Survival and Functions

BJH - 2018, issue Abstract Book BHS, february 2018

H. Haguet , J. Douxfils PhD, PharmD, C. Chatelain MD, C. Graux MD, PhD, F. Mullier PhD, PharmD, J-M. Dogné PhD, PharmD

Vascular safety profile of new generation BCR-ABL tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia

BJH - volume 8, issue 2, march 2017

H. Haguet , J. Douxfils PhD, PharmD, F. Mullier PhD, PharmD, C. Chatelain MD, C. Graux MD, PhD, J-M. Dogné PhD, PharmD

SUMMARY

Tyrosine kinase inhibitors targeting BCR-ABL have been a real revolution in the treatment of chronic myeloid leukaemia, greatly improving surrogate outcomes and overall survival. However, new generation BCR-ABL tyrosine kinase inhibitors have recently been associated with occurrence of cardiovascular events. Indeed, during ponatinib clinical development, a high rate of patients with chronic myeloid leukaemia developed a vascular occlusive event. Retrospective analyses also demonstrated an increased incidence of similar events with nilotinib. Recently, a meta-analysis of randomised clinical trials confirmed this risk with nilotinib and ponatinib, but also identified dasatinib at higher risk of cardiovascular events than imatinib. Sub-analysis of this meta-analysis and retrospective studies indicated predominance of arterial events rather than venous. The number of patients treated with dasatinib and nilotinib has considerably increased since they have been approved in first-line indication for patients with chronic-phase chronic myeloid leukaemia. In this context, the evaluation of the benefit-risk profile of these treatments is important, and implementation of measures to minimise the onset of cardiovascular events are required. They should include the selection of patients treated with new generation tyrosine kinase inhibitors, the monitoring of cardiovascular events and risk factors during treatment, and if required, the treatment of cardiovascular comorbidities. The pathophysiology of these events is probably multifactorial. Numerous hypotheses have already been advanced and suggest a worsening of the metabolic syndrome, an increase of atherosclerosis development and an impact of new generation tyrosine kinase inhibitors on off-targets related to vascular function.

(BELG J HEMATOL 2017;8(2):45–52)