Association of cardiovascular occlusive events with BCR-ABL tyrosine kinase therapy - Identification, understanding and prediction

Candidate

Hélène HAGUET

Promoters

Prof. Jonathan DOUXFILS, UNamur, Department of pharmacy (promoter)

Prof. François MULLIER, CHU UCL Namur, Hematology laboratory (co-promoter)

Jury

• Jean-Michel DOGNE, Président, Université de Namur ;
• Jonathan DOUXFILS, Promoteur, Université de Namur ;
• Carlos GRAUX, université Catholique de Louvain ;
• Violaine HAVELANGE, Université Catholique de Louvain ;
• François MULLIER, Co-promoteur, Université de Namur ;
• Giuseppe SAGLIO, Université de Turin  ;
• Pierre SONVEAUX, Université Catholique de Louvain.

Summary

The identification of the BCR-ABL tyrosine kinase as the main culprit in the pathology of chronic myeloid leukemia led to the development of one of the most successful cancer therapies, imatinib, an inhibitor designed to specifically target BCR-ABL. Imatinib reduces durably the number of leukemic cells, providing a life span of patients with chronic myeloid leukemia in chronic phase close to that of the general population. However, some patients are intolerant or resistant, inducing the development of three additional BCR-ABL tyrosine kinase inhibitors (i.e. dasatinib, nilotinib and bosutinib). Ponatinib, a BCR-ABL tyrosine kinase inhibitor classified as a third generation was finally designed to overcome a mutation in the bcr-abl gene which provides resistance to all the other BCR-ABL tyrosine kinase inhibitors. However, during the ponatinib clinical development, numerous patients had a vascular occlusion.

The aim of this thesis is to investigate the vascular toxicity associated with BCR-ABL tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia.Through meta-analyses we highlighted that in addition to ponatinib, dasatinib and nilotinib also induce vascular toxicity, and more specifically arterial occlusion. Secondarily, through a review of the literature and in vitro experiments, we determined that these three treatments affect the vasculature differently. Ponatinib is highly toxic to endothelial cells, and this toxicity could be responsible for the arterial occlusion. Dasatinib impairs endothelial cells in a lesser extent, whereas nilotinib possesses a different vascular profile. It deregulates glucose and lipid metabolism and impacts platelet functions. The identification of the precise mechanisms underlying tyrosine kinase inhibitor-induced arterial occlusions is a central element as it influences the management of the vascular toxicity by guiding treatment selection, vascular monitoring and anticipating the vascular toxicity.