Differences and similarities in ibrutinib and acalabrutinib effects on platelet functions

While efficient to treat B-cell malignancies, Bruton9s tyrosine kinase inhibitors are consistently reported to increase the bleeding risk. Analyzing platelet aggregation response to collagen in platelet-rich-plasma allowed us to identify two groups in the healthy population characterized by low or high sensitivity to ibrutinib in vitro. Inhibition of drug efflux pumps induced a shift from ibrutinib low to high sensitive platelets. At clinically relevant dose, the second-generation inhibitor, acalabrutinib, did not affect maximal collagen-induced platelet aggregation in the ibrutinib low sensitive group and inhibited aggregation in a small fraction of the ibrutinib high sensitive group. Consistently, acalabrutinib delayed aggregation, particularly in the ibrutinib high sensitive group. In chronic lymphocytic leukemia patients, acalabrutinib inhibited maximal platelet aggregation only in the ibrutinib high sensitive group. Acalabrutinib inhibited collagen-induced tyrosine-753 phosphorylation of phospholipase Cγ2 in both groups, but, in contrast to ibrutinib, did not affect Src-family kinases. Acalabrutinib impacted thrombus growth under flow only in the ibrutinib high sensitive group and potentiated the effect of cyclooxygenase and P2Y12 receptor blockers in both groups. The better profile of acalabrutinib being mainly observed in the ibrutinib low sensitive group, replacement therapy in patients may not systematically reduce the bleeding risk.