PO-54 - Clinical and laboratory characterization of platelet dysfunction caused by ibrutinib treatment in patients with chronic lymphocytic leukemia

Abstract

Ibrutinib treatment in patients with chronic lymphatic leukemia (LLC) is associated with bleeding-related adverse events. About 50% of treated patients display minor bleedings and about 5% major bleedings. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein (GP) VI, which is the receptor for collagen, has been previously described. Ibrutinib-associated bleedings and platelet dysfunction may be relevant in the context of aged patients, who are often under antithrombotic treatments. Aim of this study is to investigate and characterize the effect of ibrutinib on platelet function in vitro in patients with CLL. Nine patients recruited in ongoing ibrutinib clinical trials were studied. Assessment of spontaneous bleeding was performed using the WHO bleeding scale. The following tests were performed before and after initiation of treatment with ibrutinib: 1) Light transmission aggregometry (LTA) using platelet-rich-plasma (ADP 2-4μM, PAR1-AP 25 μM, Collagen 10 ug /mL, arachidonic acid 1 mM, ristocetin 0.6-1.2mg/mL) 2) Measurement of vWF antigen and ristocetin cofactor activities by chemiluminescent immunoassay. I) Five patients displayed grade 1 bleeding (cutaneous bleeding) and one patient grade 2 bleeding (rectal bleeding) (66.7%) after initiation of ibrutinib treatment. II) Eight patients displayed abnormalities of the aggregation by 10 ug/ml collagen after initiation of ibrutinib treatment. At high collagen concentration, only significant prolongation of the lag phase was measured (60.4±10.6sec vs basal 38.4±17sec), whereas the maximal aggregation was not impaired (67.9±21.4% vs basal 85.5±5.8%). Compared to previous reports, these results confirmed an impairment of collagen induced aggregation, but at these concentrations only the lag phase was affected. III) Five patients displayed a significant improvement of the aggregation by 2 uM (91.25±5.26% vs basal 39.3±24.62%) and 4 uM (91±2.83% vs basal 65.42±19.43%) ADP after initiation of ibrutinib treatment. IV) vWF antigen and ristocetin cofactor activity were measured in 3 patients. In all patients vWF levels were higher at the onset of the disease (169±38%) and reduced up to normal values under Ibrutinib treatment (111.4±47%). Ibrutinib treatment in LLC patients causes a mild bleeding phenotype most probably due to platelet dysfunction. In this study, collagen induced aggregation resulted impaired, whereas the aggregation by PAR1-AP, ristocetin and arachidonic acid was not affected. On the contrary, the aggregation by ADP was improved upon ibrutinib treatment. The levels of vonWillebrand factor are significantly higher in LLC patients before treatment and were normalized by ibrutinib.