Background: Therapy with irreversible Bruton's tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) is associated with bleeding. Objectives: To propose the predictive markers of such bleeding, as well as mechanisms responsible for decreased bleeding at later therapy stages. Patients/Methods: We investigate platelet functional activity in 50 CLL and 16 MCL patients on ibrutinib using flow cytometry and light transmission aggregometry. Results: Prior to treatment, both patient groups had decreased platelet counts; impaired aggregation with adenosine diphosphate (ADP); and decreased binding of CD62P, PAC1, and annexin V upon stimulation. Bleeding in patients treated with ibrutinib was observed in 28 (56%) CLL patients, who had decreased aggregation with ADP and platelet count before therapy. Their platelet count on therapy did not change, platelet aggregation with ADP steadily improved, and aggregation with collagen first decreased and then increased in anticorrellation with bleeding. Bleeding in MCL was observed in 10 (62%) patients, who had decreased dense granule release before therapy. ADP and ristocetin induced platelet aggregation in ibrutinib-treated MCL patients increased on therapy, while collagen-induced aggregation evolved similarly to CLL patients. Conclusions: Our results suggest that ibrutinib-dependent bleeding in CLL patients involves three mechanisms: decreased platelet count (the most important discriminator between bleeding and non-bleeding patients), impaired platelet response to ADP caused by CLL, and inhibition by ibrutinib. Initially, ibrutinib shifts the balance to bleeding, but then it is restored because of the improved response to ADP. | 2673 DMITRIEVA ET Al.

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effectiveness of rituximab-based chemotherapy in first-line (treatment cohort 1), but failed to demonstrate a benefit in the second-line setting (treatment cohort 2; Table 1). Furthermore, no evidence was found that prior rituximab exposure was associated with the effectiveness of rituximab-based chemotherapy in second-line (treatment cohort 3). Covariates associated with inferior TFS in that particular cohort were age per one-year increase and first-line therapy with a backbone of purine analogues, as compared with a backbone of alkylating agents. Conversely, patients with a longer time to next treatment had better TFS. Summary/Conclusion:In this comprehensive, population-based study, the effectiveness of first-line treatment with rituximab-based chemotherapy was not objectivated in second-line treatment. The lack of effectiveness of rituximab-based chemotherapy in second-line could not be explained by previous rituximab exposure.

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