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      Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

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          Abstract

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          Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets. Since the launch of the first in class Btk-inhibitor (BTKi) ibrutinib in 2013, the list of indications and further drug candidates has expanded greatly. BTKi are not only used to treat patients with B-cell malignancies and in development against various autoimmune diseases, but they have been also proposed as novel antithrombotic drugs and been tested in patients with severe COVID-19. The number of BTKi approved or in clinical studies is rapidly increasing. Although X-linked agammaglobulinemia (XLA) patients with Btk deficiency do not show impaired hemostasis, bleeding events are frequently observed upon treatment with many but not all BTKi. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Moreover, specific platelet function tests in blood are described which will help to estimate the probability of bleeding side effects of newly developed BTKi.

          Abstract

          Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi.

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          Most cited references141

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          Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.

          Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.
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            Role of Bruton’s tyrosine kinase in B cells and malignancies

            Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies. In particular, the orally administered irreversible BTK inhibitor ibrutinib is associated with high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL), including patients with high-risk genetic lesions. Because ibrutinib is generally well tolerated and shows durable single-agent efficacy, it was rapidly approved for first-line treatment of patients with CLL in 2016. To date, evidence is accumulating for efficacy of ibrutinib in various other B cell malignancies. BTK inhibition has molecular effects beyond its classic role in BCR signaling. These involve B cell-intrinsic signaling pathways central to cellular survival, proliferation or retention in supportive lymphoid niches. Moreover, BTK functions in several myeloid cell populations representing important components of the tumor microenvironment. As a result, there is currently a considerable interest in BTK inhibition as an anti-cancer therapy, not only in B cell malignancies but also in solid tumors. Efficacy of BTK inhibition as a single agent therapy is strong, but resistance may develop, fueling the development of combination therapies that improve clinical responses. In this review, we discuss the role of BTK in B cell differentiation and B cell malignancies and highlight the importance of BTK inhibition in cancer therapy.
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              The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways.

              Antiplatelet treatment is of fundamental importance in combatting functions/dysfunction of platelets in the pathogenesis of cardiovascular and inflammatory diseases. Dysfunction of anucleate platelets is likely to be completely attributable to alterations in posttranslational modifications and protein expression. We therefore examined the proteome of platelets highly purified from fresh blood donations, using elaborate protocols to ensure negligible contamination by leukocytes, erythrocytes, and plasma. Using quantitative mass spectrometry, we created the first comprehensive and quantitative human platelet proteome, comprising almost 4000 unique proteins, estimated copy numbers for ∼ 3700 of those, and assessed intersubject (4 donors) as well as intrasubject (3 different blood samples from 1 donor) variations of the proteome. For the first time, our data allow for a systematic and weighted appraisal of protein networks and pathways in human platelets, and indicate the feasibility of differential and comprehensive proteome analyses from small blood donations. Because 85% of the platelet proteome shows no variation between healthy donors, this study represents the starting point for disease-oriented platelet proteomics. In the near future, comprehensive and quantitative comparisons between normal and well-defined dysfunctional platelets, or between platelets obtained from donors at various stages of chronic cardiovascular and inflammatory diseases will be feasible.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                04 March 2021
                March 2021
                : 13
                : 5
                : 1103
                Affiliations
                [1 ]Institute for Cardiovascular Prevention, Ludwig-Maximilians University (LMU), 80336 Munich, Germany; Philipp.von_Hundelshausen@ 123456med.uni-muenchen.de
                [2 ]German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
                Author notes
                [* ]Correspondence: wsiess@ 123456med.uni-muenchen.de ; Tel.: +49-89-4400-54351
                Author information
                https://orcid.org/0000-0001-7474-9370
                https://orcid.org/0000-0003-0698-6416
                Article
                cancers-13-01103
                10.3390/cancers13051103
                7961939
                33806595
                1b8aae78-7c87-4bef-9291-6bd94acb7cbd
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 11 February 2021
                : 03 March 2021
                Categories
                Review

                btk,platelet,btk inhibitor,bleeding,tec,ibrutinib,covalent btk inhibitor,reversible btk inhibitor,hemorrhage

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