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

SIMPLE SUMMARY: 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.