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

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.

Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Targeting Pathomechanisms with Bruton Tyrosine Kinase Inhibitors

“…Approved BTKi are now widely used as standard drugs for the long term oral therapy of several B-cell malignancies with a remarkable safety profile (14) and exerted an apparently protective effect in case of coincident symptomatic COVID-19 (15,16). Of note the platelet-inhibitory concentrations of the approved BTKi ibrutinib, acalabrutinib, zanubrutinib and tirabrutinib in blood were much lower than the drug levels reached in patients treated with oral standard doses for B-cell disorders (13,17). Furthermore, intake of a single dose of ibrutinib (280 mg) by human healthy volunteers rapidly blocked (3 hours after intake) platelet aggregation and secretion on maximal stimulation of FcγRIIA on platelets in blood ex vivo (13).…”

Targeting Bruton’s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies

“…Following the production of first-line BTKi, such as ibrutinib, second-generation (mostly covalent) inhibitors with higher specificity, lower side effects, and their own unique properties were developed (Estupiñán et al, 2021;von Hundelshausen and Siess, 2021). Next to these small-molecule inhibitors, other types of inhibitors are being investigated, such as small-interfering RNAs targeting BTK production (Zhao et al, 2019).…”

“…Ibrutinib-related adverse events, including atrial fibrillation and hemorrhage, were not observed during treatment with acalabrutinib, which has improved specificity (Byrd et al, 2016). To prevent adverse events, BTKi with higher specificity are currently being developed and tested in the clinic (Estupiñán et al, 2021;von Hundelshausen and Siess, 2021). Effectiveness of strategies using combinational therapies should also be explored.…”

The Role of CLEC-2 and Its Ligands in Thromboinflammation

“…Bruton’s tyrosine kinase (Btk) is an important non-receptor signaling kinase involved in platelet aggregation. Several Btk-dependent platelet aggregation pathways such as GPVI-activation by low collagen concentrations, FcgammaRIIA (an ITAM receptor) activation by cross-linking and VWF-stimulated GPIb activation are inhibited in human blood by low nanomolar IC50 concentrations of Btk-inhibitors ( 87 ). Besides, Btk is essential for platelet CLEC-2 ( 88 ).…”