The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

Abstract

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKis are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib was the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies have evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in early-phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, and drug–drug interactions associated with the treatment of CLL with BTK inhibitors and examines their further implications.

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

“…Three irreversible covalent BTKis, viz. ibrutinib, acalabrutinib, and zanubrutinib, have been approved for the treatment of lymphoid malignancies [ 6 ]. In addition, ibrutinib has been approved for the treatment of chronic GVHD.…”

“…Of the three, ibrutinib is the most potent BTK inhibitor, followed by zanubrutinib and acalabrutinib, while acalabrutinib is the most selective, followed by zanubrutinib and ibrutinib [ 16 , 17 ]. Recently, several irreversible BTKis have been developed and are under clinical investigation ( Table 1 ) [ 6 , 18 ]. These drugs inhibit BTK activity by irreversible covalent binding with high affinity to the same cysteine 481 in BTK as ibrutinib.…”

“…BTK inhibitors have a specific safety profile that requires monitoring and management. Indeed, the most common reason for treatment discontinuation is toxicity, with BTKi-specific adverse events (AEs) including atrial fibrillation (AF), bleeding events, arthralgias, rash, diarrhea, and cytopenias [ 6 ]. Acalabrutinib and zanubrutinib have less off-target activity than ibrutinib and are better tolerated.…”

“…Acalabrutinib and zanubrutinib have less off-target activity than ibrutinib and are better tolerated. The most common AEs are headaches, observed in patients treated with acalabrutinib, and neutropenia and infections, in patients treated with zanubrutinib [ 6 , 143 ]. Patients treated with BTKis are immunocompromised and have a high risk of infections, which develop in more than 50% of patients [ 143 ].…”

“…BTKis can affect autoimmune diseases involving B cells and non-B cells through B-cell receptor, Fc receptor, and RANK receptor signaling. Therefore, BTK is currently being investigated as a promising target for the treatment of immunological disorders in addition to B-cell hematological malignancies [ 5 , 6 ]. BTK inhibitors have been investigated in various autoimmune disorders, including autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), multiple sclerosis (MS), atopic dermatitis (AD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s disease (SD), multiple sclerosis (MS), and pemphigus vulgaris (PV).…”