Challenges associated with the use of Bruton's tyrosine kinase inhibitors: A life‑saving therapy for chronic lymphocytic leukemia (Review)

The adverse effects (AEs) of chemotherapy for chronic lymphocytic leukemia (CLL) can currently be avoided using Bruton's tyrosine kinase inhibitors (BTKis) and/or B‑cell leukemia/lymphoma 2 (BCL2) inhibitors, which have increased the efficacy of therapy and improved the prognosis of patients. The progression‑free survival and overall response rate of patients are significantly longer with the use of BTKis compared with the use of combination therapy. They are standard of care for use as frontline therapy and for the treatment of refractory or relapsed CLL. The use of BTKis is also indicated for patients with active disease and del17p, TP53 mutation, or unmutated immunoglobulin heavy chain genes, for their greater efficacy compared to chemotherapy + anti‑CD20 monoclonal antibodies or BCL2 inhibitors. Ibrutinib inhibits various specific immune receptors, exerts immunomodulatory effects, and some immune manifestations respond to ibrutinib. The main limitations associated with the use of BTKis are the following: The emergence of drug resistance, low complete remission rates, the need for an indefinite treatment duration and possible AEs. The use of ibrutinib is not recommended for patients with ventricular arrhythmias, and the use of any BTKi is not recommended for those with a history of heart failure. Patients who are intolerant to ibrutinib can receive a more selective BTKi. Patients who develop resistance to covalent BTKis can be treated with a non‑covalent BTKi or with a BCL2 inhibitor. BTKis can be administered in combination with an anti‑CD20 monoclonal antibody and/or a BCL2 inhibitor to reduce the proliferation of resistant clones, and sometimes to allow the shortening of the treatment duration. Further developments include Bruton's tyrosine kinase degraders, the combination of BTKis with immune checkpoint inhibitors or chimeric antigen receptor T‑cells, or drugs that target 6,7‑dimethoxy‑N‑(pyridin‑3‑yl)quinazolin‑4‑amine or actin cytoskeleton organization.