Metabolic and toxicological considerations of Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma

ABSTRACT

Introduction

Bruton tyrosine kinase inhibitors (BTKi) have been used for the management of human diseases since the approval of the first-in class agent, ibrutinib, by the Food and Drug Administration in 2013 for the treatment of patients with mantle cell lymphoma (MCL). Ibrutinib is a covalent inhibitor along with second-class BTKis: acalabrutinib and zanubrutinib. These well-tolerated agents have transformed the treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). A new class of these inhibitors, non-covalent, might become an answer to the emerging resistance by avoiding the sustained contact with the kinase binding domain.

Areas covered

This article examines the chemical composition, mechanism of action, metabolic characteristics, and potential toxicity of inhibitors targeting Bruton tyrosine kinase. A comprehensive search was conducted across English-language articles in PubMed, Web of Science, and Google Scholar.

Expert opinion

Bruton tyrosine kinase inhibitors have greatly enhanced the armamentarium against lymphoid malignancies including CLL/SLL. Their future lies in the choice of appropriate patients who will benefit from the treatment without significant adverse reaction. Combination chemotherapy-free fixed-duration regimens with targeted molecules will allow for MRD-driven approach in patients with CLL/SLL in the near future.

KEYWORDS:

• Acalabrutinib
• Bruton tyrosine kinase inhibitor
• cardiotoxicity
• chronic lymphocytic leukemia
• ibrutinib
• pirtobrutinib
• zanubrutinib

Article highlights

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by the accumulation of clonal lymphocytes in the blood, bone marrow, and lymphoid tissues.

• Bruton’s tyrosine kinase (BTK) is an intracellular non-receptor tyrosine kinase that is a major source of pathogenic signaling in CLL/SLL.

• Ibrutinib is a first-in-class irreversible, covalent BTK inhibitor approved for use in CLL/SLL.

• Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce adverse effects.

• In randomized trials, acalabrutinib and zanubrutinib had lower toxicity rates compared with ibrutinib, particularly atrial fibrillation and bleeding.

• Pirtobrutinib is a novel oral, noncovalent, and selective BTK inhibitor that does not require binding at the C481 spot and is active in CLL/SLL patients refractory to covalent BTK inhibitors.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We thank the patients who participated in our clinical trials and their supportive families, as well as the investigators and clinical research staff from our center.

Additional information

Funding

This paper was not funded.