Approved and emerging Bruton's tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia

Introduction The Bruton's tyrosine kinase (BTK) pathway has proven to be an effective and transformative therapeutic target in the treatment of chronic lymphocytic leukemia (CLL), fueling the growth of BTK inhibitors (BTKis) and landmark approval of first-generation BTKi, ibrutinib. However, ibrutinib's side effect profile left an unmet need for BTKis with improved tolerability, thus spurring the subsequent development of second-generation acalabrutinib and zanubrutinib. The treatment landscape continues to evolve with studies using BTKi combination therapies, notably with venetoclax, with and without an anti-CD20 monoclonal antibody as well as third-generation BTKis aimed to overcome BTKi resistance. Areas covered This article details the current literature highlighting the efficacy, toxicities, and potential therapeutic combinations of approved and preclinical BTKis. Expert opinion BTKis have signaled the start of a new treatment paradigm in CLL and improved clinical outcomes, especially for patients with high-risk disease. However, drug resistance, low CR rates, and indefinite treatment necessitate the development of novel BTKis and fixed duration combination therapy. The results from recently completed and ongoing clinical trials are eagerly awaited with the potential promise of reduced treatment durations and financial burden while achieving durable remissions.

Automated summary

BTK inhibitors have revolutionized the treatment of CLL and improved clinical outcomes. However, the development of novel BTK inhibitors and fixed duration combination therapy is necessary to overcome drug resistance and achieve better response rates.