From covalent to reversible: the expanding role of BTK inhibitors in chronic lymphocytic leukemia

INTRODUCTION: BTK inhibitors are divided into two groups based on their binding mechanism: covalent, irreversible (cBTKis), and non-covalent, reversible BTK inhibitors (ncBTKis). The covalent BTK inhibitors approved for use in CLL include the first-generation inhibitor ibutinib and second-generation BTK inhibitors, acalabrutinib and zanubrutinib. Non-covalent, reversible BTKis bind reversibly to BTK and remain effective even if C481S mutations are present. AREAS COVERED: This paper reviews recent developments in the use of BTK inhibitors in the treatment of chronic lymphocytic leukemia (CLL). Google Scholar and PubMed were initially searched for articles in English, published from 2016 to Aril 2026. In addition, a manual search was performed of conference proceedings from the last five years of The American Society of Hematology, American Society of Clinical Oncology and the European Hematology Association. EXPERT OPINION: Covalent BTKis and ncBTKis revolutionized CLL treatment in the last decade Three cBTKis, ibrutinib, acalabrutinib and zanubrutinib, are approved by FDA for the treatment of CLL. The most advanced ncBTKis are pirtobrutinib and nemtabrutinib. Of these, only pirtobrutinib is recommended for patients refractory to cBTKis. However, further clinical trials focusing on dose optimization are needed, as well as combination studies with existing drugs and novel agents.