This review discusses current approaches to the treatment of chronic lymphocytic leukemia (CLL) with targeted agents, particularly Bruton tyrosine kinase (BTK) inhibitors and the Bcl-2 inhibitor venetoclax. An overview of the clinical use of the Bcl-2 inhibitor is provided, demonstrating its high efficacy both in first-line therapy and in relapsed disease, including in high-risk patient groups for whom conventional chemoimmunotherapy has shown limited benefit. Special attention is given to time-limited combination regimens in which venetoclax is combined with anti-CD20 monoclonal antibodies and/or BTK inhibitors. Such strategies achieve high rates of deep remissions and minimal residual disease (MRD)-negative status, enabling treatment discontinuation upon reaching defined biological endpoints. This approach not only reduces cumulative toxicity and improves patients’ quality of life but also decreases the economic burden on the healthcare system. Currently, novel approaches are under active development, including triple-agent combinations (venetoclax + BTK inhibitor + anti-CD20 antibody), which demonstrate even greater efficacy and the potential to provide durable progression-free survival. Another promising direction is the personalization of therapy through the use of MRD and circulating tumor DNA as dynamic biomarkers to guide optimal treatment duration. This strategy allows individualized management, avoidance of unnecessary drug exposure, and minimization of long-term complications. At the same time, the emergence of venetoclax resistance remains a relevant challenge, driving ongoing research into new combination strategies and innovative modalities, including immune-based approaches such as CAR-T cell therapy, as well as combinations of venetoclax with inhibitors of other signaling pathways. In summary, modern targeted therapy for CLL demonstrates high efficacy, shapes a new treatment paradigm, and opens perspectives for personalized strategies focused on deep remissions, controlled treatment duration, and improved long-term outcomes.

Keywords: review, targeted therapy of CLL,  Bruton tyrosine kinase inhibitors, venetoclax.