BTKi and BCL2i Therapies Revolutionize Chronic Lymphocytic Leukemia Treatment Strategies

Chronic Lymphocytic Leukemia (CLL) remains a significant hematological malignancy, historically managed with less targeted approaches. The advent of novel targeted agents, specifically Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2is), has profoundly reshaped the therapeutic landscape. These inhibitors target crucial survival pathways in CLL cells, offering more effective and tolerable options than conventional chemotherapy. Despite these advancements, challenges persist regarding treatment resistance, optimal combination strategies, and personalized patient management, necessitating a comprehensive review of current practices.

This comprehensive review synthesizes the current literature on chronic lymphocytic leukemia (CLL) treatment. It focuses on contemporary frontline and relapsed/refractory therapeutic strategies, specifically examining the impact of Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2is). The authors analyzed studies pertaining to molecular risk stratification, combination and triplet regimens, measurable residual disease (MRD)-guided therapy, and time-limited treatment approaches. Additionally, the review explores how genomic complexity, prior therapies, and sociodemographic factors influence disease progression, treatment resistance, and clinical outcomes in CLL patients.

This review highlights that targeted agents, particularly Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors (BCL2is), have fundamentally transformed chronic lymphocytic leukemia (CLL) therapy. It emphasizes the critical role of molecular risk stratification in guiding treatment decisions, moving beyond traditional chemotherapy. The authors found that combination and triplet regimens are increasingly explored to enhance efficacy and overcome resistance, with a growing focus on measurable residual disease (MRD)-guided and time-limited treatment strategies to achieve deeper, more durable remissions. > The review underscores that genomic complexity, prior treatment history, and even sociodemographic factors significantly influence disease progression, the development of treatment resistance, and overall clinical outcomes in CLL patients. Furthermore, the synthesis indicates that understanding these influencing factors is crucial for personalizing therapy and improving long-term patient prognosis, particularly in relapsed/refractory settings where resistance mechanisms to BTKis and BCL2is are a major concern. The evolving landscape necessitates continuous adaptation of therapeutic strategies to optimize patient care.