Efficacy and challenges involving combination therapies in CLL

•CLL is a multifaceted disease with risk stratification important in treatment.•Targeted therapies offer a new avenue of treating relapsed or refractory CLL.•Personalized monotherapy or in combination with Btk and BCL-2 inhibitors offer new approach.•Introduction of Btk degraders offers a new avenue of treatment in CLL to overcome mutation resistance. Chronic lymphocytic leukemia (CLL), a malignant tumour, is characterized by expansion of mature monoclonal B lymphocytes expressing CD23 and CD5 in secondary lymphocytic organs, blood, and bone marrow. Here, we provide an in-depth review of CLL, emphasizing its pathophysiology, cytogenic changes, and treatment strategies, particularly the efficacy and challenges of treatments, such as Bruton tyrosine kinase (BTK) inhibitors, B cell lymphoma 2 (BCL2) inhibitors, and phosphatidylinositol 3-kinase (PI3K) inhibitors, as well as the need to understand their role in managing disease progression, chemoresistance, and intolerance. In addition, we explore efficacy based on patient response and comparison between monotherapy and combination therapy. We also highlight the need for innovative strategies to overcome treatment resistance and enhance patient outcomes.