Chronic lymphocytic leukemia: recent advances and emerging therapeutic strategies

Chronic lymphocytic leukemia (CLL) management has evolved into a precision-medicine paradigm, with genetic risk factors such as TP53 and IGHV status serving as key determinants of frontline treatment selection. The therapeutic landscape has expanded to include fixed-duration options alongside established continuous regimens. This expansion has enabled personalized management strategies incorporating measurable residual disease-guided treatment approaches aimed at achieving deeper responses while minimizing long-term toxicity and resistance. In a relapsed/refractory setting, treatment selection must be guided by prior treatment exposure, identified molecular mechanisms of resistance, and the availability of novel agents. In this review, we have synthesized the latest clinical evidence and international guidelines to provide an updated, evidence-based algorithm for the diagnosis and management of CLL. Furthermore, we examined the clinical efficacy reported in pivotal trials involving patients with relapsed/refractory CLL and discuss the potential of next-generation therapies, including non-covalent Bruton tyrosine kinase (BTK) inhibitors, BTK degraders, and cellular immunotherapies, to expand treatment options for high-risk patients. Finally, we addressed the clinical challenges of Richter’s transformation, emphasizing the importance of clonality assessment and the urgent need for further clinical trials and innovative therapeutic approaches to improve long-term outcomes in this patient population.