INTRODUCTION: Chronic lymphocytic leukemia (CLL) management has shifted from chemotherapy to targeted therapies like BTK and BCL-2 inhibitors, significantly improving patients' survival and quality of life. Current treatment guidelines often fail to fully address the real-world challenges of patient preferences, comorbidities, and logistical constraints. Consequently, a more personalized approach is essential to enhance decision-making and optimize treatment outcomes.

AREAS COVERED: This report delves into the challenges associated with frontline CLL therapy, emphasizing BTK inhibitors and venetoclax-based regimens. It examines patient stratification based on genetic markers, such as TP53 mutations and/or del(17p), the use of geriatric assessments for older patients, and the influence of comorbidities like cardiovascular disease and renal dysfunction. Furthermore, it highlights the need for a practical decision-making framework that integrates patient-specific considerations and addresses the limitations of existing treatment guidelines.

EXPERT OPINION: The proposed framework emphasizes a patient-centered approach that integrates clinical, genetic, and logistical factors to guide CLL treatment decisions. By addressing real-world challenges such as patient preferences for all-oral regimens and quality-of-life considerations, this approach aims to deliver truly personalized care. Future updates to CLL treatment guidelines should prioritize models that align with the unique needs and priorities of CLL patients.