Stefano Molica
INTRODUCTION: Targeted therapies have improved both efficacy and safety profiles in chronic lymphocytic leukemia (CLL). Nevertheless, they present novel challenges in patient selection, particularly within aging populations wherein individuals aged over 80 years remain underrepresented in clinical trials.This review examines how frailty and biological aging intersect with CLL to inform risk stratification, treatment decisions, and supportive care. AREAS COVERED: We conducted a systematic literature search of PubMed and MEDLINE to identify studies including frail patients with CLL. Key findings indicate that frailty affects approximately 20% of patients with CLL. Alongside preexisting comorbidities, pre-malignant aging processes-such as clonal hematopoiesis of indeterminate potential (CHIP) and monoclonal B-cell lymphocytosis (MBL)-contribute to an underlying frailty predisposition, which is exacerbated by CLL. Comprehensive geriatric assessment (CGA) remains the gold standard for frailty evaluation, yet its implementation in routine clinical practice is limited by time constraints and resource demands. As frailty represents a dynamic state, initial assessments should be augmented by serial monitoring to inform adjustments in therapeutic intensity and supportive care. EXPERT OPINION: Personalized therapy planning that optimizes efficacy while mitigating toxicity in elderly/frail patients should be pursued. Future trials should ideally compare fixed-duration versus continuous therapy in well-characterized older or frail cohorts, with explicit objectives to enhance real-world applicability.