Redefining Fitness in Chronic Lymphocytic Leukemia: A Treatment-Specific Framework forthe Targeted Therapy Era.

BACKGROUND: Therapeutic advances in chronic lymphocytic leukaemia (CLL) have made treatment selection far more nuanced than in the chemoimmunotherapy era. Patients now have access to two principal therapeutic strategies: continuous therapy with Bruton's tyrosine kinase inhibitors (BTKi) or fixed-duration regimens combining venetoclax with CD20 monoclonal antibodies and/or BTKis. These strategies carry fundamentally different safety profiles, monitoring requirements, and logistical demands, necessitating a treatment-specific approach to fitness assessment. OBJECTIVE: To synthesise current evidence and propose a practical, treatment-specific fitness assessment framework for patients with CLL, enabling physicians to match patient characteristics to the most appropriate targeted therapy. METHODS: Narrative review of the literature from PubMed, Scopus, and Embase. Landmark randomised controlled trials, contemporary expert opinion papers, and current guidelines from ESMO, ASCO, and ESC were reviewed. RESULTS: Cardiovascular comorbidity is the dominant fitness determinant for continuous BTKi therapy; renal function, tumour burden, and social support for hospital visits are critical for venetoclax-based fixed-duration regimens. The landmark phase 3 CLL17 trial (N Engl J Med, 2026) demonstrated that fixed-duration venetoclax-obinutuzumab and venetoclax-ibrutinib are non-inferior to continuous ibrutinib, with superior rates of undetectable minimal residual disease and lower treatment discontinuation, particularly in older patients. Frailty, reconceptualised as lower resilience, is dynamic and may improve during targeted therapy. Geriatric screening tools (G8, VES-13, GAH) and the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA-CFS) are available instruments for structured pre-treatment screening; however, no single tool has been prospectively validated for outcome prediction specifically with BTKi or BCL-2 inhibitor therapy, representing an important evidence gap. CONCLUSION: A treatment-specific, individualised fitness assessment - rather than an age-based or aggregate comorbidity score - is the appropriate framework for CLL in the targeted therapy era. Most patients, including those with lower resilience, are candidates for targeted therapy; the clinical imperative is to match each patient to the treatment best suited to their specific fitness profile.