Redefining Fitness in Chronic Lymphocytic Leukaemia: A Treatment-Specific Framework for the Targeted Therapy Era

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 (BTKis) 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.

The objective of this article was 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. This was a 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. The two therapeutic paradigms impose distinct fitness demands. For continuous BTKi therapy, cardiovascular comorbidity is the dominant determinant, given the class-effect risk of atrial fibrillation and hypertension. For fixed-duration venetoclax-based regimens, the key determinants instead shift to renal function and tumour burden, which govern tumour lysis syndrome risk, and to the social support and hospital access required for intensive ramp-up monitoring. Building on this distinction, 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. Notably, frailty - better conceptualised as lower resilience - is dynamic rather than fixed and may improve during effective targeted therapy. Structured pre-treatment screening can be performed with validated instruments such as the G8, VES-13, GAH, and the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA-CFS); however, no single tool has yet been prospectively validated for outcome prediction specifically with BTKi or BCL-2 inhibitor therapy, and addressing this evidence gap is a priority for future research.

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.