A Value-Based Framework for CLL Care: Results of a Scoping Review

Background: Evaluating multidimensional value in chronic lymphocytic leukemia (CLL) is complicated by distinct endpoint hierarchies, patient heterogeneity, therapeutic resistance mechanisms, and healthcare costs. Consequently, addressing these multifaceted aspects of CLL management remains a significant challenge. This scoping review integrates comparative clinical evidence, surrogate endpoints, and health-economic data to formulate a value-based framework for personalized therapeutic decision-making. Methods: A literature search was conducted across PubMed/MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov from inception through June 2026. Studies were independently screened and extracted by two reviewers (S.M. and D.A.). Methodological quality and risk of bias were evaluated narratively across phase III randomized controlled trials, real-world cohorts, and economic models. Results: This scoping review evaluated 65 core publications that met stringent eligibility criteria, supplemented by 22 secondary contextual references. Findings demonstrate that continuous covalent Bruton tyrosine kinase inhibitor (BTKi) therapy provides sustained disease control, with a median progression-free survival (PFS) of up to 8.9 years in the RESONATE-2 trial, albeit at the cost of persistent low-grade toxicities and long-term financial burden. Conversely, fixed-duration, venetoclax-based regimens induce deep and durable remissions (median PFS of 104.9 months in IGHV-mutated patients in the 9-year follow-up of the CLL14 trial). By enabling treatment-free intervals, fixed-duration strategies mitigate cumulative toxicity, lower long-term healthcare costs (including a 67% post-treatment cost reduction in real-world Medicare analyses), and improve health-related quality of life (HRQoL). Furthermore, methodological considerations—such as surrogate endpoints (e.g., undetectable measurable residual disease [uMRD] and time to next treatment [TTNT]), which remain susceptible to immortal time bias, alongside monitoring frequency—are paramount in the comparative assessment of CLL trials. In clinical practice, incorporating the ESMO Magnitude of Clinical Benefit Scale for Hematological Malignancies (ESMO-MCBS:H v1.0) supports structured, patient-centered selection of therapy. Conclusions: Deciphering CLL management requires synthesizing genomic risk profiles (TP53 aberrancy, IGHV mutational status), patient physiological reserve, adverse event profiles, and resource utilization. We propose the GUIDE framework (Genetics, Unique host factors, Individual preferences, Delivery logistics, Expectations) as a conceptual model to operationalize value-based care in routine clinical practice.