Abstract
Background: Modern therapeutics in use for chronic lymphocytic leukemia (CLL), including covalent BTK inhibitors (cBTKi), time-limited (TL) BCL2 inhibitor (BCL2i) regimens, non-covalent BTKi (ncBTKi), and CAR-T cell therapy, have transformed care across multiple lines of therapy (LoT). Using targeted regimens for frontline management of CLL increases the complexity of subsequent clinical decision-making in relapsed/refractory (R/R) disease, particularly when confronting therapeutic intolerance, resistance, and rapid disease progression (Shadman M et al. Clin Lymphoma Myeloma Leuk. 2023;23:515-526; Jain N et al. Leuk Lymphoma. 2025;66:1400-1412). To assess modern treatment sequencing in a community setting, we developed a series of educational interventions designed to capture how community-based clinicians treated patients over multiple LoT and how these decisions were informed by practice-changing evidence.
Methods: A real-world outcomes initiative was conducted in collaboration with the American Oncology Network (AON), a national network of independent community oncology practices, with an initial anonymized electronic health record (EHR) data pull, followed by delivery of education and a follow-up EHR analysis to assess impact. Education consisted of two closed-network webinars attended by clinicians (N = 47) plus enduring content distributed across the AON network. Education addressed guideline updates, treatment sequencing, the challenges of BTKi-resistant CLL, and evidence supporting targeted and cellular therapies in later-line care. Learner feedback was collected post curriculum to contextualize changes in clinical behavior. To assess the impact of the initiative, EHR data were extracted via Meaningful Insights Biotech Analytics (MiBA; AI-powered data collection) from two independent patient cohorts (n = 100 each) receiving at least third-line (3L) CLL therapy before (December 2023-September 2024) and after (December 2024-May 2025) educational rollout. Age, gender, and genetic risk profile of patients was equivalent between the earlier and later EHR review cohorts.
Results: In both the earlier and later cohorts, cBTKi and BCL2i were the most commonly used options across all LoT; use of chemoimmunotherapy in later lines of care decreased in the post-intervention EHR review (from 14% to 9%), reflecting its displacement by targeted therapy. Use of ncBTKi nearly doubled following the intervention (14 to 25 treatment cycles), with the number of patients receiving the treatment increasing from eight to 12, and shifted toward earlier LoT, with five of 12 patients initiating ncBTKi as 2L therapy post intervention, compared with no use before 3L in the pre-intervention cohort. Mean LoT for ncBTKi use decreased from 4.26 (SD, 1.29) to 3.82 (SD, 2.16), indicating a measurable trend toward earlier integration (a finding that correlated with phase 3 evidence and guideline updates in CLL). Live webinar participation coupled with the broader dissemination of the curriculum appears to have influenced real-world practice across the AON network and confirmed shifts tied to changing evidence in CLL. Education delivered outside the AON network to the wider US treatment community (N = 239) also captured shifts in learners' clinical skills after exposure to the content; compared with baseline, more learners were willing to consider BTK resistance testing (57% vs 85%), address BTKi intolerance by sequencing to an appropriate strategy (74% vs 90%), and plan for the logistical complexities of CAR-T use (54% vs 89%).
Conclusions:This initiative provides evidence that education on sequential therapy in CLL developed in collaboration with community practice networks such as AON can capture shifts in clinical behavior reflected in treatment patterns. Network-wide dissemination of tailored content contributed to earlier and more confident adoption of ncBTKi, aligning with updated guidelines and clinical evidence. Wider treatment patterns (eg, 1L use of BTKi and BCL2i standards) also conformed with guideline recommendations and previously reported real-world evidence. These findings suggest that collaborative educational strategies, when combined with real-world data insights, may accelerate the uptake of novel therapies and provide meaningful resources to support community-based clinical decision-making.
