Background and Significance:

The Veterans Health Administration (VA), the largest integrated healthcare system in the United States, is enriched for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) due to alignment in demographics, including older age and male sex, and risk associated with toxic military exposures. Over the last decade, treatment of CLL/SLL in VA has increasingly favored the use of covalent oral inhibitors of Bruton's tyrosine kinase (BTKi) over alternatives (Frei CR et al, 2024; Ma H et al, 2024). This pattern likely reflects characteristics of the VA population that skew toward a higher frequency of comorbidities and rurality plus lower social support and financial means. Additionally, clinical studies in hematologic malignancies under-represent patients with these barriers, including from the VA.

BTKi are effective and convenient and are administered for CLL/SLL until intolerance or disease progression; median time on therapy is approximately 10 years in the frontline and 5 years in relapsed/refractory (R/R) settings. Extended periods on BTKi lead to accumulation of adverse events and costs. Several studies have investigated the combination of BTKi with venetoclax (ven) with the goal of an all-oral, fixed-duration treatment for treatment-naïve CLL/SLL with promising results (Tam CS et al, 2022; Brown JR et al, 2025; Shadman M et al, 2025), but they are not applicable to CLL/SLL patients already receiving therapy with BTKi.

Study Design and Methods:

Benefit VA is a randomized, multicenter, phase II study of BTKi with or without ven addition for CLL/SLL (NCT06520098). Key eligibility includes ECOG PS of 0-2, low TLS risk group, and > 6 months of BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) without evidence of progression. In addition to the traditional research sites (Kansas City VA, Durham VA, San Francisco VA, and Puget Sound VA), any of the 122 VA facilities affiliated with VA National TeleOncology (NTO) can enroll subjects through a decentralized clinical trial implementation with the VA Cancer Clinical Research Service. A total of 100 patients will be randomized 1:1 to either continue BTKi indefinitely (control) or add ven for 1 year and then discontinue both agents (experimental). Standard ven ramp-up and strategies for mitigation of tumor lysis are incorporated. Protocol-defined clinical assessments include cross sectional imaging at screening, 6, and 12 months on study, bone marrow assessment required to confirm complete response (CR), and flow cytometry for minimal residual disease (MRD). Measures of patient reported outcomes (PROs) will be collected at regular intervals using FACIT-Fatigue, QLQ-C30, QLQ-CLL17, and FACT-COST questionnaires.

The primary endpoint is CR rate at 1-year per international workshop on CLL criteria; secondary endpoints include safety, 2-year progression-free and overall survival, overall response rate, undetectable MRD at 1 year, and PROs. Subjects will be stratified by BTKi line of therapy (frontline vs R/R) and presence of TP53aberration. We hypothesize that ven consolidation will increase CR rate and result in long-term improvement of PROs. Fifty patients per arm provides 90% power to detect an increase in the CR rate from 10% on BTKi to 40% on BTKi + ven with 2-sided Type I error of 5%. Comparison of secondary outcomes between treatment arms will be based on interval estimation of differences.

Benefit VA is the first randomized, prospective, multisite trial in CLL/SLL to be conducted exclusively within VA. Decentralized clinical trial access through NTO will significantly extend the reach of this trial to Veterans from underserved regions, including rural and remote sites. The pragmatic aspects will maximize interest and eligibility. Adding ven for patients with CLL/SLL responding to BTKi has the potential to improve clinical outcomes and PROs, while minimizing the financial impact on patients and healthcare systems. Benefit VA is supported by VA Clinical Merit Award CX002685-01A1 and AbbVie.

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2025
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