Dr Shadman on Ongoing Questions Surrounding Zanubrutinib Plus Venetoclax in Frontline CLL/SLL

"With longer follow-up, it would be interesting to see how long it takes for patients to get to these deep remissions. This study used a strict and comprehensive MRD assessment, so we may learn a lot about [this]."

Mazyar Shadman, MD, MPH, Innovators Network Endowed Chair, associate professor, Clinical Research Division, Fred Hutchinson Cancer Center; associate professor, Medical Oncology Division, University of Washington School of Medicine, highlighted future research directions and unresolved questions regarding the combination of zanubrutinib (Brukinsa) and venetoclax (Venclexta) as frontline therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), based on findings from arm D of the trial.

Data presented at the 2025 ASCO Annual Meeting showed that, at a median follow-up of 31.2 months (range, 0.4-58.0), the overall response rate (ORR) in this arm was 97.4% (n = 114), supporting the feasibility of this all-oral, chemotherapy-free regimen. Shadman noted that the combination regimen is both efficacious and well tolerated, offering a potentially practice-changing approach for treatment-naive patients with CLL/SLL. However, several key questions remain, particularly regarding the optimal duration of therapy.

Among patients with TP53 abnormalities, the best undetectable measurable residual disease (uMRD) rates were comparable to those with normal TP53, though responses took longer to deepen. In this subgroup, uMRD rates improved from 21% to 49% with nearly 1 additional year of therapy, ultimately reaching 59%. This delayed kinetics of MRD conversion underscores the need for longer follow-up to determine whether extended therapy improves durability of remission and clinical outcomes.

Shadman emphasized the importance of continued MRD monitoring using rigorous and standardized assessment methods, which may help refine response-adapted treatment strategies. Longitudinal data will also be critical in understanding relapse patterns and treatment-free intervals, especially in high-risk genomic subsets. Additionally, the study raises questions about the potential for therapy discontinuation based on sustained uMRD, as well as how best to personalize treatment in the context of evolving resistance mechanisms or minimal residual disease dynamics.

Collectively, these findings suggest that zanubrutinib plus venetoclax represents a promising therapeutic platform in CLL/SLL, with ongoing studies poised to further define its role and optimize its implementation across molecular risk groups.