SEQUOIA Arm D—Updated Data on Zanubrutinib Plus Venetoclax in Treatment-Naive Patients With CLL

SEQUOIA Arm D—Updated Data on Zanubrutinib Plus Venetoclax in Treatment-Naive Patients With CLL

The SEQUOIA Arm D study represents a significant advancement in understanding all-oral doublet therapy for treatment-naive patients with CLL, combining zanubrutinib with venetoclax without rituximab. This cohort is particularly noteworthy because more than half of the enrolled patients had TP53 gene abnormalities, either deletions or mutations, making it one of the largest studies to evaluate oral doublet therapy specifically in high-risk patient populations. The study design intentionally incorporated stringent stopping criteria to ensure treatment discontinuation only occurred under optimal conditions, requiring documented complete remission via bone marrow biopsy and 2 independent undetectable minimal residual disease assessments.

The study revealed important insights about treatment kinetics and efficacy across risk groups. The best undetectable minimal residual disease rate reached approximately 60% regardless of TP53 status, demonstrating comparable deep response rates between high-risk and standard-risk patients. However, a crucial finding was that high-risk patients required significantly longer treatment duration to achieve optimal responses. After cycle 16, only 21% of high-risk patients achieved undetectable minimal residual disease, but this percentage increased to 49% by cycle 28, ultimately reaching 59% at best response with a median follow-up of 39 months.

These results suggest that oral doublet therapy is feasible and effective across risk categories, but optimal treatment duration may need individualization based on genomic risk factors rather than fixed time frames. The study challenges the concept of standardized 1-year treatment duration, indicating that high-risk patients may benefit from extended therapy until achieving deeper responses. With current follow-up data showing only 1 progression event among 11 patients who met stopping criteria, the approach appears promising. However, longer follow-up is needed to fully assess durability of responses after treatment discontinuation. These data raise important questions about optimal duration strategies for oral doublet regimens and whether personalized treatment length based on response kinetics and risk stratification may be superior to fixed-duration approaches.