SEQUOIA Arm C—First-Line CLL Treatment Considerations

SEQUOIA Arm C—First-Line CLL Treatment Considerations

The SEQUOIA Arm C study represents the largest prospective frontline trial specifically designed for high-risk patients with CLL with TP53 disruption, providing crucial insights into continuous BTK inhibitor therapy outcomes. This cohort included 111 patients receiving zanubrutinib as continuous first-line therapy, with more than 40% also harboring TP53 mutations, offering comprehensive data beyond the limited patient numbers available from previous studies. The extended follow-up of more than 5 years demonstrates exceptional efficacy outcomes, with progression-free survival reaching 72% at 5 years, remarkably similar to outcomes observed in standard-risk patient populations without TP53 disruption in other trials.

The quality of responses continues to improve with extended treatment duration, challenging traditional expectations about BTK inhibitor therapy outcomes. Complete response rates have increased from initial reports to approximately 21% overall and 18% specifically in the high-risk cohort, demonstrating that response deepening occurs over time with continuous therapy. The overall response rate remains robust at 92%, whereas the safety profile shows no new concerning signals with prolonged follow-up. These findings establish zanubrutinib as a benchmark for continuous BTK inhibitor therapy in high-risk patients, with efficacy that appears to overcome the traditionally poor prognostic impact of TP53 disruption.

The unexpectedly deep responses achieved with continuous BTK inhibitor therapy raise important questions about treatment monitoring and potential future modifications to standard practice. Although minimal residual disease testing is not routinely performed in patients receiving continuous BTK inhibitors, the improving response rates suggest that some patients may achieve undetectable disease levels previously thought uncommon with this therapeutic approach. For patients who discontinue BTK inhibitor therapy after prolonged treatment, either by choice or necessity, the option exists to convert to time-limited approaches by adding venetoclax, although this represents off-label use. These evolving response patterns suggest that future study designs should incorporate minimal residual disease monitoring to better understand the depth of responses achievable with continuous BTK inhibition and potentially identify patients who might benefit from treatment modification or discontinuation strategies.