SEQUOIA's 5 Year Outcomes Reinforce Zanubrutinib as a Preferred Frontline Therapy for Untreated CLL/SLL

High-risk patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) experienced a benefit in progression-free survival (PFS) when treated with zanubrutinib compared with bendamustine plus rituximab (BR), according to a 5-year review of the SEQUOIA trial. The findings were published in the Journal of Clinical Oncology and presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. Zanubrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor, which targets the BTK protein and interferes with B-cell signaling pathways.

This phase 3, open-label trial enrolled 479 people across North America, Europe, and the Asia-Pacific region. Researchers randomly assigned 241 patients without the 17p deletion  to receive zanubrutinib 160 mg orally twice daily in 28-day cycles until disease progression occurred or patients could not tolerate adverse effects. The other arm (238 patients) received BR  intravenously for six cycles. Both groups had similar demographic characteristics in age range and sex. Sixty-four patients in the zanubrutinib arm and 56 in the BR arm were aged 75 years or older. About half of each group had an unmutated immunoglobulin heavy-chain variable region gene (IGHV), which can affect survival time and prognosis.

The most common adverse event was infection of any grade, experienced by 79.6% of patients in the zanubrutinib arm and 65.6% in the BR arm. Approximately half (52.1%) of patients in the zanubrutinib arm experienced bleeding, although this group had less neutropenia (17.1% vs 56.8%), which is critical in reducing the risk of or mitigating infection. Only 13.2% in the BR arm experienced bleeding. Second primary malignancies occurred in both groups (zanubrutinib, 23.8%; BR, 15%), with skin cancer being the most common (zanubrutinib, 12.9%; BR, 8.8%).

At around the 5-year mark (61.2 months), 77 patients in the zanubrutinib arm of the study dropped out either due to disease progression or intolerance to adverse effects. Neither group reached median overall survival. After 5 years, approximately 85.8% of patients treated with zanubrutinib and 85.0% of those treated with BR were still alive.

Zanubrutinib appears to be a favorable treatment for patients with CLL and SLL who have not been previously treated for hematologic malignancies. Larger studies will further inform the efficacy and safety of this treatment option, which appears to be promising.