Durable Frontline Benefit With Zanubrutinib: Long-Term Lessons From High-Risk CLL

Both Ian Flinn, MD, PhD; and Danielle Brander, MD, note that the 6-year follow-up reinforces what has increasingly become expected with modern Bruton tyrosine kinase (BTK) inhibitors: durable remissions, excellent progression-free survival, and consistent benefit across biologic risk groups.

Flinn highlights that zanubrutinib continues to demonstrate sustained disease control over time, including in patients with del(17p), a group historically associated with poor outcomes. Although he expresses some surprise at the durability of remissions observed, he also acknowledges that expectations for novel agents have risen as outcomes continue to improve year after year. These data further solidify BTK inhibition as a reliable long-term strategy in frontline chronic lymphocytic leukemia (CLL).

Brander underscores a unique strength of the SEQUOIA study: the inclusion of a large, dedicated cohort of more than 100 treatment-naive patients with del(17p). This robust sample allows for meaningful assessment of frontline outcomes in one of the highest-risk CLL populations rather than extrapolating from smaller subgroups or from relapsed/refractory disease studies. She emphasizes that outcomes in treatment-naive patients at high risk may differ significantly from those treated later in the disease course, reinforcing the value of these data.

The discussion returns to the importance of comprehensive biomarker testing. Although highly effective therapies such as zanubrutinib may perform well across risk groups, both experts agree that baseline prognostic testing remains essential. Biomarker data help guide expectations, inform decisions around continuous vs time-limited therapy, and provide critical context if complications such as resistance, transformation, or new symptoms arise. Overall, this segment reinforces the importance of long-term follow-up data and thoughtful risk assessment in optimizing frontline CLL management.