SEQUOIA Trial Long-Term Data Support Second-Generation BTK Inhibitors in CLL

Catherine Coombs, MD UCI Health | Daniel Ermann, MD University of Utah Health

Key Points

• Long-term follow-up from the SEQUOIA trial validated second-generation Bruton tyrosine kinase (BTK) inhibitors as durable frontline options in chronic lymphocytic leukemia (CLL).

• Noncovalent BTK inhibition, particularly pirtobrutinib, is emerging as a promising strategy that may expand into earlier lines.

• Combination therapy data from the CLL17 study reinforced current practice patterns rather than prompting an immediate treatment shift.

Six-year follow-up data from the SEQUOIA trial presented at the 2025 ASH Annual Meeting supported the long-term efficacy of BTK inhibition in CLL. During a discussion at the conference, Catherine Coombs, MD, of UCI Health, and Daniel Ermann, MD, of University of Utah Health, highlighted how these outcomes continue to refine the role of BTK inhibitors in the disease.

Although first-generation ibrutinib demonstrated durable efficacy, including progression-free survival of 8.9 years, its safety profile has led many clinicians to move away from routine use.

Attention has increasingly turned to second-generation BTK inhibitors, including zanubrutinib and acalabrutinib, in the frontline setting. In SEQUOIA, zanubrutinib showed durable disease control, with a large proportion of patients remaining progression free. Dr. Coombs also emphasized the advantage of zanubrutinib’s once-daily dosing.

The doctors further discussed growing interest in noncovalent BTK inhibitors, such as pirtobrutinib, and their potential movement into earlier lines of therapy based on data from the BRUIN-CLL-314 study. Results from CLL17, which examined fixed-duration combination therapy compared with continuous treatment for CLL, were not practice-changing but reinforced existing approaches and offered insight into how the field may evolve, Dr. Coombs said.