Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
With five years of follow-up, zanubrutinib continues to provide greater progression-free survival in treatment-naïve patients with CLL / SLL compared with chemoimmunotherapy. It also continues to be well-tolerated, with no new safety signals emerging.
Who Performed the Research and Where Was it Presented:
Dr. Mazyar Shadman from Fred Hutchinson Cancer Research Center and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
Ibrutinib was the first Bruton tyrosine kinase inhibitor (BTKi) to be used for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). It significantly improved patient outcomes compared to chemoimmunotherapy, the previous standard of care, and revolutionized the treatment of CLL / SLL. However, ibrutinib also has some cardiovascular side effects of concern, including atrial fibrillation (abnormal heart rhythm) and high blood pressure. This led to the development of next-generation BTKi, such as acalabrutinib and zanubrutinib, which improved the safety profile of BTKi while maintaining efficacy. Zanubrutinib received FDA approval for the treatment of CLL / SLL in 2023 based on data from the SEQUOIA study, which showed efficacy in previously untreated CLL / SLL, and the ALPINE study which showed efficacy in relapsed / refractory CLL / SLL. Here, we get an update on the long-term safety and efficacy of zanubrutinib after five years of follow-up in the SEQUOIA study.
Methods and Participants:
The SEQUOIA study is a Phase 3 clinical trial comparing zanubrutinib vs. bendamustine plus rituximab (chemoimmunotherapy) in patients with treatment-naïve CLL / SLL without deletion 17p. Patients with deletion 17p were excluded because they do not respond well to chemoimmunotherapy, and thus, it would be unethical to randomize them to bendamustine-rituximab. Zanubrutinib was given continuously until disease progression or intolerance.
Results:
- In total, 241 patients received zanubrutinib, and 238 received bendamustine-rituximab.
- With a median follow-up of 5 years (61 months), zanubrutinib remains superior to bendamustine-rituximab.
- Median progression-free survival was not reached in zanubrutinib-treated patients and was 44 months in bendamustine-rituximab-treated patients.
- The estimated 60-month progression-free survival rates were 76% for zanubrutinib and 40% for bendamustine-rituximab.
- The progression-free survival benefit with zanubrutinib was seen regardless of IGHV mutation status.
- Approximately 20% of zanubrutinib-treated patients have experienced complete remissions.
- Disease progression occurred in 12% of zanubrutinib-treated patients and 41% of bendamustine-rituximab treated patients.
- No new safety signals have been observed with longer follow-up, and the safety and tolerability remain similar to earlier reports.
- For zanubrutinib, the rate of atrial fibrillation was 7% (which is lower than or comparable to other BTKi), bleeding was seen in more than half of the subjects, and high blood pressure was noted in 23%.
- With the chemoimmunotherapy arm of bendamustine-rituximab, the rates of low platelets, neutrophils, and anemia were much higher than with zanubrutinib.
- Infections were common in both arms, but most were mild.
- Approximately 20% of zanubrutinib-treated patients discontinued treatment due to side effects.
Conclusions:
With five years of follow-up, zanubrutinib continues to provide greater progression-free survival in treatment-naïve patients with CLL / SLL compared with chemoimmunotherapy. It also continues to be well-tolerated, with no new safety signals emerging. Zanubrutinib was effective regardless of IGHV mutation status, and other arms of the SEQUOIA trial are evaluating the efficacy of zanubrutinib and zanubrutinib plus venetoclax in patients with deletion 17p.
While this is important research and this trial was started many years ago, it is now time to stop using bendamustine-rituximab as a comparator arm in clinical trials.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Sustained Superiority of Zanubrutinib vs Bendamustine + Rituximab in Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (TN CLL): 5-Year Follow-Up of Cohort 1 from the SEQUOIA Study
The full paper reporting these results is available here: Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA.
