Background
Deletion 17p, written del(17p), is a high risk cytogenetic change in chronic lymphocytic leukemia, or CLL. Patients with del(17p) tend to do poorly with standard chemoimmunotherapy. For many of these patients, continuous targeted therapy is now the preferred approach to keep the disease under control. Zanubrutinib is a covalent Bruton tyrosine kinase (BTK) inhibitor, and it has been tested in several trials, including the phase 3 SEQUOIA trial zanubrutinib, which includes a dedicated group of treatment naive patients with centrally confirmed del(17p).
Study design, del(17p) cohort
SEQUOIA is a global, open label, phase 3 study in treatment naive CLL and SLL. The randomized portion compared zanubrutinib with bendamustine plus rituximab in patients without del(17p). Patients who did have del(17p) were put into a separate, single arm group and given zanubrutinib alone. This design reflects real clinical practice where chemoimmunotherapy is often not the best option for del(17p) disease. Zanubrutinib was taken continuously until the disease progressed or side effects became unacceptable. The study included regular checks for response, progression free survival, and safety.
Six year efficacy in del(17p)
Earlier reports from SEQUOIA showed high response rates and promising progression free survival in patients with del(17p). With about 72 months of follow up, those responses have remained durable for many patients. A sizable portion of the cohort remain free from progression at six years and overall survival remains in line with earlier updates. Because this group was not randomized, direct comparisons with other treatments need to be made carefully and usually rely on cross trial context and clinical judgment.
Putting SEQUOIA in a broader context
In addition to the SEQUOIA results, indirect comparisons have been done to help place zanubrutinib in the current treatment landscape. A recent matching adjusted indirect comparison, reported in Blood Advances, compared patients treated with zanubrutinib in SEQUOIA to patients who received acalabrutinib plus venetoclax in another study. After adjusting for differences in patient characteristics, zanubrutinib showed numerically better estimates of investigator assessed progression free survival in the matched groups. Network analyses have also suggested favorable relative outcomes for zanubrutinib compared with some other BTK based approaches, but these methods have limits. Indirect comparisons cannot replace randomized trials, and they can be affected by differences in how patients were selected, how outcomes were measured, and other factors. Still, these analyses offer useful context for clinicians when they consider SEQUOIA data along with other evidence on BTK inhibitors.
Clinical interpretation
For clinicians, the long lasting disease control seen in SEQUOIA is meaningful when choosing first line therapy for high risk patients. Keeping a durable first remission can influence choices about sequencing, monitoring, and how to manage treatment if the patient cannot tolerate therapy. The added context from indirect comparisons may help inform those choices, but it should be weighed alongside trial details, patient comorbidities, and patient preferences.
Safety and tolerability with long term use
Long term BTK inhibitor therapy requires a careful balance between benefit and side effects. In the del(17p) cohort, zanubrutinib’s safety profile aligns with what has been seen across the program. Common events with BTK inhibition include infections, low blood counts, bleeding, high blood pressure, and atrial arrhythmias. These events were tracked during follow up, and the extended observation period gives more practical information on ongoing risk management. Individual comorbidities and other drugs that a patient takes should guide monitoring and any dose adjustments.
Practical implications and future directions
The six year data support continuous BTK inhibition as a durable option for many patients with del(17p) CLL. At the same time, clinicians should plan individually. Decisions about switching to other targeted agents, timing further interventions, and long term supportive care will benefit from combining SEQUOIA results with real world experience and patient goals. Future reports with subgroup results, reasons for stopping therapy, and details on treatments given after progression will help refine which patients get the most benefit from zanubrutinib.
Where to find detailed results
For full numerical results, survival curves, and response rates, see the SEQUOIA 6 year abstract, poster, or related publications. The Blood Advances indirect comparison article listed below gives added context on how zanubrutinib compares, across studies, with some other BTK based strategies.
References
- https://beonemedaffairs.com/us/congress-resources/ash-2025/phase-3-sequoia-6-year-long-term-data-of-zanubrutinib-vs-bendamustine-plus-rituximab-in-tn-cll-sll/
- https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2025018536/566249/An-Indirect-Comparison-of-Zanubrutinib-vs
- https://pubmed.ncbi.nlm.nih.gov/41587482/
