Zanubrutinib Delivers 74% Progression-Free Survival at 6 Years in Frontline CLL

Zanubrutinib (Brukinsa, BeiGene) maintained durable progression-free survival (PFS) benefits in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including those with high-risk del(17p) disease, according to 6-year follow-up data from the phase 3 SEQUOIA trial (NCT03336333). The data reports 74% of patients treated with zanubrutinib remained progression-free at 72 months in comparison with 32% of patients treated with bendamustine (Bendeka, Teva and Eagle Pharmaceuticals) plus rituximab (Rituxan, Genentech) (BR).¹

Constantine Tam, MD, and colleagues presented these findings at the 2025 American Society of Hematology (ASH) Annual Meeting. This data progressively reinforces zanubrutinib’s role as a frontline standard of care in CLL.¹

Zanubrutinib and Its Role in CLL

Zanubrutinib is a next-generation covalent Bruton tyrosine kinase (BTK) inhibitor designed to provide more selective BTK inhibition with fewer off-target effects compared with earlier agents such as ibrutinib. The treatment landscape is for CLL is rapidly transforming due to BTK inhibitors through interrupting B-cell receptor signaling pathways critical for malignant B-cell survival and proliferation.²

Patients with del(17p), a chromosomal deletion associated with the dysfunction of TP53, has historically undergone poor outcomes with chemoimmunotherapy and frequently had survival measured in only a few years following treatment initiation.³ Along with the development of targeted therapies such as zanubrutinib, the expectations for these high-risk patients were significantly altered. Zanubrutinib has also shown to improve PFS in comparison with BR and to demonstrate superiority over ibrutinib in relapsed or refractory CLL in the ALPINE trial (NCT03734016) according to prior data.^4,5

BTK is currently listed as inhibitor-based regimens among preferred frontline treatment options for CLL/SLL, particularly for those with high-risk molecular features such as del(17p) or TP53 mutation, according the The National Comprehensive Cancer Network (NCCN).⁶

SEQUOIA Trial Study Design

Zanubrutinib was evaluated through the phase 3 SEQUOIA trial in treatment-naïve CLL/SLL across multiple treatment arms. Patients without del(17p) were randomized to receive continuous zanubrutinib monotherapy or 6 cycles of BR. Patients with del(17p) were enrolled into a nonrandomized cohort receiving zanubrutinib monotherapy because chemoimmunotherapy is generally considered inadequate for this high-risk population.¹

The trial participants were randomly assigned to receive either zanubrutinib (n = 241) and or BR (n = 238). The median follow-up reached about 73 months, which represents one of the longest follow-up periods currently available for frontline BTK inhibitor therapy in CLL.¹

Key Efficacy Findings

The data observed sustained superiority for zanubrutinib over BR across multiple clinical end points. An estimate of 72-month PFS rates were approximately 74% with zanubrutinib compared with 32% for BR, which translates to a 72% reduction in the risk of disease progression or death. The patients receiving zanubrutinib also required fewer subsequent therapies, with only 27 patients initiating additional treatment compared with 84 patients in the BR arm, including crossover participants.¹

The authors noted that outcomes remained durable among patients with del(17p). In the high-risk cohort, an estimation of 72-month PFS was 64%, while 83% of patients had not yet required subsequent treatment. Despite the historically poor prognosis associated with del(17p), the overall survival rates also remained favorable.¹

The safety profile remained generally consistent with prior BTK inhibitor experience. Rates of atrial fibrillation, hypertension, and infections were comparable between zanubrutinib and BR when adjusted for exposure, although zanubrutinib was associated with higher rates of hemorrhage and major hemorrhage. Conversely, BR demonstrated higher rates of neutropenia. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 72% of zanubrutinib-treated patients and 74% of BR-treated patients.¹

The data from the SEQUOIA trial further validates zanubrutinib as an effective frontline option capable of producing durable long-term responses, even in patients who historically faced limited therapeutic success.¹

REFERENCES

1. Tam C, Munir T, Robak T, et al. Sustained efficacy of zanubrutinib (zanu) vs bendamustine + rituximab (BR) in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN SLL/CLL) and continued favorable survival in non-randomized patients with del(17p): 6-year follow-up in the phase 3 SEQUOIA study. Blood. 2025;146(Supplement 1):2129. doi:10.1182/blood-2025-2129

2. BRUKINSA (zanubrutinib) prescribing information. BRUKINSA Official Website. Accessed May 15th, 2026. https://www.brukinsa.com/

3. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910-1916. doi:10.1056/NEJM200012283432602

4. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-5

5. Hillmen P, Brown JR, Eichhorst BF, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020;16(10):517-523. doi:10.2217/fon-2019-0844

6. NCCN Guidelines for CLL/SLL. Accessed May 15th, 2026. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf