Zanubrutinib for patients with previously untreated CLL/SLL: Insights from the SEQUOIA trial

During the Lymphoma Hub Steering Committee Meeting on April 20, 2026, key opinion leaders met to discuss results from the long-term follow-up of the phase III SEQUOIA trial (NCT03336333) evaluating zanubrutinib in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The session opened with a presentation by Jacob Soumerai and included a discussion featuring Gilles Salles, Ulrich Jäger, Sonali Smith, Martin Dreyling, Astrid Pavlovsky, Michael Dickinson, and Jennifer Crombie. 

During his presentation, Soumerai provided an overview of the rationale and design of the phase III SEQUOIA trial. SEQUOIA was conducted to evaluate zanubrutinib, a second-generation covalent Bruton’s tyrosine kinase inhibitor, in patients with treatment-naïve CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment, who had measurable disease by computed tomography/magnetic resonance imaging, and who were unsuitable for fludarabine + cyclophosphamide + rituximab.¹ Patients were allocated to one of four arms (Figure 1).^1,2 The primary endpoint was progression-free survival (PFS), and key secondary endpoints included overall response rate (ORR), overall survival (OS), undetectable measurable residual disease (in Arm D), and safety per Common Terminology Criteria for Adverse Events (CTCAE).^1,2 In his presentation, Soumerai went on to summarize the results from the SEQUOIA trial and provided key efficacy and safety data from long-term follow-up of Arms A, B, and C, as well as data from Arm D. The presentation was followed by a discussion in which the steering committee reviewed the results of the SEQUOIA trial, factors influencing the selection of fixed-duration vs continuous therapy, and the role of doublet vs triplet therapies.  

Key points 

• At a median follow-up of 72.8 months in Arms A and B, a sustained PFS benefit was demonstrated with zanubrutinib vs bendamustine + rituximab (BR; hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.20–0.38; p < 0.0001).¹  
• In Arm C, at a median follow-up of 76.7 months, the 72-month PFS rate was 64%.¹ 
• The 72-month OS rates in Arms A, B, and C were 84%, 80%, and 83%, respectively.¹  
• The ORRs were 98%, 89%, and 97%, with a complete response/complete response with incomplete count recovery (CR/CRi) in 24%, 24%, and 21% of patients in Arms A, B, and C, respectively.¹  
• At a median follow-up of 31.2 months, the median PFS with zanubrutinib + venetoclax in Arm D was not reached (NR), with a 24-month PFS rate of 92%.²  
• When stratified by del(17p)/TP53 mutational status, the 24-month PFS rates were similar.²  
• The median OS was NR, and the estimated 24-month OS rate was 96%.²  
• In Arm D, the ORR in the intention-to-treat (ITT) population was 97%, with 48% of patients achieving a CR/CRi; response rates were similar between patients with del(17p) and/or TP53 mutation (ORR, 99%; CR/CRi, 47%) and patients without del(17p) and TP53 mutation (ORR, 96%; CR/CRi, 49%).² 
• In Arm D, peripheral blood-undetectable measurable residual disease (PB-uMRD)-guided treatment duration was found to be feasible​. 
• The rate of PB-uMRD increased over time, with a median time to first PB-uMRD of 19.0 months in patients with TP53-aberrant disease and 11.0 months in those without.² 
• The best PB-uMRD rates were similar between the ITT population, patients with del(17p) and/or TP53 mutation, and those without del(17p) or TP53 mutation (59% vs 59% vs 60%).² 
• The safety profile of zanubrutinib was consistent with previous reports, with no new safety signals.¹ Similarly, the safety profile of zanubrutinib + venetoclax was manageable.² 
• Overall, the long-term follow-up results from Arms A, B, and C of the SEQUOIA trial continue to support the use of zanubrutinib as an effective first-line therapy for the treatment of patients with treatment-naïve CLL/SLL, including those with high-risk genetic features such as del(17p).¹  
• Similarly, results from Arm D demonstrated encouraging efficacy and a manageable safety profile for zanubrutinib + venetoclax in patients with treatment-naïve CLL/SLL, regardless of TP53 aberration status, with PB-uMRD-guided treatment duration demonstrating feasibility in this patient population.²  
• Together, the panel emphasized the importance of patient preference, the severity of adverse events, and mutational status when making treatment decisions.  

This educational resource is independently supported by BeOne Medicines. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence.