Interpretation and Clinical Implications of SEQUOIA Arm D Results in CLL/SLL
Experts discuss the growing role of time-limited Bruton tyrosine kinase (BTK) inhibitor plus venetoclax therapy for high-risk chronic lymphocytic leukemia (CLL)—particularly in patients with deletion 17p—emphasizing the SEQUOIA R&D data that support flexible, minimal residual disease (MRD)-guided treatment durations and all-oral regimens as effective, convenient, and patient-centered options for achieving deep, durable responses.
EP: 1.Zanubrutinib Monotherapy in Patients With Del(17p) and Treatment-Naive CLL/SLL (SEQUOIA Arm C)
EP: 2.Interpretation and Clinical Implications of SEQUOIA Arm C Results in CLL/SLL
EP: 3.Zanubrutinib + Venetoclax for Treatment-Naive CLL/SLL (SEQUOIA Arm D)
EP: 4.Interpretation and Clinical Implications of SEQUOIA Arm D Results in CLL/SLL
This discussion centers on the evolving role of time-limited therapy in treating high-risk patients with CLL, particularly those with deletion 17p or TP53 mutations. The speakers reflect on how the SEQUOIA R&D cohort provides some of the most robust prospective data supporting the feasibility of fixed-duration therapy in this population. While BTK monotherapy has shown strong progression-free survival outcomes in high-risk groups, patients and clinicians increasingly value other factors, such as convenience and reduced treatment burden. The current data suggest that even in patients with deletion 17p, a time-limited doublet of a BTK inhibitor and venetoclax can provide deep and durable responses without evidence of inducing resistance mutations.
A key insight from the trial was that high-risk patients may require longer treatment durations to achieve deep responses, such as undetectable MRD, but they still benefit meaningfully. In practice, this supports flexibility in treatment planning—extending therapy based on patient characteristics and MRD status, rather than a rigid schedule. The discussion also introduces the concept of staggered intensification—starting with BTK monotherapy and later adding venetoclax based on disease response or patient readiness. While this approach may extend beyond current trial designs, it reflects real-world needs and highlights the advantages of all-oral regimens in terms of scheduling and adaptability.
Finally, there is optimism around using second-generation BTK inhibitors in time-limited combinations, particularly as more trials mature and new approvals are anticipated. The speakers view deletion 17p as the most clinically significant high-risk feature, and the data from SEQUOIA R&D provide reassurance that even these patients can be effectively treated with fixed-duration doublet therapy. Long-term follow-up will be critical to confirming durability, but the early results support BTK plus venetoclax as a viable, flexible, and patient-centered option in populations with high-risk and wild-type CLL.
