Zanubrutinib + Venetoclax for Treatment-Naive CLL/SLL (SEQUOIA Arm D)
Experts discuss the promising results of a SEQUOIA trial substudy evaluating Bruton tyrosine kinase (BTK) inhibitor plus venetoclax combination therapy in patients with chronic lymphocytic leukemia (CLL)—including those with TP53 mutations or deletion 17p—highlighting high progression-free survival (PFS), deep minimal residual disease (MRD)-driven remissions, and strong safety outcomes that support this doublet as a flexible, effective frontline option for high-risk disease.
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 section of the discussion focuses on the R&D component of the SEQUOIA trial, which evaluated the combination of a BTK inhibitor with venetoclax in patients with CLL, specifically exploring how this regimen performs in those with high-risk genetic features such as TP53 mutations or deletion 17p. What sets this study apart is its relatively large number of high-risk patients—something most earlier trials lacked. The study was also designed with an MRD-guided stopping strategy using stringent criteria. Patients had to achieve a confirmed complete response (CR)/complete response with incomplete count recovery (CRi) and sustained undetectable MRD in both peripheral blood and bone marrow to discontinue therapy. This unique approach helps assess not just response rates but also the depth and durability of remission.
The trial included 2 cohorts: one with abnormal TP53 (n=66) and one with wild-type TP53 (n=48). Patients began with a BTK inhibitor for 3 cycles, followed by combination therapy with venetoclax. The early results were promising. At 24 months, PFS for the high-risk group was 94%, and even at 36 months, it remained high at 88%. For the wild-type cohort, 24-month PFS was 92%, suggesting that this combination may help overcome some of the historically poor outcomes associated with TP53 abnormalities. CR/CRi rates were around 47% to 48% across both groups, and undetectable MRD (uMRD) was achieved in 59% of patients, regardless of risk status. However, high-risk patients took longer to reach uMRD, highlighting the need for prolonged treatment duration in this subgroup.
From a safety standpoint, the combination was well tolerated, with no new or unexpected toxicities and no COVID-19–related deaths, despite the trial overlapping with the pandemic. The study provides strong evidence that doublet oral therapy (BTK inhibitor + venetoclax) is a safe and effective frontline option for CLL, including in patients with deletion 17p. The data support flexible treatment durations based on disease biology and MRD response. They also validate the rationale for combining these agents, particularly as more clinicians shift toward second-generation BTK inhibitors and look to optimize fixed-duration regimens in high-risk populations.
