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ASH 2021: SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine plus Rituximab (BR) in Patients with Treatment Naive (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL / SLL)

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This abstract from the American Society of Hematology Annual Meeting and Exposition (ASH 2021) presented interim results of the Phase 3 randomized SEQUOIA study which evaluated the efficacy and safety of zanubrutinib versus BR in previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL / SLL) patients without the high-risk mutation,17p deletion [del(17p)].

Zanubrutinib is a selective, next-generation Bruton’s tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimized off-target effects. When drugs bind to sites other than their intended target, side effects may result.

This was an open-label, global registration trial with the hope of leading to drug approval. Patients were subgrouped by age, disease stage, high-risk characteristics (unmutated IgHV and 11q deletion), as well as by geographic region. Average age of patients was 70 years. Treatment groups were balanced for demographic and disease characteristics.

Progression free survival (PFS) was the primary outcome assessed for each treatment group. Secondary outcomes were overall response rate (ORR), overall survival (OS), and safety, measured in terms of adverse events.

Significant relative treatment benefit for zanubrutinib versus BR was observed across subgroups for age, stage, mutation, and deletion status (except for the lower risk IgHV mutated subgroup).


  • 479 patients were randomized to zanubrutinib (241) or BR (238) treatment groups.
  • Median follow up was 26 months.
  • Estimated 24-month PFS for zanubrutinib was 86% vs 70% for BR.
  • ORR was 95% for zanubrutinib vs 85% for BR.
  • Estimated overall survival (OS) for both zanubrutinib and BR was close to 95% (94.3% vs 94.6% respectively).
  • Adverse events (AEs) including heart rhythm disturbance, hypertension and infection were modestly higher for zanubrutinib than for BR. Bleeding events were over 3 times more frequent in patients receiving zanubrutinib than in those receiving BR.
  • Significantly low white blood cell counts (neutropenia) were over 3 times more frequent for patients receiving BR than for those receiving zanubrutinib.
  • Treatment discontinuation due to AEs occurred in 8.3% receiving zanubrutinib vs 13.7% receiving BR.
  • Deaths occurred in 4.6% receiving zanubrutinib vs 5.3% receiving BR.


Significant superiority in PFS and ORR for zanubrutinib vs BR was demonstrated statistically. Zanubrutinib was generally well tolerated with low rates of atrial fibrillation consistent with those observed in Phase 3 ASPEN and ALPINE studies. These data support the potential utility of zanubrutinib in frontline management of patients with CLL / SLL. It might even prove to be better tolerated than the approved BTK inhibitors, ibrutinib and acalabrutinib. The only way to know for sure would be a head-to-head trial in TN CLL patients, and that may never happen.

Click to read the ASH 2021 abstract: SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL / SLL).

Dr. Robert Hander,

CLL Patient and Physician