Zanubrutinib vs Bendamustine/Rituximab in Previously Untreated Patients With CLL or SLL

Get Permission

As reported in The Lancet Oncology by Constantine S. Tam, MBBS, PhD, and colleagues, an interim analysis in the phase III SEQUOIA trial has shown significantly improved progression-free survival with first-line zanubrutinib vs bendamustine/rituximab in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) without the high-risk del(17)(p13.1) abnormality.

Constantine S. Tam, MBBS, PhD

Constantine S. Tam, MBBS, PhD

Study Details

Five hundred and ninety patients aged ≥ 65 years or ≥ 18 years with comorbidities from sites in 14 countries were enrolled in the open-label trial between October 2017 and July 2019. A total of 479 patients without del(17)(p13.1) were randomly assigned to receive zanubrutinib (n = 241) or bendamustine/rituximab (n = 238); 92% of patients in each group had CLL.

Treatment consisted of:

  • Zanubrutinib at 160 mg twice daily
  • Bendamustine at 90 mg/m² on days 1 and 2 for six cycles, plus rituximab at 375 mg/m² the day before or on day 1 of cycle 1 and at 500 mg/m² on day 1 of cycles 2 to 6.

Patients with del(17)(p13.1) received zanubrutinib (n = 111).

The primary endpoint was progression-free survival on independent review committee assessment in the intention-to-treat population in the randomly assigned zanubrutinib vs bendamustine/rituximab groups.

Progression-Free Survival

At interim analysis, with a median follow-up of 26.2 months (interquartile range = 23.7–29.6 months), progression-free survival events had occurred in 15% of patients in the zanubrutinib group vs 30% of the bendamustine/rituximab group; the improvement with zanubrutinib was significant, with a hazard ratio (HR) of 0.42 (95% confidence interval [CI] = 0.28–0.63, P < .0001). Median progression-free survival was not reached (95% CI = not estimable–not estimable) vs not reached (95% CI = 28.1 months–not estimable, with estimated 24-month rates of 85.5% vs 69.5%).

Death occurred in 7% vs 6% of patients (HR = 1.07, 95% CI = 0.51–2.22, P = .87). Median overall survival was not reached (95% CI = not estimable–not estimable) vs not reached (95% CI = 30.6 months–not estimable), with estimated 24-month rates of 94.3% vs 94.6%.

Initial findings in the group of patients with del(17)(p13.1) treated with zanubrutinib were previously reported. An updated analysis at median follow-up of 30.5 months showed that progression-free survival events on independent review committee assessment had occurred in 14% of patients. Median progression-free survival was not reached, with an estimated 24-month rate of 88.9%.


  • At interim analysis, zanubrutinib significantly improved progression-free survival vs bendamustine/rituximab.
  • Progression-free survival events had occurred in 15% vs 30% of patients; estimated progression-free survival rates at 24 months were 85.5% vs 69.5%.

Adverse Events

In the randomly assigned population, grade 3 or 4 adverse events occurred in 48% of the zanubrutinib group vs 75% of the bendamustine/rituximab group, with the most common in both groups being neutropenia (11% vs 51%). Grade ≥ 3 infections occurred in 16% vs 19%. Serious adverse events occurred in 37% vs 50% of patients.

Zanubrutinib adverse events of interest included any grade atrial fibrillation in 3% of the zanubrutinib group, major bleeding events in 5% vs 2% of patients, and other cancers in 13% vs 9% of patients. Adverse events led to death in 11 patients (5%) in the zanubrutinib group and 12 patients (5%) in the bendamustine/rituximab group; the most common causes were COVID-19 in the zanubrutinib group (n = 5) and diarrhea (n = 2) and aspiration pneumonia (n = 2) in the bendamustine/rituximab group.

The investigators concluded, “Zanubrutinib significantly improved progression-free survival versus bendamustine/rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.”

Dr. Tam, of Peter MacCallum Cancer Centre, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by BeiGene. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.