Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial.

Background: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. Method(s): We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13.1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13.1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided alpha of 0.05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. Finding(s): Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13.1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26.2 months (IQR 23.7