Zanubrutinib Approved for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Small lymphocytic lymphoma marrow biopsy.

The FDA has approved zanubrutinib (Brukinsa®, BeiGene USA, Inc.) for treatment of chronic lymphocytic leukemia (CLL) and its tissue counterpart, small lymphocytic lymphoma (SLL).

“Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed CLL and SLL,” wrote Constantine Tam, MD, the Director of Hematology at St. Vincent’s Hospital in Melbourne, Australia, and colleagues, in their abstract of the SEQUOIA trial (NCT03336333), one of the studies on which approval was based.

Safety and efficacy of the drug were evaluated in two separate trials: SEQUOIA, a phase 3, open-label trial in which 479 treatment-naive patients with CLL or SLL without 17p deletion were randomized 1:1 to receive either zanubrutinib, until disease progression or unacceptable toxicity, or bendamustine plus rituximab (BR) for six cycles; and ALPINE (NCT03734016), a phase 3, open-label trial in which 652 patients with relapsed or refractory CLL/SLL were randomized 1:1 to receive either zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Additionally, in the SEQUOIA trial, a separate non-randomized cohort of 110 patients with previously untreated CLL/SLL with 17p deletion was evaluated with zanubrutinib.

The primary end point studied in the SEQUOIA trial in the randomized groups including patients without 17p deletion was progression-free survival, determined by an independent review committee (IRC). Progression-free survival was not reached in the zanubrutinib arm versus 33.7 months in the BR arm. In the separate non-randomized cohort of 110 patients with previously untreated CLL/SLL with 17p deletion, the primary end points measured were overall response rate and duration of response, also determined by IRC. Overall response rate with zanubrutinib was 88%, and duration of response was not reached at a median follow-up of 25.1 months.

In the ALPINE trial, two primary end points were measured: overall response rate and duration of response, as determined by IRC. The overall response rate was 80% in the zanubrutinib arm and 73% in the ibrutinib arm. At a median follow-up of 14.1 months, the duration of response was not reached in either arm.

The most common adverse events in ≥30% of patients across either clinical trial were decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%). Second primary malignancies developed in 13% of patients, including non-skin carcinomas. Atrial fibrillation or flutter were reported in 3.7% of patients. Grade ≥3 ventricular arrhythmias were reported in 0.2% of patients.

“Benefits with respect to both progression-free survival and overall response were observed across all major subgroups, including high-risk patients,” concluded Jennifer Brown, MD, PhD, the Director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, and colleagues, in their publication of the ALPINE trial. “Furthermore, the incidence of treatment discontinuation was lower in the zanubrutinib group. . . and patients who received zanubrutinib had fewer cardiac events, including fewer deaths.”

The recommended dosage of zanubrutinib is 160 mg taken orally twice daily or 320 mg taken orally once daily until disease progression or unacceptable toxicity.

For More Information

Tam CS, Brown JR, Kahl BS, et al (2022). Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol, 23(8):1031-1043. DOI:10.1016/S1470-2045(22)00293-5

Brown JR, Eichhorst B, Hillmen P, et al (2022). Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med, 0028-4793. DOI:10.1056/NEJMoa2211582 (2022). A study comparing zanubrutinib with bendamustine plus rituximab in participants with previously untreated CLL or SLL (SEQUOIA). NLM identifier: NCT03336333. (2022). A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia (ALPINE). NLM identifier: NCT03734016.

Brukinsa® (zanubrutinib) prescribing information (2023). BeiGene. Available at:

US Food and Drug Administration (2023). FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. Available at:

Image credit: Ed Uthman. Licensed under CC BY-SA 2.0

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