Long-Term ALPINE Data Demonstrate Zanubrutinib’s Efficacy in R/R CLL/SLL

New long-term data from the phase 3 ALPINE trial (NCT03734016) show most patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia (R/R CLL or SLL) experienced lengthy progression-free survival with zanubrutinib (Brukinsa).

The findings were reported in an abstract at the American Society of Hematology’s 2025 Meeting and Exposition, which was held December 6 to 9 in Orlando.¹

Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor that was approved by the FDA to treat CLL and SLL in 2023.² Corresponding author Constantine Tam, MD, MBBS, of Monash University, in Australia, and colleagues, said zanubrutinib was designed to have greater specificity and potency compared to earlier BTK inhibitors. It also has fewer off-target toxicities, they said.

The drug was approved in part on the strength of the 2022 ALPINE study, which found that zanubrutinib had a superior overall response rate (ORR) and progression-free survival (PFS) compared to the first-generation BTK inhibitor ibrutinib (Imbruvica).³ That trial had a median follow-up of 29.6 months. It was also found to have a favorable safety profile compared to ibrutinib, with fewer cardiac events and fewer adverse events leading to discontinuation.

At the conclusion of the trial, eligible participants were given the option to continue into the long-term extension trial. The newly released data provides an update on patients who were initially enrolled in the zanubrutinib arm. The data represent up to 6 years of follow-up.

A total of 324 patients were initially randomized into the zanubrutinib arm and received treatment. Of those, 176 patients enrolled in the long-term extension and continued receiving zanubrutinib. Another 13 patients continued in the extension for survival follow-up purposes only. Patients who continued taking zanubrutinib were given the same dose as their last dose in the original ALPINE study. Safety data was assessed every 3 months, and efficacy was assessed at least every 6 months, the investigators said.

At baseline, the ALPINE zanubrutinib cohort had a median age of 67 years and a median of 1 prior line of therapy (mean, 1.7 lines). Approximately 1 in 7 patients (13.8%) had del17p. The median follow-up as of April 1, 2025, was 54.2 months, and follow-up ranged up to 73.5 months.

The new data showed a median PFS for all patients of 52.5 months and a median PFS of 49.9 months among the patients with del17p. The 60-month PFS rate for the overall cohort was 47.3% (50.4% after adjusting for the effects of COVID-19). The 60-month PFS rate for patients with del17p was 38.2 months (40.5% adjusted for COVID-19).

Tam and colleagues said the percentage of patients with complete responses (CR) or CR with incomplete bone marrow recovery (CRi) continued to increase during approximately 12 months of follow-up. In the trial’s last report, the rate of CR/CRi was 11.6%, but 4 patients initially assessed as having a partial response were later assessed to have achieved CR/CRi following the study’s closure.

After a median treatment exposure of 52.5 months, 60.2% of patients had experienced a serious adverse event, and 79% had experienced a grade 3 or above adverse event. Treatment-related grade 3 or above adverse events were reported in 42.3% of patients, 20.4% of patients discontinued due to adverse events, and 14.5% of patients experienced fatal treatment-emergent adverse events, the most common cause of which was infections. The safety profile was similar among patients in the del17p cohort, the investigators said.

“With up to 6 years of follow-up in patients with R/R CLL/SLL, zanubrutinib continued to demonstrate durable efficacy with sustained PFS benefit and a consistent safety profile,” Tam and colleagues concluded.

References

1. Tam C, Mital A, Weinkove, et al. Long-term results of patients receiving zanubrutinib in the phase 3 ALPINE study confirm sustained benefit in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic leukemia (R/R CLL/SLL): Up to 6 years follow-up with the long-term extension (LTE1). Presented at: ASH 2025; December 6-9, 2025; Orlando, Florida. Abstract 2123.

2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. Updated January 19, 2023. Accessed December 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma

3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582