Zanubrutinib: toward a new era in CLL?

By Ana Espino | Published on January 27, 2026 | 3 min read



Chronic lymphocytic leukemia (CLL) is a malignant hematologic disorder characterized by the slow but progressive accumulation of mature B lymphocytes in the blood, bone marrow, and lymphoid organs. Although often indolent at onset, the disease may evolve into more aggressive forms, with an increased risk of infections, bone marrow failure, and transformation into high-grade lymphoma.

For several years, standard management has relied on combinations of chemotherapy and monoclonal antibodies, particularly the bendamustine–rituximab (BR) regimen. While effective in the short term, these treatments are associated with significant toxicity, limited tolerability in elderly or frail patients, and reduced efficacy in genetically high-risk disease, such as cases with 17p deletion or TP53 mutation.

These limitations have driven the development of targeted therapies, notably Bruton tyrosine kinase (BTK) inhibitors, which block a key signaling pathway in malignant B cells. Zanubrutinib, a next-generation BTK inhibitor, was designed to provide more selective inhibition, with fewer cardiovascular adverse effects than first-generation agents such as ibrutinib. The objective of this study was to compare, in a population of treatment-naïve CLL patients, the efficacy and safety of zanubrutinib versus the BR regimen, in order to assess the relevance of this novel therapeutic strategy as first-line treatment.

Less chemotherapy, more efficacy?

A total of 479 previously untreated CLL patients were enrolled in the study. Patients without 17p deletion were randomized 1:1 to receive either continuous zanubrutinib or six cycles of bendamustine plus rituximab. A non-randomized cohort of 110 patients with del(17p) received zanubrutinib alone, due to their high-risk profile. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), safety, and overall survival (OS).

Among patients without del(17p), zanubrutinib significantly improved PFS. At 36 months, 85.5% of patients treated with zanubrutinib were progression-free, compared with 69.5% in the BR group. In patients with 17p deletion, the 36-month PFS reached 79.4%. The benefit was consistent regardless of age, IGHV status, or the presence of cytogenetic abnormalities.

The overall response rate was similar between groups, but the duration of response was markedly longer with zanubrutinib. The treatment was also better tolerated, with fewer grade ≥3 adverse events, particularly neutropenia and serious infections. The most common adverse events with zanubrutinib included bruising, diarrhea, and mild hypertension, with a low incidence of atrial fibrillation compared with other BTK inhibitors such as ibrutinib.

A milestone in first-line therapy

CLL is a chronic hematologic malignancy characterized by the accumulation of abnormal B lymphocytes, most often diagnosed in older patients. Its management remains challenging, particularly in genetically high-risk disease and in frail populations. This study aimed to compare zanubrutinib, a next-generation BTK inhibitor, with the standard bendamustine–rituximab regimen as first-line therapy in treatment-naïve patients.

The results confirm the superior efficacy of zanubrutinib in terms of progression-free survival, along with a more favorable safety profile, including in patients with 17p deletion. However, limitations of this study remain and justify further research. Future investigations will include head-to-head comparisons with other BTK inhibitors, particularly ibrutinib, as well as long-term real-world studies. The goal will be to assess the impact of zanubrutinib on overall survival, quality of life, and adverse event management, in order to define the optimal personalized first-line therapeutic strategy.

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