Zanubrutinib Strengthens Case as Preferred BTK Inhibitor in CLL

Zanubrutinib for chronic lymphocytic leukemia (CLL) demonstrated stronger progression-free survival (PFS) and lower rates of cardiac toxicities than ibrutinib, particularly in patients with relapsed or refractory disease, per a comprehensive analysis published in Oncology and Therapy.¹ More than a decade after Bruton tyrosine kinase (BTK) inhibitors transformed treatment for the hematologic malignancy, this new review suggests second-generation therapies are redefining the standard of care.

The authors summarized data from more than a dozen clinical trials involving over 2000 patients with CLL or small lymphocytic lymphoma (SLL), concluding that zanubrutinib’s (Brukinsa; BeOne Medicines) improved selectivity for BTK appears to reduce off-target toxicities that have historically limited long-term use of earlier BTK inhibitors.

The review arrives as treatment decisions in CLL increasingly hinge not only on efficacy but also on tolerability and long-term safety in an aging patient population.^2,3

Why Analyze the Role of Zanubrutinib in CLL?

The authors wanted to provide “a comprehensive overview of the pharmacology of zanubrutinib, together with a summary of existing and ongoing clinical studies informing its current and potential role in the treatment of CLL/SLL.”

BTK inhibitors have become a backbone of chemotherapy-free treatment for CLL and SLL. However, first-generation agent ibrutinib (Imbruvica; Pharmacyclics/Janssen Biotech) has been associated with significant adverse effects (AEs), including atrial fibrillation, hypertension, infections, diarrhea, and rash.⁴ These toxicities frequently lead patients to discontinue therapy.

The review noted that treatment discontinuation due to ibrutinib-related AEs ranged from 16% to 28% in controlled clinical trials and as high as 51% in some real-world studies. Zanubrutinib was specifically developed to improve BTK selectivity and reduce those off-target effects while maintaining durable disease control.

How Did Zanubrutinib Perform Against Ibrutinib and in Treatment-Naive Patients?

The strongest evidence came from the phase 3 ALPINE trial (NCT03734016), which directly compared twice daily 160-mg zanubrutinib with daily 420-mg ibrutinib in 652 patients with relapsed or refractory CLL/SLL. Patients had received at least 1 prior therapy, and 42% had undergone 2 or more prior treatment lines. Investigators reported superior PFS with zanubrutinib after a median follow-up of 42.5 months.

Estimated 3-year PFS rates were 65.4% for zanubrutinib and 54.4% for ibrutinib. Benefits appeared especially pronounced among high-risk patients with del(17p) or TP53 mutations, with 3-year PFS rates of 59.2% and 38.5%, respectively. Response rates also favored zanubrutinib, with overall response rates (ORRs) of 85.6% vs 75.4% for ibrutinib.

The review emphasized that zanubrutinib’s advantage extended beyond efficacy alone. A sensitivity analysis showed the PFS benefit was “substantially driven by efficacy, not tolerability.”

Also highlighted were results from the phase 3 SEQUOIA trial (NCT03336333) evaluating zanubrutinib in treatment-naive CLL/SLL. Among patients without del(17p), the estimated 5-year PFS reached 75.8% with zanubrutinib vs 40.1% with bendamustine-rituximab chemotherapy. In patients with del(17p), the estimated 5-year PFS was 72.2%. The review noted that zanubrutinib maintained efficacy regardless of age, disease stage, bulky disease status, or immunoglobulin heavy chain variable mutation status.

What Safety Advantages Were Observed?

Cardiac toxicity emerged as one of the clearest differentiators between therapies. In the ALPINE trial, atrial fibrillation occurred in 7.1% of patients treated with zanubrutinib vs 17.0% of those receiving ibrutinib. Overall cardiac AEs were also lower, occurring in 25.9% and 35.5% of patients, respectively. Importantly, no cardiac-related deaths occurred in the zanubrutinib arm, while 6 were reported among patients receiving ibrutinib.

The authors attributed much of this improved tolerability to zanubrutinib’s greater BTK selectivity and reduced interaction with kinases associated with bleeding, arrhythmias, diarrhea, and rash. “Zanubrutinib and acalabrutinib are recommended over ibrutinib owing to their superior safety profiles (particularly reduced cardiotoxicity),” the authors wrote.

Still, zanubrutinib was not without toxicities. Neutropenia occurred more frequently in several studies, including pooled analyses across B-cell malignancies.

Could Combination Regimens Expand Zanubrutinib’s Role?

The investigators also pointed to emerging combination strategies that may eventually support time-limited treatment approaches rather than indefinite therapy. Several studies pairing zanubrutinib with venetoclax, obinutuzumab, or the investigational BCL2 inhibitor sonrotoclax produced high rates of undetectable minimal residual disease. The BGB-11417-101 early-phase study (NCT04277637) combining zanubrutinib with sonrotoclax achieved 100% ORRs and undetectable minimal residual disease rates of 78% at week 24 and 91% at week 48, at a sensitivity of less than 10⁻⁴, or 1 cancer cell per 10,000 normal cells.

Sonrotoclax recently received accelerated approval from the FDA for relapsed or refractory mantle cell lymphoma.⁵

The authors concluded that the growing body of evidence positions zanubrutinib as a leading BTK inhibitor in modern CLL care. “Zanubrutinib monotherapy [was] highly effective and well tolerated,” they wrote, adding that second-generation BTK inhibitors are now preferred over ibrutinib in contemporary treatment guidelines.

References

1. Ghia P, Brown JR, Shadman M, Wendtner CM. A comprehensive review of the role of zanubrutinib for patients with chronic lymphocytic leukemia. Oncol Ther. Published online May 14, 2026. doi:10.1007/s40487-026-00443-w.
2. Shaw ML. Zanubrutinib demonstrates favorable tolerability in R/R CLL/SLL. AJMC^®. April 3, 2026. Accessed May 26, 2026. https://www.ajmc.com/view/zanubrutinib-demonstrates-favorable-tolerability-in-r-r-cll-sll
3. Shaw ML, Rogers K. Breaking down frontline BTK inhibitor selection in CLL: Kerry Rogers, MD. AJMC. May 7, 2026. Accessed May 26, 2026. https://www.ajmc.com/view/breaking-down-frontline-btk-inhibitor-selection-in-cll-kerry-rogers-md
4. Imbruvica. Prescribing information. Pharmacyclics/Janssen Biotech; 2025. Accessed May 26, 2026. https://www.rxabbvie.com/pdf/imbruvica_pi.pdf
5. Caffrey M. Sonrotoclax granted accelerated approval for R/R mantle cell lymphoma. AJMC. May 13, 2026. Accessed May 26, 2026. https://www.ajmc.com/view/sonrotoclax-granted-accelerated-approval-for-r-r-mantle-cell-lymphoma