Zanubrutinib Shows Longer PFS Than FCR in CLL

Zanubrutinib may provide longer progression-free survival (PFS) than fludarabine, cyclophosphamide, and rituximab (FCR) in treatment-naïve patients with chronic lymphocytic leukemia (CLL), according to a matching-adjusted indirect comparison published online in the Journal of Comparative Effectiveness Research.¹ Study authors noted that their analysis addressed an evidence gap because these regimens have not been compared head-to-head before.

FCR is a first-line therapy for physically fit patients with CLL who also have a favorable genetic risk profile, but its use is associated with hematologic adverse effects, myelosuppression, immunosuppression, and infections. Zanubrutinib is a highly potent and selective next-generation Bruton tyrosine kinase inhibitor and a nonchemotherapy treatment.

Who Were the Patients Included in This Analysis?

The investigators gleaned patient-level data from the phase 3 SEQUOIA trial (NCT03336333), which compared zanubrutinib with bendamustine plus rituximab (BR), and aggregate data from the phase 3 CLL10 trial (NCT00769522), which compared FCR with BR. Both trials enrolled previously untreated patients with CLL, excluding those with deletion 17p.

Specifically, SEQUOIA enrolled patients considered unfit for FCR because of their age (65 years and older), if they were younger with comorbidities, or had a Cumulative Illness Rating Scale (CIRS) score above 6, creatinine clearance below 70 mL/min—indicating reduced glomerular filtration rate²—or a history of serious or frequent infections. CLL10 enrolled physically fit patients with advanced disease and an Eastern Cooperative Oncology Group performance status (ECOG PS) between 0 and 2. Before adjustment, 76.4% of patients in SEQUOIA were older than 65 vs 34.6% in CLL10. Male patients comprised 62.2% and 72.7% of the study populations, respectively, and SEQUOIA had more patients with an ECOG PS of 1/2 (55.9% vs 35.9%) and Binet stage A/B disease (70.8% vs 60.1%).

Zanubrutinib Bests FCR

Because the patient populations differed, the investigators used an anchored matching-adjusted indirect comparison, with BR serving as the common comparator. Patients from SEQUOIS were statistically weighted to resemble the CLL population according to age, Binet stage, β2-microglobulin level, immunoglobulin heavy chain variable mutation status, and deletion of 11q. Additional analyses separately accounted for sex, geographic region, and fitness measures, such as creatinine clearance, ECOG PS, and history of infection.

Before matching, zanubrutinib was associated with longer PFS than FCR, but the difference was not considered statistically significant (HR, 0.69; 95% CI, 0.43-1.12). After matching, zanubrutinib demonstrated a 59% lower risk of progression or death vs FCR (HR, 0.41; 95% CI, 0.20-0.81), and by 16 months, Kaplan-Meier curves show treatment differentiation.

Overall results remained generally favorable for zanubrutinib in sensitivity analyses, with HRs of 0.43 (95% CI, 0.21-0.90), 0.44 (95% CI, 0.22-0.89), and 0.45 (95% CI, 0.22-0.93) when geographic region, sex, and previous infections, respectively, were included. Adjusting for ECOG PS improved upon these results (HR, 0.30; 95% CI, 0.14-0.64). Analyses that considered creatine clearance also favored zanubrutinib, while one incorporating CIRS showed only a numerical advantage (HR, 0.45; 95% CI, 0.16-1.24) that did not reach statistical significance, in part because of a smaller effective sample size in that model.

What Do These Findings Mean for First-Line CLL Treatment?

The authors noted that their analysis did not establish a definitive head-to-head advantage. They also could not simultaneously adjust for all fitness-related characteristics. There was limited overlap between the trial populations, as reflected by a matched sample-size population of 174 patients, down from 479 SEQUOIA patients with complete data. Some variables—bulky disease, cytopenias, and complex karyotype—were not reported in CLL10. Further, they highlight that they did not directly compare safety outcomes, although reported trial data showed fewer grade 3/4 adverse events with zanubritunib vs FCR (53% vs 94%), treatment discontinuations because of adverse events (8% vs 23%), and neutropenia (11% vs 84%).

The authors overall characterized their findings as exploratory and noted residual confounding was also a potential outcome.

They concluded that zanubtutinib was associated with clinically meaningful improvements in PFS compared with FCR and said their findings support its use as a first-line treatment for fit patients with CLL. They emphasized, however, that additional real-world evidence could help clarify comparative effectiveness, especially because their current analysis also “supports zanubrutinib as a standard treatment in patients with CLL regardless of fitness, particularly considering the increased risk of adverse events associated with FCR.”

References

1. Munir T, Barnieh L, Mohseninejad, et al. Zanubrutinib versus fludarabine, cyclophosphamide and rituximab in fit, treatment-naïve patients with chronic lymphocytic leukemia: a matching-adjusted indirect comparison. J Comp Eff Res. 2026:e250192.doi:10.57264/cer-2025-0192
2. Devkota B. Creatinine clearance. Medscape. Updated August 25, 2026. Accessed August 26, 2026. https://emedicine.medscape.com/article/2117892-overview