Zanubrutinib versus fludarabine, cyclophosphamide and rituximab in fit, treatment-naïve patients with chronic lymphocytic leukemia: a matching-adjusted indirect comparison

Aim: Fludarabine, cyclophosphamide and rituximab (FCR) is a first-line therapy for fit treatment-naive patients with chronic lymphocytic leukemia (CLL); however, its hematotoxicity and related infections necessitate more efficacious, safer treatments. Zanubrutinib is a highly potent and selective next-generation Bruton tyrosine kinase inhibitor approved for treatment-naive patients with CLL and small lymphocytic lymphoma. Given the absence of clinical trials providing head-to-head comparisons, the aim of this analysis was to conduct a matching-adjusted indirect comparison between zanubrutinib and FCR. Materials & methods: Patient-level data from SEQUOIA (zanubrutinib vs bendamustine + rituximab [BR]) was adjusted for interpopulation differences through propensity-score matching with aggregate data from the CLL10 trial (FCR vs BR). Progression-free survival (PFS) was compared among populations matched for immunoglobulin heavy-chain gene mutation, 11q deletion, β2-microglobulin, Binet stage and age. Sensitivity analyses incorporated geographic region, sex, creatinine clearance, the Cumulative Illness Rating Scale, Eastern Cooperative Oncology Group performance status and previous infections. Results: Zanubrutinib improved PFS compared with FCR, with a hazard ratio of 0.41 (95% CI: 0.20–0.81; effective sample size 174). Including geographic region, Eastern Cooperative Oncology Group performance status or previous infections as matching factors one by one in the propensity score model showed similar results. Incorporating Cumulative Illness Rating Scale or creatinine clearance showed numerically favorable PFS with zanubrutinib (hazard ratio [95% CI] 0.45 [0.16–1.24] and 0.52 [0.24–1.13], respectively), owing to the low effective sample size of the expanded model (64 and 123, respectively). Conclusion: Our findings suggest that zanubrutinib offers improved PFS over FCR in fit, treatment-naive patients with CLL, further supporting zanubrutinib as a first-line CLL treatment for multiple patient profiles.