Adverse event profiles of acalabrutinib and zanubrutinib in chronic lymphocytic leukemia: A real-world comparison

Abstract

Abstract Background: Bruton's tyrosine kinase inhibitors (BTKis), like acalabrutinib and zanubrutinib, have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Each agent has reported efficacy, but real-world data are limited on each of their safety profiles. Method: We conducted a retrospective cohort study using the TriNetX global health research network, including patients aged ≥18 years diagnosed with CLL who were treated with either acalabrutinib or zanubrutinib. Propensity score matching was performed based on age, sex, and race. Primary outcomes included the incidence of fatal hemorrhage, infections, cytopenias, cardiac arrhythmias, and hepatic-related adverse events. Result: After propensity score matching, baseline characteristics were well balanced between the zanubrutinib and acalabrutinib groups, with 1,964 patients in each cohort. The mean follow-up duration was 408.5 days for zanubrutinib and 625.7 days for acalabrutinib. The average age at index was 72.1 years, and males comprised 63.3% of the zanubrutinib group and 62.1% of the acalabrutinib group. The racial distribution was comparable, with the majority identifying as White (79.9% vs. 79.0%), followed by African American (7.7% vs. 7.7%), Asian (1.5% vs. 1.7%), and Native Hawaiian or other Pacific Islander (0.5% in both groups). Zanubrutinib was associated with a statistically significant reduction in several adverse outcomes compared to acalabrutinib, including fatal hemorrhage (3.67% vs. 5.05%, p = 0.0044), sepsis (6.21% vs. 9.53%, p = 0.0003), pneumonia (7.92% vs. 13.63%, p < 0.0001), candidiasis (1.89% vs. 2.96%, p = 0.0346), grade ≥3 anemia (8.59% vs. 12.90%, p = 0.0001), grade ≥3 thrombocytopenia (4.76% vs. 6.89%, p = 0.0071), and grade ≥3 neutropenia (5.64% vs. 7.33%, p = 0.0045). Cardiotoxicity events were also lower in the zanubrutinib group, including atrial fibrillation/flutter (4.82% vs. 8.05%, p = 0.0002) and cardiac arrhythmias (4.77% vs. 8.11%, p = 0.0001). No significant differences were observed between the two groups in the incidence of paroxysmal tachycardia (2.90% vs. 4.03%, p = 0.0617) or hepatic-related adverse events, including drug-induced liver disease (0.51% in both groups, p = 1.000) and acute hepatic failure (0.51% vs. 0.67%, p = 0.528). Conclusion: The study highlights a more favorable safety profile for zanubrutinib compared to acalabrutinib, with significant differences in fatal hemorrhage, infections, cytopenias, and cardiotoxicity. Safety alone is not enough to inform treatment decisions and it is critical to consider differences in efficacy, since a safer drug that is less effective is arguably not in the best interest of patients. A network meta-analysis provided further insight, suggesting that zanubrutinib was significantly associated with lower rates of disease progression or death when compared to acalabrutinib, with a favorable trend toward being better for overall survival despite this being non-statistically significant due to the confidence intervals. The real-world data supported this finding, with longer time to treatment discontinuation for zanubrutinib, indicating greater tolerability and persistence of treatment. The data we have, taken together, supported the consideration of zanubrutinib as potentially the preferred BTKi in CLL treatment, particularly in the high-risk population who may be at greater risk of limiting side effects. Our study was designed to assess differences in efficacy and safety and the mean follow-up time in the zanubrutinib cohort was shorter than the acalabrutinib cohort, which likely underestimated late-onset adverse events. Ideally, prospective and controlled head-to-head studies are required to confirm these findings and guide optimal treatment selection.