Acalabrutinib vs zanubrutinib as first-line therapy in CLL: A propensity score–matched study

Abstract INTRODUCTION: Covalent Bruton tyrosine kinase inhibitors (cBTKis) have transformed the treatment paradigm of chronic lymphocytic leukemia (CLL) over the past decade. Ibrutinib, the first-generation cBTKi, has consistently demonstrated survival benefits compared to chemoimmunotherapy; however, its use has been limited by cardiac toxicity. This toxicity is believed to result from off-target inhibition of other kinases expressed in cardiac myocytes. As a result, more selective second-generation cBTKis—such as acalabrutinib and zanubrutinib—have been approved and are now preferred first-line therapies for CLL, as they have shown comparable or superior efficacy relative to ibrutinib. However, these conclusions are primarily based on extrapolated data from clinical trials involving patients with relapsed or refractory CLL, and direct head-to-head comparisons between second-generation cBTKis remain lacking. This study aimed to evaluate and compare clinical outcomes among comparable CLL patients who received either acalabrutinib or zanubrutinib as initial treatment.METHODS: We conducted a retrospective observational cohort study using the TriNetX Global Collaborative Network to compare acalabrutinib versus zanubrutinib as first-line treatment in patients with treatment-naïve CLL. Cohorts were defined according to the BTK inhibitors received. A propensity score matching was performed to adjust for variables such as age, race, sex and different comorbidities, including hypertension, atrial fibrillation, chronic kidney disease, diabetes, heart failure and cardiomyopathy. Patients with prior venetoclax-based regimens, chemoimmunotherapy and relapse/refractory CLL were excluded. Clinical outcomes within one year of treatment initiation were compared between the cohorts. These outcomes included overall survival (OS) and the incidence of adverse events, such as pneumonia, sepsis, headaches, neutropenia/neutropenic fever, gastrointestinal symptoms and new onset of atrial fibrillation/atrial flutter. Risk differences (RD), risk ratios (RR), 95% confidence intervals (CI) and p-values were calculated to assess statistical significance. RESULTS: Each cohort consisted of 1132 patients after matching. At 1 year, the OS was similar between cohorts, with a death rate of 5.48% in the acalabrutinib group and 5.12% in the zanubrutinib group (RD 0.35%; 95% CI: –1.49% to 2.20%; p = 0.7075). Kaplan-Meier survival curves were nearly identical, supporting this finding. The incidence of adverse events, including pneumonia (6.63% vs 5.92%, p = 0.4880; RR: 1.119%, 95% CI: 0.814% to 1.54), sepsis (4.51% vs 3.53%, p = 0.2392; RR: 1.275, 95% CI: 0.85 to 1.913), GI symptoms (6.98% vs 5.83%, p = 0.2645; RR: 1.197, 95% CI: 0.872 to 1.699), and atrial fibrillation/flutter (7.98% vs 7.18%, p = 0.4741; RR: 1.11, 95% CI: 0.833 to 1.483), was slightly higher with acalabrutinib, though differences were not statistically significant between cohorts. Rates of headache (RD: 0.297, p = 0.6955; RR: 1.11; 95% CI: 0.67–1.82), neutropenia/neutropenic fever (RD: 1.237, p = 0.1442; RR: 1.341, 95% CI: 0.903 to 1.993) and thrombocytopenia (RD: -0.618%, p = 0.6716; RR: 0.957, 95% CI: 0.78 to 1.174) did not differ significantly. CONCLUSIONS: Acalabrutinib and zanubrutinib showed a similar 1-year survival and safety profile. These findings support clinical equivalence between the two drugs. However, randomized controlled trials are warranted to confirm these findings and support clinical decision-making.