Covalent Bruton tyrosine kinase (BTK) inhibitors revolutionized the treatment of Chronic Lymphocytic Leukemia (CLL) and are well- established in clinical practice. However, their use is associated with varying safety profiles, particularly concerning cardiovascular (CV) events, which can impact the economic burden on healthcare systems. Understanding the cost implications of these events is imperative for informed reimbursement/funding decision-making, especially in resource-sensitive settings.

To evaluate the costs of grade ≥ 3 CV events with acalabrutinib vs. ibrutinib and zanubrutinib in first-line (1L) and relapsed/refractory (R/R) CLL in the Brazilian private healthcare context.

The incident CLL population was estimated using data from the Brazilian supplementary health system (ANS) and adjusted according to available epidemiological data. Direct hospital costs were calculated based on clinical protocols and official Brazilian sources using a micro-costing approach. Drug prices were retrieved from the Brazilian Drug Market Regulation Chamber (CMED) list. The average cost per patient was estimated using the annual frequency of grade 3 and 4 CV events in the eligible population, as reported in ELEVATE-TN, ELEVATE-RR and ALPINE phase III trials. For each event (atrial fibrillation, hypertension, major bleeding, ventricular arrhythmia), a fixed cost per occurrence was considered, according to each type of event, based on healthcare resource utilization. These unit costs were weighted by the frequency of each event in patients treated with acalabrutinib, zanubrutinib, and ibrutinib. The total cost per cohort was divided by the number of exposed patients to obtain the average cost per patient.

RESULTS: The average cost per patient for grade 3 and 4 CV-related events, for both 1L and R/R, was R$438.21 for acalabrutinib, R$1,776.32 for zanubrutinib, and R$2,437.44 for ibrutinib. Including drug costs, the total per-patient cost was R$826.63 for acalabrutinib, R$2,265.45 for zanubrutinib, and R$2,780.86 for ibrutinib. Considering the eligible population for 1L and R/R settings, acalabrutinib could generate annual savings of approximately R$2,189,868.33 compared to ibrutinib and R$1,488,004,83 compared to zanubrutinib. Acalabrutinib shows consistently lower incidence rates of atrial fibrillation and hypertension. In 1L treatment, atrial fibrillation with ibrutinib is over 9 times more frequent, and hypertension nearly 6 times more common with zanubrutinib. In the R/R setting, atrial fibrillation, and hypertension with ibrutinib are 3.6 times more frequent than with acalabrutinib. CONCLUSION: The improved safety profile of acalabrutinib vs. ibrutinib and zanubrutinib when considering severe CV events can result in significant savings in the Brazilian private healthcare context. These should be considered as part of a holistic decision-making approach in reimbursement/funding decisions of CLL treatments.