Background: : Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common leukemia in adults. Treatment options range from targeted agents to immune-based therapies, with covalent Bruton tyrosine kinase inhibitors (cBTKi) among the most widely used. First-in-class cBTKi ibrutinib entered CLL/SLL in 2014, followed by 2nd generation cBTKi acalabrutinib in 2019 and zanubrutinib in 2023.
Objective: : To review and synthesize real-world clinical and healthcare resource utilization (HCRU) outcomes in patients with CLL/SLL treated with first-generation cBTKi (ibrutinib) or second-generation cBTKi (acalabrutinib, zanubrutinib) in observational studies published between 2020 and 2025.
Methods: : A systematic literature review was conducted in accordance with PRISMA guidelines. Comprehensive searches of PubMed and Embase were performed for studies published between 2020 and 2025, in addition to manual searches of abstracts and posters from major conferences. Duplicates were removed, followed by titles/abstracts screening and full-text review, using predefined inclusion and exclusion criteria. Studies were included if they were real-world observational research in patients with CLL/SLL, receiving ibrutinib, acalabrutinib, or zanubrutinib, and reporting clinical survival or duration of therapy endpoints and/or HCRU outcomes. Both U.S. and ex-U.S. studies published in English were included. Data were extracted into Excel, capturing study characteristics, interventions, comparators, and relevant results. Included studies were classified as clinical or HCRU records, and results were reported accordingly.
Results: : A total of 515 records were identified; after removal of duplicates, 416 were screened and 126 underwent full-text review. Inclusion criteria were met by 53 clinical studies and 10 HCRU studies. Among clinical studies, 25 were conducted outside the U.S. and 28 within the U.S. Of the U.S.-based studies, 13 compared two or more cBTKi agents, while 6 evaluated ibrutinib vs. non-BTKi comparators, 4 examined dosing or treatment interruption, and 5 reported subgroup analyses. Most records were conference abstracts or posters (n=16) and retrospective cohort designs (n=26). Among the 10 HCRU studies, 6 assessed both ibrutinib and acalabrutinib, and only 1 included all three cBTKi agents. Publication types were evenly divided between full-text articles and conference abstracts/posters (n=5 each).
Conclusions: : Real-world evidence on 1st and 2nd generation cBTKi use in CLL/SLL includes both single-agent and comparative studies, offering a broad view of clinical and HCRU outcomes across diverse settings.
