In 2025, two phase 3 randomized clinical trials of pirtobrutinib, a non-covalent BTK inhibitor, were reported, demonstrating improved outcomes versus comparator therapies in the treatment-naïve setting (NCT05254743 and NCT05023980).<h4>Methods</h4>A systematic literature review was conducted to identify RCTs in the first-line setting for CLL. This evidence concerns the gene BTK and B-cell chronic lymphocytic leukemia.