Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. Traditional treatment relied on chemoimmunotherapy, especially in elderly or comorbid patients. However, the advent of Bruton's Tyrosine Kinase inhibitors (BTKis)—notably ibrutinib, acalabrutinib, and zanubrutinib—has transformed the therapeutic landscape. With the emergence of second-generation BTKis and their improved safety, comparing their effectiveness has become essential.

To synthesize and compare current evidence on the effectiveness and safety of ibrutinib, acalabrutinib, and zanubrutinib in CLL, focusing on progression-free survival, adverse events, and treatment trends.

A systematic review was conducted following PRISMA guidelines. Searches were performed in PubMed, Embase, and Scopus for studies published between 2016 and 2025, using descriptors related to “chronic lymphocytic leukemia” and BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib). After removing duplicates, studies were screened by title, abstract, and full text. Inclusion criteria comprised randomized trials, network meta-analyses, or indirect comparisons reporting efficacy or safety outcomes in adult CLL patients. A total of 11 articles met the eligibility criteria and were included in the narrative synthesis.

BTKis demonstrated superior efficacy over chemoimmunotherapy in both frontline and relapsed/refractory settings. In network meta-analyses, ibrutinib reduced disease progression risk by ∼40% versus chlorambucil in fit patients. Acalabrutinib and zanubrutinib showed non-inferior or superior PFS compared to ibrutinib, with fewer adverse events, especially atrial fibrillation and bleeding. In previously treated patients, ibrutinib extended median PFS to ∼44 months, compared to ∼17 months with physician’s choice therapies. In high-risk subgroups, such as those with autoimmune cytopenias, ibrutinib led to durable hematologic responses and reduced immunosuppression need. Pooled data from over 1,500 patients indicated that statin co-use may improve overall survival in those on ibrutinib. In total, data from more than 10,000 patients were analyzed, showing BTKis are consistently associated with high response rates (>85%) and tolerable safety profiles. This review reinforces the pivotal role of BTKis in the evolving treatment landscape of CLL. Their consistent superiority over chemoimmunotherapy validates the shift toward targeted, chemo-free regimens. The emergence of second-generation agents offers improved tolerability, particularly for patients with cardiovascular risk. The observed benefits in high-risk populations, including autoimmune complications, highlight the broad applicability of BTKis. Furthermore, findings on adjunctive statin use suggest potential strategies for outcome optimization. A clear temporal transition was observed: while chlorambucil-based regimens dominated before 2018, recent data (post-2019) show a strong preference for BTKi-based protocols in both clinical trials and real-world settings.BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—have become essential components of CLL therapy. Their superior efficacy, manageable toxicity, and applicability across diverse clinical contexts support their widespread adoption. These findings consolidate the role of BTKis as standard-of-care agents and provide insight into factors that may further enhance treatment outcomes.