OBJECTIVE: The aim of this study was to perform an adjusted indirect treatment comparison, according to the cytogenetic profile, in terms of efficacy between different Bruton tyrosine kinase inhibitors used as first-line monotherapy for chronic lymphocytic leukemia. Safety outcomes considered of interest were also evaluated to establish whether these options can be considered equivalent therapeutic alternatives. METHOD: A literature search was conducted in Pubmed and Embase on November 10, 2022 for phase III clinical trials studying Bruton tyrosine kinase inhibitors in monotherapy in the first-line setting for chronic lymphocytic leukemia. Results were filtered according to whether the combination of bendamustine and rituximab was used as comparator and whether they had similar populations and follow-up times. Subgroup results were meta-analyzed according to mutational characteristics by classifying patients into high and low cytogenetic risk. An adjusted indirect comparison was developed using Bucher's method. Possible therapeutic equivalence was determined by applying the guide to equivalent therapeutic alternatives. RESULT: Of the 39 studies obtained in the review, 2 clinical trials were selected: 1 for zanubrutinib and 1 for ibrutinib. The remaining studies were not included because they did not meet the inclusion criteria. The results obtained in the adjusted indirect treatment comparison for both cytogenetic risk subgroups showed no statistically significant differences. The most relevant safety differences were atrial fibrillation, hypertension, and cardiovascular events in patients treated with ibrutinib and higher incidence of secondary cancers in patients treated with zanubrutinib. Applying the equivalent therapeutic alternatives guideline criteria, both treatments cannot be considered equivalent therapeutic alternatives. CONCLUSIONS: Assuming the uncertainty associated with the adjusted indirect comparison, zanubrutinib could be considered equivalent in efficacy to ibrutinib, however, the presence of differentiating safety features precludes assigning the 2 alternatives as equivalent therapeutic alternatives.