Pirtobrutinib in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Objectives: Pirtobrutinib, a noncovalent Bruton tyrosine kinase inhibitor, was developed to overcome resistance mutations that limit covalent BTK inhibitors and to offer improved tolerability. Three phase III randomized trials (BRUIN CLL-321, CLL-313, and CLL-314) have evaluated pirtobrutinib against distinct comparators in different chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) populations, but no pooled evidence exists, as of now. Methods: Following PRISMA 2020 guidance for systematic reviews without meta-analysis, we searched Embase, Scopus, and PubMed from inception to July 2026 for double-arm randomized trials of pirtobrutinib in CLL/SLL. We extracted safety and efficacy data from the trials and synthesized it narratively. Results: Of 500 identified records, 3 trials met eligibility criteria. In relapsed/refractory patients previously treated with a covalent BTK inhibitor (CLL-321), pirtobrutinib reduced progression or death by 46% versus investigator’s-choice therapy (HR: 0.54). In treatment-naive patients (CLL-313), pirtobrutinib reduced risk by 80% versus bendamustine-rituximab (HR: 0.20). In CLL-314, pirtobrutinib was noninferior to ibrutinib on objective response rate (87.0% vs. 78.5%) with a favorable early progression-free survival trend (HR: 0.57). Overall survival data remained inconclusive across trials, complicated by substantial crossover. Importantly, pirtobrutinib consistently showed lower rates of grade ≥3 adverse events, discontinuations, and cardiovascular toxicity, including markedly reduced atrial fibrillation versus ibrutinib. Conclusions: Pirtobrutinib demonstrates consistent efficacy and a favorable safety profile across relapsed/refractory and treatment-naive CLL/SLL settings, with the strongest evidence in patients who progressed on covalent BTK inhibitors. However, longer follow-up and head-to-head comparisons with other covalent inhibitors are warranted to establish its frontline role in this population.