Background/Objectives: Covalent Bruton’s tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) improve outcomes in advanced chronic lymphocytic leukemia (CLL) but resistance, largely driven by BTK C481 mutations, and adverse events limit long-term benefit. Noncovalent BTK inhibitors (e.g., pirtobrutinib) reversibly inhibit the BTK ATP-binding pocket independent of C481, potentially overcoming resistance and reducing toxicity. This review summarizes clinical evidence for pirtobrutinib in CLL. Methods: A PubMed search of articles through July 2025 was conducted, focusing on clinical trials of pirtobrutinib. We extracted efficacy, safety, and resistance data, emphasizing the BRUIN CLL-321 phase 3 trial and related studies. Results: Pirtobrutinib demonstrates activity against BTK resistance mutations with a favorable safety profile, partly due to high kinase selectivity. In BRUIN CLL-321, pirtobrutinib achieved an overall response rate (ORR) of 62% and a median progression-free survival (PFS) of 20 months in heavily pretreated patients, including those with resistance mutations. Yet, resistance mechanisms—such as alternative pathway activation and additional BTK mutations—emerge in a subset. Baseline genetic features, including BTK mutation status and cytogenetics, influence response durability and outcomes. Ongoing phase 3 trials comparing pirtobrutinib with covalent BTK inhibitors will clarify its potential as a first-line option and its integration into treatment algorithms. In relapsed/refractory CLL, noncovalent BTK inhibitors may be incorporated into personalized pathways, including bridging to CAR-T therapy, to optimize long-term disease control. Conclusions: Pirtobrutinib offers a promising strategy to address resistance and potentially improve durable disease control in CLL. Definitive trials will define its role relative to covalent BTK inhibitors and its utility across treatment lines within personalized, multimodal regimens.
背景/目的：共价布鲁顿酪氨酸激酶（BTK）抑制剂（伊布替尼、阿卡替尼、泽布替尼）改善了晚期慢性淋巴细胞白血病（CLL）的预后，但主要由BTK C481突变驱动的耐药性及不良事件限制了其长期获益。非共价BTK抑制剂（如吡托布鲁替尼）可逆地抑制BTK ATP结合口袋，且不依赖于C481位点，有望克服耐药并降低毒性。本综述总结了吡托布鲁替尼在CLL中的临床证据。方法：检索截至2025年7月的PubMed文献，重点关注吡托布鲁替尼的临床试验。我们提取了疗效、安全性和耐药性数据，重点分析了BRUIN CLL-321 III期试验及相关研究。结果：吡托布鲁替尼对BTK耐药突变表现出活性，且安全性良好，部分归因于其高激酶选择性。在BRUIN CLL-321试验中，吡托布鲁替尼在经重度预处理（包括携带耐药突变）的患者中实现了62%的总缓解率（ORR）和20个月的中位无进展生存期（PFS）。然而，部分患者仍出现替代通路激活或额外BTK突变等耐药机制。基线遗传特征（包括BTK突变状态和细胞遗传学）影响缓解持续性和临床结局。正在进行的III期试验将比较吡托布鲁替尼与共价BTK抑制剂的疗效，以明确其作为一线治疗选择的潜力及其在治疗路径中的整合方式。在复发/难治性CLL中，非共价BTK抑制剂可能被纳入个体化治疗路径（包括作为CAR-T治疗的桥接方案），以优化长期疾病控制。结论：吡托布鲁替尼为应对CLL耐药性和改善长期疾病控制提供了有前景的策略。关键性试验将明确其相对于共价BTK抑制剂的作用，以及在个体化多模式治疗方案中各线治疗中的应用价值。
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