共价布鲁顿酪氨酸激酶抑制剂 (cBTKi) 与 BTK C481 残基结合，目前是慢性淋巴细胞白血病 (CLL) 的主要治疗药物。 C481（主要是 C481S）的改变会阻止 cBTKi 结合并导致抗性克隆的出现。 Pirtobrutinib 是一种非共价 BTKi，可与野生型 (WT) 和 C481S 突变 BTK 结合，并在 BTK-WT 和 C481S 突变 CLL 患者组中显示出疗效。为了比较这 2 组的基线临床、转录组和蛋白质组特征及其治疗期间的变化，我们使用了 18 名 CLL 患者（11 名 BTK 突变型、7 名 BTK 突变型）在吡托布替尼治疗前 3 个周期中获得的 67 份纵向外周血样本。 WT）参加了 BRUIN 试验。东部肿瘤合作组两组的体力状况、年龄和 Rai 分期相似。在基线时，BTK 突变队列中的淋巴结更大。所有患者均在 4 个周期的 pirtobrutinib 内获得部分缓解。 1个治疗周期后，两个队列的乳酸脱氢酶和2-微球蛋白水平均下降。表达分析表明，BTK 突变组中有 35 个基因上调，6 个基因下调。基因集富集分析表明，BTK突变细胞中富集的主要通路涉及细胞增殖、代谢和应激反应。在吡托布替尼治疗期间，两组与代谢和增殖相关的通路均下调。蛋白质组数据证实了转录组发现。我们的数据确定了 BTK 突变和 WT CLL 之间的内在差异，并证明了两组 pirtobrutinib 治疗后血浆和组学参数的分子正常化。版权所有 © 2024 美国血液学会。

Covalent Bruton's tyrosine kinase inhibitors (cBTKi), which bind to the BTK C481 residue, are now primary therapeutics for chronic lymphocytic leukemia (CLL). Alterations at C481, primarily C481S, prevent cBTKi binding and lead to the emergence of resistant clones. Pirtobrutinib is a noncovalent BTKi that binds to both wild-type (WT) and C481S-mutated BTK and has shown efficacy in BTK-WT and -mutated CLL patient groups. To compare baseline clinical, transcriptomic, and proteomic characteristics and their changes during treatment in these 2 groups, we used 67 longitudinal peripheral blood samples obtained during the first 3 cycles of treatment with pirtobrutinib from 18 CLL patients (11 BTK-mutated, 7 BTK-WT) enrolled in the BRUIN trial. Eastern Cooperative Oncology Group performance status, age, and Rai stage were similar in both groups. At baseline, lymph nodes were larger in the BTK-mutated cohort. All patients achieved partial remission within 4 cycles of pirtobrutinib. Lactate dehydrogenase and 2-microglobulin levels decreased in both cohorts after 1 treatment cycle. Expression analysis demonstrated upregulation of 35 genes and downregulation of 6 in the BTK-mutated group. Gene set enrichment analysis revealed that the primary pathways enriched in BTK-mutated cells were involved in cell proliferation, metabolism, and stress response. Pathways associated with metabolism and proliferation were downregulated in both groups during pirtobrutinib treatment. Proteomic data corroborated transcriptomic findings. Our data identified inherent differences between BTK-mutated and -WT CLL and demonstrated molecular normalization of plasma and omics parameters with pirtobrutinib treatment in both groups.Copyright © 2024 American Society of Hematology.