信迪利单抗（抗 PD-1 抗体）联合高剂量甲氨蝶呤、替莫唑胺和利妥昔单抗（抗 CD20 抗体）治疗原发性中枢神经系统淋巴瘤：一项 2 期研究。
Sintilimab (anti-PD-1 antibody) combined with high-dose methotrexate, temozolomide, and rituximab (anti-CD20 antibody) in primary central nervous system lymphoma: a phase 2 study.
发表日期：2024 Sep 04
作者：
Zhiyong Zeng, Apeng Yang, Jingke Yang, Sheng Zhang, Zhen Xing, Xingfu Wang, Wenzhong Mei, Changzhen Jiang, Junfang Lin, Xiyue Wu, Yihui Xue, Zanyi Wu, Lianghong Yu, Dengliang Wang, Jianwu Chen, Shufa Zheng, Qiaoxian Lin, Qingjiao Chen, Jinfeng Dong, Xiaoqiang Zheng, Jizhen Wang, Jinlong Huang, Zhenying Chen, Ping Chen, Meihong Zheng, Xiaofang Zhou, Youwen He, Yuanxiang Lin, Junmin Chen
来源：
Signal Transduction and Targeted Therapy
摘要：
原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见且常常致命的淋巴瘤亚型。程序性死亡-1 (PD-1) 通路已成为潜在的治疗靶点，但 PD-1 抗体信迪利单抗联合免疫化疗作为 PCNSL 一线治疗的有效性仍有待确定。在这项具有安全性磨合的 2 期试验 (ChiCTR1900027433) 中，我们纳入了 18-70 岁新诊断 PCNSL 的患者。参与者接受了六个为期 21 天的 SMTR 方案周期，其中包括信迪利单抗（200 mg，第 0 天）、利妥昔单抗（375 mg/m2，第 0 天）、甲氨蝶呤（3.0 g/m2，第 1 天或患者 1.0 g/m2）年龄≥65岁）和替莫唑胺（150mg/m2/d，第1-5天）。在 27 名可评估患者中，总缓解率 (ORR) 为 96.3%（95% 置信区间：81-99.9%），其中 25 名完全缓解。在中位随访 24.4 个月时，尚未达到缓解持续时间、无进展生存期 (PFS) 和总生存期的中位值。最常见的 3-4 级治疗相关毒性是丙氨酸转氨酶 (17.9%) 和天冬氨酸转氨酶 (14.3%) 水平升高。此外，干扰素-α 的基线水平和脑脊液中的 IL10/IL6 比值成为 PFS 的潜在预测因子，2 年时曲线下面积分别达到 0.88 和 0.84。全外显子组测序显示，持久临床受益组中 RTK-RAS 和 PI3K 通路突变的发生率较高，而无持久受益组中 Notch 和 Hippo 通路突变的发生率较高。这些发现表明 SMTR 方案对于新诊断的 PCNSL 非常有效且耐受，值得进一步研究。© 2024。作者。
Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18-70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1-5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81-99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.© 2024. The Author(s).