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Sintilimab（抗PD-1抗体）联合大剂量甲氨蝶呤、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

Nature 等信源发布 2024-09-04 07:07

可切换为仅中文

AbstractPrimary 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.

摘要原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见且致命的淋巴瘤亚型。程序性死亡-1（PD-1）途径已成为潜在的治疗靶点，但PD-1抗体sintilimab联合免疫化疗作为PCNSL一线治疗的有效性仍有待确定。

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).

在这项安全磨合的2期试验（ChiCTR1900027433）中，我们纳入了18-70岁的新诊断PCNSL患者。参与者接受了6个21天的SMTR方案周期，其中包括辛替利单抗（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1.0 g/m2，年龄≥65岁的患者）和替莫唑胺（150 mg/m2/d，第1-5天）。

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%).

在27名可评估患者中，总有效率（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，未达到反应持续时间，无进展生存期（PFS）和总生存期的中位数。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。

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.

此外，脑脊液中干扰素-α的基线水平和IL10/IL6比值成为PFS的潜在预测因子，在2年时分别达到0.88和0.84的曲线下面积。全外显子组测序显示，在持久性临床获益组中，RTK-RAS和PI3K途径突变的发生率较高，而在无持久性获益组中，Notch和Hippo途径突变的发生率较高。

These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation..

这些发现表明，SMTR方案对新诊断的PCNSL非常有效且可耐受，值得进一步研究。。

IntroductionPrimary central nervous system lymphoma (PCNSL), predominantly a diffuse large B-cell lymphoma (DLBCL) subtype, presents unique clinical challenges due to its aggressive nature. Historically, median overall survival (OS) for PCNSL patients was only 1.3 years.1 However, recent advancements in treatment have extended this to 25.3 months.2 High-dose methotrexate (HD-MTX)-based regimens remain the cornerstone of front-line induction therapy for PCNSL, often followed by consolidation strategies like radiation or autologous stem cell transplantation (ASCT) to prolong the response duration.

引言原发性中枢神经系统淋巴瘤（PCNSL）主要是弥漫性大B细胞淋巴瘤（DLBCL）亚型，由于其侵袭性，因此具有独特的临床挑战。从历史上看，PCNSL患者的中位总生存期（OS）仅为1.3年[1]。然而，最近的治疗进展已将其延长至25.3个月[2]。基于高剂量甲氨蝶呤（HD-MTX）的方案仍然是PCNSL一线诱导治疗的基石，通常随后是放疗或自体干细胞移植（ASCT）等巩固策略，以延长反应持续时间。

In a phase 2 trial, patients undergoing intensive combination therapies, such as high-dose chemotherapy followed by ASCT (HDC-ASCT), demonstrated significantly higher survival rates, with a 5-year OS rate of approximately 79%.3 Despite these efforts, relapse is common and 5-year survival rates remain around 30% to 40% in real-world settings,4 highlighting the urgent need for innovative treatments.

在一项2期临床试验中，接受强化联合治疗的患者，如大剂量化疗后进行ASCT（HDC-ASCT），其生存率显着提高，5年OS率约为79%[3]。尽管做出了这些努力，但复发很常见，在现实环境中5年生存率仍保持在30%至40%左右，4突出了对创新治疗的迫切需求。

The optimal combination of medications with methotrexate (MTX) remains undetermined due to the paucity of head-to-head clinical trials.4 Recent research has focused on integrating rituximab into HD-MTX-based regimens, as evidenced by several clinical trials for PCNSL.5,6,7,8In 2012, Wieduwilt and colleagues pioneered the MTR regimen (MTX (8.0 g/m2), temozolomide, rituximab), followed by high-dose consolidation using etoposide and cytarabine (EA).9 This approach achieved an overall response rate (ORR) of 58% and a complete response (CR) rate of 52%, demonstrating initial success in PCNSL management.

由于缺乏头对头的临床试验，药物与甲氨蝶呤（MTX）的最佳组合仍未确定。4最近的研究集中在将利妥昔单抗整合到基于HD-MTX的方案中，PCNSL的多项临床试验证明了这一点。5,6,7,8 2012年，Wieduwilt及其同事开创了MTR方案（MTX（8.0 g/m2），替莫唑胺，利妥昔单抗），然后使用依托泊苷和阿糖胞苷（EA）进行大剂量巩固。9这种方法的总有效率（ORR）为58%，完全缓解率（CR）为52%，表明PCNSL管理取得了初步成功。

Subsequent studies, including the CALGB 50202 trial and retrospective analyses,5,10 validated these findings but also revealed significant challenges, notably a high discontinuation rate of .

随后的研究，包括CALGB 50202试验和回顾性分析，5,10验证了这些发现，但也揭示了重大挑战，特别是高停药率。

Data availability

数据可用性

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA007993) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human..

本文报道的原始序列数据已保存在中国国家生物信息中心/中国科学院北京基因组研究所国家基因组学数据中心（GSA Human:HRA007993）的基因组序列档案中，可在https://ngdc.cncb.ac.cn/gsa-human..

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Download referencesAcknowledgementsWe thank all the patients and their families who participated in this study. We appreciate Professor Fei Liang from Fudan University for his assistance in statistics. We thank Ms. Kong Li for her assistance in the process of revising the manuscript.

下载参考文献致谢我们感谢所有参与本研究的患者及其家属。我们感谢复旦大学费亮教授在统计方面的帮助。我们感谢孔丽女士在修改稿件过程中的帮助。

This work was supported by grants from Fujian Provincial Health Technology Project [grant number 2023CXA028], .Joint Funds for the Innovation of Science and Technology, Fujian Province (grant number 2023Y9021), the National Science Foundation of Fujian Province [grant number 2022J02036], Clinical research project of Wu Jieping Medical Foundation [grant number 320.6750.19094-41], and the National Natural Science Foundation of China [grant number 82070218, 81400160].Author informationAuthors and AffiliationsDepartment of Hematology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, ChinaZhiyong Zeng, Apeng Yang, Junfang Lin, Qiaoxian Lin, Qingjiao Chen, Jinfeng Dong, Xiaoqiang Zheng, Jizhen Wang, Jinlong Huang, Ping Chen, Meihong Zheng & Junmin ChenDepartment of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, ChinaZhiyong Zeng & Junmin ChenFujian Lymphoma and Multiple Myeloma Working Group, Fuzhou, ChinaZhiyong Zeng & Junmin ChenParexel International, Durham, North Carolina, USAJingke YangDepartment of Pathology, the First Affiliated Hospital of Fujian Medical University, Fuzhou, ChinaSheng Zhang & Xingfu WangDepartment of Imaging, the First Affiliated Hospital of Fujian Medical University, Fuzhou, ChinaZhen Xing & Xiaofang ZhouDepartment of Neurosurgery, the First Affiliated Hospital of Fujian Medical University, Fuzhou, ChinaWenzhong Mei, Changzhen Jiang, Xiyue Wu, Yihui Xue, Z.

这项工作得到了福建省卫生技术项目（批准号2023CXA028）的资助。福建省科技创新联合基金（批准号2023Y9021），福建省国家科学基金（批准号2022J02036），吴洁平医学基金临床研究项目（批准号320.6750.19094-41）和国家自然科学基金（批准号8207021881400160）。作者信息作者和附属机构福建医科大学第一附属医院血液科，中国福州曾志勇，杨阿鹏，林俊芳，林巧贤，陈庆娇，董金峰，郑晓强，王吉珍，黄金龙，陈萍，郑美红，陈俊民福建医科大学第一附属医院滨海校区国家区域医学中心血液科，中国福州市曾志勇，陈俊民福建淋巴瘤和多发性骨髓瘤工作组，中国福州市曾志勇，陈俊民国际，北卡罗莱纳州达勒姆，美国杨景科福建医科大学第一附属医院病理科中国福州大学张胜福和王兴福福建医科大学第一附属医院影像科，中国福州邢振芳和周晓芳福建医科大学第一附属医院神经外科，中国福州梅文忠，蒋长珍，吴西岳，薛一辉，Z。

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PubMed Google ScholarContributionsZ.Y.Z. and J.M.C. contributed to study design and manuscript writing. Z.Y.Z., A.P.Y., W.Z.M., C.Z.J., J.F.L., X.Y.W., Y.H.X., Z.Y.W., L.H.Y., D.L.W., J.W.C., S.F.Z., Q.X.L., Q.J.C., J.F.D., X.Q.Z., J.Z.W., J.L.H., Z.Y.C., P.C., M.H.Z., Y.X.L., and J.M.C.

PubMed谷歌学术贡献。Y、 Z.和J.M.C.为研究设计和手稿撰写做出了贡献。Z、 Y.Z.，A.P.Y.，W.Z.M.，C.Z.J.，J.F.L.，X.Y.W.，Y.H.X.，Z.Y.W.，L.H.Y.，D.L.W.，J.W.C.，S.F.Z.，Q.X.L.，Q.J.C.，J.F.D.，X.Q.Z.，J.Z.W.，J.L.H.，Z.Y.C.，P.C.，M.H.Z.，Y.X.L.，和J.M.C。

contributed to patient registration and treatment. S.Z. and X.F.W. did the pathology review. Z.X. and X.F.Z. did the radiology review. All authors collected and interpreted the data. Z.Y.Z., Y.X.L., and J.M.C. contributed to the study conduct, data acquisition, analysis of biomarkers, and interpretation.

为患者登记和治疗做出了贡献。S、 Z.和X.F.W.进行了病理学检查。Z、 X.和X.F.Z.进行了放射学检查。所有作者都收集并解释了数据。Z、 Y.Z.，Y.X.L。和J.M.C.为研究行为，数据采集，生物标志物分析和解释做出了贡献。

Z.Y.Z., J.K.Y., and Y.W.H. revised the manuscript. All authors have read and approved the final manuscript. All authors were responsible for all aspects of the work.Corresponding authorsCorrespondence to.

Z、 Y.Z.，J.K.Y。和Y.W.H.修改了手稿。所有作者都阅读并批准了最终手稿。所有作者都对工作的各个方面负责。通讯作者通讯。

Zhiyong Zeng, Yuanxiang Lin or Junmin Chen.Ethics declarations

曾志勇、林元祥或陈俊民。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleZeng, Z., Yang, A., Yang, J. et al. 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.

转载和许可本文引用本文Zeng，Z.，Yang，A.，Yang，J。等人Sintilimab（抗PD-1抗体）联合大剂量甲氨蝶呤，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。

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中枢神经系统癌症药物开发