High-dose chemotherapy followed by autologous stem-cell transplantation versus non-myeloablative consolidation in primary CNS lymphoma (MATRix/IELSG43): a randomised phase 3 trial.

This study aimed to provide randomised comparative evidence on the efficacy and safety of thiotepa-based HCT-ASCT versus non-myeloablative R-DeVIC consolidation after uniform MATRix induction in newly diagnosed PCNSL.

本研究旨在提供关于使用噻替派为基础的HCT-ASCT与非骨髓消融性R-DeVIC巩固治疗在新诊断的PCNSL中经过统一MATRix诱导后的疗效和安全性的随机对照证据。

Methods

This open-label, randomised, phase 3 trial was conducted across 56 university and academic non-university hospitals with established transplantation facilities in five European countries.

这是一项开放标签、随机、第三阶段的试验，在五个欧洲国家的56所大学和非大学学术医院进行，这些医院都有成熟的移植设施。

Eligible for inclusion were untreated, immunocompetent patients with B-cell PCNSL, aged 18-65 years regardless of Eastern Cooperative Oncology Group (ECOG) performance status, or 66-70 years with ECOG performance status 0-2.

符合条件的包括未接受治疗、免疫功能正常的18-65岁B细胞原发性中枢神经系统淋巴瘤（PCNSL）患者，或66-70岁且东部肿瘤协作组（ECOG）表现状态为0-2的患者。

Pretreatment corticosteroids were permitted.

允许使用治疗前皮质类固醇。

Exclusion criteria included lymphoma manifestation outside the CNS, and congenital or acquired immunodeficiency.

排除标准包括中枢神经系统以外的淋巴瘤表现，以及先天性或获得性免疫缺陷。

Patients received four cycles of MATRix induction (comprising rituximab, high-dose cytarabine, and thiotepa, in addition to high-dose methotrexate).

患者接受了四周期的MATRix诱导治疗（包括利妥昔单抗、大剂量阿糖胞苷和硫鸟嘌呤，以及大剂量甲氨蝶呤）。

Patients reaching at least partial response were randomly assigned (1:1) to two cycles of R-DeVIC (rituximab plus dexamethasone, etoposide, ifosfamide, and carboplatin) or HCT-ASCT with carmustine and thiotepa.

达到至少部分缓解的患者被随机分配（1:1）接受两周期的R-DeVIC治疗（利妥昔单抗联合地塞米松、依托泊苷、异环磷酰胺和卡铂）或接受卡莫司汀和硫鸟嘌呤预处理的造血干细胞移植（HCT-ASCT）。

The primary endpoint was progression-free survival, assessed in the full analysis set (excluding patients with major violations of entry criteria).

主要终点是无进展生存期，在全分析集（排除了有重大违反入组标准的患者）中进行评估。

The safety analysis set contained all randomised patients who initiated therapy.

安全性分析集包含了所有已启动治疗的随机患者。

This study is registered with ClinicalTrials.gov (NCT02531841) and the EU Clinical Trials Register (EudraCT number 2012-000620-17).

该研究已在ClinicalTrials.gov (NCT02531841)和欧盟临床试验注册处(EudraCT编号2012-000620-17)注册。

The study is completed.

该研究已完成。

Results

Between July 16, 2014, and Aug 31, 2019, 368 patients were enrolled. 346 (94%) patients started induction treatment, and 230 were randomly assigned; 229 patients were analysed (R-DeVIC group, n=115; HCT-ASCT group, n=114).

2014年7月16日至2019年8月31日期间，共有368名患者被纳入研究。其中346名（94%）患者开始了诱导治疗，并有230名患者被随机分配；最终分析了229名患者（R-DeVIC组，n=115；HCT-ASCT组，n=114）。

After a median follow-up of 45·3 months, 3-year progression-free survivalwas significantly superior in the HCT-ASCT group (hazard ratio0·43 [95% CI 0·27-0·68]; p=0·0003).

中位随访时间为45.3个月后，HCT-ASCT组的3年无进展生存期显著优于其他组（风险比0.43 [95% 置信区间0.27-0.68]；p=0.0003）。

The 3-year progression-free survivalwas 78% (95% CI 69-85) in the HCT-ASCT group compared with 51% (41-60) in the R-DeVIC group.

HCT-ASCT组的3年无进展生存率为78%（95%置信区间69-85），而R-DeVIC组为51%（41-60）。

The mean number of adverse events per patient was 9·3 (SD 4·4) in the R-DeVIC group and 14·6 (5·8) in the HCT-ASCT group.

R-DeVIC组每位患者的不良事件平均数为9.3（标准差4.4），而HCT-ASCT组为14.6（5.8）。

Fatal serious adverse events following consolidation treatment occurred in two patients in the R-DeVIC group (both acute myeloid leukaemia) and in five patients in the HCT-ASCT group (infections and infestations [n=4], pulmonary embolism [n=1]); all of these events apart from the pulmonary embolism were judged to be possibly related to treatment.

在R-DeVIC组中有两名患者（均为急性髓细胞性白血病）和在HCT-ASCT组中有五名患者（感染和寄生虫病[n=4]，肺栓塞[n=1]）发生了致命的严重不良事件；除了肺栓塞外，所有这些事件都被认为可能与治疗有关。

interpretation

In the largest randomised trial in untreated PCNSL to date, HCT-ASCT significantly improved progression-free and overall survivalcompared with non-myeloablative consolidation in patients who had completed induction treatment, establishing it as the preferred consolidation strategy in fit patients.

在迄今为止最大的未治疗PCNSL的随机试验中，与非骨髓抑制性巩固治疗相比，HCT-ASCT显著改善了完成诱导治疗患者的无进展生存和总生存，确立了其作为健康患者首选的巩固策略的地位。

funding

German Federal Ministry of Research, Technology and Space; Swiss Cancer Research Foundation; and Riemser Pharma.

德国联邦研究、技术和空间部；瑞士癌症研究基金会；以及Riemser Pharma公司。