Department of Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
Department of Hematology, Middlemore Hospital, Auckland, New Zealand.
Lancet Oncol. 2019 Feb;20(2):216-228. doi: 10.1016/S1470-2045(18)30747-2. Epub 2019 Jan 7.
The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood-brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma.
This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18-70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group-WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m on days 1 and 15, intravenous carmustine 100 mg per m on day 4, intravenous teniposide 100 mg per m on days 2 and 3, and oral prednisone 60 mg per m on days 1-5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing.
Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55-67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9-51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39-58) in the MBVP group (no rituximab) and 52% (42-61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70-1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes.
We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma.
Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren.
采用大剂量甲氨蝶呤为基础的化疗后，原发性中枢神经系统淋巴瘤的预后有所改善，但患者结局仍较差。利妥昔单抗是一种靶向 CD20 细胞表面蛋白的嵌合单克隆抗体，在全身性 CD20 阳性弥漫性大 B 细胞淋巴瘤中具有显著活性，但在原发性中枢神经系统淋巴瘤中的疗效尚不清楚，并且大分子量的利妥昔单抗分子穿透血脑屏障的能力有限，可能会限制其疗效。我们旨在研究利妥昔单抗联合大剂量甲氨蝶呤为基础的化疗方案在新诊断的原发性中枢神经系统淋巴瘤患者中的作用。
这是一项在荷兰、澳大利亚和新西兰的 23 家医院进行的、组间、多中心、开放性、随机、3 期临床试验。新诊断为原发性中枢神经系统淋巴瘤、年龄为 18-70 岁、无免疫功能低下的患者，按 1:1 比例随机分配（1:1）接受以甲氨蝶呤为基础的化疗联合或不联合利妥昔单抗静脉注射。我们使用基于网络的随机系统，按中心、年龄和东部肿瘤协作组-世界卫生组织体能状态进行分层，并采用最小化程序。所有分组均为开放性，研究者和患者均不设盲。所有患者均接受两个 28 天的诱导化疗周期，包括第 1 和第 15 天静脉注射甲氨蝶呤 3 g/m2、第 4 天静脉注射卡莫司汀 100 mg/m2、第 2 和第 3 天静脉注射依托泊苷 100 mg/m2、第 1-5 天口服泼尼松 60 mg/m2，第 1 周期（R-MBVP）或第 2 周期（MBVP）在第 0、7、14 和 21 天给予 375 mg/m2的利妥昔单抗静脉注射，在第 0 和 14 天给予 100 mg/m2的利妥昔单抗静脉注射。在诱导治疗结束时达到缓解的患者随后接受高剂量阿糖胞苷治疗，年龄在 60 岁以下的患者接受低剂量全脑放疗。主要终点是无事件生存，无事件定义为未达到完全缓解或治疗结束时不完全缓解未确认、缓解后进展或死亡；分析时调整了年龄和体能评分。按改良意向治疗进行患者分析。该试验在荷兰临床试验注册中心（NTR2427）和澳大利亚新西兰临床试验注册中心（ACTRN12610000908033）注册。该试验于 2016 年 5 月 27 日完成入组，随访正在进行中。
2010 年 8 月 3 日至 2016 年 5 月 27 日，我们招募了 200 名患者（男性 109 名，女性 91 名；中位年龄 61 岁[IQR 55-67]）。我们将 100 名患者随机分配至 MBVP 组，99 名患者随机分配至 R-MBVP 组。一名患者被随机分配至 R-MBVP 组，但因诊断错误被排除在所有分析之外。中位随访 32.9 个月（IQR 23.9-51.5）后，98 名患者发生了事件（MBVP 组 51 例，R-MBVP 组 47 例），其中 79 名死亡（MBVP 组 41 例，R-MBVP 组 38 例）。MBVP 组（未用利妥昔单抗）和 R-MBVP 组（用利妥昔单抗）的 1 年无事件生存率分别为 49%（95%CI 39-58）和 52%（42-61），风险比 1.00（95%CI 0.70-1.43，p=0.99）。MBVP 组有 58 名（58%）患者发生 3 级或 4 级不良事件，R-MBVP 组有 63 名（64%）患者发生 3 级或 4 级不良事件，最常见的是感染（MBVP 组 24 例[24%]，R-MBVP 组 21 例[21%]）、血液学毒性（MBVP 组 15 例[15%]，R-MBVP 组 12 例[12%]）和神经系统疾病（MBVP 组 10 例[10%]，R-MBVP 组 15 例[15%]）。MBVP 组有 12 名（12%）患者发生危及生命或致命的严重不良事件，R-MBVP 组有 10 名（10%）患者发生危及生命或致命的严重不良事件，MBVP 组有 5 名（5%）患者和 R-MBVP 组有 3 名（3%）患者死于治疗相关原因。
我们发现利妥昔单抗联合甲氨蝶呤、卡莫司汀、依托泊苷和泼尼松化疗方案对原发性中枢神经系统淋巴瘤没有明显益处。因此，该研究结果不支持利妥昔单抗作为原发性中枢神经系统淋巴瘤标准治疗的一部分。
罗氏、荷兰癌症协会和 Stichting STOPhersentumoren。
