Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial
Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial
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DOI：
10.1016/s2352-3026(17)30174-6
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发表时间：
2017-11-01
影响因子：
24.7
通讯作者：
Illerhaus, Gerald
中科院分区：
文献类型：
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作者：
Ferreri, Andres J. M.;Cwynarski, Kate;Illerhaus, Gerald
国际结外淋巴瘤研究组-32（IELSG 32）试验是一项国际随机2期研究，旨在解决新诊断原发性CNS淋巴瘤患者治疗中的两个关键临床问题。首次随机化的结果表明，与检测的其他诱导组合相比，甲氨蝶呤、阿糖胞苷、塞替派和利妥昔单抗（称为MATRix方案）是与显著更好的结局相关的诱导组合。在这里，我们报告了第二次随机分组的结果，该结果讨论了自体干细胞移植（ASCT）支持的清髓性化疗作为全脑放疗（WBRT）的替代方案的疗效，作为巩固后，高剂量甲氨蝶呤为基础的化学免疫治疗。（年龄18-70岁），新诊断的原发性CNS淋巴瘤，东部肿瘤协作组体能状态为0- 3例随机分为甲氨蝶呤3.5g/m2（第1天）+阿糖胞苷2g/m2（第2、3天），每日2次，共4个疗程（A组）; B组：利妥昔单抗375 mg/m2，第-5天和第0天;或同样的甲氨蝶呤-阿糖胞苷-利妥昔单抗联合治疗加塞替派30 mg/m2，第4天（C组），三组每3周重复治疗。诱导治疗后病情缓解或稳定、自体外周血干细胞采集充足且无持续性医源性副作用的患者，有资格在WBRT之间进行第二次随机化。（4-10 MeV的光子;每周5次;剂量大小180 cGy;从最后一次诱导过程开始4周内; D组：卡莫司汀-塞替派条件性ASCT（卡莫司汀400 mg/m2，第-6天;塞替派5 mg/kg，第-5天和第-4天，每12 h 1次，随后回输自体外周血干细胞; E组）。两次随机化均采用排列区组随机化设计，每个分层均使用计算机生成的随机化列表。分配干预后不设盲。主要终点为2年无进展生存期，以诱导组和诱导化疗反应作为分层参数。在改良的意向治疗基础上进行分析。本研究已在ClinicalTrials注册。结果在2010年2月19日至2014年8月27日期间，从5个国家的53个中心招募了227名患者。227例入组患者中有219例可评估。在符合第二次随机化条件的122例患者中，118例患者被随机分配至WBRT或ASCT组（每组59例患者），构成研究人群。WBRT和ASCT均有效，并且在D组和E组的前52例患者中达到了2年时至少40例无进展生存者的预定疗效阈值。WBRT和ASCT之间的2年无进展生存期无显著差异：D组为80%（95% CI 70-90），E组为69%（59-79）（风险比1.50，95% CI 0.83-2.71; p=0.17）。两种巩固治疗均耐受良好。4级非血液学毒性不常见;正如预期，血液学毒性在接受ASCT治疗的患者中比接受WBRT的患者更常见。两个毒性死亡（感染）记录，无论是在接受ASCT.Interpretation WBRT和ASCT的患者都是可行的和有效的巩固治疗后，大剂量的蛋氨酸为基础的化学免疫治疗70岁或以下的原发性中枢神经系统淋巴瘤患者。WBRT后认知功能障碍的风险和影响应在治疗决策时予以考虑。
Background The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy.Methods HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3.5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m(2) on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials. gov, number NCT01011920.Findings Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1.50, 95% CI 0.83-2.71; p=0.17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT.Interpretation WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision.