Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network
Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network
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DOI：
10.1016/s0140-6736(16)00739-x
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发表时间：
2016-08-06
期刊：
影响因子：
168.9
通讯作者：
Dreyling, Martin
中科院分区：
文献类型：
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作者：
Hermine, Olivier;Hoster, Eva;Dreyling, Martin
背景套细胞淋巴瘤的特点是远期预后较差。欧洲外套层细胞淋巴瘤网络旨在调查在自体干细胞移植(ASCT)前将大剂量阿糖胞苷引入免疫化疗是否会改善结果。方法这项随机、开放标签、平行分组的3期试验在德国、法国、比利时和波兰的128个血液肿瘤医院科室或私人诊所进行。将年龄在65岁或以下的未经治疗的II-IV期套细胞淋巴瘤患者采用计算机辅助随机区组选择(1：1)，接受6个疗程的R-CHOP(利妥昔单抗加环磷酰胺、阿霉素、长春新碱和强的松)，然后接受清髓性放化疗和AS CT(对照组)，或6个疗程交替的R-CHOP或R-DHAP(利妥昔单抗加地塞米松、大剂量阿糖胞苷和顺铂)，然后接受含大剂量阿糖胞苷的预适应方案和AS CT(阿糖胞素组)。根据研究组和国际预后指数对患者进行分层。主要结果是在至少四个诱导周期、进展或因任何原因死亡后，从随机到稳定疾病的治疗失败的时间。如果根据随机分组开始治疗，则将II、IV期套细胞淋巴瘤患者包括在初步分析中。对于安全性分析，根据实际开始的治疗对患者进行评估。这项研究在ClinicalTrials.gov注册，编号NCT00209222。从2004年7月20日到2010年3月18日随机选择的497名患者(中位年龄55岁[IQR 49-60])的研究结果纳入了初步分析，对照组249名患者中有234名，阿糖胞苷组248名中有232名。中位随访6.1年(95%可信区间5.4~6.4年)，阿糖胞苷组治疗失败时间(中位数9.1年[95%可信区间6.3未达]，5年率65%[95%可信区间57~71])显著长于对照组(3“9年[3.2年~4年]，40%[33~46]；危险比0.56；p=0.038)。在诱导免疫化疗期间，接受大剂量阿糖胞苷治疗的患者有3级或4级的血液毒性(241名对照组中，血红蛋白71名[29%]对227名对照组19名[8%]；血小板176名[73%]，240名对照组中21名[9%])；3级或4级发热性中性粒细胞减少症(230名患者中39名[17%]对224名[8%])；1级或2级肾毒性(肌酐102[43%]236名比224名22[10%])。两组的AS CT相关死亡人数相似(8例[3.4%])。对于65岁或以下的套细胞淋巴瘤患者，应考虑使用包含大剂量阿糖胞苷的解释性免疫化疗，然后进行ASCT。
Background Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome.Methods This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and AS CT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and AS CT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222.Findings Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20,2004, to March 18,2010,234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3 not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3 " 9 years [3.2-4 " 4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241 vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of AS CT-related deaths was similar (eight [3.4%]) in both groups.Interpretation Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma.