BACKGROUND Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma. METHODS We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 106 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenously on day 1, and prednisone 100 mg/m2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR [aHR]). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation. FINDINGS Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 [53%] in the autologous HSCT group and 81 [47%] in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39%) of 174 patients. The median progression-free survival was 3·3 years (95% CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p<0·0001; aHR 0·50 [95% CI 0·36-0·69]). The median overall survival was 7·5 years (95% CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 [95% CI 0·46-0·95]). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab. INTERPRETATION Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma. FUNDING Deutsche Krebshilfe, the European Community, and the Bundesministerium für Bildung und Forschung, Kompetenznetz Maligne Lymphome.

中文翻译：

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自体造血干细胞移植首次缓解后套细胞淋巴瘤患者的长期生存：一项开放标签、多中心、随机、3 期试验的事后分析。

背景 首次缓解的自体造血干细胞移植 (HSCT) 是目前适合套细胞淋巴瘤患者的标准治疗方法。在这项长期随访研究中，我们的目的是在原发性晚期套细胞淋巴瘤患者中评估自体造血干细胞移植与化疗后不加利妥昔单抗或加用利妥昔单抗的干扰素α维持治疗的疗效。方法 我们对在 6 个欧洲国家的 121 家参与医院或实践中进行的开放标签、多中心、随机、3 期试验进行了事后长期分析。年龄在 18-65 岁之间、患有先前未经治疗的 III-IV 期套细胞淋巴瘤且 ECOG 表现评分为 0-2 的患者有资格参与。患者被随机分配（1：主要结局是从诱导结束到缓解患者进展或死亡的无进展生存期，次要结局是从诱导结束到任何原因死亡的总生存期。我们根据意向治疗原则对两组有反应的患者进行了无进展生存期和总生存期的比较，并根据无或有利妥昔单抗的诱导治疗探索了亚组的疗效。针对套细胞淋巴瘤国际预后指数 (MIPI) 数值评分调整了风险比 (HR)，并且在总组中也针对利妥昔单抗的使用（调整后的 HR [aHR]）进行了调整。该试验在实施预注册之前开始，因此未注册，招聘已结束，这是最终评估。9 月 30 日之间的调查结果，1996 年和 2004 年 7 月 1 日，269 名患者被随机分配接受自体造血干细胞移植或干扰素 α 维持治疗。中位随访时间为 14 年（IQR 10-16），意向治疗人群包括 174 名患者（自体 HSCT 组 93 名 [53%]，干扰素 α 维持组 81 名 [47%] ) 对诱导治疗有反应的人。中位年龄为 55 岁（IQR 47-60），174 名患者中有 68 名（39%）使用了 R-CHOP。自体造血干细胞移植组的中位无进展生存期为 3·3 年（95% CI 2·5-4·3），而干扰素 α 维持组的中位无进展生存期为 1·5 年（1·2-2·0）（log -等级 p<0·0001；aHR 0·50 [95% CI 0·36-0·69])。自体造血干细胞移植组的中位总生存期为 7·5 年（95% CI 5·7-12·0），而干扰素 α 维持组的中位总生存期为 4·8 年（4·0-6·6）（对数秩p=0·019；aHR 0·66 [95% CI 0·46-0·95]）。对于未接受利妥昔单抗治疗的患者，自体 HSCT 与干扰素 α 的无进展生存调整后 HR 为 0·40 (0·26-0·61)，而患者为 0·72 (0·42-1·24)用利妥昔单抗治疗。对于总生存期，未使用利妥昔单抗的 HSCT 与干扰素 α 的调整风险比为 0·52 (0·33-0·82)，接受利妥昔单抗的患者为 1·05 (0·55-1·99)。解释 我们的结果证实了自体造血干细胞移植治疗利妥昔单抗前时代确立的套细胞淋巴瘤的长期疗效。由于抗体维持、高剂量阿糖胞苷和靶向治疗改变了套细胞淋巴瘤患者的护理标准，因此建议免疫化疗后疗效降低支持重新评估的必要性。资助 Deutsche Krebshilfe、欧洲共同体和 Bundesministerium für Bildung und Forschung、Kompetenznetz Maligne Lymphome。