Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
Unit of Oncology-Haematology, Humanitas Gavazzeni, Bergamo, Italy.
Lancet Haematol. 2021 Jan;8(1):e34-e44. doi: 10.1016/S2352-3026(20)30358-6. Epub 2020 Dec 22.
Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.
This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).
Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.
Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.
Fondazione Italiana Linfomi and Celgene.
年龄在 18-65 岁的适合接受治疗的套细胞淋巴瘤患者通常接受基于阿糖胞苷和利妥昔单抗的诱导方案，随后进行自体造血干细胞移植（HSCT）。我们研究了自体 HSCT 后接受来那度胺维持治疗是否能改善这一人群的无进展生存期。
这是一项在意大利和葡萄牙的 49 个血液科和肿瘤科进行的开放性、随机、多中心、3 期临床试验。符合条件的患者患有未经治疗的套细胞淋巴瘤（或 I-IV 期伴大肿块[≥5 cm]或 B 症状），且 cyclin D1 过表达或存在 t(11;14)(q13;q32) 易位。患者年龄在 18-59 岁，东部肿瘤协作组（ECOG）体能状态 0-3 分，或 60-65 岁，ECOG 0-2 分。在可选的预阶段使用长春新碱和皮质类固醇（静脉注射长春新碱 1.4 mg/m2，第 1 天；口服泼尼松 100 mg[总剂量]，第 1-5 天）后，患者接受 3 个周期的 R-CHOP（21 天周期，第 1 天静脉注射利妥昔单抗 375 mg/m2；第 2 天静脉注射阿霉素 50 mg/m2、长春新碱 1.4 mg/m2 和环磷酰胺 750 mg/m2；第 2-6 天口服泼尼松 100 mg/m2）。然后，患者接受一个周期的高剂量 CTX（第 1 天静脉注射环磷酰胺 4 g/m2，第 4 天静脉注射利妥昔单抗 375 mg/m2）。在重新分期后，患者接受 2 个周期的 R-HD-阿糖胞苷（高剂量静脉注射阿糖胞苷 2 g/m2，每天 12 小时，第 1-3 天；第 4 天和第 10 天静脉注射利妥昔单抗 375 mg/m2）。完全缓解或部分缓解的患者进行自体 HSCT，有血液学恢复的缓解患者（完全缓解或部分缓解）被随机分配（1:1）接受 24 个疗程的口服来那度胺维持治疗（血小板>100×109/L 的患者每天 15 mg，血小板 60-100×109/L 的患者每天 10 mg，每 28 天服用 21 天），持续 24 个月，或观察。主要终点是无进展生存期，在随机人群中进行测量。这项研究在 EudraCT（2009-012807-25）和 ClinicalTrials.gov（NCT02354313）上注册。
2010 年 5 月 4 日至 2015 年 8 月 24 日，共筛选了 303 名患者入组，300 名患者入组（中位年龄 57 岁，IQR 51-62；235 [78%] 为男性）。95 名患者在随机分组前被排除，主要原因是疾病进展、不良事件和恢复不足。104 名患者被随机分配到来那度胺维持组，101 名患者分到观察组。分配到来那度胺组的 104 名患者中有 11 名（11%）未开始治疗（3 名退出，6 名出现不良事件或违反方案，2 名失访）。在随机分组后中位随访 38 个月（IQR 24-50）时，来那度胺组的 3 年无进展生存期为 80%（95%CI 70-87），观察组为 64%（53-73）（对数秩检验 p=0.012；风险比 0.51，95%CI 0.30-0.87）。104 名患者中有 41 名（39%）因死亡或进展等原因停止来那度胺治疗。来那度胺组有 2 名（2%）患者（1 例肺炎，1 例血栓性血小板减少性紫癜）和观察组有 1 名（1%）患者（肺炎）发生与治疗相关的死亡。来那度胺组有 93 名患者中有 59 名（63%）发生 3-4 级血液学不良事件，观察组有 101 名患者中有 12 名（12%）（p<0.0001）。来那度胺组有 93 名患者中有 29 名（31%）和观察组有 101 名患者中有 8 名（8%）发生 3-4 级非血液学不良事件（p<0.0001），其中感染最常见。来那度胺组有 22 名（24%）患者和观察组有 5 名（5%）患者发生严重不良事件。肺炎和其他感染是最常见的严重不良事件。
尽管存在不可忽视的毒性，自体 HSCT 后接受来那度胺治疗仍改善了套细胞淋巴瘤患者的无进展生存期，突出了维持治疗在套细胞淋巴瘤中的作用。
意大利淋巴瘤基金会和 Celgene。
