Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study
Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study
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DOI：
10.1016/s2352-3026(17)30235-1
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发表时间：
2018-02-01
影响因子：
24.7
通讯作者：
Leblond, Veronique
中科院分区：
文献类型：
--
作者：
Dartigeas, Caroline;Van den Neste, Eric;Leblond, Veronique
背景 大多数慢性淋巴细胞白血病患者在化疗与利妥昔单抗联合初始治疗后会复发。我们评估了使用氟达拉滨、环磷酰胺和利妥昔单抗 (FCR) 一线简化诱导后缓解的老年患者的利妥昔单抗维持治疗与观察的疗效和安全性。方法 这项在法国 89 个中心进行的随机、开放标签、多中心 3 期试验纳入了 65 岁或以上的初治且健康的患有慢性淋巴细胞白血病的无 del(17p) 患者。符合条件的患者的东部肿瘤合作组表现状态为 0-1，并且肾功能和肝功能良好。对四个月全剂量 FCR 疗程和第 1 周期和第 2 周期第 14 天两次临时利妥昔单抗剂量的完全诱导治疗有反应的患者（每个周期的前 3 天口服氟达拉滨 [40 mg/m(2) 每天] 和口服环磷酰胺 [250 mg/m(2) 每天]，第 1 周期第 0 天静脉注射 375 mg/m(2) 利妥昔单抗并随后在第 1 周期第 14 天、第 2 周期第 1 和 14 天以及第 3 和 4 周期第 1 天以 500 mg/m(2) 进行随机分组。从 FCR 毒性中恢复以及患者继续试验的意愿是强制性的。我们将患者随机分配 (1:1)，要么每 8 周接受静脉注射利妥昔单抗 (500 mg/m(2))，持续长达 2 年，要么接受观察，并使用中央计算机生成的随机列表，使用不同大小的随机排列块。根据 IGHV 突变状态、del(11q) 是否存在以及对诱导治疗的反应水平对随机分组进行分层。主要终点是无进展生存期，目的是评估利妥昔单抗维持相对于观察的优越性。最终分析是在意向治疗人群中进行的。对利妥昔单抗组中接受至少一剂研究药物的所有患者和观察组中的所有患者进行安全性分析。该试验已结束，同时继续对患者进行随访。该研究已在 ClinicalTrials.gov 注册，编号为 NCT00645606。调查结果 2007 年 12 月 14 日至 2014 年 2 月 18 日期间，共招募了 542 名患者，其中 525 名开始进行 FCR 诱导。 2008年6月10日至2014年8月14日期间，409名(78%)患者被随机分配至利妥昔单抗维持治疗组(n=202)或观察组(n=207)。利妥昔单抗组中有四名 (2%) 患者未接受分配的治疗（疾病进展 [n=1]、不良事件 [n=3]）。中位随访47.7个月（IQR 30.4-65.8）后，与观察组（49.0个月，39.9-60.5）相比，利妥昔单抗组的中位无进展生存期（59.3个月，95% CI 49.6-不可估计）有所改善；风险比0.55，95% CI 0.40-0.75； p=0.0002）。研究期间，利妥昔单抗维持治疗时中性粒细胞减少症和 3-4 级感染更为常见（分别为 198 名患者中的 105 名患者 [53%] 和 207 名患者中的 74 名患者 [36%]，以及 38 名患者中的 38 名患者 [19%] 和 21 名患者中的 21 名患者 [10%]。最常见的 3-4 级感染是下呼吸道感染（24 例 [12%] vs 8 例 [4%]）。除基底细胞癌外，两组的第二种癌症的发生率相似（29 [15%] vs 23 [11%]）。利妥昔单抗组中有 23 名患者 (11%) 死亡，而观察组有 16 名患者 (8%) 死亡与不良事件有关。 解释 在选定的老年患者中，2 年维持利妥昔单抗可改善无进展生存期，并显示出可接受的安全性。即使在靶向治疗时代，免疫治疗维持策略也是慢性淋巴细胞白血病一线治疗的相关选择。
Background Most patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR).Methods This randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m(2) per day] and oral cyclophosphamide [250 mg/m(2) per day] for the first 3 days of each cycle, rituximab at 375 mg/m(2) intra-venously on day 0 of cycle 1 and subsequently at 500 mg/m(2) on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1: 1) patients to either receive intravenous rituximab (500 mg/m(2)) every 8 weeks for up to 2 years or undergo observation, with a central computer-generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606.Findings Between Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47.7 months (IQR 30.4-65.8), median progression-free survival in the rituximab group (59.3 months, 95% CI 49.6-not estimable) was improved compared with the observation group (49.0 months, 39.9-60.5; hazard ratio 0.55, 95% CI 0.40-0.75; p=0.0002). Neutropenia and grade 3-4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3-4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group.Interpretation 2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy.