Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial
Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial
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DOI：
10.1016/s2352-3026(17)30168-0
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发表时间：
2017-11-01
影响因子：
24.7
通讯作者：
Foa, Robin
中科院分区：
文献类型：
--
作者：
Chanan-Khan, Asher A.;Zaritskey, Andrey;Foa, Robin
背景来那度胺作为慢性淋巴细胞白血病化疗二线治疗后维持治疗的有效性和安全性尚不清楚。虽然激酶抑制剂可以改善一些复发和难治性疾病患者的预后，但并不是所有的患者都能获得这些新药。在这项研究中，我们旨在评估来那度胺作为维持治疗在既往治疗过的慢性淋巴细胞白血病患者中的有效性和安全性。方法这项随机、双盲、安慰剂对照的3期试验在21个国家的111家医院、医疗中心和诊所进行。患者符合以下条件：患有慢性淋巴细胞白血病；年龄18岁或以上；接受过两个疗程的治疗(二线治疗后至少有部分反应)；接受了嘌呤类似物、苯达莫司汀、抗CD20抗体、氯氨丁苯或阿仑珠单抗作为一线或二线治疗；以及东方合作肿瘤学小组表现评分为0-2。符合条件的患者被交互式语音应答系统随机分配(1：1)，接受口服来那度胺(2.5毫克/天)或匹配的口服安慰剂胶囊(2.5毫克/天)，周期为28天，直到疾病进展或不可接受的毒性。如果药物耐受性良好，可以增加来那度胺的剂量(每天增加到5毫克或10毫克)。患者、研究人员和那些完成数据分析的人被屏蔽到治疗分配中。随机分组按年龄、对二线治疗的反应和预后因素进行分层。共同的主要终点是无进展存活率和总体存活率；在本分析的数据截断后，主要终点后来改为总体存活率。次要终点是从随机到第二次疾病进展或死亡的时间(PFS2)、(32)肿瘤反应(反应和反应持续时间的改善)、安全性和与健康相关的生活质量(HRQL)。在意向治疗人群中进行了疗效分析。对所有接受至少一剂研究药物的患者进行了安全性分析。这项试验在ClinicalTrials.gov注册，编号NCT00774345，接近应计，但后续调查仍在进行中。在2009年2月16日至2015年9月29日期间，314名慢性淋巴细胞白血病患者入选并随机分配接受来那度胺(n=160)或安慰剂(n=154)治疗。中位随访时间为31.5个月(IQR 18.9-50.8)，来那度胺组和安慰剂组的总生存期无显著差异(中位数70.4个月，95%可信区间57.5-不可估测的NE，95%可信区间62.8-NE；风险比[HR]0.96，95%可信区间0.63-1.48；p=0.86)。来那度胺组的无进展生存期(中位数33.9个月，95%可信区间25.5-52.5)显著长于安慰剂组(9.2个月，7.4-13.6个月；HR 0.40，95%可信区间0)。29-0。55；宝洁；0.0001)。来那度胺组的PFS2显著长于安慰剂组(中位数57。5个月[47.7-东北]VS 32。7个月[26.4~49.0]；心率0.46，95%可信区间0.29~0.70；P<；0.01)。在接受来那度胺治疗的160名患者中，有10名(6%)的患者的反应较基线有所改善，而在154名接受安慰剂治疗的患者中，有4名(3%)有改善(p=0.12)。来那度胺组改善反应的中位时间为12.2周(IQR7.2-22.5)，而安慰剂组为76.3周(20.2-182.6)。改善反应的持续时间在两组中都不可估量(来那度胺组的95%可信区间22.9-NE与安慰剂组的NE-NE相比)。在维持治疗期间，用FACT-Leu和EQ-5D衡量，来那度胺治疗的患者和安慰剂治疗的患者之间的HRQL没有临床意义的差异。在安全人群中，最常见的3级或4级不良反应包括中性粒细胞减少(来那度胺组157名患者中94名[60%]对安慰剂组154名患者中35名[23%])、血小板减少症(26名[17%]比10名[6%])和腹泻(13名[8%]比1名[1%])。有5个致命的不良事件(来那度胺组3例[2%]患者和安慰剂组2例[1%]患者)。解释来那度胺可能会延迟后续治疗的时间，并且不会对后续治疗的反应产生不利影响。对于无法获得激酶抑制剂的慢性淋巴细胞白血病患者，化学免疫治疗和来那度胺维持治疗可能是一种有效的治疗选择。
Background The efficacy and safety of lenalidomide as maintenance therapy after chemotherapy-based second-line therapy in patients with chronic lymphocytic leukaemia is unknown. Although kinase inhibitors can improve outcomes for some patients with relapsed and refractory disease, not all patients have access to these novel drugs. In this study, we aimed to assess the efficacy and safety of lenalidomide as maintenance therapy in patients with previously treated chronic lymphocytic leukaemia.Methods This randomised, double-blind, placebo-controlled, phase 3 trial (CONTINUUM) was done at 111 hospitals, medical centres, and clinics in 21 countries. Patients were eligible if they had chronic lymphocytic leukaemia; were aged 18 years or older; had been treated with two lines of therapy (with at least a partial response after second-line therapy); had received a purine analogue, bendamustine, anti-CD20 antibody, chlorambucil, or alemtuzumab as first-line or second-line treatment; and had an Eastern Cooperative Oncology Group performance score of 0-2. Eligible patients were randomly assigned (1:1) by an interactive voice-response system to receive either oral lenalidomide (2.5 mg/day) or matching oral placebo capsules (2.5 mg/day) for 28-day cycles, until disease progression or unacceptable toxicity. Lenalidomide dose escalation (to 5 mg or 10 mg per day) was permitted if the drug was well tolerated. Patients, investigators, and those completing data analyses were masked to treatment allocation. Randomisation was stratified by age, response to second-line therapy, and prognostic factors. Co-primary endpoints were progression-free survival and overall survival; the primary endpoint was later changed to overall survival after the data cutoff for this analysis. Secondary endpoints were time from randomisation to second disease progression or death (PFS2),(32) tumour response (improvement in response and duration of response), safety, and health-related quality of life (HRQoL). Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00774345, and is closed to accrual, but follow-up is ongoing.Findings Between Feb 16, 2009 and Sept 29, 2015, 314 patients with chronic lymphocytic leukaemia were enrolled and randomly assigned to receive either lenalidomide (n=160) or placebo (n=154). With a median follow-up of 31.5 months (IQR 18.9-50.8), there was no significant difference in overall survival between the lenalidomide and the placebo groups (median 70.4 months, 95% CI 57.5-not estimable [NE] vs NE, 95% CI 62.8-NE; hazard ratio [HR] 0.96, 95% CI 0.63-1.48; p=0.86). Progression-free survival was significantly longer in the lenalidomide group (median 33.9 months, 95% CI 25.5-52.5) than in the placebo group (9.2 months, 7.4-13.6; HR 0.40, 95% CI 0 . 29-0 . 55; p < 0.0001). PFS2 was significantly longer in the lenalidomide group than in the placebo group (median 57 . 5 months [47.7-NE] vs 32 . 7 months [26.4-49.0]; HR 0.46, 95% CI 0.29-0.70; p < 0.01). Improved responses from baseline were observed in ten (6%) of 160 lenalidomide-treated patients versus four (3%) of 154 placebo-treated patients (p=0.12). Median time to improved response was 12.2 weeks (IQR 7.2-22.5) in the lenalidomide group versus 76.3 weeks (20.2-182.6) in the placebo group. Duration of improved response was not estimable in either group (95% CI 22.9-NE in the lenalidomide group vs NE-NE for placebo). There were no clinically meaningful differences in HRQoL between lenalidomide-treated patients and placebo-treated patients, as measured by FACT-Leu and EQ-5D, during maintenance treatment. In the safety population, the most common grade 3 or 4 adverse events included neutropenia (94 [60%] of 157 patients in the lenalidomide group vs 35 [23%] of 154 patients in the placebo group), thrombocytopenia (26 [17%] vs ten [6%]), and diarrhoea (13 [8%] vs one [< 1%]). There were five fatal adverse events (three [2%] patients in the lenalidomide group and two [1%] patients in the placebo group).Interpretation Lenalidomide might delay time to subsequent therapy and does not adversely affect response to subsequent therapy. Chemoimmunotherapy followed by lenalidomide maintenance could be an effective treatment option for patients with chronic lymphocytic leukaemia who do not have access to kinase inhibitors.