Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial
Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial
复制标题
DOI：
10.1016/s1470-2045(15)00363-0
复制
发表时间：
2015-12-01
期刊：
影响因子：
51.1
通讯作者：
Silverman, Lewis B.
中科院分区：
文献类型：
--
作者：
Place, Andrew E.;Stevenson, Kristen E.;Silverman, Lewis B.
背景L-天冬酰胺酶是治疗儿童急性淋巴细胞白血病的通用成分，通常肌肉注射。聚乙二醇化的大肠杆菌天冬酰胺酶(聚乙二醇天冬酰胺酶)具有较长的半衰期，与天然的大肠杆菌制剂相比，其免疫原性可能较低，而且可以更容易地静脉给药。Dana-Farber癌症研究所急性淋巴细胞性白血病协议书05-001(DFCI 05-001)的目的是比较静脉注射聚乙二醇天冬酰胺酶和肌肉注射天然大肠杆菌L天冬酰胺酶治疗新诊断急性淋巴细胞白血病的相对毒性和疗效。方法DFCI 05-001纳入来自美国和加拿大11个联合体的1-18岁新诊断急性淋巴细胞白血病患者。患者根据他们的基线特征被分配到初始风险组，然后接受32天的诱导治疗。诱导治疗后完全缓解的患者被分配到最终风险组，并有资格参加随机比较，从研究开始后7周开始静脉注射聚乙二醇门冬酰胺酶(15剂，每2周2500IU/m(2))或肌肉注射天然大肠杆菌L天冬酰胺酶(30剂，每周25000IU/m(2))。随机(1：1)不加掩蔽，并由统计学家生成的分配序列使用置换区块算法(区块大小为4)完成，按最终风险组分层。随机比较的主要终点是与天冬酰胺酶相关的毒性反应(定义为过敏、胰腺炎和血栓形成或出血并发症)的总发生率。预先定义的次要终点是无病生存期、血清天冬酰胺酶活性和PedsQL调查评估的治疗期间的生活质量。所有分析均按意向处理进行。这项研究已在临床试验中注册。GOV，编号NCT00400946。在2005年4月22日至2010年2月12日期间，共有551名符合条件的患者入选。526例患者诱导后完全缓解，其中463例患者被随机分为肌肉注射天然大肠杆菌L-天冬酰胺酶组231例和静脉注射聚乙二醇组-天冬酰胺酶组232例。两组在门冬酰胺酶相关毒副作用发生率(静脉注射聚乙二醇组2 32例中65例(2 8%)，肌肉注射天然大肠杆菌L天冬酰胺酶组2 31例中59例[2 6%]，p=0.6 0)、过敏(p=0.36)、胰腺炎(p=0.5 5)、血栓或出血并发症(p=0.2 6)方面无显著差异。中位随访期为6.0年(IQR 5.0~7.1)。静脉注射聚乙二醇门冬酰胺酶的患者5年无瘤生存率为90%(95%可信区间86~94)，肌肉内注射L天冬酰胺酶的患者5年无瘤生存率为89%(85~93)(p=0.58)。静脉注射聚乙二醇天冬酰胺酶患者的血清天冬酰胺酶活性中位数显著高于肌肉注射天然大肠杆菌L天冬酰胺酶患者。肌肉注射天然大肠杆菌L-天冬酰胺酶组的患者和家长报告的焦虑明显多于静脉注射聚乙二醇天冬酰胺酶组。其他领域的分数在两组之间是相似的。最常见的3级或更严重的不良反应是细菌或真菌感染(静脉注射聚乙二醇组2 32例中47例(2 0%)，肌肉注射L天冬酰胺酶组2 31例患者中5 1例(2 2%))，以及与门冬酰胺酶相关的过敏反应(14例[6%]对6例[3%])。静脉注射聚乙二醇天冬酰胺酶的毒性不高于肌肉注射天然大肠杆菌L天冬酰胺酶，但与肌肉注射L天冬酰胺酶相比可降低焦虑，支持将其用作新诊断的急性淋巴细胞性白血病儿童的一线门冬酰胺酶制剂。
Background L-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia.Methods DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m(2) every 2 weeks) or intramuscular native E coli l-asparaginase (30 doses of 25 000 IU/m(2) weekly), beginning at week 7 after study entry. Randomisation (1: 1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials. gov, number NCT00400946.Findings Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E coli l-asparaginase group, p=0.60), or in the individual frequency of allergy (p=0.36), pancreatitis (p=0.55), or thrombotic or bleeding complications (p=0.26). Median follow-up was 6.0 years (IQR 5.0-7.1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E coli l-asparaginase (p=0.58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E coli l-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]).Interpretation Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia.