Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial
Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s0140-6736(14)61495-1
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发表时间：
2015-04-25
期刊：
影响因子：
168.9
通讯作者：
Holme, Pal Andre
中科院分区：
文献类型：
--
作者：
Ghanima, Waleed;Khelif, Abderrahim;Holme, Pal Andre
背景免疫性血小板减少症的特征是免疫介导的破坏和不适宜的血小板生成。尽管缺乏支持证据，美罗华经常用于免疫性血小板减少症患者的标签外。我们的目的是评估利妥昔单抗与安慰剂在先前接受过皮质类固醇治疗的患者中作为非脾切除治疗的有效性。方法在这项多中心、随机、双盲、安慰剂对照试验中，我们招募了对糖皮质激素无反应的成年患者(年龄18岁)，他们患有原发免疫性血小板减少症，每升血小板数低于30×10(9)。患者被随机分配(1：1)，每周四次输注375 mg/m(2)利妥昔单抗或安慰剂。在研究期间，只允许同时使用皮质类固醇。主要终点是78周内的治疗失败率--对所有接受至少一剂研究治疗的患者进行评估，包括脾切除或12周后符合脾切除标准的脾切除。次要终点是应答率、复发率和反应持续时间。疗效终点采用Kaplan-Meier方法进行评估。对所有接受至少一次剂量的患者进行安全终点评估。这项试验在ClinicalTrials.gov注册，编号NCT00344149。结果在2006年8月17日至2011年6月30日期间，我们招募了112名患者。利妥昔单抗组55名患者中有32名(58%)和安慰剂组54名患者中37名(69%)在78周内治疗失败(卡普兰-迈耶累积发生率利妥昔单抗组46%对安慰剂组52%(危险比[HR]0.89，95%可信区间0.55-1.45；p=0.65)。总有效率在利妥昔单抗组为81%，安慰剂组为73%(p=0.15)，完全有效率在利妥昔单抗组为58%，安慰剂组为50%(p=0.12)。在总有效率中，利妥昔单抗组的复发率为68%，安慰剂组为78%；完全应答者中，利妥昔单抗组的复发率为50%，安慰剂组的复发率为62%。在利妥昔单抗组中，总有效率(36周比7周；p=0.01)但不完全有效(76周比49周；p=0.19)的患者复发时间更长。两组的出血率相似(利妥昔单抗组21例[38%]与安慰剂组27例[50%]；p=0.08)，感染率(22例[40%]vs13例[24%]；p=0.09)。尽管利妥昔单抗的长期治疗失败率没有降低，但不能排除小的益处，因为利妥昔单抗的有效时间明显更长，数字上的应答率更高。
Background Immune thrombocytopenia is characterised by immune-mediated destruction and suboptimum production of platelets. Despite the absence of supporting evidence, rituximab is frequently used off-label in patients with immune thrombocytopenia. We aimed to assess the efficacy of rituximab as compared with placebo as a splenectomy-sparing treatment in patients who were previously treated with corticosteroids.Methods In this multicentre, randomised, double-masked, placebo-controlled trial, we enrolled corticosteroid unresponsive adult patients (aged >= 18 years) with primary immune thrombocytopenia and a platelet count of less than 30 x 10(9) platelets per L. Patients were randomly assigned (1: 1) to four weekly infusions of 375 mg/m(2) rituximab or placebo. Concurrent treatment with corticosteroids only was allowed during the study. The primary endpoint was rate of treatment failure within 78 weeks-a composite of splenectomy or meeting criteria for splenectomy after week 12 if splenectomy was not done, assessed in all patients who received at least one dose of study treatment. Secondary endpoints were response rates, relapse rates, and duration of response. Efficacy endpoints were assessed with the Kaplan-Meier method. Safety endpoints were assessed in all patients who received at least one dose. This trial is registered with ClinicalTrials.gov, number NCT00344149.Findings Between Aug 17, 2006, and June 30, 2011, we enrolled 112 patients. 32 (58%) of 55 patients in the rituximab group and 37 (69%) of 54 patients in the placebo group had treatment failure within 78 weeks (Kaplan-Meier cumulative incidence 46% for rituximab vs 52% for placebo (hazard ratio [HR] 0.89, 95% CI 0.55-1.45; p=0.65). The cumulative incidence of overall response was 81% in the rituximab group versus 73% in the placebo group (p=0.15) and complete response was 58% in the rituximab group versus 50% in the placebo group (p=0.12). Of those achieving an overall response, 68% relapsed in the rituximab group and 78% relapsed in the placebo group, and of those achieving complete response, 50% relapsed in the rituximab group and 62% relapsed in the placebo group. Time to relapse in the rituximab group was longer in patients who achieved overall response (36 vs 7 weeks; p=0.01) but not complete response (76 vs 49 weeks; p=0.19). Rates of bleeding were similar in the two groups (21 [38%] in the rituximab group vs 27 [50%] in the placebo group; p=0.08) as were rates of infection (22 [40%] vs 13 [24%]; p=0.09).Interpretation Despite no reduction in the rate of long-term treatment failure with rituximab, a small benefit cannot be ruled out, as suggested by an apparently longer duration of response and numerically higher response rates with rituximab.