Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis
Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis
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DOI：
10.1056/nejmoa1911326
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发表时间：
2020-05-07
影响因子：
158.5
通讯作者：
de Min, C.
中科院分区：
文献类型：
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作者：
Locatelli, F.;Jordan, M. B.;de Min, C.
背景：原发性噬血细胞淋巴组织细胞增多症是一种罕见的以免疫失调和过度炎症为特征的综合征。它通常表现在婴儿期，并与高死亡率有关。方法：在一项开放标签、单组、2-3期研究中，我们研究了emapalumab（一种人抗干扰素γ抗体）与地塞米松联合使用的有效性和安全性，该研究涉及入组前接受常规治疗的患者（先前接受治疗的患者）和先前未接受治疗的18岁或以下原发性嗜血球淋巴组织细胞增生症患者。患者可以进入长期随访研究，直到异基因造血干细胞移植后1年，或者直到最后一次给药emapalumab后1年，如果没有进行移植。计划的8周治疗期可根据移植时机的需要缩短或延长。主要疗效终点是总体反应，根据客观的临床和实验室标准对先前治疗的患者进行评估。结果截止日期为2017年7月20日，共有34例患者（27例既往治疗患者和7例既往未治疗患者）接受了emapalumab；26名患者完成了这项研究。63%的先前接受治疗的患者和65%接受emapalumab输注的患者有反应；这些百分比显著高于预先设定的零假设40% （P = 0.02和P = 0.005）。在先前接受治疗的组中，70%的患者能够进行移植，接受emapalumab治疗的患者中有65%能够进行移植。在最后一次观察中，74%的既往治疗患者和71%的接受emapalumab治疗的患者存活。Emapalumab与任何器官毒性无关。在emapalumab治疗期间，10例患者出现严重感染。1例患者因播散性组织胞浆菌病停药。结论semapalumab是治疗原发性噬血细胞淋巴组织细胞病的有效药物。（由NovImmune和欧盟委员会资助；NI-0501-04和NI-0501-05 ClinicalTrials.gov编号，NCT01818492和NCT02069899。）
BACKGROUNDPrimary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality.METHODSWe investigated the efficacy and safety of emapalumab (a human anti-interferon-gamma antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria.RESULTSAt the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.CONCLUSIONSEmapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.)