From the Department of Pediatrics, Sapienza, University of Rome (F.L.), and the Department of Pediatric Hematology-Oncology (F.L.) and Division of Rheumatology (F.D.B.), IRCCS Bambino Gesù Children's Hospital, Rome, Pediatric Hematology-Oncology, Woman and Child Hospital, Azienda Ospedaliera Universitaria Integrata, Verona (S.C.), the Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano-Bicocca, Monza Brianza per il Bambino e la sua Mamma Foundation, Monza (C.R.), the Clinic of Pediatric Hematology-Oncology, University Hospital of Padova, Padua (M.-C.P.), and the Division of Pediatric Onco-Hematology, Regina Margherita Hospital, Turin (F.F.) - all in Italy; the Divisions of Immunobiology and Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics (M.B.J.), and the Division of Rheumatology (A.G.), Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine (M.B.J.) - all in Cincinnati; the Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston (C.A.); the Department of Hematology, Great Ormond Street Hospital for Children, London (A.R.); the Department of Pediatric Hematology-Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston (B.D.); the Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora (T.P.G.); the Departments of Pediatric Hematology-Oncology and Hematology and Oncology, Fundación para la Investigación Biomédica Hospital Infantil Universitario Niño Jesús, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid (J.S.), and the Department of Pediatric Hematology and Oncology, Hospital Universitari Vall d'Hebron, Barcelona (J.-L.D.D.); the Department of Pediatric Hematology and Oncology, University Children's Hospital, Muenster, Germany (M.A.); the Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ (M.H.); NovImmune, Plan-les-Ouates, Switzerland (G.L., M.B., C.M.); and MnS Modelling and Simulation, Dinant, Belgium (P.J.).
N Engl J Med. 2020 May 7;382(19):1811-1822. doi: 10.1056/NEJMoa1911326.
BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality. METHODS: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ 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. RESULTS: At 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. CONCLUSIONS: Emapalumab 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.).
背景：原发性噬血细胞性淋巴组织细胞增生症是一种罕见的综合征，其特征为免疫失调和炎症过度活跃。它通常在婴儿期发病，死亡率较高。
方法：我们开展了一项开放性标签、单组、2 期-3 期研究，调查了在入组前接受过常规治疗的患者（既往治疗患者）和年龄为 18 岁及以下、患有原发性噬血细胞性淋巴组织细胞增生症且未接受过治疗的患者使用emapalumab（一种人源抗干扰素-γ 抗体）联合地塞米松治疗的效果和安全性。患者可参加长期随访研究，直至异基因造血干细胞移植后 1 年，或直至未进行移植时 emapalumab 的最后 1 次给药后 1 年。如果不进行移植，可根据移植时间缩短或延长计划的 8 周治疗期。主要疗效终点是总体缓解率，既往治疗患者根据客观临床和实验室标准进行评估。
结果：截至 2017 年 7 月 20 日，共有 34 例患者（27 例既往治疗患者和 7 例未接受过治疗的患者）接受了 emapalumab 治疗；26 例患者完成了研究。既往治疗患者中，63%的患者和接受 emapalumab 输注的患者有缓解；这两个百分比显著高于预设的 40%的无效假设（P=0.02 和 P=0.005）。既往治疗组中，70%的患者能够进行移植，接受 emapalumab 治疗的患者中这一比例为 65%。最后一次观察时，既往治疗患者中 74%和接受 emapalumab 治疗的患者中 71%存活。emapalumab 没有引起任何器官毒性。在 emapalumab 治疗期间，10 例患者发生严重感染。1 例患者因播散性组织胞浆菌病而停止使用 emapalumab。
结论：emapalumab 是一种治疗原发性噬血细胞性淋巴组织细胞增生症患者的有效靶向治疗药物。（由 NovImmune 和欧盟委员会资助；NI-0501-04 和 NI-0501-05 临床试验.gov 编号，NCT01818492 和 NCT02069899。）
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