BACKGROUND Hemophagocytic lymphohistiocytosis is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality. Overall survival in adult patients with secondary haemophagocytic lymphohistiocytosis remains suboptimal, and novel therapeutic strategies are needed. The phosphorylation-dependent activation of the Janus family kinases JAK1 and JAK2 are hallmarks of the final common pathway in this disease. We therefore aimed to determine the activity and safety of ruxolitinib, a JAK inhibitor, in adults with secondary haemophagocytic lymphohistiocytosis. METHODS We performed an open-label, single-centre, pilot study of ruxolitinib in adults with secondary haemophagocytic lymphohistiocytosis at the University of Michigan Rogel Cancer Center (Ann Arbor, MI, USA). We included patients aged 18 years or more who fulfilled at least five of the eight HLH-2004 criteria for hemophagocytic lymphohistiocytosis. Discontinuation of corticosteroids was not required for enrolment in this study. Patients received oral ruxolitinib (15 mg twice a day) on a continuous 28-day cycle, or until disease progression or unacceptable toxicity. The primary endpoint was overall survival at 2 months from the first dose of ruxolitinib. Secondary endpoints included the assessment of adverse events, response (defined as the assessment of all quantifiable signs and laboratory abnormalities included in the diagnostic criteria for haemophagocytic lymphohistiocytosis), and pharmacodynamic biomarkers. Analyses were done in all treated patients with available data. This study is registered with ClinicalTrials.gov, number NCT02400463, and is still recruiting. FINDINGS As of Feb 7, 2019, five patients had been enrolled. The first patient was enrolled in February, 2016. No deaths were recorded, with a median follow-up of 490 days (IQR 190-1075). 2-month overall survival was 100% (95% CI 57-100). Regarding response, resolution of symptoms (either partial or complete) and disease-associated laboratory abnormalities was observed in all five patients. Cytopenias improved in all patients within the first week of treatment, leading to relatively rapid transfusion independence, discontinuation of corticosteroids, and hospital discharge. A single serious adverse event (ie, grade 4 febrile neutropenia) was reported. One patient discontinued treatment because of grade 2 extremity pain and no treatment-related deaths were observed. Improvements in inflammatory markers (eg, ferritin, soluble IL-2 receptor) and T cells and monocytes activation (ie, decreased STAT1 phosphorylation) were observed following treatment. INTERPRETATION These preliminary data suggest that ruxolitinib is active, well tolerated, and manageable in the outpatient setting in patients with secondary haemophagocytic lymphohistiocytosis. Given the paucity of effective, non-myelosuppressive therapies, these preliminary findings have important therapeutic implications for patients with haemophagocytic lymphohistiocytosis and other cytokine-release syndromes and warrant further investigation. FUNDING National Cancer Institute, the University of Michigan Rogel Cancer Center, and Incyte Corporation.

中文翻译：

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Ruxolitinib 在继发性噬血细胞淋巴组织细胞增生症成人患者中的应用：一项开放标签、单中心、试点试验。

背景噬血细胞性淋巴组织细胞增生症是一种细胞因子驱动的炎症综合征，与大量的发病率和死亡率相关。继发性噬血细胞性淋巴组织细胞增生症成年患者的总生存率仍不理想，需要新的治疗策略。Janus 家族激酶 JAK1 和 JAK2 的磷酸化依赖性激活是该疾病最终共同途径的标志。因此，我们旨在确定鲁索替尼（一种 JAK 抑制剂）在继发性噬血细胞淋巴组织细胞增生症成人中的活性和安全性。方法 我们在密歇根大学罗杰尔癌症中心（美国密歇根州安娜堡市）对患有继发性噬血细胞淋巴组织细胞增生症的成人进行了鲁索替尼的开放标签、单中心、初步研究。我们纳入了 18 岁或以上的患者，他们至少满足 HLH-2004 八项噬血细胞性淋巴组织细胞增生症标准中的五项。参加本研究不需要停用皮质类固醇。患者以连续 28 天的周期接受口服鲁索替尼（15 毫克，每天两次），或直至疾病进展或出现不可接受的毒性。主要终点是从第一剂鲁索替尼开始 2 个月的总生存期。次要终点包括不良事件的评估、反应（定义为对噬血细胞性淋巴组织细胞增生症诊断标准中包括的所有可量化体征和实验室异常的评估）和药效生物标志物。对所有接受治疗的患者进行了分析，并获得了可用数据。本研究已在 ClinicalTrials.gov 注册，编号 NCT02400463，并且还在招募中。结果 截至 2019 年 2 月 7 日，已招募了 5 名患者。第一位患者于 2016 年 2 月入组。无死亡记录，中位随访时间为 490 天 (IQR 190-1075)。2 个月总生存率为 100% (95% CI 57-100)。关于反应，在所有 5 名患者中均观察到症状（部分或完全）消退和疾病相关实验室异常。在治疗的第一周内，所有患者的血细胞减少症都有所改善，导致相对较快的输血独立、停用皮质类固醇和出院。报告了单一严重不良事件（即 4 级发热性中性粒细胞减少症）。一名患者因 2 级肢体疼痛而停止治疗，未观察到与治疗相关的死亡。炎症标志物（如铁蛋白、可溶性 IL-2 受体）和 T 细胞和单核细胞活化（即 STAT1 磷酸化降低）在治疗后观察到。解释 这些初步数据表明，鲁索替尼在门诊继发性噬血细胞淋巴组织细胞增生症患者中具有活性、耐受性良好且易于管理。鉴于缺乏有效的非骨髓抑制疗法，这些初步发现对噬血细胞淋巴组织细胞增生症和其他细胞因子释放综合征患者具有重要的治疗意义，值得进一步研究。资助国家癌症研究所、密歇根大学罗格尔癌症中心和 Incyte 公司。解释 这些初步数据表明，鲁索替尼在门诊继发性噬血细胞性淋巴组织细胞增生症患者中具有活性、耐受性良好且易于控制。鉴于缺乏有效的非骨髓抑制疗法，这些初步发现对噬血细胞性淋巴组织细胞增生症和其他细胞因子释放综合征患者具有重要的治疗意义，值得进一步研究。资助国家癌症研究所、密歇根大学罗格尔癌症中心和 Incyte 公司。解释 这些初步数据表明，鲁索替尼在门诊继发性噬血细胞性淋巴组织细胞增生症患者中具有活性、耐受性良好且易于控制。鉴于缺乏有效的非骨髓抑制疗法，这些初步发现对噬血细胞性淋巴组织细胞增生症和其他细胞因子释放综合征患者具有重要的治疗意义，值得进一步研究。资助国家癌症研究所、密歇根大学罗格尔癌症中心和 Incyte 公司。这些初步发现对噬血细胞性淋巴组织细胞增生症和其他细胞因子释放综合征患者具有重要的治疗意义，值得进一步研究。资助国家癌症研究所、密歇根大学罗格尔癌症中心和 Incyte 公司。这些初步发现对噬血细胞性淋巴组织细胞增生症和其他细胞因子释放综合征患者具有重要的治疗意义，值得进一步研究。资助国家癌症研究所、密歇根大学罗格尔癌症中心和 Incyte 公司。