Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial.
Ruxolitinib in adult patients with secondary haemophagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial.
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DOI：
10.1016/s2352-3026(19)30156-5
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Wilcox RA
中科院分区：
文献类型：
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作者：
Ahmed A;Merrill SA;Alsawah F;Bockenstedt P;Campagnaro E;Devata S;Gitlin SD;Kaminski M;Cusick A;Phillips T;Sood S;Talpaz M;Quiery A;Boonstra PS;Wilcox RA
噬血细胞淋巴组织细胞增多症是一种细胞因子驱动的炎症综合征，与相当大的发病率和死亡率有关。继发性噬血细胞淋巴组织细胞增多症成人患者的总体存活率仍然不理想，需要新的治疗策略。Janus家族激酶JAK1和JAK2的磷酸化依赖激活是该病最终共同途径的标志。因此，我们的目标是确定JAK抑制剂ruxolitinib在成人继发性噬血细胞淋巴组织细胞增多症中的活性和安全性。我们在密歇根大学罗杰尔癌症中心(密歇根大学罗杰尔癌症中心，美国密西西比州安娜堡)进行了一项鲁索利替尼的开放式、单中心、先导性研究，研究对象为继发性噬血细胞淋巴组织细胞增多症患者。我们纳入了年龄在18岁或以上的患者，他们至少符合2004年HLH-2004标准中的八项噬血细胞淋巴组织细胞增多症标准中的五项。在这项研究中，不需要停用皮质类固醇。患者接受口服Ruxolitinib(每天两次，15 mg)，连续28天为一个周期，或直到疾病进展或不可接受的毒性。主要终点是第一次服用鲁索利替尼后2个月的总存活率。次要终点包括对不良事件、反应(定义为对吞噬血细胞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)和药效学生物标志物的评估。对所有接受治疗的患者进行了分析，并获得了可用的数据。这项研究已在临床试验中注册。GOV，编号NCT02400463，仍在招聘中。截至2019年2月7日，已有5名患者入选。第一名患者是在2016年2月登记的。没有死亡记录，中位随访时间为490天(IQR190-1075)。2个月总生存率为100%(95%可信区间57-100)。关于反应，所有五名患者的症状(部分或完全)和与疾病相关的实验室异常都得到了观察。在治疗的第一周内，所有患者的细胞减少都有所改善，导致相对较快的输液独立、停用皮质类固醇和出院。报告了一例严重不良反应(即4级发热性中性粒细胞减少症)。1名患者因2级肢体疼痛而停止治疗，没有观察到与治疗相关的死亡。治疗后炎症标志物(如铁蛋白、可溶性IL-2受体)、T细胞和单核细胞活化(即STAT1磷酸化降低)均有改善。这些初步数据表明，鲁索利替尼在继发性噬血细胞淋巴组织细胞增多症患者的门诊治疗中是有效的、耐受性好的和可管理的。鉴于缺乏有效的非骨髓抑制疗法，这些初步发现对吞噬血细胞淋巴组织细胞增多症和其他细胞因子释放综合征的患者具有重要的治疗意义，值得进一步研究。
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. 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. 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. 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.