BACKGROUND Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).

中文翻译：

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Ruxolitinib 用于糖皮质激素难治性急性移植物抗宿主病。

背景 急性移植物抗宿主病 (GVHD) 仍然是同种异体干细胞移植的主要限制因素。并非所有患者对标准糖皮质激素治疗都有反应。在一项 2 期试验中，鲁索替尼是一种选择性 Janus 激酶（JAK1 和 JAK2）抑制剂，在糖皮质激素难治性急性 GVHD 患者中显示出潜在疗效。方法 我们进行了一项多中心、随机、开放标签的 3 期试验，比较口服鲁索替尼（10 毫克，每天两次）与研究者从 12 年患者中从九种常用选项（对照）中选择的治疗方案的疗效和安全性同种异体干细胞移植后患有糖皮质激素难治性急性 GVHD 的年龄或以上。主要终点是第 28 天的总体反应（完全反应或部分反应）。关键的次要终点是第 56 天的持久总体反应。结果 共有 309 名患者接受了随机分组；154 名患者被分配到鲁索替尼组，155 名患者被分配到对照组。鲁索替尼组第 28 天的总体反应高于对照组（62% [96 名患者] vs. 39% [61]；优势比，2.64；95% 置信区间 [CI]，1.65 至 4.22；P< 0.001）。鲁索替尼组在第 56 天的持久总体缓解率高于对照组（40% [61 名患者] vs. 22% [34]；优势比，2.38；95% CI，1.43 至 3.94；P<0.001）。鲁索替尼组 6 个月时反应丧失的估计累积发生率为 10%，对照组为 39%。ruxolitinib 的中位无失败生存期明显长于对照组（5.0 个月 vs. 1.0 个月；血液系统疾病复发或进展、非复发相关死亡或增加新的急性 GVHD 全身治疗的风险比，0.46；95% CI，0.35 至 0.60）。鲁索替尼组的中位总生存期为 11.1 个月，对照组为 6.5 个月（死亡风险比，0.83；95% CI，0.60 至 1.15）。直到第 28 天，最常见的不良事件是血小板减少症（鲁索替尼组 152 名患者中有 50 名 [33%]，对照组 150 名患者中有 27 名 [18%]）、贫血（46 名 [30%] 和 42 [33%] 28%]）和巨细胞病毒感染（39 [26%] 和 31 [21%]）。结论 Ruxolitinib 治疗显着改善了疗效结果，与对照治疗观察到的相比，血小板减少症的发生率更高，这是最常见的毒性作用。（由诺华资助；REACH2 临床试验。