AbstractNewly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group).

摘要新诊断的高危急性移植物抗宿主病（aGVHD）患者通常临床结果不佳，完全缓解率低。在我们的I期研究中，Ruxolitinib联合皮质类固醇在改善反应和无失败生存方面显示出有希望的疗效。本研究（ClinicalTrials.gov:NCT04061876）旨在评估ruxolitinib（RUX，5mg/天）与皮质类固醇（1mg/kg/天甲基强的松龙，RUX/类固醇联合组）联合使用的安全性和有效性，而单独使用甲基强的松龙（2mg/kg/天，仅类固醇组）。

Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment.

包括新诊断的中度或高危aGVHD患者，风险水平按明尼苏达aGVHD风险评分或生物标志物评估进行分类。患者以1:1的比例随机分为2组：99名患者接受RUX联合甲基强的松龙治疗，另外99名患者单独接受甲基强的松龙作为初始治疗。

The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4–14.0; P < 0.001). Similarly, the ORR on day 56 was higher in the RUX/steroids group (85.9% vs. 46.5%; OR = 7.07; 95% CI, 3.36–15.75; P < 0.001).

与仅使用类固醇组相比，RUX/类固醇组在第28天的总有效率（ORR）显着更高（92.9%）（70.7%，优势比（OR）=5.8；95%置信区间（CI），2.4-14.0；P<0.001）。同样，RUX/类固醇组第56天的ORR较高（85.9%比46.5%；OR=7.07；95%置信区间，3.36-15.75；P<0.001）。

Additionally, the 18-month failure-free survival was significantly better in the RUX/steroids group (57.2%) compared to the steroids-only group (33.3%; Hazard Ratio = 0.46; 95% CI, 0.31–0.68; P < 0.001). Adverse events (AEs) frequencies were comparable between both groups, with the exception of fewer grade 4 AEs in the RUX/steroids group (26.3% vs.

此外，与仅类固醇组（33.3%；风险比=0.46）相比，RUX/类固醇组（57.2%）的18个月无失败生存率显着更好；95%置信区间，0.31-0.68；P<0.001）。两组之间的不良事件（AE）频率相当，但RUX/类固醇组的4级AE较少（26.3%vs。

50.5% P = 0.005). To our knowledge, this study is the first prospective, randomized controlled trial to demonstrate that adding ruxolitinib to the standar.

。据我们所知，这项研究是第一项前瞻性随机对照试验，证明将ruxolitinib添加到标准中。

IntroductionThe standard initial treatment for Acute graft-versus-host disease (aGVHD) has traditionally consisted of methylprednisolone at a dose of 2 mg/kg/day or prednisone at 2.0–2.5 mg/kg/day.1,2,3 The response rate to corticosteroids monotherapy is around 50%, and the 6-month overall survival rate for patients with intermediate- and high-risk aGVHD, as determined by the Minnesota aGVHD risk score and biomarker risk, is approximately 60%.4,5,6 There is currently a lack of new treatment strategies for intermediate- and high-risk aGVHD that can improve treatment effectiveness and patient outcomes.

引言急性移植物抗宿主病（aGVHD）的标准初始治疗传统上由甲基强的松龙（剂量为2 mg/kg/天）或泼尼松（剂量为2.0-2.5 mg/kg/天）组成。1,2,3皮质类固醇单药治疗的有效率约为50%，由明尼苏达州aGVHD风险评分和生物标志物风险确定的中高危aGVHD患者的6个月总生存率约为60%。4,5,6目前缺乏针对中高危aGVHD的新治疗策略可以提高治疗效果和患者预后。

Current guidelines do not recommend combined first-line therapy. Previous studies have shown that using corticosteroids at a dose of 2 mg/kg/day with a second agent as first-line treatment for newly diagnosed aGVHD offered no significant clinical benefit compared to standard methylprednisolone treatment.7,8,9,10,11,12,13,14,15,16,17 Importantly, survival at 100 days was shorter with those escalated immunosuppression.18 Effectively controlling GVHD without subjecting aGVHD patients to more intense and prolonged immunosuppression remains a primary concern.Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, is approved for managing steroid-refractory aGVHD.19,20,21,22,23 Jan H reported that neutrophils infiltrating the ileum migrate to the mesenteric lymph nodes during the early phase of GVHD, contributing to its development.24 Ruxolitinib was shown to reduce neutrophil infiltration into the mesenteric lymph nodes and decrease MHC-II expression, thus mitigating an early event in the pathogenesis of acute GVHD.

目前的指南不建议联合一线治疗。先前的研究表明，与标准甲基强的松龙治疗相比，使用2 mg/kg/天剂量的皮质类固醇联合第二种药物作为新诊断aGVHD的一线治疗没有显着的临床益处[7,8,9,10,11,12,13,14,15,16,17]。重要的是，随着免疫抑制程度的升高，100天的生存期缩短[18]。有效控制GVHD而不使aGVHD患者受到更强烈和更长时间的免疫抑制仍然是一个主要问题。Ruxolitinib是一种选择性Janus激酶（JAK）1/2抑制剂，被批准用于治疗类固醇难治性aGVHD[19,20,21,22,23]。Jan H报道，浸润回肠的中性粒细胞在GVHD早期迁移至肠系膜淋巴结，有助于其发展[24]。Ruxolitinib被证明可以减少中性粒细胞浸润肠系膜淋巴结并降低MHC-II表达，从而减轻急性GVHD发病机制的早期事件。

Additionally, enhanced JAK-STAT signaling has been identified as a factor responsible for the severe GVHD phenotype induced by MicroRNA-146a deficient dendritic c.

此外，增强的JAK-STAT信号传导已被确定为导致MicroRNA-146a缺陷型树突状c诱导的严重GVHD表型的因素。

Data availability

数据可用性

De-identified individual participant data underlying the results reported in this article will be available beginning 9 months after publication and ending 24 months post-publication. Data will be provided to investigators whose proposed use of the data has been approved. Data requests should be directed to the corresponding author (daihongrm@163.com) and will be evaluated by an independent review committee on a case-by-case basis.

本文报告的结果所依据的未识别的个人参与者数据将在出版后9个月开始提供，并在出版后24个月结束。数据将提供给建议使用数据已获得批准的调查人员。(daihongrm@163.com)并将由独立审查委员会根据具体情况进行评估。

After 24 months, participant data will be available upon request to the corresponding author and, after de-identification, following the moderated access approach of the data repository unit at Chinese PLA General Hospital, Beijing, China..

24个月后，参与者数据将根据要求提供给通讯作者，并在取消身份后，按照中国人民解放军总医院数据存储单元的适度访问方法。。

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Download referencesAcknowledgementsThis work was partially supported by grants from the National Key R&D Program of China (2023YFC2507800, 2021YFA1100904), the National Natural Science Foundation of China (Nos. 82270162, 82270224, 82200169), the Beijing Natural Science Foundation of China (No.

下载参考文献致谢这项工作得到了中国国家重点研发计划（2023YFC25078002021YFA1100904），国家自然科学基金（822701628227022482200169），北京自然科学基金（No。

7222175), the Military medical support innovation and generate special program (21WQ034), the Special Research Found for Health Protection (21BJZ30), Beijing Nova Program cross-cutting Project (20230484407), the Logistics Independent Research Program (2023hqzz09), Capital’s Funds for Health Improvement and Research (2024-2-5063).Author informationAuthor notesThese authors contributed equally: Liping Dou, Yanli Zhao, Jingjing Yang, Lei Deng, Nan Wang.Authors and AffiliationsState Key Laboratory of Experimental Hematology, Senior Department of Hematology, The Fifth Medical Center of PLA General Hospital, Beijing, ChinaLiping Dou, Jingjing Yang, Nan Wang, Xiawei Zhang, Qingyang Liu, Yifan Jiao, Fei Li, Songhua Luan, Liangding Hu & Daihong LiuDepartment of Hematology, Hebei Yanda Lu Daopei Hospital, Langfang, ChinaYanli Zhao, Zhijie Wei & Peihua LuDepartment of Hematology, The 960th Hospital of The People’s Liberation Army (PLA) Joint Logistics Support Force, Jinan, ChinaLei Deng & Fang ZhouDepartment of Hematology, The Second Hospital of Dalian Medical University, Dalian, ChinaYan Yang & Jinsong YanDepartment of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, ChinaFuxu Wang & Xuejun ZhangDepartment of Hematology, The First Hospital of Jilin University, Changchun, ChinaSujun GaoDepartment of Hematology, Qilu Hospital, Shandong University, Jinan, ChinaChuanfang LiuBeijing BFR Gene Diagnostics, Beijing, ChinaXiangjun LiuAuthorsLiping DouView au.

7222175），军事医疗支持创新与生成特别计划（21WQ034），健康保护特别研究发现（21BJZ30），北京新星计划交叉项目（20230484407），后勤独立研究计划（2023HQZ09），首都健康改善与研究基金（2024-2-5063）。作者信息作者注意到这些作者做出了同样的贡献：窦丽萍，赵燕丽，杨晶晶，邓磊，王楠。，中国刘向军（音）作者李平（音）。

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PubMed Google ScholarContributionsLiping Dou: Conceptualization, Project administration, Funding acquisition, Writing-original draft; Yanli Zhao: Investigation, Data curation, Formal analysis; Jingjing Yang: Data curation, Methodology, Validation, Visualization; Lei Deng: Investigation, Data curation, Methodology; Nan Wang: Data curation, Validation, Visualization; Xiawei Zhang: Data curation; Qingyang Liu: Data curation; Yan Yang: Investigation; Zhijie Wei: Investigation; Fuxu Wang: Investigation; Yifan Jiao: Data curation; Fei Li: Investigation; Songhua Luan: Investigation; Liangding Hu: Project administration, Supervision; Sujun Gao: Project administration; Chuanfang Liu: Project administration; Xiangjun Liu: Project administration; Jinsong Yan:Project administration, Supervision; Xuejun Zhang: Project administration, Supervision; Fang Zhou: Project administration, Supervision; Peihua Lu: Project administration, Supervision; Daihong Liu: Conceptualization, Funding acquisition, Supervision, Writing-Reviewing and Editing.

PubMed谷歌学术贡献Sliping Dou：概念化，项目管理，资金获取，撰写原稿；赵燕丽：调查，数据整理，形式分析；杨晶晶：数据管理，方法论，验证，可视化；雷登：调查，数据管理，方法论；；张夏伟：数据管理；刘庆阳：数据管理；晏阳：调查；魏志杰：调查；王福旭：调查；焦一凡：数据管理；费丽：调查；松花鸾：调查；胡良定：项目管理、监督；高苏军：项目管理；刘传芳：项目管理；刘向军：项目管理；严劲松：项目管理、监督；张学军：项目管理、监督；方舟：项目管理、监督；陆培华：项目管理、监督；刘代红：概念化，资金获取，监督，写作审查和编辑。

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Reprints and permissionsAbout this articleCite this articleDou, L., Zhao, Y., Yang, J. et al. Ruxolitinib plus steroids for acute graft versus host disease: a multicenter, randomized, phase 3 trial.

转载和许可本文引用本文Dou，L.，Zhao，Y.，Yang，J。等人。Ruxolitinib加类固醇治疗急性移植物抗宿主病：一项多中心，随机，3期临床试验。

Sig Transduct Target Ther 9, 288 (2024). https://doi.org/10.1038/s41392-024-01987-xDownload citationReceived: 22 May 2024Revised: 30 August 2024Accepted: 18 September 2024Published: 23 October 2024DOI: https://doi.org/10.1038/s41392-024-01987-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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