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芦可替尼治疗糖皮质激素难治性急性移植物抗宿主病
Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease


Robert Zeiser ... 其他 • 2020.05.07
相关阅读
• 急性移植物抗宿主病的新疗法 • 微生物群作为异基因造血细胞移植患者死亡率的预测因素

摘要


背景

急性移植物抗宿主病(GVHD)仍然是异基因干细胞移植的主要局限,标准糖皮质激素治疗并不能使所有患者达到缓解。在一项2期试验中,芦可替尼(选择性Janus激酶[JAK1和JAK2]抑制剂)对糖皮质激素难治性急性GVHD患者表现出潜在疗效。

 

方法

我们开展了一项多中心、随机、开放标签3期试验,本试验在异基因干细胞移植后患糖皮质激素难治性急性GVHD的≥12岁患者中比较了芦可替尼口服治疗(每日2次,每次10 mg)与研究者选择的治疗(从9种常用治疗方案中选择,用作对照)的疗效和安全性。主要终点是第28日的总缓解率(完全缓解或部分缓解)。关键次要终点是第56日的持久总缓解率。

 

结果

共计309例患者被随机分组,其中154例被分配至芦可替尼组,155例被分配至对照组。芦可替尼组第28日的总缓解率高于对照组(62%[96例患者] vs. 39%[61];比值比,2.64;95%置信区间[CI],1.65~4.22;P<0.001)。芦可替尼组第56日的持久总缓解率高于对照组(40%[61例患者] vs. 22%[34];比值比,2.38;95% CI,1.43~3.94;P<0.001)。在芦可替尼组和对照组中,6个月时缓解消失的估计累积发生率分别为10%和39%。芦可替尼组的中位无失败生存期显著超过对照组(5.0个月vs. 1.0个月;血液学疾病复发或进展、与复发不相关死亡或因急性GVHD加用新的全身性治疗的风险比,0.46;95% CI,0.35~0.60)。芦可替尼组和对照组的中位总生存期分别为11.1个月和6.5个月(死亡的风险比,0.83;95% CI,0.60~1.15)。截至第28日的最常见不良事件包括血小板减少(芦可替尼组152例患者中的50例[33%]和对照组150例患者中的27例[18%])、贫血(分别为46例[30%]和42例[28%])和巨细胞病毒感染(分别为39例[26%]和31例[21%])。

 

结论

芦可替尼显著改善了疗效结局,最常见毒性作用血小板减少的发生率高于对照组(由诺华制药资助,REACH2在ClinicalTrials.gov注册号为NCT02913261)。





作者信息

Robert Zeiser, M.D., Nikolas von Bubnoff, M.D., Jason Butler, F.R.A.C.P., Mohamad Mohty, M.D., Ph.D., Dietger Niederwieser, M.D., Reuven Or, M.D., Jeff Szer, F.R.A.C.P., Eva M. Wagner, M.D., Tsila Zuckerman, M.D., Bruyère Mahuzier, Pharm.D., Judith Xu, M.Sc., Celine Wilke, M.D., Kunal K. Gandhi, M.D., M.P.H., and Gérard Socié, M.D., Ph.D. for the REACH2 Trial Group*
From the Department of Medicine I, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg (R.Z.), the Department of Hematology and Oncology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck (N.B.), the Department of Hematology and Oncology, University of Leipzig, Leipzig (D.N.), and the Department of Hematology, Oncology, and Pneumology, University Medical Center Mainz, Mainz (E.M.W.) — all in Germany; the Department of Bone Marrow Transplantation, Royal Brisbane and Women’s Hospital, Brisbane, QLD (J.B.), and the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC (J.S.) — all in Australia; Hôpital Saint-Antoine, Assistance Publique–Hôpitaux de Paris (AP-HP), Université Sorbonne and INSERM Unité Mixte de Recherche (UMR) 938 (M.M.), and AP-HP, Hématologie–Transplantation, Hôpital St. Louis, Université de Paris and INSERM UMR 976 (G.S.), Paris, and Novartis Pharma, Rueil-Malmaison (B.M.) — all in France; the Cancer Immunotherapy and Immunobiology Research Center, Hadassah University Hospital, Jerusalem (R.O.), and the Hematology Institute and Bone Marrow Transplantation, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa (T.Z.) — both in Israel; Novartis Pharmaceuticals, East Hanover, NJ (J.X., K.K.G.); and Novartis Pharma, Basel, Switzerland (C.W.). Address reprint requests to Dr. Zeiser at the Department of Hematology, Oncology, and Stem Cell Transplantation, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany, or at robert.zeiser@uniklinik-freiburg.de. *A list of the investigators in the REACH2 Trial Group is provided in the Supplementary Appendix, available at NEJM.org.

 

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