芦可替尼治疗糖皮质激素难治性慢性移植物抗宿主病。
Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.
机构信息
From the Department of Medicine I, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg (R.Z.), and Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden (J.M.M.) - both in Germany; the Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, ASST Spedali Civili di Brescia, University of Brescia, Brescia (N.P.), UOC di Oncoematologia e TMO, Dipartimento Oncologico "la Maddalena," Palermo (M.M.), and Dipartimento di Oncoematologia Pediatrica, IRCCS, Ospedale Pediatrico Bambino Gesu', Sapienza, Università di Roma, Rome (F.L.) - all in Italy; the BMT Unit, Tel Aviv (Sourasky) Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (R.R.); the Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (S.K.H.); the Department of Medicine, Sheikh Shakhbout Medical City, Mayo Clinic, Abu Dhabi, United Arab Emirates (S.K.H.); UCL Cancer Institute, Institute of Immunity and Transplantation, London (R.C.); the Department of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland (S.G.); Acibadem University Hospital, Hematology Department, Istanbul, Turkey (A.U.); Incyte, Wilmington, DE (P.L.); Novartis Pharma, Basel, Switzerland (N.H., T.S.); Novartis Pharmaceuticals, East Hanover, NJ (M.G.); the Fred Hutchinson Cancer Research Center, Seattle (S.J.L.); and the Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan (T.T.).
出版信息
N Engl J Med. 2021 Jul 15;385(3):228-238. doi: 10.1056/NEJMoa2033122.
BACKGROUND
Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.
METHODS
This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24.
RESULTS
A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups.
CONCLUSIONS
Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).
背景
慢性移植物抗宿主病（GVHD）是所有异基因干细胞移植的主要并发症，约有 50%的患者会发展为糖皮质激素难治或依赖。缺乏针对慢性 GVHD 的二线治疗的 3 期随机研究的有力数据。在回顾性调查中，Janus 激酶（JAK1-JAK2）抑制剂鲁索利替尼在糖皮质激素难治或依赖的慢性 GVHD 患者中显示出潜在疗效。
方法
这项 3 期开放标签、随机试验评估了 10 毫克每日两次的鲁索利替尼的疗效和安全性，与研究者从 10 种常用选择中选择的治疗方案（对照）相比，这些方案被认为是最佳可用护理，在 12 岁或以上患有中度或重度糖皮质激素难治或依赖的慢性 GVHD 的患者中。主要终点是第 24 周的总体反应（完全或部分反应）；关键次要终点是第 24 周时无失败生存率和改良 Lee 症状量表评分的改善。
结果
共有 329 名患者接受了随机分组；165 名患者接受鲁索利替尼治疗，164 名患者接受对照治疗。第 24 周时，鲁索利替尼组的总体反应大于对照组（49.7%对 25.6%；优势比，2.99；P<0.001）。鲁索利替尼的无失败生存率高于对照组（>18.6 个月对 5.7 个月；风险比，0.37；P<0.001），症状反应更高（24.2%对 11.0%；优势比，2.62；P=0.001）。截至第 24 周时，最常见（发生率≥10%）的 3 级或更高级别的不良事件为血小板减少症（鲁索利替尼组为 15.2%，对照组为 10.1%）和贫血（12.7%和 7.6%）。两组间巨细胞病毒感染和再激活的发生率相似。
结论
在糖皮质激素难治或依赖的慢性 GVHD 患者中，鲁索利替尼显著提高了总体反应、无失败生存率和症状反应。鲁索利替尼的血小板减少症和贫血发生率较高。（由诺华公司和因塞特公司资助；REACH3 临床试验.gov 编号，NCT03112603。）
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