芦可替尼挽救性治疗激素难治性移植物抗宿主病:一项单中心回顾性分析

赵菲; 王佳丽; 施圆圆; 杨栋林; 魏嘉璘; 庞爱明; 何祎; 姜尔烈; 冯四洲; 韩明哲

doi:10.13201/j.issn.1004-2806.2020.01.005

芦可替尼挽救性治疗激素难治性移植物抗宿主病:一项单中心回顾性分析

- 中国医学科学院北京协和医学院血液学研究所血液病医院(天津, 300020)
基金项目:
国家自然科学基金(No:81670171)

中国医学科学院医学与健康科技创新工程(No:2016-I2M-3-023)

详细信息

通讯作者: 何祎,E-mail:heyi@ihcams.ac.cn

中图分类号: R457.7

收稿日期: 2019-09-03

The utility of ruxolitinib in patients with steroid-refractory graft-versus-host disease:retrospective analysis of a single center

- Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China

More Information

Corresponding author: HE Yi, E-mail: heyi@ihcams.ac.cn

Received Date: 03 September 2019

摘要

摘要: 目的:分析芦可替尼治疗异基因造血干细胞移植后合并糖皮质激素难治性移植物抗宿主病(SR-GVHD)的疗效及预后。方法:回顾性分析42例移植后合并SR-GVHD患者的临床资料,其中糖皮质激素难治性急性移植物抗宿主病(SR-aGVHD)20例(均为Ⅲ~Ⅳ度),糖皮质激素难治性慢性移植物抗宿主病(SR-cGVHD)22例(均为中/重度)。确诊SR-GVHD的患者给予芦可替尼挽救性治疗,在初始治疗的第28天进行疗效评估,并对影响疗效的相关因素进行分析。结果:20例SR-aGVHD患者治疗28天整体反应率(ORR)为60.0%(12/20),其中完全缓解(CR)率为20.0%(4/20);中位随访时间37.7(1~107)周,其6个月和1年的总体生存率(OS)分别为55.0%(95%CI 33.24%~76.76%)、45.0%(95%CI 23.24%~66.76%);6个月和1年的无失败生存率(FFS)分别为50.0%(95%CI 28.05%~71.95%)、40.0%(95%CI 18.44%~61.56%)。22例SR-cGVHD患者治疗28天ORR为72.7%(16/22),其中CR率9.1%(2/22);中位随访时间76.9(5~110)周,治疗6个月及1年的OS分别为77.3%(95%CI 59.86%~94.74%)、72.7%(95%CI 54.06%~91.32%),6个月及1年的FFS分别为77.3%(95%CI 59.86%~94.74%)、72.7%(95%CI 54.06%~91.32%)。单因素分析显示,Ⅳ度aGVHD、重度cGVHD可能预示芦可替尼治疗疗效不佳(ORR:Ⅲ度vsⅣ度为88.9%vs 36.4%,P=0.028;中度vs重度为92.3%vs 44.4%,P=0.023)。结论:芦可替尼是挽救性治疗SR-GVHD安全、有效的药物,需要大规模的前瞻性研究证实。
- 糖皮质激素难治性移植物抗宿主病 /
- 异基因造血干细胞移植 /
- 芦可替尼
Abstract: Objective:To evaluate the efficacy and prognosis of ruxolitinib in the treatment of steroid-refractory graft-versus-host disease(SR-GVHD) after allogeneic hematopoietic stem cell transplantation.Method:A total of 42 patients who had SR-GVHD were analyzed retrospectively.The 42 patients were classified to SR-aGVHD(n=20,all grade Ⅲ or Ⅳ) or SR-cGVHD(n=22,all moderate or severe) group.All patients enrolled were given ruxolitinib as salvage therapy.The efficacy of ruxolitinib was evaluated at day 28 of the initial treatment.The associated factors on clinical outcome were analyzed.Result:The overall response rate(ORR) was 60.0% [20.0% complete response(CR)] in SR-aGVHD group,while for SR-cGVHD group the ORR was 72.7%(9.1% CR).The 6-month and 1-year overall survival(OS) were 55.0%(95%CI 33.24%-76.76%) and 45.0%(95%CI 23.24%-66.76%) respectively in SR-aGVHD group.The median follow-up time was 37.7(1-107) weeks,the 6-month and 1-year failure-free survival(FFS) were 50.0%(95%CI 28.05%-71.95%) and 40.0%(95%CI 18.44%-61.56%) respectively in SR-aGVHD patients.While for SR-cGVHD patients,the median follow-up time was 76.9(5-110) weeks,the 6-month and 1-year OS were 77.3%(95%CI 59.86%-94.74%) and 72.7%(95%CI 54.06%-91.32%)respectively.The 6-month and 1-year FFS was equal to data of OS.Univariate analysis showed that gradeⅣaGVHD and severe cGVHD may indicate poor efficacy of ruxolitinib(ORR:grade Ⅲ vs Ⅳ was 88.9% vs 36.4%,P=0.028;moderate vs severe was 92.3% vs 44.4%,P=0.023).Conclusion:Ruxolitinib may constitute a promising new salvage treatment option for SR-GVHD,which should be verified in prospective trials and more clinical practice.
- steroid-refractory graft-versus-host disease /
- allogeneic hematopoietic stem cell transplantation /
- ruxolitinib

HTML全文

参考文献(22)

[1]	Martin PJ,Rizzo JD,Wingard JR,et al.First-and second-line systemic treatment of acute graft-versus-host disease:recommendations of the American Society of Blood and Marrow Transplantation[J].Biol Blood Marrow Transplant,2012,18:1150-1163.
[2]	Arai S,Margolis J,Zahurak M,et al.Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment[J].Biol Blood Marrow Transplant,2002,8:155-160.
[3]	Zeiser R,Burchert A,Lengerke C,et al.Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation:a multicenter survey[J].Leukemia,2015,29:2062-2068.
[4]	Modi B,Hernandez-Henderson M,Yang D,et al.Ruxolitinib as Salvage Therapy for Chronic Graft-versus-Host Disease[J].Biol Blood Marrow Transplant,2019,25:265-269.
[5]	Jaglowski SM,Devine SM.Graft-versus-host disease:why have we not made more progress?[J].Curr Opin Hematol,2014,21:141-147.
[6]	Martin PJ,Lee SJ,Przepiorka D,et al.National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:VI.The 2014 Clinical Trial Design Working Group Report[J].Biol Blood Marrow Transplant,2015,21:1343-1359.
[7]	Rowlings PA,Przepiorka D,Klein JP,et al.IBMTR Severity Index for grading acute graft-versus-host disease:retrospective comparison with Glucksberg grade[J].Br J Haematol,1997,97:855-864.
[8]	Jagasia MH,Greinix HT,Arora M,et al.National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:I.The 2014 Diagnosis and Staging Working Group report[J].Biol Blood Marrow Transplant,2015,21:389-401.e1.
[9]	Pavletic SZ.Response as an end point in treatment trials for acute GVHD[J].Bone Marrow Transplant,2012,47:161-163.
[10]	Yalniz FF,Hefazi M,McCullough K,et al.Safety and Efficacy of Infliximab Therapy in the Setting of Steroid-Refractory Acute Graft-versus-Host Disease[J].Biol Blood Marrow Transplant,2017,23:1478-1484.
[11]	De Jong CN,Saes L,Klerk CPW,et al.Etanercept for steroid-refractory acute graft-versus-host disease:A single center experience[J].PLoS One,2017,12:e0187184.
[12]	Furlong T,Martin P,Flowers ME,et al.Therapy with mycophenolate mofetil for refractory acute and chronic GVHD[J].Bone Marrow Transplant,2009,44:739-748.
[13]	Kim JG,Sohn SK,Kim DH,et al.Different efficacy of mycophenolate mofetil as salvage treatment for acute and chronic GVHD after allogeneic stem cell transplant[J].Eur J Haematol,2004,73:56-61.
[14]	Spoerl S,Mathew NR,Bscheider M,et al.Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease[J].Blood,2014,123:3832-3842.
[15]	Neumann T,Schneidewind L,Weigel M,et al.Ruxolitinib for Therapy of Graft-versus-Host Disease[J].Bio Med Res Int,2019,2019:8163780.
[16]	Escamilla Gomez V,García Gutiérrez V,Caballero-Velázquez T,et al.Ruxolitinib in Refractory Acute and Chronic Graft-Versus-Host Disease:A Multi-Center Survey Study[J].Blood,2017,130(Suppl 1):1983.
[17]	Jagasia M,Perales MA,Schroeder MA,et al.Results from REACH1,a Single-Arm Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease[J].Blood,2018,132(Suppl 1):601.
[18]	Ferreira AM,Pontes da Silva CA,Pereira AD,et al.Ruxolitinib in steroid-refractory chronic graft-versus-host disease:experience of a single center[J].Bone Marrow Transplant,2018,53:503-506.
[19]	Zhao Y,Shi J,Li X,et al.Ruxolitinib Combined with Etanercept for Patients with Corticosteroid-Refractory Acute Graft Versus Host Disease after Allogeneic Stem Cell Transplantation:A Multi-Center Prospective Study[J].Blood,2018,132(Suppl 1):4561.
[20]	Gorospe Sarasua L,Chinea-Rodriguez A,Almonacid-Sanchez C,et al.Radiological Improvement of Bronchiolitis Obliterans Following Hematopoietic Stem Cell Transplantation in a Patient Treated with Ruxolitinib[J].Arch Bronconeumol,2018,54:640-642.
[21]	Schoettler M,Subramaniam M,Margossian SP.Ruxolitinib and Steroid Refractory/Dependent Bronchiolitis Obliterans after Hematopoietic Cell Transplantation:A Steroid Sparing Agent That Also Resulted in Improved Lung Function in Children[J].Blood,2018,132(Suppl 1):3407.
[22]	Gor D,Sabin C,Prentice HG,et al.Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients:relationship between peak virus load,donor/recipient serostatus,acute GVHD and CMV disease[J].Bone Marrow Transplant,1998,21:597-605.