EB病毒特异细胞毒T淋巴细胞治疗造血干细胞移植术后伴急性移植物抗宿主病的EBV感染的临床分析
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摘要
目的:研究EBV特异杀伤T淋巴细胞(EBV-CTL)治疗造血干细胞移植术后合并急性移植物抗宿主病的EBV感染的疗效和安全性。方法:回顾性分析北京大学航天中心医院血液科2015年1月至2017年5月31日接受EBV-CTL输注治疗异基因造血干细胞移植后EBV感染12例的临床特征,疗效和安全性指标。结果:12例移植后接受EBV-CTL治疗的病例中,9例未接受利妥昔单克隆抗体治疗,4例发展为移植后淋巴细胞增殖性疾病(PTLD)(含3例使用利妥昔单克隆抗体病例)。出现EBV感染中位时间47(22-71)d,CTL输注前抗病毒治疗中位时间10(8-33)d,开始CTL治疗中位时间为移植后59(34-86)d。43例次细胞输注过程顺利,无相关不良事件发生,未见原有GVHD加重。第1疗程结束后9例获得CR,1例获得PR,2例获得NR,治疗后复发4例。第2疗程结束时复发4例均获得再次CR,PR病例最终仍未获得CR,移植后5个月死于GVHD。2例NR中仅1例获得CR,另1例仍处于NR,移植后5个月死于移植相关感染。4例PTLD病例均获得PTLD治愈。结论:初步结果显示,异基因造血干细胞移植术后合并急性移植物抗宿主病的EBV感染接受EBV-CTL治疗具有较好的安全性,但是其疗效仍需要进一步临床深入研究和证实。
Objective: To investigate the efficiency and safety of treating Epstein-Barr virus(EBV) infection of acute graft versus host disease(GVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT) by EBV specific cytotoxic T lymphocytes(EBV-CTL). Methods: The Clinical characteristics, therapeutic efficacy and safety of 12 patients with EBV infection treated by EBV-CTL infusion after allo-HSCT in Department of Hemahlogy of Aero Space Center Hospital between Jan 2015 and May 2017 were analyzed retrospectioely. Results: Our of 12 cases received EBVCTL infusion after transplantation, 9 did not received Rituximab therapy due to the active infection, 4 cases including3 received Ritaximab progressed into posttransplantation lymphoroliferetive disease(PTLD). The median time of EBV infection was 47(22-71) days, median time of antivirus therapy before tramplantation was 10(8-33) days, median time of first CTL infusion was 59(34-86) days after transplatation. The 43 cases-time CTL infusion was performed smoothly,no related harmful evnts occoured, no progression of GVHD was observed. After the first course of infusion, complete remission(CR), Partial remssion(PR) and no remssion(NR) were obtained in 9, 1 and 2 patients respectively, the relapse was observed in 4 patients who then received the socond course of infusion and all reached CR, the patient in PR did not reathed CR finally and died of GVGD at 5 months after transpplantation. Only 1 out of 2 cases of NR obtained CR,another 1 still was in NR, and died of transplantation related infection at 5 months after transplantation. 4 cases of PTLD were all cared. Conclusion: Preliminary results of this study suggest that EBV-CTL infusion is safe for the EBV infection combined with acute GVHD after all-HSCT. However, a further larger scale clinical studies are needed to prove the efficiency.
Objective: To investigate the efficiency and safety of treating Epstein-Barr virus(EBV) infection of acute graft versus host disease(GVHD) after allogeneic hematopoietic stem cell transplantation(allo-HSCT) by EBV specific cytotoxic T lymphocytes(EBV-CTL). Methods: The Clinical characteristics, therapeutic efficacy and safety of 12 patients with EBV infection treated by EBV-CTL infusion after allo-HSCT in Department of Hemahlogy of Aero Space Center Hospital between Jan 2015 and May 2017 were analyzed retrospectioely. Results: Our of 12 cases received EBVCTL infusion after transplantation, 9 did not received Rituximab therapy due to the active infection, 4 cases including3 received Ritaximab progressed into posttransplantation lymphoroliferetive disease(PTLD). The median time of EBV infection was 47(22-71) days, median time of antivirus therapy before tramplantation was 10(8-33) days, median time of first CTL infusion was 59(34-86) days after transplatation. The 43 cases-time CTL infusion was performed smoothly,no related harmful evnts occoured, no progression of GVHD was observed. After the first course of infusion, complete remission(CR), Partial remssion(PR) and no remssion(NR) were obtained in 9, 1 and 2 patients respectively, the relapse was observed in 4 patients who then received the socond course of infusion and all reached CR, the patient in PR did not reathed CR finally and died of GVGD at 5 months after transpplantation. Only 1 out of 2 cases of NR obtained CR,another 1 still was in NR, and died of transplantation related infection at 5 months after transplantation. 4 cases of PTLD were all cared. Conclusion: Preliminary results of this study suggest that EBV-CTL infusion is safe for the EBV infection combined with acute GVHD after all-HSCT. However, a further larger scale clinical studies are needed to prove the efficiency.
引文
1古再丽努尔·吾甫尔,杨栋林,冯四洲,等.异基因造血干细胞移植后EB病毒相关性淋巴组织增殖性疾病的临床分析.临床血液学杂志,2017;30(2):225-228.
2陈静,顾晶.异基因造血干细胞移植后EB病毒感染的治疗进展.世界临床药物,2013;34(3):140-143.
3张钦,张斌,陈虎.造血干细胞移植后EB病毒感染的细胞免疫治疗.中国实验血液学杂志,2015;23(6):1763-1768.
4曹星辉,范志平,江千里,等.异基因造血干细胞移植后EB病毒再激活的危险因素分析.中国组织工程研究与临床康复,2011;15(23):4257-4261.
5鲍协炳,朱倩,仇惠英,等.异基因造血干细胞移植后EBV感染临床危险因素分析.中华血液学杂志,2016;37(2):138-143.
6韩婷婷,许兰平,刘代红,等.异基因造血干细胞移植后EB病毒感染情况分析.中华血液学杂志,2013;34(8):651-654.
7 Styczynski J,van der Velden W,Fox CP,et al.Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation:Sixth European Conference on Infections in Leukemia(ECIL-6)guidelines.Haematologica,2016;101(7):803-811.
8罗荣牡,吴晓雄,王静波,等.异基因造血干细胞移植后34例肠道重度移植物抗宿主病临床特点及预后分析.中国实验血液学杂志,2011;19(6):1501-1504.
9韩伟,黄晓军,陈欢,等.HLA配型不合造血干细胞移植GIAC方案100例临床分析.中华血液学杂志,2004;25(8):7-11.
10王莉红,任汉云,孙玉华,等.造血干细胞移植后单个核细胞EBV-DNA定量监测预测移植后淋巴增殖性疾病.中华血液学杂志,2010;31(2):73-76.
11牛国敏.CD20单克隆抗体治疗异基因造血干细胞移植后EB病毒相关性淋巴细胞增殖性疾病:2例报告并文献复习.2008.
12周健,韩利杰,祖璎玲,等.异基因造血干细胞移植后EB病毒相关中枢神经系统疾病六例.中华器官移植杂志,2016;37(8):477-481.
13 Yan CH,Liu QF,Wu DP,et al.Prophylactic Donor Lymphocyte Infusion(DLI)Followed by Minimal Residual Disease and Graftversus-Host Disease-Guided Multiple DLIs Could Improve Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Refractory/Relapsed Acute Leukemia.Biol Blood Marrow Transplant,2017;23(8):1311-1319.
14 Liu QF,Fan ZP,Zhang Y,et al.Sequential intensified conditioning and tapering of prophylactic immunosuppressants for graft-versushost disease in allogeneic hematopoietic stem cell transplantation for refractory leukemia.Biol Blood Marrow Transplant,2009;15(11):1376-1385.
15 Solomon SR,Sizemore CA,Ridgeway M,et al.Corticosteroid-free primary treatment of chronic extensive graft-versus-host disease incorporating rituximab.Biol Blood Marrow Transplant,2015;21(9):1576-1582.
16 Ceppi F,Duval M,Teira P,et al.Calcineurin inhibitor-free graftversus-host disease prophylaxis with sirolimus and mycophenolate mofetil in a second allogeneic stem cell transplantation forengraftment failure and rituximab-refractory Epstein-Barr virusinduced posttransplant lymphoproliferative disease.J Pediatr Hematol Oncol,2014;36(5):e319-321.
17 Van Hoef ME.Towards a rational graft-versus-host disease(GVHD)prophylaxis:rituximab should not be forgotten.Haematologica,2013;98(4):e40-41.
18邓锐,易海,范方毅,等.EB病毒-细胞毒性T细胞免疫治疗改善EB病毒相关非霍奇金淋巴瘤化疗效果的实验研究观察.中国输血杂志,2015;28(11):1304-1308.
19姜华.EB病毒特异性细胞毒性T淋巴细胞与肿瘤免疫治疗研究进展.国外医学(免疫学分册),2001;(5):240-243.
20 Heslop HE,Slobod KS,Pule MA,et al.Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients.Blood,2010;115(5):925-935.
21 Arasaratnam RJ,Leen AM.Adoptive T cell therapy for the treatment of viral infections.Ann Transl Med,2015;3(18):278.
22 Tzannou I,Leen AM.Preventing stem cell transplantationassociated viral infections using T-cell therapy.Immunotherapy,2015;7(7):793-810.
23 Heslop HE,Leen AM.T-cell therapy for viral infections.Hematology Am Soc Hematol Educ Program,2013;2013:342-347.
24 Dong L,Gao ZY,Chang LJ,et al.Adoptive transfer of cytomegalovirus/Epstein-Barr virus-specific immune effector cells for therapeutic and preventive/preemptive treatment of pediatric allogeneic cell transplant recipients.J Pediatr Hematol Oncol,2010;32(1):e31-37.
2陈静,顾晶.异基因造血干细胞移植后EB病毒感染的治疗进展.世界临床药物,2013;34(3):140-143.
3张钦,张斌,陈虎.造血干细胞移植后EB病毒感染的细胞免疫治疗.中国实验血液学杂志,2015;23(6):1763-1768.
4曹星辉,范志平,江千里,等.异基因造血干细胞移植后EB病毒再激活的危险因素分析.中国组织工程研究与临床康复,2011;15(23):4257-4261.
5鲍协炳,朱倩,仇惠英,等.异基因造血干细胞移植后EBV感染临床危险因素分析.中华血液学杂志,2016;37(2):138-143.
6韩婷婷,许兰平,刘代红,等.异基因造血干细胞移植后EB病毒感染情况分析.中华血液学杂志,2013;34(8):651-654.
7 Styczynski J,van der Velden W,Fox CP,et al.Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation:Sixth European Conference on Infections in Leukemia(ECIL-6)guidelines.Haematologica,2016;101(7):803-811.
8罗荣牡,吴晓雄,王静波,等.异基因造血干细胞移植后34例肠道重度移植物抗宿主病临床特点及预后分析.中国实验血液学杂志,2011;19(6):1501-1504.
9韩伟,黄晓军,陈欢,等.HLA配型不合造血干细胞移植GIAC方案100例临床分析.中华血液学杂志,2004;25(8):7-11.
10王莉红,任汉云,孙玉华,等.造血干细胞移植后单个核细胞EBV-DNA定量监测预测移植后淋巴增殖性疾病.中华血液学杂志,2010;31(2):73-76.
11牛国敏.CD20单克隆抗体治疗异基因造血干细胞移植后EB病毒相关性淋巴细胞增殖性疾病:2例报告并文献复习.2008.
12周健,韩利杰,祖璎玲,等.异基因造血干细胞移植后EB病毒相关中枢神经系统疾病六例.中华器官移植杂志,2016;37(8):477-481.
13 Yan CH,Liu QF,Wu DP,et al.Prophylactic Donor Lymphocyte Infusion(DLI)Followed by Minimal Residual Disease and Graftversus-Host Disease-Guided Multiple DLIs Could Improve Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Refractory/Relapsed Acute Leukemia.Biol Blood Marrow Transplant,2017;23(8):1311-1319.
14 Liu QF,Fan ZP,Zhang Y,et al.Sequential intensified conditioning and tapering of prophylactic immunosuppressants for graft-versushost disease in allogeneic hematopoietic stem cell transplantation for refractory leukemia.Biol Blood Marrow Transplant,2009;15(11):1376-1385.
15 Solomon SR,Sizemore CA,Ridgeway M,et al.Corticosteroid-free primary treatment of chronic extensive graft-versus-host disease incorporating rituximab.Biol Blood Marrow Transplant,2015;21(9):1576-1582.
16 Ceppi F,Duval M,Teira P,et al.Calcineurin inhibitor-free graftversus-host disease prophylaxis with sirolimus and mycophenolate mofetil in a second allogeneic stem cell transplantation forengraftment failure and rituximab-refractory Epstein-Barr virusinduced posttransplant lymphoproliferative disease.J Pediatr Hematol Oncol,2014;36(5):e319-321.
17 Van Hoef ME.Towards a rational graft-versus-host disease(GVHD)prophylaxis:rituximab should not be forgotten.Haematologica,2013;98(4):e40-41.
18邓锐,易海,范方毅,等.EB病毒-细胞毒性T细胞免疫治疗改善EB病毒相关非霍奇金淋巴瘤化疗效果的实验研究观察.中国输血杂志,2015;28(11):1304-1308.
19姜华.EB病毒特异性细胞毒性T淋巴细胞与肿瘤免疫治疗研究进展.国外医学(免疫学分册),2001;(5):240-243.
20 Heslop HE,Slobod KS,Pule MA,et al.Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients.Blood,2010;115(5):925-935.
21 Arasaratnam RJ,Leen AM.Adoptive T cell therapy for the treatment of viral infections.Ann Transl Med,2015;3(18):278.
22 Tzannou I,Leen AM.Preventing stem cell transplantationassociated viral infections using T-cell therapy.Immunotherapy,2015;7(7):793-810.
23 Heslop HE,Leen AM.T-cell therapy for viral infections.Hematology Am Soc Hematol Educ Program,2013;2013:342-347.
24 Dong L,Gao ZY,Chang LJ,et al.Adoptive transfer of cytomegalovirus/Epstein-Barr virus-specific immune effector cells for therapeutic and preventive/preemptive treatment of pediatric allogeneic cell transplant recipients.J Pediatr Hematol Oncol,2010;32(1):e31-37.