异基因造血干细胞移植治疗10例重型再生障碍性贫血
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摘要
背景:再生障碍性贫血目前的一线治疗方案为免疫抑制治疗或造血干细胞移植治疗,其中同胞全合异基因造血干细胞疗效最好。近年来,随着各移植中心技术的进步,单倍体移植也越来越多应用于再生障碍性贫血的治疗。目的:探讨异基因造血干细胞移植治疗重型再生障碍性贫血的临床效果。方法:回顾性分析2014年3月至2018年2月进行异基因造血干细胞移植的10例重型再生障碍性贫血患者的临床资料,行同胞相合异基因造血干细胞移植患者7例,行单倍体异基因造血干细胞移植患者3例。结果与结论:①所有患者移植后均获得造血重建,粒系植入中位时间为移植后10(9-18) d,血小板植入中位时间为移植后15.5(8-39) d,红系植入中位时间为移植后16(11-35) d;移植后1个月骨穿检查均获得疾病缓解;②Ⅱ-Ⅳ度急性移植物抗宿主病发生率40%,Ⅲ-Ⅳ度急性移植物抗宿主病发生率20%。巨细胞病毒血症发生率90%,EB病毒血症发生率60%;③中位随访时间7.3(2.5-49.7)个月,总生存率达80%,同胞相合移植者总生存率为100%;④结果表明,同胞相合异基因造血干细胞移植是治愈重型再生障碍性贫血的首选方法;缺乏同胞相合供者时,单倍体造血干细胞移植也可以作为治疗重型再生障碍性贫血的一种重要移植方式。
BACKGROUND: Nowadays the first-line therapy for aplastic anemia is immunosuppressive therapy or hematopoietic stem cell transplantation. Human leukocyte antigen(HLA)-matched sibling donor allogeneic hematopoietic stem cell transplantation achieves best outcomes. With the development of hematopoietic stem cell transplantation technique, HLA haploidentical hematopoietic stem cell transplantation is popularized in the treatment of aplastic anemia.OBJECTIVE: To evaluate the clinical efficacy of allogeneic hematopoietic stem cell transplantation for severe aplastic anemia.METHODS: Ten cases of severe aplastic anemia who had been treated with HLA matched sibling(n=7) or haploidentical allogeneic hematopoietic stem cell transplantation(n=3) from March 2014 to February 2018 were retrospectively analyzed and reviewed.RESULTS AND CONCLUSION:(1) Hematopoiesis reconstitution was achieved in all the 10 cases. The median time of neutrophils, platelets and reticulocytes was 10(9-18), 15.5(8-39) and 16(11-35) days after transplantation, respectively. One month after transplantation, remission of aplastic anemia was achieved in each case, as confirmed by bone marrow biopsy.(2) Grade II-IV acute graft-versus-host disease occurred in 40% patients, grade III-IV acute graft-versus-host disease in 20% patients, cytomegalovirus viremia in 90% patients, and epstein-barr virus infection in 60% patients.(3) The median follow-up time was 7.3(2.5-49.7) months. The overall survival rate was 80%, and the survival rate of sibling recipients was 100%. To conclude, HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation is the first choice to cure severe aplastic anemia, and haploidentical hematopoietic stem cell transplantation can also be used as an important transplantation method for severe aplastic anemia when lack of matched sibling donors.
BACKGROUND: Nowadays the first-line therapy for aplastic anemia is immunosuppressive therapy or hematopoietic stem cell transplantation. Human leukocyte antigen(HLA)-matched sibling donor allogeneic hematopoietic stem cell transplantation achieves best outcomes. With the development of hematopoietic stem cell transplantation technique, HLA haploidentical hematopoietic stem cell transplantation is popularized in the treatment of aplastic anemia.OBJECTIVE: To evaluate the clinical efficacy of allogeneic hematopoietic stem cell transplantation for severe aplastic anemia.METHODS: Ten cases of severe aplastic anemia who had been treated with HLA matched sibling(n=7) or haploidentical allogeneic hematopoietic stem cell transplantation(n=3) from March 2014 to February 2018 were retrospectively analyzed and reviewed.RESULTS AND CONCLUSION:(1) Hematopoiesis reconstitution was achieved in all the 10 cases. The median time of neutrophils, platelets and reticulocytes was 10(9-18), 15.5(8-39) and 16(11-35) days after transplantation, respectively. One month after transplantation, remission of aplastic anemia was achieved in each case, as confirmed by bone marrow biopsy.(2) Grade II-IV acute graft-versus-host disease occurred in 40% patients, grade III-IV acute graft-versus-host disease in 20% patients, cytomegalovirus viremia in 90% patients, and epstein-barr virus infection in 60% patients.(3) The median follow-up time was 7.3(2.5-49.7) months. The overall survival rate was 80%, and the survival rate of sibling recipients was 100%. To conclude, HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation is the first choice to cure severe aplastic anemia, and haploidentical hematopoietic stem cell transplantation can also be used as an important transplantation method for severe aplastic anemia when lack of matched sibling donors.
引文
[1]张然,夏凌辉.重型再生障碍性贫血的移植治疗[J].临床内科杂志,2017,34(12):803-806.
[2]Bacigalupo A,Brand R,Oneto R,et al.Treatment of acquired severe aplastic anemia:bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience.Semin Hematol.2000;37(1):69-80.
[3]付蓉.再生障碍性贫血诊断与治疗中国专家共识(2017年版)[J].中华血液学杂志,2017,38(1):1-5.
[4]Bacigalupo A.How I treat acquired aplastic anemia.Blood.2017;129(11):1428-1436.
[5]Killick SB,Bown N,Cavenagh J,et al.Guidelines for the diagnosis and management of adult aplastic anaemia.Br JHaematol.2016;172(2):187-207.
[6]Gupta V,Eapen M,Brazauskas R,et al.Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors.Haematologica.2010;95(12):2119-2125.
[7]Sangiolo D,Storb R,Deeg HJ,et al.Outcome of allogeneic hematopoietic cell transplantation from HLA-identical siblings for severe aplastic anemia in patients over 40 years of age.Biol Blood Marrow Transplant.2010;16(10):1411-1418.
[8]Shibuya A,Ishii S,Obinata K.Successful bone marrow plus cord blood stem cell transplantation in a girl who developed myelodysplastic syndrome from hepatitis-associated aplastic anemia treated with long-term immunosuppressants and growth factors.Hematology.2002;7(5):301-304.
[9]Fernández MN.Improving the outcome of cord blood transplantation:use of mobilized HSC and other cells from third party donors.Br J Haematol.2009;147(2):161-176.
[10]Sánchez-Ortega I,Arnan M,Pati?o B,et al.Early engraftment and full-donor chimerism after single-cord blood plus third-party donor dual transplantation in patients with high-risk acute leukemia.Bone Marrow Transplant.2014;49(1):145-147.
[11]van Besien K,Hari P,Zhang MJ,et al.Reduced intensity haplo plus single cord transplant compared to double cord transplant:improved engraftment and graft-versus-host disease-free,relapse-free survival.Haematologica.2016;101(5):634-643.
[12]Yamei W,Rongmu L,Yongbin C,et al.Improved outcome of haploidentical transplantation in severe aplastic anemia using reduced-intensity fludarabine-based conditioning.Oncotarget.2017;8(48):83817-83830.
[13]Xu L,Liu Z,Wu Y,et al.Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia.Eur JMed Res.2018;23(1):12.
[14]郭智,陈惠仁,刘晓东,等.低强度预处理联合移植后诱导免疫耐受的单倍体相合Allo-HSCT治疗重型再生障碍性贫血的临床疗效研究[J].中国实验血液学杂志,2016,24(6):1811-1816.
[15]Xu LP,Jin S,Wang SQ,et al.Upfront haploidentical transplant for acquired severe aplastic anemia:registry-based comparison with matched related transplant.J Hematol Oncol.2017;10(1):25.
[16]Im HJ,Koh KN,Choi ES,et al.Excellent outcome of haploidentical hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia.Biol Blood Marrow Transplant.2013;19(5):754-759.
[17]Penack O,Tridello G,Hoek J,et al.Influence of pre-existing invasive aspergillosis on allo-HSCT outcome:a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties.Bone Marrow Transplant.2016;51(3):418-423.
[18]Maury S,Bacigalupo A,Anderlini P,et al.Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning:a comparison with conventional conditioning regimen.Haematologica.2009;94(9):1312-1315.
[19]吴祥元.外周血干细胞移植的临床应用[J].实用医学杂志,2000,16(1):8.
[20]胡亮钉,陈虎,江岷,等.异基因外周血造血干细胞移植治疗骨髓增生异常综合征23例疗效分析[J].中华血液学杂志,2006,27(8):522-524.
[21]Schrezenmeier H,Passweg JR,Marsh JC,et al.Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia.Blood.2007;110(4):1397-1400.
[22]Bacigalupo A,SociéG,Schrezenmeier H,et al.Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia:survival advantage for bone marrow in all age groups.Haematologica.2012;97(8):1142-1148.
[23]黄晓军,陈育红,许兰平,等.G-CSF动员的骨髓及外周血干细胞移植治疗重型再生障碍性贫血[J].基础医学与临床,2004,24(3):54-57.
[24]刘会兰,孙自敏,耿良权,等.G-CSF动员后异基因骨髓联合外周血干细胞移植治疗血液病[J].临床内科杂志,2008,25(6):374-376.
[25]Ali AS,Al-Shraim M,Al-Hakami AM,et al.Epstein-Barr Virus:Clinical and Epidemiological Revisits and Genetic Basis of Oncogenesis.Open Virol J.2015;9:7-28.
[26]刘丽,冯四洲.异基因造血干细胞移植后EB病毒相关淋巴增殖性疾病研究进展[J].中华血液学杂志,2017,38(9):817-821.
[27]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[J].中华血液学杂志,2013,34(8):651-654.
[28]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.
[29]Morscio J,Tousseyn T.Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders.World JTransplant.2016;6(3):505-516.
[30]Patriarca F,Medeot M,Isola M,et al.Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab.Transpl Infect Dis.2013;15(3):259-267.
[31]Kobayashi S,Sano H,Mochizuki K,et al.Pre-emptive rituximab for Epstein-Barr virus reactivation after haplo-hematopoietic stem cell transplantation.Pediatr Int.2017;59(9):973-978.
[2]Bacigalupo A,Brand R,Oneto R,et al.Treatment of acquired severe aplastic anemia:bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience.Semin Hematol.2000;37(1):69-80.
[3]付蓉.再生障碍性贫血诊断与治疗中国专家共识(2017年版)[J].中华血液学杂志,2017,38(1):1-5.
[4]Bacigalupo A.How I treat acquired aplastic anemia.Blood.2017;129(11):1428-1436.
[5]Killick SB,Bown N,Cavenagh J,et al.Guidelines for the diagnosis and management of adult aplastic anaemia.Br JHaematol.2016;172(2):187-207.
[6]Gupta V,Eapen M,Brazauskas R,et al.Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors.Haematologica.2010;95(12):2119-2125.
[7]Sangiolo D,Storb R,Deeg HJ,et al.Outcome of allogeneic hematopoietic cell transplantation from HLA-identical siblings for severe aplastic anemia in patients over 40 years of age.Biol Blood Marrow Transplant.2010;16(10):1411-1418.
[8]Shibuya A,Ishii S,Obinata K.Successful bone marrow plus cord blood stem cell transplantation in a girl who developed myelodysplastic syndrome from hepatitis-associated aplastic anemia treated with long-term immunosuppressants and growth factors.Hematology.2002;7(5):301-304.
[9]Fernández MN.Improving the outcome of cord blood transplantation:use of mobilized HSC and other cells from third party donors.Br J Haematol.2009;147(2):161-176.
[10]Sánchez-Ortega I,Arnan M,Pati?o B,et al.Early engraftment and full-donor chimerism after single-cord blood plus third-party donor dual transplantation in patients with high-risk acute leukemia.Bone Marrow Transplant.2014;49(1):145-147.
[11]van Besien K,Hari P,Zhang MJ,et al.Reduced intensity haplo plus single cord transplant compared to double cord transplant:improved engraftment and graft-versus-host disease-free,relapse-free survival.Haematologica.2016;101(5):634-643.
[12]Yamei W,Rongmu L,Yongbin C,et al.Improved outcome of haploidentical transplantation in severe aplastic anemia using reduced-intensity fludarabine-based conditioning.Oncotarget.2017;8(48):83817-83830.
[13]Xu L,Liu Z,Wu Y,et al.Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia.Eur JMed Res.2018;23(1):12.
[14]郭智,陈惠仁,刘晓东,等.低强度预处理联合移植后诱导免疫耐受的单倍体相合Allo-HSCT治疗重型再生障碍性贫血的临床疗效研究[J].中国实验血液学杂志,2016,24(6):1811-1816.
[15]Xu LP,Jin S,Wang SQ,et al.Upfront haploidentical transplant for acquired severe aplastic anemia:registry-based comparison with matched related transplant.J Hematol Oncol.2017;10(1):25.
[16]Im HJ,Koh KN,Choi ES,et al.Excellent outcome of haploidentical hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia.Biol Blood Marrow Transplant.2013;19(5):754-759.
[17]Penack O,Tridello G,Hoek J,et al.Influence of pre-existing invasive aspergillosis on allo-HSCT outcome:a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties.Bone Marrow Transplant.2016;51(3):418-423.
[18]Maury S,Bacigalupo A,Anderlini P,et al.Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning:a comparison with conventional conditioning regimen.Haematologica.2009;94(9):1312-1315.
[19]吴祥元.外周血干细胞移植的临床应用[J].实用医学杂志,2000,16(1):8.
[20]胡亮钉,陈虎,江岷,等.异基因外周血造血干细胞移植治疗骨髓增生异常综合征23例疗效分析[J].中华血液学杂志,2006,27(8):522-524.
[21]Schrezenmeier H,Passweg JR,Marsh JC,et al.Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia.Blood.2007;110(4):1397-1400.
[22]Bacigalupo A,SociéG,Schrezenmeier H,et al.Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia:survival advantage for bone marrow in all age groups.Haematologica.2012;97(8):1142-1148.
[23]黄晓军,陈育红,许兰平,等.G-CSF动员的骨髓及外周血干细胞移植治疗重型再生障碍性贫血[J].基础医学与临床,2004,24(3):54-57.
[24]刘会兰,孙自敏,耿良权,等.G-CSF动员后异基因骨髓联合外周血干细胞移植治疗血液病[J].临床内科杂志,2008,25(6):374-376.
[25]Ali AS,Al-Shraim M,Al-Hakami AM,et al.Epstein-Barr Virus:Clinical and Epidemiological Revisits and Genetic Basis of Oncogenesis.Open Virol J.2015;9:7-28.
[26]刘丽,冯四洲.异基因造血干细胞移植后EB病毒相关淋巴增殖性疾病研究进展[J].中华血液学杂志,2017,38(9):817-821.
[27]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[J].中华血液学杂志,2013,34(8):651-654.
[28]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.
[29]Morscio J,Tousseyn T.Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders.World JTransplant.2016;6(3):505-516.
[30]Patriarca F,Medeot M,Isola M,et al.Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab.Transpl Infect Dis.2013;15(3):259-267.
[31]Kobayashi S,Sano H,Mochizuki K,et al.Pre-emptive rituximab for Epstein-Barr virus reactivation after haplo-hematopoietic stem cell transplantation.Pediatr Int.2017;59(9):973-978.