单倍体相合造血干细胞移植治疗儿童重型再生障碍性贫血
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摘要
背景:目前治疗儿童再生障碍性贫血的主要方法为强化免疫抑制治疗或干细胞移植,后者由于供者来源少而受到限制,HLA单倍体相合的异基因造血干细胞在白血病治疗中常见应用,在再生障碍性贫血治疗中较少应用。目的:探讨单倍体相合的造血干细胞移植联合胎盘来源的间充质干细胞移植治疗重型儿童再生障碍性贫血的疗效。方法:患儿,女,7岁,确诊重型再生障碍性贫血1年半,2012-07-09接受HLA单倍体相合的异基因骨髓及外周血单个核细胞联合胎盘来源间充质干细胞移植,供者为母亲。预处理采用氟达拉滨联合环磷酰胺和抗胸腺细胞球蛋白方案。结果与结论:移植后+9 d中性粒细胞>0.5×109 L-1,+12 d完成造血重建,+100 d查STR提示植入完成。移植后+8个月停用免疫抑制药物,未发生急、慢性移植物抗宿主病。患儿随访18个月,无病生存。结果表明,HLA单倍体相合的造血干细胞联合胎盘来源间充质细胞移植治疗儿童重型再生障碍性贫血是一种安全有效、值得探索的方法。
BACKGROUND: The main therapy of severe aplastic anemia in children is immunosuppressive therapy or stem cell transplantation, but the latter one is restricted due to few donor sources. Haploidentical hematopoietic stem cell transplantation is commonly used in leukemia, but it is still rarely reported in the treatment of aplastic anemia. OBJECTIVE: To investigate the effect of haploidentical hematopoietic stem cell transplantation combined with placenta-derived mesenchymal stem cell transplantation for children with severe aplastic anemia. METHODS: A 7-year-old girl who had been confirmed as having severe aplastic anemia for 1.5 years received a cotransplantation of haploidentical hematopoietic stem cells combined with placenta-derived mesenchymal stem cells on July 9th, 2012. The donor was her mother. The preconditioning regimen consisted of fludarabine, cyclophosphamide, and anti-thymocyte globulin. RESULTS AND CONCLUSION: Time of neutrophil recovery(> 0.5×109/L) was +9 days, and hematopoietic reconstruction was complete at +12 days. The short tandem repeat analysis showed 100% donor's genotype at +100 days. Immunosuppressive drugs were stopped at +8 months, and no acute or chronic graft-versus-host disease occurred. With a follow-up of 18 months, she was in the disease-free survival period. Our findings suggest that the cotransplantation of allogeneic haploidentical hematopoietic stem cells and placenta-derived mesenchymal stem cells is a new effective approach for children with severe aplastic anemia, which is worth exploring in the future.
BACKGROUND: The main therapy of severe aplastic anemia in children is immunosuppressive therapy or stem cell transplantation, but the latter one is restricted due to few donor sources. Haploidentical hematopoietic stem cell transplantation is commonly used in leukemia, but it is still rarely reported in the treatment of aplastic anemia. OBJECTIVE: To investigate the effect of haploidentical hematopoietic stem cell transplantation combined with placenta-derived mesenchymal stem cell transplantation for children with severe aplastic anemia. METHODS: A 7-year-old girl who had been confirmed as having severe aplastic anemia for 1.5 years received a cotransplantation of haploidentical hematopoietic stem cells combined with placenta-derived mesenchymal stem cells on July 9th, 2012. The donor was her mother. The preconditioning regimen consisted of fludarabine, cyclophosphamide, and anti-thymocyte globulin. RESULTS AND CONCLUSION: Time of neutrophil recovery(> 0.5×109/L) was +9 days, and hematopoietic reconstruction was complete at +12 days. The short tandem repeat analysis showed 100% donor's genotype at +100 days. Immunosuppressive drugs were stopped at +8 months, and no acute or chronic graft-versus-host disease occurred. With a follow-up of 18 months, she was in the disease-free survival period. Our findings suggest that the cotransplantation of allogeneic haploidentical hematopoietic stem cells and placenta-derived mesenchymal stem cells is a new effective approach for children with severe aplastic anemia, which is worth exploring in the future.
引文
[1]DeZern AE,Guinan EC.Therapy for aplastic anemia.Hematology Am Soc Hematol Educ Program.2011;2011:82-83.
[2]Locasciulli A,Oneto R,Bacigalupo A,et al.Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade:a report from the European Group for Blood and Marrow Transplantation(EBMT).Haematologica.2007;92(1):11-18.
[3]罗成娟,陈静,薛惠良,等.125例儿童再生障碍性贫血患者疗效分析[J].中华血液学杂志,2010,31(8):531-535.
[4]Young NS,Calado RT,Scheinberg P.Current concepts in the pathophysiology and treatment of aplastic anemia.Blood.2006;108(8):2509-2519.
[5]Deeg HJ,O'Donnell M,Tolar J,et al.Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy.Blood.2006;108(5):1485-1491.
[6]Scheinberg P,Wu CO,Nunez O,et al.Long-term outcome of pediatric patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine.J Pediatr.2008;153(6):814-819.
[7]Socie G,Mary JY,Schrezenmeier H,et al.Granulocytestimulating factor and severe aplastic anemia:a survey by the European Group for Blood and Marrow Transplantation(EBMT).Blood.2007;109(7):2794-2796.
[8]Afable MG 2nd,Tiu RV,Maciejewski JP.Clonal evolution in aplastic anemia.Hematology Am Soc Hematol Educ Program.2011;2011:90-95.
[9]Buchholz S,Dammann E,Koenecke Ch,et al.Allogeneic stem cell transplantation from related and unrelated donors for aplastic anaemia in adults--a single-centre experience.Ann Hematol.2008;87(7):551-556.
[10]Lacerda JF,Martins C,Carmo JA,et al.Haploidentical stem cell transplantation with purified CD34+cells after a chemotherapy-alone conditioning regimen in heavily transfused severe aplastic anemia.Biol Blood Marrow Transplant.2005;11(5):399-400.
[11]孙万军,黄雅静,胡海兰,等.HLA单倍型相合外周血干细胞联合间充质干细胞共移植治疗儿童重型再生障碍性贫血一例[J].中华血液学杂志,2012,33(3):242.
[12]冯术青,高峰,朱梦波,等.亲缘单倍体相合外周血造血干细胞移植治疗重症再生障碍性贫血[J/CD].中华移植杂志,2011,5(4):282-285.
[13]徐丽昕,曹永彬,王志红,等.单倍体相合造血干细胞联合脐带血间充质干细胞移植治疗急性重型再生障碍性贫血的疗效观察[J].中国实验血液学杂志,2011,19(5):1241-1245.
[14]Wang H,Yan H,Wang Z,et al.Cotransplantation of allogeneic mesenchymal and hematopoietic stem cells in children with aplastic anemia.Pediatrics.2012;129(6):e1612-1615.
[15]Passweg JR,Marsh JC.Aplastic anemia:first-line treatment by immunosuppression and sibling marrow transplantation.Hematology Am Soc Hematol Educ Program.2010;2010:36-42.
[16]徐勇,欧阳建,陈兵,等.HLA全相合异基因造血干细胞移植与免疫抑制剂治疗重型再生障碍性贫血的比较[J].中国组织工程研究与临床康复,2011,15(45):8513-8517.
[17]Armand P,Antin JH.Allogeneic stem cell transplantation for aplastic anemia.Biol Blood Marrow Transplant.2007;13(5):505-16.
[18]Karanes C,Nelson GO,Chitphakdithai P,et al.Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program.Biol Blood Marrow Transplant.2008;14(9 Suppl):8-15.
[19]鹿全意,郭勇,蔡玉贤,等.父母为供者的异基因外周血干细胞移植治疗白血病六例[J].中华器官移植杂志,2006,27(1):56-57.
[20]闫洪敏,王志东,朱玲,等.多种来源造血干细胞移植治疗重型再生障碍性贫血[J].中国组织工程研究与临床康复,2011,15(10):1884-1888.
[21]陈欣,冯四洲.异基因造血干细胞移植治疗重型再生障碍性贫血研究进展[J].中华血液学杂志,2012,33(11):963-967.
[22]韩伟,黄晓军,刘开彦,等.配型不合造血干细胞移植治疗重型再生障碍性贫血的疗效及安全性[J].中华内科杂志,2011,50(4):287-290.
[23]Fouillard L,Bensidhoum M,Bories D,et al.Engraftment of allogeneic mesenchymal stem cells in the bone marrow of a patient with severe idiopathic aplastic anemia improves stroma.Leukemia.2003;17(2):474-476.
[24]Champlin RE,Perez WS,Passweg JR,et al.Bone marrow transplantation for severe aplastic anemia:a randomized controlled study of conditioning regimens.Blood.2007;109(10):4582-4585.
[25]George B,Mathews V,Viswabandya A,et al.Fludarabine based reduced intensity conditioning regimens in children undergoing allogeneic stem cell transplantation for severe aplastic anemia.Pediatr Transplant.2008;12(1):14-19.
[26]Bacigalupo A,Socie'G,Lanino E,et al.Fludarabine,cyclophosphamide,antithymocyte globulin,with or without low dose total body irradiation,for alternative donor transplants,in acquired severe aplastic anemia:a retrospective study from the EBMT-SAA Working Party.Haematologica.2010;95(6):976-982.
[27]孙新.造血干细胞移植治疗再生障碍性贫血[J].中国小儿血液与肿瘤杂志,2009,14(4):145-146,150.
[28]Huang XJ,Chen YH,Xu LP,et al.Combined transplantation of G-CSF primed allogeneic bone marrow cells and peripheral blood stem cells in treatment of severe aplastic anemia.Chin Med J(Engl).2004;117(4):604-607.
[29]鹿全意,牛小青,郭勇,等.G-CSF动员的异基因外周血干细胞和骨髓联合移植治疗白血病[J].中国实验血液学杂志,2005,13(2):326-328.
[30]何丽,肖扬.再生障碍性贫血患者骨髓间充质干细胞体外生物学特性与其免疫调节缺陷[J].中国组织工程研究与临床康复,2010,14(1):179-182.
[31]黄永兰,黄绍良,黄科,等.再生障碍性贫血患儿骨髓间充质干细胞体外生物学特性及其与免疫抑制疗效的关系[J].中国当代儿科杂志,2008,10(1):9-13.
[2]Locasciulli A,Oneto R,Bacigalupo A,et al.Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade:a report from the European Group for Blood and Marrow Transplantation(EBMT).Haematologica.2007;92(1):11-18.
[3]罗成娟,陈静,薛惠良,等.125例儿童再生障碍性贫血患者疗效分析[J].中华血液学杂志,2010,31(8):531-535.
[4]Young NS,Calado RT,Scheinberg P.Current concepts in the pathophysiology and treatment of aplastic anemia.Blood.2006;108(8):2509-2519.
[5]Deeg HJ,O'Donnell M,Tolar J,et al.Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy.Blood.2006;108(5):1485-1491.
[6]Scheinberg P,Wu CO,Nunez O,et al.Long-term outcome of pediatric patients with severe aplastic anemia treated with antithymocyte globulin and cyclosporine.J Pediatr.2008;153(6):814-819.
[7]Socie G,Mary JY,Schrezenmeier H,et al.Granulocytestimulating factor and severe aplastic anemia:a survey by the European Group for Blood and Marrow Transplantation(EBMT).Blood.2007;109(7):2794-2796.
[8]Afable MG 2nd,Tiu RV,Maciejewski JP.Clonal evolution in aplastic anemia.Hematology Am Soc Hematol Educ Program.2011;2011:90-95.
[9]Buchholz S,Dammann E,Koenecke Ch,et al.Allogeneic stem cell transplantation from related and unrelated donors for aplastic anaemia in adults--a single-centre experience.Ann Hematol.2008;87(7):551-556.
[10]Lacerda JF,Martins C,Carmo JA,et al.Haploidentical stem cell transplantation with purified CD34+cells after a chemotherapy-alone conditioning regimen in heavily transfused severe aplastic anemia.Biol Blood Marrow Transplant.2005;11(5):399-400.
[11]孙万军,黄雅静,胡海兰,等.HLA单倍型相合外周血干细胞联合间充质干细胞共移植治疗儿童重型再生障碍性贫血一例[J].中华血液学杂志,2012,33(3):242.
[12]冯术青,高峰,朱梦波,等.亲缘单倍体相合外周血造血干细胞移植治疗重症再生障碍性贫血[J/CD].中华移植杂志,2011,5(4):282-285.
[13]徐丽昕,曹永彬,王志红,等.单倍体相合造血干细胞联合脐带血间充质干细胞移植治疗急性重型再生障碍性贫血的疗效观察[J].中国实验血液学杂志,2011,19(5):1241-1245.
[14]Wang H,Yan H,Wang Z,et al.Cotransplantation of allogeneic mesenchymal and hematopoietic stem cells in children with aplastic anemia.Pediatrics.2012;129(6):e1612-1615.
[15]Passweg JR,Marsh JC.Aplastic anemia:first-line treatment by immunosuppression and sibling marrow transplantation.Hematology Am Soc Hematol Educ Program.2010;2010:36-42.
[16]徐勇,欧阳建,陈兵,等.HLA全相合异基因造血干细胞移植与免疫抑制剂治疗重型再生障碍性贫血的比较[J].中国组织工程研究与临床康复,2011,15(45):8513-8517.
[17]Armand P,Antin JH.Allogeneic stem cell transplantation for aplastic anemia.Biol Blood Marrow Transplant.2007;13(5):505-16.
[18]Karanes C,Nelson GO,Chitphakdithai P,et al.Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program.Biol Blood Marrow Transplant.2008;14(9 Suppl):8-15.
[19]鹿全意,郭勇,蔡玉贤,等.父母为供者的异基因外周血干细胞移植治疗白血病六例[J].中华器官移植杂志,2006,27(1):56-57.
[20]闫洪敏,王志东,朱玲,等.多种来源造血干细胞移植治疗重型再生障碍性贫血[J].中国组织工程研究与临床康复,2011,15(10):1884-1888.
[21]陈欣,冯四洲.异基因造血干细胞移植治疗重型再生障碍性贫血研究进展[J].中华血液学杂志,2012,33(11):963-967.
[22]韩伟,黄晓军,刘开彦,等.配型不合造血干细胞移植治疗重型再生障碍性贫血的疗效及安全性[J].中华内科杂志,2011,50(4):287-290.
[23]Fouillard L,Bensidhoum M,Bories D,et al.Engraftment of allogeneic mesenchymal stem cells in the bone marrow of a patient with severe idiopathic aplastic anemia improves stroma.Leukemia.2003;17(2):474-476.
[24]Champlin RE,Perez WS,Passweg JR,et al.Bone marrow transplantation for severe aplastic anemia:a randomized controlled study of conditioning regimens.Blood.2007;109(10):4582-4585.
[25]George B,Mathews V,Viswabandya A,et al.Fludarabine based reduced intensity conditioning regimens in children undergoing allogeneic stem cell transplantation for severe aplastic anemia.Pediatr Transplant.2008;12(1):14-19.
[26]Bacigalupo A,Socie'G,Lanino E,et al.Fludarabine,cyclophosphamide,antithymocyte globulin,with or without low dose total body irradiation,for alternative donor transplants,in acquired severe aplastic anemia:a retrospective study from the EBMT-SAA Working Party.Haematologica.2010;95(6):976-982.
[27]孙新.造血干细胞移植治疗再生障碍性贫血[J].中国小儿血液与肿瘤杂志,2009,14(4):145-146,150.
[28]Huang XJ,Chen YH,Xu LP,et al.Combined transplantation of G-CSF primed allogeneic bone marrow cells and peripheral blood stem cells in treatment of severe aplastic anemia.Chin Med J(Engl).2004;117(4):604-607.
[29]鹿全意,牛小青,郭勇,等.G-CSF动员的异基因外周血干细胞和骨髓联合移植治疗白血病[J].中国实验血液学杂志,2005,13(2):326-328.
[30]何丽,肖扬.再生障碍性贫血患者骨髓间充质干细胞体外生物学特性与其免疫调节缺陷[J].中国组织工程研究与临床康复,2010,14(1):179-182.
[31]黄永兰,黄绍良,黄科,等.再生障碍性贫血患儿骨髓间充质干细胞体外生物学特性及其与免疫抑制疗效的关系[J].中国当代儿科杂志,2008,10(1):9-13.