重型再生障碍性贫血的免疫抑制治疗现状_West China Medical Journal

Authors：

 曹九芳 ,  李晓明

泸州医学院附属医院血液内科（四川泸州，646000）;

Corresponding author：

李晓明, Email: lxm63582@21cn.com

Keywords：

重型再生障碍性贫血; 免疫抑制治疗; 抗淋巴细胞球蛋白/抗胸腺细胞球蛋白

DOI：

10.7507/1002-0179.20140197

Video：

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免疫抑制治疗是目前重型再生障碍性贫血的主要治疗方法，其药物主要包括抗淋巴细胞球蛋白/抗胸腺细胞球蛋白、环孢素A、环磷酰胺、粒细胞集落刺激因子等，药物既可单独应用也可及联合使用。通过简要综述免疫抑制治疗主要药物的作用机制、临床应用情况、治疗预后及新药展望，旨在指导重型再生障碍性贫血患者的临床治疗以期获得更好的临床疗效。

Citation： 曹九芳, 李晓明. 重型再生障碍性贫血的免疫抑制治疗现状. West China Medical Journal, 2014, 29(4): 651-654. doi: 10.7507/1002-0179.20140197 Copy

1.	Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia[J]. N Engl J Med, 1997, 336(19):1365-1372.
2.	Frickhofen N, Rosenfeld SJ. Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine[J]. Semin Hematol, 2000, 37(1):56-68.
3.	Killick SB, Marsh JC, Gordon-Smith EC, et al. Effects of antithymocyte globulin on bone marrow CD34⁺ cells in aplastic anaemia and myelodysplasia[J]. Br J Haematol, 2000, 108(3):582-591.
4.	Killick SB, Cox CV, Marsh JC, et al. Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin:examination of the role of the Fas-Fas-L interaction[J]. Br J Haematol, 2000, 111(4):1164-1169.
5.	张乃红. 环孢霉素A治疗再生障碍性贫血的疗效和机制[J]. 中华血液学杂志, 1998, 19(4):51-53.
6.	Nabel GJ. A transformed view of cyclosporine[J]. Nature, 1999, 397(6719):471-472.
7.	Tisdale JF, Dunn DE, Maciejewski J. Cyclophosphamide and other new agents for the treatment of severe aplastic anemia[J]. Semin Hematol, 2000, 37(1):102-109.
8.	Ikebuchi K, Clark SC, Ihle JN. Granulocyte colony-stimulating factor enhances interleukin 3-dependent proliferation of multipotential hemopoietic progenitors[J]. Proc Natl Acad Sci USA, 1988, 85(10):3445-3449.
9.	郑以州. 抗淋巴细胞球蛋白/抗胸腺细胞球蛋白治疗严重型再生障碍性贫血的现状[J].国外医学·输血及血液学分册, 1996, 19(2):65-68.
10.	Bacigalupo A, Hows J, Gluckman E, et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA):a report of the EBMT SAA working party[J]. Br J Haematol, 1988, 70(2):177-182.
11.	Gluckman E, Esperoubourdeau H, Baruchel A, et al. A multicenter randomized study comparing cyclosporine-a alone and antithymocyte globulin with prednisone for treatment of severe aplastic-anemia[J]. Blood, 1992, 5(A):271-275.
12.	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[J]. Semin Hematol, 2000, 37(1):69-80.
13.	Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia:an update of the GITMO/EBMT study on 100 patients[J]. Blood, 2000, 95(6):1931-1934.
14.	Führer M, Rampf U, Baumann I, et al. Immunosuppressive therapy for aplastic anemia in children:a more severe disease predicts better survival[J]. Blood, 2005, 106(6):2102-2104.
15.	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[J]. Haematologica, 2007, 92(1):11-18.
16.	Rosenfeld SJ, Kimball J, Vining D, et al. Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia[J]. Blood, 1995, 85(11):3058-3065.
17.	何广胜, 邵宗鸿, 张益枝, 等. 序贯强化免疫抑制并用造血生长因子治疗重型再生障碍性贫血[J]. 中华血液学杂志, 2001, 22(4):8-12.
18.	Scheinberg P, Wu CO, Nunez O, et al. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia[J]. Br J Haematol, 2009, 144(2):206-216.
19.	曹慧敏, 王慧君, 张莉, 等. 一线应用兔源抗胸腺细胞球蛋白联合环孢素治疗成人重型再生障碍性贫血疗效分析[J]. 中华血液学杂志, 2011, 32(1):38-42.
20.	Atta EH, Dias DS, Marra VL, et al. Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia:a single-center retrospective study[J]. Ann Hematol, 2010, 89(9):851-859.
21.	Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with replased or refractory severe aplastic anemia[J]. Br J Haematol, 2006, 133(6):622-627.
22.	Calistri E, Tiribelli M, Battista M, et al. Epstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia[J]. Am J Hematol, 2006, 81(5):355-357.
23.	Scheinberg P, Young NS, Barrett J. Monitoring of EBV reactivation in the immunosuppression:to treat or not to treat?[J]. Blood, 2008, 111(3):1739.
24.	刘丽媛, 王慧君, 张莉, 等. 一线应用兔抗胸腺细胞球蛋白联合环孢素治疗儿童重型再生障碍性贫血[J]. 中华血液学杂志, 2009, 30(11):749-753.
25.	韩冰, 严思益, 邹农, 等. 抗淋巴细胞免疫球蛋白(猪)联合环孢素治疗重型再生障碍性贫血[J]. 中华血液学杂志, 2011, 32(4):241-244.
26.	Bacigalupo A, Broccia G, Corda G, et al. Antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia (SAA):a pilot study of the EBMT SAA Working Party[J]. Blood, 1995, 85(5):1348-1353.
27.	李英梅, 李星鑫, 葛美丽, 等. 强化免疫抑制疗法联合不同方案G-CSF治疗重型再生障碍性贫血患者的长期随访研究[J]. 中华血液学杂志, 2010, 31(7):470-474.
28.	Rosenfeld S, Follmann D, Nunez O, et al. Antithymocyte globulin and cyclosporine for severe aplastic anemia:association between hematologic response and long-term outcome[J]. JAMA, 2003, 289(9):1130-1135.
29.	Saracco P, Quarello P, Iori AP, et al. Cyclosporin a response and dependence in children with acquired aplastic anaemia:a multicentre retrospective study with long-term observation follow-up[J]. Br J Haematol, 2008, 140(2):197-205.
30.	Marsh JC, Ball SE, Cavenagh JA, et al. Guidelines for the diagnosis and management of aplastic anaemia[J]. Br J Haematol, 2009, 147(1):43-70.
31.	Frickhofen N, Heimpel H, Kaltwasser JP, et al. Antithymocyte globulin with or without cyclosporin A:11-year follow-up of a randomized trial comparing treatments of aplastic anemia[J]. Blood, 2003, 101(4):1236-1242.
32.	Sugimori C, Chuhjo T, Feng X, et al. Minor population of CD55-CD59-blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia[J]. Blood, 2006, 107(4):1308-1314.
33.	Scheinberg P, Nunez O, Wu C, et al. Treatment of severe aplastic anaemia with combined immunosuppression:anti-thymocyte globulin, ciclosporin and mycophenolate mofetil[J]. Br J Haematol, 2006, 133(6):606-611.
34.	Scheinberg P, Wu CO, Nunez O, et al. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus:a prospective randomized study[J]. Haematologica, 2009, 94(3):348-354.
35.	Tichelli A, Passweg J, Nissen C, et al. Repeated treatment with horse antithymocyte globulin for severe aplastic anemia[J]. Br J Haematol, 1998, 100(2):393-400.
36.	Brodsky RA, Sensenbrenner LL, Smith BD, et al. Durable treatment-free remission after high-dose cyclophophamide therapy for previously untreated severe aplastic anemia[J]. Ann Intern Med, 2001, 135(7):477-483.
37.	Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamide in severe aplastic anaemia:a randomised trial[J]. Lancet, 2000, 356(9241):1554-1559.

1. Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia[J]. N Engl J Med, 1997, 336(19):1365-1372.
2. Frickhofen N, Rosenfeld SJ. Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine[J]. Semin Hematol, 2000, 37(1):56-68.
3. Killick SB, Marsh JC, Gordon-Smith EC, et al. Effects of antithymocyte globulin on bone marrow CD34⁺ cells in aplastic anaemia and myelodysplasia[J]. Br J Haematol, 2000, 108(3):582-591.
4. Killick SB, Cox CV, Marsh JC, et al. Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin:examination of the role of the Fas-Fas-L interaction[J]. Br J Haematol, 2000, 111(4):1164-1169.
5. 张乃红. 环孢霉素A治疗再生障碍性贫血的疗效和机制[J]. 中华血液学杂志, 1998, 19(4):51-53.
6. Nabel GJ. A transformed view of cyclosporine[J]. Nature, 1999, 397(6719):471-472.
7. Tisdale JF, Dunn DE, Maciejewski J. Cyclophosphamide and other new agents for the treatment of severe aplastic anemia[J]. Semin Hematol, 2000, 37(1):102-109.
8. Ikebuchi K, Clark SC, Ihle JN. Granulocyte colony-stimulating factor enhances interleukin 3-dependent proliferation of multipotential hemopoietic progenitors[J]. Proc Natl Acad Sci USA, 1988, 85(10):3445-3449.
9. 郑以州. 抗淋巴细胞球蛋白/抗胸腺细胞球蛋白治疗严重型再生障碍性贫血的现状[J].国外医学·输血及血液学分册, 1996, 19(2):65-68.
10. Bacigalupo A, Hows J, Gluckman E, et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA):a report of the EBMT SAA working party[J]. Br J Haematol, 1988, 70(2):177-182.
11. Gluckman E, Esperoubourdeau H, Baruchel A, et al. A multicenter randomized study comparing cyclosporine-a alone and antithymocyte globulin with prednisone for treatment of severe aplastic-anemia[J]. Blood, 1992, 5(A):271-275.
12. 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[J]. Semin Hematol, 2000, 37(1):69-80.
13. Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia:an update of the GITMO/EBMT study on 100 patients[J]. Blood, 2000, 95(6):1931-1934.
14. Führer M, Rampf U, Baumann I, et al. Immunosuppressive therapy for aplastic anemia in children:a more severe disease predicts better survival[J]. Blood, 2005, 106(6):2102-2104.
15. 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[J]. Haematologica, 2007, 92(1):11-18.
16. Rosenfeld SJ, Kimball J, Vining D, et al. Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia[J]. Blood, 1995, 85(11):3058-3065.
17. 何广胜, 邵宗鸿, 张益枝, 等. 序贯强化免疫抑制并用造血生长因子治疗重型再生障碍性贫血[J]. 中华血液学杂志, 2001, 22(4):8-12.
18. Scheinberg P, Wu CO, Nunez O, et al. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia[J]. Br J Haematol, 2009, 144(2):206-216.
19. 曹慧敏, 王慧君, 张莉, 等. 一线应用兔源抗胸腺细胞球蛋白联合环孢素治疗成人重型再生障碍性贫血疗效分析[J]. 中华血液学杂志, 2011, 32(1):38-42.
20. Atta EH, Dias DS, Marra VL, et al. Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia:a single-center retrospective study[J]. Ann Hematol, 2010, 89(9):851-859.
21. Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with replased or refractory severe aplastic anemia[J]. Br J Haematol, 2006, 133(6):622-627.
22. Calistri E, Tiribelli M, Battista M, et al. Epstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia[J]. Am J Hematol, 2006, 81(5):355-357.
23. Scheinberg P, Young NS, Barrett J. Monitoring of EBV reactivation in the immunosuppression:to treat or not to treat?[J]. Blood, 2008, 111(3):1739.
24. 刘丽媛, 王慧君, 张莉, 等. 一线应用兔抗胸腺细胞球蛋白联合环孢素治疗儿童重型再生障碍性贫血[J]. 中华血液学杂志, 2009, 30(11):749-753.
25. 韩冰, 严思益, 邹农, 等. 抗淋巴细胞免疫球蛋白(猪)联合环孢素治疗重型再生障碍性贫血[J]. 中华血液学杂志, 2011, 32(4):241-244.
26. Bacigalupo A, Broccia G, Corda G, et al. Antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia (SAA):a pilot study of the EBMT SAA Working Party[J]. Blood, 1995, 85(5):1348-1353.
27. 李英梅, 李星鑫, 葛美丽, 等. 强化免疫抑制疗法联合不同方案G-CSF治疗重型再生障碍性贫血患者的长期随访研究[J]. 中华血液学杂志, 2010, 31(7):470-474.
28. Rosenfeld S, Follmann D, Nunez O, et al. Antithymocyte globulin and cyclosporine for severe aplastic anemia:association between hematologic response and long-term outcome[J]. JAMA, 2003, 289(9):1130-1135.
29. Saracco P, Quarello P, Iori AP, et al. Cyclosporin a response and dependence in children with acquired aplastic anaemia:a multicentre retrospective study with long-term observation follow-up[J]. Br J Haematol, 2008, 140(2):197-205.
30. Marsh JC, Ball SE, Cavenagh JA, et al. Guidelines for the diagnosis and management of aplastic anaemia[J]. Br J Haematol, 2009, 147(1):43-70.
31. Frickhofen N, Heimpel H, Kaltwasser JP, et al. Antithymocyte globulin with or without cyclosporin A:11-year follow-up of a randomized trial comparing treatments of aplastic anemia[J]. Blood, 2003, 101(4):1236-1242.
32. Sugimori C, Chuhjo T, Feng X, et al. Minor population of CD55-CD59-blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia[J]. Blood, 2006, 107(4):1308-1314.
33. Scheinberg P, Nunez O, Wu C, et al. Treatment of severe aplastic anaemia with combined immunosuppression:anti-thymocyte globulin, ciclosporin and mycophenolate mofetil[J]. Br J Haematol, 2006, 133(6):606-611.
34. Scheinberg P, Wu CO, Nunez O, et al. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus:a prospective randomized study[J]. Haematologica, 2009, 94(3):348-354.
35. Tichelli A, Passweg J, Nissen C, et al. Repeated treatment with horse antithymocyte globulin for severe aplastic anemia[J]. Br J Haematol, 1998, 100(2):393-400.
36. Brodsky RA, Sensenbrenner LL, Smith BD, et al. Durable treatment-free remission after high-dose cyclophophamide therapy for previously untreated severe aplastic anemia[J]. Ann Intern Med, 2001, 135(7):477-483.
37. Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamide in severe aplastic anaemia:a randomised trial[J]. Lancet, 2000, 356(9241):1554-1559.

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