重型再生障礙性貧血的免疫抑制治療現狀_West China Medical Journal

Authors：

 曹九芳 ,  李曉明

瀘州醫學院附屬醫院血液內科（四川瀘州，646000）;

Corresponding?author：

李曉明, Email: lxm63582@21cn.com

Keywords：

重型再生障礙性貧血; 免疫抑制治療; 抗淋巴細胞球蛋白/抗胸腺細胞球蛋白

DOI：

10.7507/1002-0179.20140197

Video：

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免疫抑制治療是目前重型再生障礙性貧血的主要治療方法，其藥物主要包括抗淋巴細胞球蛋白/抗胸腺細胞球蛋白、環孢素A、環磷酰胺、粒細胞集落刺激因子等，藥物既可單獨應用也可及聯合使用。通過簡要綜述免疫抑制治療主要藥物的作用機制、臨床應用情況、治療預后及新藥展望，旨在指導重型再生障礙性貧血患者的臨床治療以期獲得更好的臨床療效。

Citation： 曹九芳, 李曉明. 重型再生障礙性貧血的免疫抑制治療現狀. 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.	張乃紅. 環孢霉素A治療再生障礙性貧血的療效和機制[J]. 中華血液學雜志, 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.	鄭以州. 抗淋巴細胞球蛋白/抗胸腺細胞球蛋白治療嚴重型再生障礙性貧血的現狀[J].國外醫學·輸血及血液學分冊, 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.	何廣勝, 邵宗鴻, 張益枝, 等. 序貫強化免疫抑制并用造血生長因子治療重型再生障礙性貧血[J]. 中華血液學雜志, 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, 張莉, 等. 一線應用兔源抗胸腺細胞球蛋白聯合環孢素治療成人重型再生障礙性貧血療效分析[J]. 中華血液學雜志, 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.	劉麗媛, 王慧君, 張莉, 等. 一線應用兔抗胸腺細胞球蛋白聯合環孢素治療兒童重型再生障礙性貧血[J]. 中華血液學雜志, 2009, 30(11):749-753.
25.	韓冰, 嚴思益, 鄒農, 等. 抗淋巴細胞免疫球蛋白(豬)聯合環孢素治療重型再生障礙性貧血[J]. 中華血液學雜志, 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, 葛美麗, 等. 強化免疫抑制療法聯合不同方案G-CSF治療重型再生障礙性貧血患者的長期隨訪研究[J]. 中華血液學雜志, 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. 張乃紅. 環孢霉素A治療再生障礙性貧血的療效和機制[J]. 中華血液學雜志, 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. 鄭以州. 抗淋巴細胞球蛋白/抗胸腺細胞球蛋白治療嚴重型再生障礙性貧血的現狀[J].國外醫學·輸血及血液學分冊, 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. 何廣勝, 邵宗鴻, 張益枝, 等. 序貫強化免疫抑制并用造血生長因子治療重型再生障礙性貧血[J]. 中華血液學雜志, 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, 張莉, 等. 一線應用兔源抗胸腺細胞球蛋白聯合環孢素治療成人重型再生障礙性貧血療效分析[J]. 中華血液學雜志, 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. 劉麗媛, 王慧君, 張莉, 等. 一線應用兔抗胸腺細胞球蛋白聯合環孢素治療兒童重型再生障礙性貧血[J]. 中華血液學雜志, 2009, 30(11):749-753.
25. 韓冰, 嚴思益, 鄒農, 等. 抗淋巴細胞免疫球蛋白(豬)聯合環孢素治療重型再生障礙性貧血[J]. 中華血液學雜志, 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, 葛美麗, 等. 強化免疫抑制療法聯合不同方案G-CSF治療重型再生障礙性貧血患者的長期隨訪研究[J]. 中華血液學雜志, 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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重型再生障礙性貧血的免疫抑制治療現狀

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