Effectiveness and Safety of Rabbit Antithymocyte Globulins for the Prevention of Graft-versus-host Disease: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

LIU Yun , YUAN Jin , MA Liangliang ,  JIA Yongqian

Department of Hematology, West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

JIA Yongqian, Email: jia_yq@scu.edu.cn

Keywords：

Antithymocyte globulin (ATG); Graft-versus-host disease (GVHD); Survival rate; Mortality rate; Meta-analysis; Systematic review

DOI：

10.7507/1672-2531.20110117

Video：

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Objective 　Through conducting a meta-analysis using the methodology of Cochrane review, to assess the effectiveness and safety of graft-versus-host disease (GVHD) prophylaxis with antithymocyte globulins (ATGs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods 　Such databases as PubMed (1966 to March 2011), EMbase (1974 to March 2011), the Science Citation Index databases (1900 to March 2011), The Cochrane Library (1996 to March 2011), CBMdisc (1978 to March 2011), and CNKI (1979 to March 2011) were electronical1y searched. The references of all identified studies were retrieved for collecting more randomized controlled trials (RCTs) and non-RCTs. Two reviewers independently screened the trials according to inclusion and exclusion criteria, abstracted the data, and assessed the methodology quality of the included studies. Meta-analyses were performed using RevMan 5.0.2 software.
Results 　Thirteen clinical trials were included, of which 2 were RCTs involving 310 patients and the other 11 were non-RCTs involving 1480 patients. The results of meta-analyses showed that compared with the Non-ATG group, the pooled risk ratio (RR) and 95%CI of the ATG group in acute GVHD II-IV incidence rate, acute GVHD III-IV incidence rate, chronic GVHD (limited plus extensive) incidence rate, chronic GVHD (extensive) incidence rate, overall survival (OS) rate, non-relapse mortality (NRM) rate, and relapse rate were 0.77 (0.67, 0.87), 0.54 (0.44, 0.68), 0.58 (0.51, 0.65), 0.35 (0.26, 0.46), 1.14 (1.04, 1.25), 0.81 (0.69, 0.93), and 1.24 (0.98, 1.57), respectively.
Conclusion 　The addition of ATGs to GVHD prophylaxis can reduce the incidence of acute and chronic GVHD, decrease NRM, and increase OS, but has no obvious interference with relapse rate.

Citation： LIU Yun,YUAN Jin,MA Liangliang,JIA Yongqian. Effectiveness and Safety of Rabbit Antithymocyte Globulins for the Prevention of Graft-versus-host Disease: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2011, 11(6): 661-669. doi: 10.7507/1672-2531.20110117 Copy

1.	1 Lee SJ, Klein JP, Barrett AJ, et al . Severity o f chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood , 2002, 100(2): 406-14.
2.	2 Bolwell B, Sobecks R, Pohlman B, et al . A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant , 2004, 34(7): 621-625.
3.	3 Ram R, Gafter-Gvili A, Yeshurun M, et al . Prophylaxis regimens for GVHD: systematic review and meta-analysis. Bone Marrow Transplant , 2009, 43(8): 643-653.
4.	4 Pavletic SZ, Carter SL, Kernan NA, et al . Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation. Blood , 2005, 106(9): 3308-3313.
5.	5 Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood , 2001, 98(12): 3192-3204.
6.	6 Storb R, Gluckman E, Thomas ED, et al . Treatment of established human graft-versus-host disease by antithymocyte globulin. Blood , 1974, 44(1): 56-75.、.
7.	9 Michallet M, Le QH, Mohty M, et al . Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Exp Hematol , 2008, 36(5): 535-544.
8.	10 Wagner JE, Thompson JS, Carter SL, et al . Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomized phase II-III trial. Lancet , 2005, 366(9487): 733-741.
9.	11 Lu DP, Dong L, Wu T, et al . Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/ haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood , 2006, 107(8): 3065-3073.
10.	12 Tanosaki R, Uike N, Utsunomiya A, et al . Allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning for adult T cell leukemia/lymphoma: impact of antithymocyte globulin on clinical outcome. Biol Blood Marrow Transplant , 2008, 14(6): 702-708.
11.	13 Finke J, Schmoor C, Lang H , et al . Matched and mismatched allogeneic stem-cell transplantation from unrelated donors using combined graft-versus-host disease prophylaxis including rabbit anti-T lymphocyte globulin. J Clin Oncol , 2003, 21(3): 506-513.
12.	14 Bacigalupo A, Lamparelli T, Bruzzi P, et al . Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood , 2001, 98(10): 2942-2947.
13.	15 Finke J, Bethge WA, Schmoor C, et al . Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol , 2009, 10(9): 855-864.
14.	16 Bacigalupo A, Lamparelli T, Gualandi F, et al . Prophylactic antithymocyte globulin reduces the risk of chronic graft-versus-host disease in alternative-donor bone marrow transplants. Biol Blood Marrow Transplant , 2002, 8(12): 656-661.
15.	17 Ayuk F, Perez-Simon JA, Shimoni A, et al . Clinical impact of human Jurkat T-cell-line-derived antithymocyte globulin in multiple myeloma patients undergoing allogeneic stem cell transplantation. Haematologica , 2008, 93(9): 1343-1350.
16.	18 Schetelig J, Bornhäuser M, Kiehl M, et al . Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation-a retrospective analysis. Bone Marrow Transplant , 2004, 33(5): 483-490.
17.	19 Russell JA, Turner AR, Larratt L, et al . Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis. Biol Blood Marrow Transplant , 2007, 13(3): 299-306.
18.	20 Mohty M, Labopin M, Balère ML, et al . Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire. Leukemia , 2010, 24(11): 1867-1874.
19.	21 Remberger M, Storer B, Ringdén O, et al . Association between pretransplant Thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors. Bone Marrow Transplant , 2002, 29(5): 391-397.
20.	22 Basara N, Baurmann H, Kolbe K, et al . Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant , 2005, 35(10): 1011-1018.
21.	23 Zander AR, Kröger N, Schleuning M, et al . ATG as part of the conditioning regimen reduces transplant-related mortality (TRM) and improves overall survival after unrelated stem cell transplantation in patients with chronic myelogenous leukemia (CML). Bone Marrow Transplant , 2003, 32(4): 355-361.
22.	24 Bonifazi F, Bandini G, Stanzani M, et al . In vivo T-cell depletion with low-dose ATG is effective in reducing cGVHD after peripheral blood stem cell myeloablative sibling transplants in CML: results from a prospective phase II study. Bone Marrow Transplant , 2005, 35(10): 1025-1026.
23.	28 Beiras-Fernandez A, Thein E, Hammer C. Induction of immunosuppression with polyclonal anti-thymocyte globulins: an overview. Exp Clin Transplant , 2003, 1(2): 79-84.
24.	29 Genestier L, Fournel S, Flacher M, et al . Induction of Fas (Apo-1, CD95)-mediated apoptosis of activated lymphocytes by polyclonal antithymocyte globulins. Blood , 1998, 91(7): 2360-2368.
25.	30 Michallet MC, Preville X, Flacher M, et al . Functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. Transplantation , 2003, 75(5): 657-662.
26.	31 Zand MS, Vo T, Huggins J, et al . Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation , 2005, 79(11): 1507-1515.
27.	32 Fang L, Fehse B, Engel M, et al . Antithymocyte globulin induces ex vivo and in vivo depletion of myeloid and plasmacytoid dendritic cells. Transplantation , 2005, 79(3): 369-371.
28.	33 Préville X, Nicolas L, Flacher M, et al . A quantitative flow cytometry assay for the preclinical testing and pharmacological monitoring of rabbit antilymphocyte globulins (rATG). J Immunol Methods , 2000, 245(1-2): 45-54.
29.	35 Weisdorf DJ, Anasetti C, Antin JH, et al . Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood , 2002, 99(6): 1971-1977.
30.	36 Marks DI, Cullis JO, Ward KN, et al . Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors. A comparison of complications in the first 2 years. Ann Intern Med , 1993, 119(3): 207-214.
31.	37 Schmitz N, Beksac M, Hasenclever D, et al . Transplantation of mobilized peripheral blood cells to HLA identical siblings with standard risk leukaemia. Blood , 2002, 100(3): 761-767.
32.	38 Cutler C, Giri S, Jeyapalan S, et al . Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol , 2001, 19(16): 3685-3691.
33.	39 Duggan P, Booth K, Chaudhry A, et al . Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis. Bone Marrow Transplant , 2002, 30(10): 681-686.
34.	40 Remberger M, Mattsson J, Hausenberger D, et al . Genomic tissue typing and optimal antithymocyte globuline dose using unrelated donors results in similar survival and relapse as HLA-identical siblings in haematopoietic stem-cell transplantation for leukaemia. Eur J Haematol , 2008, 80(5): 419-428.
35.	41 Kröger N, Zabelina T, Binder T, et al . HLA-mismatched unrelated donors as an alternative graft source for allogeneic stem cell transplantation after antithymocyte globulin-containing conditioning regimen. Biol Blood Marrow Transplant , 2009, 15(4): 454-462.
36.	Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 (updated September 2009). The Cochrane Collaboration, 2009. Available from: URL: http://www.cochrane-handbook.org/.
37.	刘建平. 非随机研究的系统评价方法（一）. 中国循证医学, 2001, 1(4): 239-243.
38.	吴秉毅, 郭坤元, 宋朝阳, 等. 预处理方案中加抗胸腺细胞球蛋白减少异基因造血干细胞移植慢性移植物抗宿主病. 中华血液学杂志, 2004, 25(2): 91-94.
39.	刘代红, 刘婧, 刘开彦, 等. 含与不含抗胸腺细胞球蛋白的两种预处理方案早期毒性的比较. 中华血液学杂志, 2009, 30(8): 519-523.
40.	张晓辉, 黄晓军, 刘开彦, 等. 抗胸腺细胞球蛋白在HLA配型部分相合的造血干细胞移植患者的药代动力学. 中国实验血液学杂志, 2007, 15(1): 152-155.
41.	黄晓军. 移植物抗宿主病的预防与抗胸腺细胞球蛋白. 中华血液学杂志, 2010, 31(8): 568-571.

1. 1 Lee SJ, Klein JP, Barrett AJ, et al . Severity o f chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood , 2002, 100(2): 406-14.
2. 2 Bolwell B, Sobecks R, Pohlman B, et al . A prospective randomized trial comparing cyclosporine and short course methotrexate with cyclosporine and mycophenolate mofetil for GVHD prophylaxis in myeloablative allogeneic bone marrow transplantation. Bone Marrow Transplant , 2004, 34(7): 621-625.
3. 3 Ram R, Gafter-Gvili A, Yeshurun M, et al . Prophylaxis regimens for GVHD: systematic review and meta-analysis. Bone Marrow Transplant , 2009, 43(8): 643-653.
4. 4 Pavletic SZ, Carter SL, Kernan NA, et al . Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation. Blood , 2005, 106(9): 3308-3313.
5. 5 Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood , 2001, 98(12): 3192-3204.
6. 6 Storb R, Gluckman E, Thomas ED, et al . Treatment of established human graft-versus-host disease by antithymocyte globulin. Blood , 1974, 44(1): 56-75.、.
7. 9 Michallet M, Le QH, Mohty M, et al . Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Exp Hematol , 2008, 36(5): 535-544.
8. 10 Wagner JE, Thompson JS, Carter SL, et al . Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomized phase II-III trial. Lancet , 2005, 366(9487): 733-741.
9. 11 Lu DP, Dong L, Wu T, et al . Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/ haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood , 2006, 107(8): 3065-3073.
10. 12 Tanosaki R, Uike N, Utsunomiya A, et al . Allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning for adult T cell leukemia/lymphoma: impact of antithymocyte globulin on clinical outcome. Biol Blood Marrow Transplant , 2008, 14(6): 702-708.
11. 13 Finke J, Schmoor C, Lang H , et al . Matched and mismatched allogeneic stem-cell transplantation from unrelated donors using combined graft-versus-host disease prophylaxis including rabbit anti-T lymphocyte globulin. J Clin Oncol , 2003, 21(3): 506-513.
12. 14 Bacigalupo A, Lamparelli T, Bruzzi P, et al . Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood , 2001, 98(10): 2942-2947.
13. 15 Finke J, Bethge WA, Schmoor C, et al . Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol , 2009, 10(9): 855-864.
14. 16 Bacigalupo A, Lamparelli T, Gualandi F, et al . Prophylactic antithymocyte globulin reduces the risk of chronic graft-versus-host disease in alternative-donor bone marrow transplants. Biol Blood Marrow Transplant , 2002, 8(12): 656-661.
15. 17 Ayuk F, Perez-Simon JA, Shimoni A, et al . Clinical impact of human Jurkat T-cell-line-derived antithymocyte globulin in multiple myeloma patients undergoing allogeneic stem cell transplantation. Haematologica , 2008, 93(9): 1343-1350.
16. 18 Schetelig J, Bornhäuser M, Kiehl M, et al . Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation-a retrospective analysis. Bone Marrow Transplant , 2004, 33(5): 483-490.
17. 19 Russell JA, Turner AR, Larratt L, et al . Adult recipients of matched related donor blood cell transplants given myeloablative regimens including pretransplant antithymocyte globulin have lower mortality related to graft-versus-host disease: a matched pair analysis. Biol Blood Marrow Transplant , 2007, 13(3): 299-306.
18. 20 Mohty M, Labopin M, Balère ML, et al . Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire. Leukemia , 2010, 24(11): 1867-1874.
19. 21 Remberger M, Storer B, Ringdén O, et al . Association between pretransplant Thymoglobulin and reduced non-relapse mortality rate after marrow transplantation from unrelated donors. Bone Marrow Transplant , 2002, 29(5): 391-397.
20. 22 Basara N, Baurmann H, Kolbe K, et al . Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant , 2005, 35(10): 1011-1018.
21. 23 Zander AR, Kröger N, Schleuning M, et al . ATG as part of the conditioning regimen reduces transplant-related mortality (TRM) and improves overall survival after unrelated stem cell transplantation in patients with chronic myelogenous leukemia (CML). Bone Marrow Transplant , 2003, 32(4): 355-361.
22. 24 Bonifazi F, Bandini G, Stanzani M, et al . In vivo T-cell depletion with low-dose ATG is effective in reducing cGVHD after peripheral blood stem cell myeloablative sibling transplants in CML: results from a prospective phase II study. Bone Marrow Transplant , 2005, 35(10): 1025-1026.
23. 28 Beiras-Fernandez A, Thein E, Hammer C. Induction of immunosuppression with polyclonal anti-thymocyte globulins: an overview. Exp Clin Transplant , 2003, 1(2): 79-84.
24. 29 Genestier L, Fournel S, Flacher M, et al . Induction of Fas (Apo-1, CD95)-mediated apoptosis of activated lymphocytes by polyclonal antithymocyte globulins. Blood , 1998, 91(7): 2360-2368.
25. 30 Michallet MC, Preville X, Flacher M, et al . Functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. Transplantation , 2003, 75(5): 657-662.
26. 31 Zand MS, Vo T, Huggins J, et al . Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation , 2005, 79(11): 1507-1515.
27. 32 Fang L, Fehse B, Engel M, et al . Antithymocyte globulin induces ex vivo and in vivo depletion of myeloid and plasmacytoid dendritic cells. Transplantation , 2005, 79(3): 369-371.
28. 33 Préville X, Nicolas L, Flacher M, et al . A quantitative flow cytometry assay for the preclinical testing and pharmacological monitoring of rabbit antilymphocyte globulins (rATG). J Immunol Methods , 2000, 245(1-2): 45-54.
29. 35 Weisdorf DJ, Anasetti C, Antin JH, et al . Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood , 2002, 99(6): 1971-1977.
30. 36 Marks DI, Cullis JO, Ward KN, et al . Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors. A comparison of complications in the first 2 years. Ann Intern Med , 1993, 119(3): 207-214.
31. 37 Schmitz N, Beksac M, Hasenclever D, et al . Transplantation of mobilized peripheral blood cells to HLA identical siblings with standard risk leukaemia. Blood , 2002, 100(3): 761-767.
32. 38 Cutler C, Giri S, Jeyapalan S, et al . Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol , 2001, 19(16): 3685-3691.
33. 39 Duggan P, Booth K, Chaudhry A, et al . Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis. Bone Marrow Transplant , 2002, 30(10): 681-686.
34. 40 Remberger M, Mattsson J, Hausenberger D, et al . Genomic tissue typing and optimal antithymocyte globuline dose using unrelated donors results in similar survival and relapse as HLA-identical siblings in haematopoietic stem-cell transplantation for leukaemia. Eur J Haematol , 2008, 80(5): 419-428.
35. 41 Kröger N, Zabelina T, Binder T, et al . HLA-mismatched unrelated donors as an alternative graft source for allogeneic stem cell transplantation after antithymocyte globulin-containing conditioning regimen. Biol Blood Marrow Transplant , 2009, 15(4): 454-462.
36. Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 (updated September 2009). The Cochrane Collaboration, 2009. Available from: URL: http://www.cochrane-handbook.org/.
37. 刘建平. 非随机研究的系统评价方法（一）. 中国循证医学, 2001, 1(4): 239-243.
38. 吴秉毅, 郭坤元, 宋朝阳, 等. 预处理方案中加抗胸腺细胞球蛋白减少异基因造血干细胞移植慢性移植物抗宿主病. 中华血液学杂志, 2004, 25(2): 91-94.
39. 刘代红, 刘婧, 刘开彦, 等. 含与不含抗胸腺细胞球蛋白的两种预处理方案早期毒性的比较. 中华血液学杂志, 2009, 30(8): 519-523.
40. 张晓辉, 黄晓军, 刘开彦, 等. 抗胸腺细胞球蛋白在HLA配型部分相合的造血干细胞移植患者的药代动力学. 中国实验血液学杂志, 2007, 15(1): 152-155.
41. 黄晓军. 移植物抗宿主病的预防与抗胸腺细胞球蛋白. 中华血液学杂志, 2010, 31(8): 568-571.

Chinese Journal of Evidence-Based Medicine

Effectiveness and Safety of Rabbit Antithymocyte Globulins for the Prevention of Graft-versus-host Disease: A Meta-analysis

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