Skip to main content
Top
Published in: International Journal of Hematology 3/2019

01-03-2019 | Aplastic Anemia | Original Article

Immunosuppressive therapy with rabbit antithymocyte globulin therapy for acquired aplastic anemia: a multi-institutional retrospective study in Japanese adult patients

Authors: Nana Sasaki, Kazuho Shimura, Mihoko Yoshida, Nobuhiko Uoshima, Miki Kiyota, Mayumi Hatsuse, Hitoji Uchiyama, Yoshiaki Chinen, Tsutomu Kobayashi, Mitsushige Nakao, Ryoichi Takahashi, Sonoko Nakano-Akamatsu, Hiroto Kaneko, Yutaka Kobayashi, Chihiro Shimazaki, Masafumi Taniwaki, Junya Kuroda, The Kyoto Clinical Hematology Study Group (KOTOSG) investigators

Published in: International Journal of Hematology | Issue 3/2019

Login to get access

Abstract

We retrospectively analyzed efficacy and safety of therapy with rabbit antithymocyte globulin (rATG) in combination with cyclosporine A (CsA) in 30 Japanese adult patients with acquired aplastic anemia (AA) in the Kyoto Clinical Hematology Study Group. The median observation period was 31 months and the median age of the patients was 54 years. The objective response rates (ORRs) to rATG plus CsA increased over time until 18 months after the start of treatment; the rate of achievement of better than partial response at 18 months was 66.7%. The 2-year overall survival (OS) rate was 79% in all patients. In eight patients aged ≥ 75 years old, the ORR was 62.5% and the 2-year OS rate of 50% was not significantly inferior to that in patients aged ≤ 74 years old. The overall mortality rate was 16.7% in our cohort, while the mortality rate in patients aged ≥ 75 years old was 37.5%, which was higher than that in patients aged ≤ 74 years old (9.1%), although the difference was not statistically significant. Collectively, rATG combined with CsA is an effective and feasible treatment for AA, while patients should be appropriately selected.
Appendix
Available only for authorised users
Literature
1.
go back to reference Bacigalupo A, Bruno B, Saracco P, Di Bona E, Locasciulli A, Locatelli F, 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. Blood. 2000;95(6):1931–4.PubMed Bacigalupo A, Bruno B, Saracco P, Di Bona E, Locasciulli A, Locatelli F, 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. Blood. 2000;95(6):1931–4.PubMed
2.
go back to reference Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H, German Aplastic Anemia Study Group. Antithymocyte globulin with or without cyclosporin A. 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2003;101(4):1236–42.CrossRefPubMed Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H, German Aplastic Anemia Study Group. Antithymocyte globulin with or without cyclosporin A. 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2003;101(4):1236–42.CrossRefPubMed
3.
go back to reference Feng X, Scheinberg P, Biancotto A, Rios O, Donaldson S, Wu C, et al. In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia. Haematologica. 2014;99(9):1433–40.CrossRefPubMedPubMedCentral Feng X, Scheinberg P, Biancotto A, Rios O, Donaldson S, Wu C, et al. In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia. Haematologica. 2014;99(9):1433–40.CrossRefPubMedPubMedCentral
4.
go back to reference Marsh JC, Bacigalupo A, Schrezenmeier H, Tichelli A, Risitano AM, Passweg JR, et al. European Blood and Marrow Transplant Group Severe Aplastic Anaemia Working Party. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. Blood. 2012;119(23):5391–6.CrossRefPubMed Marsh JC, Bacigalupo A, Schrezenmeier H, Tichelli A, Risitano AM, Passweg JR, et al. European Blood and Marrow Transplant Group Severe Aplastic Anaemia Working Party. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. Blood. 2012;119(23):5391–6.CrossRefPubMed
5.
go back to reference Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365(5):430–8.CrossRefPubMedPubMedCentral Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365(5):430–8.CrossRefPubMedPubMedCentral
6.
go back to reference Vallejo C, Montesinos P, Polo M, Cuevas B, Morado M, Rosell A, Bone Marrow Failure Spanish Study Group (Pethema-GETH), et al. Rabbit antithymocyte globulin versus horse antithymocyte globulin for treatment of acquired aplastic anemia: a retrospective analysis. Ann Hematol. 2015;94(6):947–54.CrossRefPubMed Vallejo C, Montesinos P, Polo M, Cuevas B, Morado M, Rosell A, Bone Marrow Failure Spanish Study Group (Pethema-GETH), et al. Rabbit antithymocyte globulin versus horse antithymocyte globulin for treatment of acquired aplastic anemia: a retrospective analysis. Ann Hematol. 2015;94(6):947–54.CrossRefPubMed
7.
go back to reference Liu L, Ding L, Hao L, Zhang X, Li X, Zhang L, et al. Efficacy of porcine antihuman lymphocyte immunoglobulin compared to rabbit antithymocyte immunoglobulin as a first-line treatment against acquired severe aplastic anemia. Ann Hematol. 2015;94(5):729–37.CrossRefPubMed Liu L, Ding L, Hao L, Zhang X, Li X, Zhang L, et al. Efficacy of porcine antihuman lymphocyte immunoglobulin compared to rabbit antithymocyte immunoglobulin as a first-line treatment against acquired severe aplastic anemia. Ann Hematol. 2015;94(5):729–37.CrossRefPubMed
8.
go back to reference Sakamoto T, Obara N, Kurita N, Sakata-Yanagimoto M, Nishikii H, Yokoyama Y, et al. Effectiveness and safety of rabbit anti-thymocyte globulin in Japanese patients with aplastic anemia. Int J Hematol. 2013;98(3):319–22.CrossRefPubMed Sakamoto T, Obara N, Kurita N, Sakata-Yanagimoto M, Nishikii H, Yokoyama Y, et al. Effectiveness and safety of rabbit anti-thymocyte globulin in Japanese patients with aplastic anemia. Int J Hematol. 2013;98(3):319–22.CrossRefPubMed
9.
go back to reference Suzuki T, Kobayashi H, Kawasaki Y, Okazuka K, Hatano K, Fujiwara S, et al. Efficacy of combination therapy with anti-thymocyte globulin and cyclosporine A as a first-line treatment in adult patients with aplastic anemia: a comparison of rabbit and horse formulations. Int J Hematol. 2016;104(4):446–53.CrossRefPubMed Suzuki T, Kobayashi H, Kawasaki Y, Okazuka K, Hatano K, Fujiwara S, et al. Efficacy of combination therapy with anti-thymocyte globulin and cyclosporine A as a first-line treatment in adult patients with aplastic anemia: a comparison of rabbit and horse formulations. Int J Hematol. 2016;104(4):446–53.CrossRefPubMed
10.
go back to reference Chuncharunee S, Wong R, Rojnuckarin P, Chang CS, Chang KM, Lu MY, et al. Efficacy of rabbit antithymocyte globulin as first-line treatment of severe aplastic anemia: an Asian multicenter retrospective study. Int J Hematol. 2016;104(4):454–61.CrossRefPubMed Chuncharunee S, Wong R, Rojnuckarin P, Chang CS, Chang KM, Lu MY, et al. Efficacy of rabbit antithymocyte globulin as first-line treatment of severe aplastic anemia: an Asian multicenter retrospective study. Int J Hematol. 2016;104(4):454–61.CrossRefPubMed
11.
go back to reference Hayakawa J, Kanda J, Akahoshi Y, Harada N, Kameda K, Ugai T, et al. Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia. Int J Hematol. 2017;105(5):578–86.CrossRefPubMed Hayakawa J, Kanda J, Akahoshi Y, Harada N, Kameda K, Ugai T, et al. Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia. Int J Hematol. 2017;105(5):578–86.CrossRefPubMed
12.
go back to reference Yang N, Chen J, Zhang H, Dai Z, Yao H, Ma X, et al. Horse versus rabbit antithymocyte globulin in immunosuppressive therapy of treatment-naïve aplastic anemia: a systematic review and meta-analysis. Ann Hematol. 2017;96(12):2031–43.CrossRefPubMed Yang N, Chen J, Zhang H, Dai Z, Yao H, Ma X, et al. Horse versus rabbit antithymocyte globulin in immunosuppressive therapy of treatment-naïve aplastic anemia: a systematic review and meta-analysis. Ann Hematol. 2017;96(12):2031–43.CrossRefPubMed
13.
go back to reference Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144(2):206–16.CrossRefPubMed Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144(2):206–16.CrossRefPubMed
14.
go back to reference Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009;147:43–70.CrossRefPubMed Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009;147:43–70.CrossRefPubMed
15.
go back to reference Sugimori C, Chuhjo T, Feng X, Yamazaki H, Takami A, Teramura M, et al. Minor population of CD55-CD59-blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107:1308–14.CrossRefPubMed Sugimori C, Chuhjo T, Feng X, Yamazaki H, Takami A, Teramura M, et al. Minor population of CD55-CD59-blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107:1308–14.CrossRefPubMed
16.
go back to reference Nakao S, Takamatsu H, Chuhjo T, Ueda M, Shiobara S, Matsuda T, et al. Identification of a specific HLA class αhaplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia. Blood. 1994;84:4257–61.PubMed Nakao S, Takamatsu H, Chuhjo T, Ueda M, Shiobara S, Matsuda T, et al. Identification of a specific HLA class αhaplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia. Blood. 1994;84:4257–61.PubMed
17.
18.
go back to reference Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMed Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMed
19.
go back to reference Vaht K, Göransson M, Carlson K, Isaksson C, Lenhoff S, Sandstedt A, et al. Low response rate to ATG-based immunosuppressive therapy in very severe aplastic anaemia—a Swedish nationwide cohort study. Eur J Haematol. 2018;100(6):613–20.CrossRefPubMed Vaht K, Göransson M, Carlson K, Isaksson C, Lenhoff S, Sandstedt A, et al. Low response rate to ATG-based immunosuppressive therapy in very severe aplastic anaemia—a Swedish nationwide cohort study. Eur J Haematol. 2018;100(6):613–20.CrossRefPubMed
20.
go back to reference Atta EH, Lima CBL, Dias DSP, Clé DV, Bonduel MM, Sciuccati GB, et al. Predictors of early mortality after rabbit antithymocyte globulin as first-line treatment in severe aplastic anemia. Ann Hematol. 2017;96(11):1907–1914.CrossRefPubMed Atta EH, Lima CBL, Dias DSP, Clé DV, Bonduel MM, Sciuccati GB, et al. Predictors of early mortality after rabbit antithymocyte globulin as first-line treatment in severe aplastic anemia. Ann Hematol. 2017;96(11):1907–1914.CrossRefPubMed
21.
go back to reference Tichelli A, Schrezenmeier H, Socié G, Marsh J, Bacigalupo A, Dührsen U, et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2011;117(17):4434–41.CrossRefPubMed Tichelli A, Schrezenmeier H, Socié G, Marsh J, Bacigalupo A, Dührsen U, et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2011;117(17):4434–41.CrossRefPubMed
22.
go back to reference Bacigalupo A, Oneto R, Schrezenmeier H, Hochsmann B, Dufour C, Kojima S, et al. First line treatment of aplastic anemia with thymoglobuline in Europe and Asia: outcome of 955 patients treated 2001–2012. Am J Hematol. 2018;93(5):643–8.CrossRefPubMedPubMedCentral Bacigalupo A, Oneto R, Schrezenmeier H, Hochsmann B, Dufour C, Kojima S, et al. First line treatment of aplastic anemia with thymoglobuline in Europe and Asia: outcome of 955 patients treated 2001–2012. Am J Hematol. 2018;93(5):643–8.CrossRefPubMedPubMedCentral
23.
go back to reference Shin SH, Lee JW. The optimal immunosuppressive therapy for aplastic anemia. Int J Hematol. 2013;97(5):564–72.CrossRefPubMed Shin SH, Lee JW. The optimal immunosuppressive therapy for aplastic anemia. Int J Hematol. 2013;97(5):564–72.CrossRefPubMed
24.
go back to reference Clé DV, Atta EH, Dias DSP, Lima CBL, Bonduel M, Sciuccati G, et al. Rabbit antithymocyte globulin dose does not affect response or survival as first-line therapy for acquired aplastic anemia: a multicenter retrospective study. Ann Hematol. 2018;97(11):2039–46.CrossRefPubMed Clé DV, Atta EH, Dias DSP, Lima CBL, Bonduel M, Sciuccati G, et al. Rabbit antithymocyte globulin dose does not affect response or survival as first-line therapy for acquired aplastic anemia: a multicenter retrospective study. Ann Hematol. 2018;97(11):2039–46.CrossRefPubMed
25.
go back to reference Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006;133(6):622–7.CrossRefPubMed Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006;133(6):622–7.CrossRefPubMed
26.
go back to reference Stadler M, Germing U, Kliche KO, Josten KM, Kuse R, Hofmann WK, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004;18(3):460–5.CrossRefPubMed Stadler M, Germing U, Kliche KO, Josten KM, Kuse R, Hofmann WK, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004;18(3):460–5.CrossRefPubMed
27.
go back to reference Hertig A, Zuckermann A. Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: an update. Transpl Immunol. 2015;32(3):179–87.CrossRefPubMed Hertig A, Zuckermann A. Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: an update. Transpl Immunol. 2015;32(3):179–87.CrossRefPubMed
28.
go back to reference Mashima K, Yano S, Yokoyama H, Saito T, Machishima T, Shimada T, et al. Epstein–Barr virus-associated lymphoproliferative disorder with encephalitis following anti-thymocyte globulin for aplastic anemia resolved with rituximab therapy: a case report and literature review. Intern Med. 2017;56(6):701–6.CrossRefPubMedPubMedCentral Mashima K, Yano S, Yokoyama H, Saito T, Machishima T, Shimada T, et al. Epstein–Barr virus-associated lymphoproliferative disorder with encephalitis following anti-thymocyte globulin for aplastic anemia resolved with rituximab therapy: a case report and literature review. Intern Med. 2017;56(6):701–6.CrossRefPubMedPubMedCentral
29.
go back to reference Matsumoto H, Kimura Y, Murao T, Osawa M, Akiyama T, Mannoji K, et al. Severe colitis associated with both Epstein–Barr Virus and cytomegalovirus reactivation in a patient with severe aplastic anemia. Case Rep Gastroenterol. 2014;8(2):240–4.CrossRefPubMedPubMedCentral Matsumoto H, Kimura Y, Murao T, Osawa M, Akiyama T, Mannoji K, et al. Severe colitis associated with both Epstein–Barr Virus and cytomegalovirus reactivation in a patient with severe aplastic anemia. Case Rep Gastroenterol. 2014;8(2):240–4.CrossRefPubMedPubMedCentral
Metadata
Title
Immunosuppressive therapy with rabbit antithymocyte globulin therapy for acquired aplastic anemia: a multi-institutional retrospective study in Japanese adult patients
Authors
Nana Sasaki
Kazuho Shimura
Mihoko Yoshida
Nobuhiko Uoshima
Miki Kiyota
Mayumi Hatsuse
Hitoji Uchiyama
Yoshiaki Chinen
Tsutomu Kobayashi
Mitsushige Nakao
Ryoichi Takahashi
Sonoko Nakano-Akamatsu
Hiroto Kaneko
Yutaka Kobayashi
Chihiro Shimazaki
Masafumi Taniwaki
Junya Kuroda
The Kyoto Clinical Hematology Study Group (KOTOSG) investigators
Publication date
01-03-2019
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 3/2019
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-018-02583-w

Other articles of this Issue 3/2019

International Journal of Hematology 3/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine