Skip to main content

Advertisement

SpringerLink
Log in

Different effects of thymoglobulin on acute leukemia with pre-transplant residual blasts in HLA mismatch transplantation

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Anti-thymocyte globulin (ATG) is widely used to reduce acute and chronic graft-versus-host disease (a/cGVHD), one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). As the removal of alloreactive T cells by ATG may also reduce the graft-versus-leukemia effect, the question of whether ATG use affects relapse incidence and survival outcomes in acute leukemia patients with pre-transplant bone marrow residual blasts (PRB) remains controversial. Here, we evaluated the impact of ATG on transplant outcomes in acute leukemia patients with PRB (n = 994) who underwent HSCT from HLA 1-allele mismatched unrelated donors (MMUD) or HLA 1-antigen mismatched related donors (MMRD). In MMUD with PRB (n = 560), multivariate analysis demonstrated that ATG use significantly decreased grade II–IV aGVHD (hazard ratio [HR], 0.474; P = 0.007) and non-relapse mortality (HR, 0.414; P = 0.029) and marginally improved extensive cGVHD (HR, 0.321; P = 0.054) and GVHD-free/relapse-free survival (HR, 0.750; P = 0.069). We concluded that ATG had different effects on transplant outcomes using MMRD and MMUD, and its use would be beneficial to decrease a/cGVHD without increasing non-relapse mortality and relapse incidence in acute leukemia patients with PRB following HSCT from MMUD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

TRUMP data from this study is not shared for public access without permission.

References

  1. Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011;29(16):2230–9. https://doi.org/10.1200/JCO.2010.33.7212.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091–101. https://doi.org/10.1056/NEJMoa1004383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Murata M, Teshima T. Treatment of steroid-refractory acute graft-versus-host disease using commercial mesenchymal stem cell products. Front Immunol. 2021;12:724380. https://doi.org/10.3389/fimmu.2021.724380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Saidu NEB, Bonini C, Dickinson A, Grce M, Inngjerdingen M, Koehl U, et al. New approaches for the treatment of chronic graft-versus-host disease: current status and future directions. Front Immunol. 2020;11:578314. https://doi.org/10.3389/fimmu.2020.578314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(11):1504–18. https://doi.org/10.1016/j.bbmt.2010.01.007.

    Article  PubMed  Google Scholar 

  6. Burnham AJ, Daley-Bauer LP, Horwitz EM. Mesenchymal stromal cells in hematopoietic cell transplantation. Blood Adv. 2020;4(22):5877–87. https://doi.org/10.1182/bloodadvances.2020002646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Luo Y, Jin M, Tan Y, Zhao Y, Shi J, Zhu Y, et al. Antithymocyte globulin improves GVHD-free and relapse-free survival in unrelated hematopoietic stem cell transplantation. Bone Marrow Transplant. 2019;54(10):1668–75. https://doi.org/10.1038/s41409-019-0502-8.

    Article  CAS  PubMed  Google Scholar 

  8. Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012;18(8):1150–63. https://doi.org/10.1016/j.bbmt.2012.04.005.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kroger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374(1):43–53. https://doi.org/10.1056/NEJMoa1506002.

    Article  CAS  PubMed  Google Scholar 

  10. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, 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):855–64. https://doi.org/10.1016/S1470-2045(09)70225-6.

    Article  CAS  PubMed  Google Scholar 

  11. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo 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):2942–7. https://doi.org/10.1182/blood.v98.10.2942.

    Article  CAS  PubMed  Google Scholar 

  12. Baron F, Mohty M, Blaise D, Socie G, Labopin M, Esteve J, et al. Anti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017;102(2):224–34. https://doi.org/10.3324/haematol.2016.148510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wakamatsu M, Terakura S, Ohashi K, Fukuda T, Ozawa Y, Kanamori H, et al. Impacts of thymoglobulin in patients with acute leukemia in remission undergoing allogeneic HSCT from different donors. Blood Adv. 2019;3(2):105–15. https://doi.org/10.1182/bloodadvances.2018025643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tachibana T, Kanda J, Ishizaki T, Najima Y, Tanaka M, Doki N, et al. Pre-conditioning intervention in patients with relapsed or refractory acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation: a KSGCT multicenter retrospective analysis. Ann Hematol. 2021;100(11):2763–71. https://doi.org/10.1007/s00277-021-04607-8.

    Article  CAS  PubMed  Google Scholar 

  15. Shimomura Y, Sobue T, Hirabayashi S, Kondo T, Mizuno S, Kanda J, et al. Comparing cord blood transplantation and matched related donor transplantation in non-remission acute myeloid leukemia. Leukemia. 2021. https://doi.org/10.1038/s41375-021-01474-0.

    Article  PubMed  Google Scholar 

  16. Shimomura Y, Hara M, Hirabayashi S, Kondo T, Mizuno S, Uchida N, et al. Comparison of fludarabine, a myeloablative dose of busulfan, and melphalan vs conventional myeloablative conditioning regimen in patients with relapse and refractory acute myeloid leukemia in non-remission status. Bone Marrow Transplant. 2021;56(9):2302–4. https://doi.org/10.1038/s41409-021-01380-0.

    Article  CAS  PubMed  Google Scholar 

  17. Venditti A, Maurillo L, Buccisano F, Del Poeta G, Mazzone C, Tamburini A, et al. Pretransplant minimal residual disease level predicts clinical outcome in patients with acute myeloid leukemia receiving high-dose chemotherapy and autologous stem cell transplantation. Leukemia. 2003;17(11):2178–82. https://doi.org/10.1038/sj.leu.2403138.

    Article  CAS  PubMed  Google Scholar 

  18. Kekre N, Antin JH. ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint. Blood Adv. 2017;1(9):573–6. https://doi.org/10.1182/bloodadvances.2016001552.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nagler A, Dholaria B, Labopin M, Socie G, Huynh A, Itala-Remes M, et al. The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation. Leukemia. 2020;34(4):1144–53. https://doi.org/10.1038/s41375-019-0631-5.

    Article  CAS  PubMed  Google Scholar 

  20. Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86(3):269–74. https://doi.org/10.1532/IJH97.06239.

    Article  PubMed  Google Scholar 

  21. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15(3):367–9. https://doi.org/10.1016/j.bbmt.2008.12.497.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone marrow Transplant. 1995;15(6):825–8.

    CAS  PubMed  Google Scholar 

  23. Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP-EBMT analysis on patients with AML in remission. Bone Marrow Transplant. 2016;51(4):610–1. https://doi.org/10.1038/bmt.2015.305.

    Article  CAS  PubMed  Google Scholar 

  24. Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123(23):3664–71. https://doi.org/10.1182/blood-2014-01-552984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Soiffer RJ, Kim HT, McGuirk J, Horwitz ME, Johnston L, Patnaik MM, et al. Prospective, randomized, double-blind, phase iii clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35(36):4003–11. https://doi.org/10.1200/JCO.2017.75.8177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chang YJ, Wang Y, Mo XD, Zhang XH, Xu LP, Yan CH, et al. Optimal dose of rabbit thymoglobulin in conditioning regimens for unmanipulated, haploidentical, hematopoietic stem cell transplantation: long-term outcomes of a prospective randomized trial. Cancer. 2017;123(15):2881–92. https://doi.org/10.1002/cncr.30540.

    Article  CAS  PubMed  Google Scholar 

  27. Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17(2):164–73. https://doi.org/10.1016/S1470-2045(15)00462-3.

    Article  CAS  PubMed  Google Scholar 

  28. Spierings E, Kim YH, Hendriks M, Borst E, Sergeant R, Canossi A, et al. Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(8):1244–53. https://doi.org/10.1016/j.bbmt.2013.06.001.

    Article  CAS  PubMed  Google Scholar 

  29. Spellman S, Warden MB, Haagenson M, Pietz BC, Goulmy E, Warren EH, et al. Effects of mismatching for minor histocompatibility antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants. Biol Blood Marrow Transplant. 2009;15(7):856–63. https://doi.org/10.1016/j.bbmt.2009.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shiratori S, Sugita J, Fuji S, Aoki J, Sawa M, Ozawa Y, et al. Low-dose antithymocyte globulin inhibits chronic graft-versus-host disease in peripheral blood stem cell transplantation from unrelated donors. Bone Marrow Transplant. 2021;56(9):2231–40. https://doi.org/10.1038/s41409-021-01314-w.

    Article  CAS  PubMed  Google Scholar 

  31. Heelan F, Mallick R, Bryant A, Radhwi O, Atkins H, Huebsch L, et al. Does lymphocyte count impact dosing of anti-thymocyte globulin in unrelated donor stem cell transplantation? Biol Blood Marrow Transplant. 2020;26(7):1298–302. https://doi.org/10.1016/j.bbmt.2020.02.026.

    Article  CAS  PubMed  Google Scholar 

  32. Kennedy VE, Chen H, Savani BN, Greer J, Kassim AA, Engelhardt BG, et al. Optimizing antithymocyte globulin dosing for unrelated donor allogeneic hematopoietic cell transplantation based on recipient absolute lymphocyte count. Biol Blood Marrow Transplant. 2018;24(1):150–5. https://doi.org/10.1016/j.bbmt.2017.08.029.

    Article  CAS  PubMed  Google Scholar 

  33. Battipaglia G, Labopin M, Kroger N, Vitek A, Afanasyev B, Hilgendorf I, et al. Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019;134(11):892–9. https://doi.org/10.1182/blood.2019000487.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all the physicians and staff members of the collaborating institutes of the Japan Society for Hematopoietic Stem Cell Transplantation.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8560, Japan

    Manabu Wakamatsu

  2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, Aichi, 466-8560, Japan

    Makoto Murata & Seitaro Terakura

  3. Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Junya Kanda

  4. Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan

    Kentaro Fukushima

  5. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  6. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Yuho Najima

  7. Division of Hematology, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan

    Yuta Katayama

  8. Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  9. Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan

    Masatsugu Tanaka

  10. Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan

    Yoshinobu Kanda

  11. Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan

    Tetsuya Eto

  12. Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan

    Satoru Takada

  13. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

    Shinichi Kako

  14. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida

  15. Department of Hematology, National Hospital Organization, Kumamoto Medical Center, Kumamoto, Japan

    Toshiro Kawakita

  16. Department of Pediatrics, Osaka International Cancer Institute, Osaka, Japan

    Hashii Yoshiko

  17. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Tatsuo Ichinohe

  18. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  19. Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan

    Yoshiko Atsuta

Authors
  1. Manabu Wakamatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makoto Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junya Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kentaro Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takahiro Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuho Najima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuta Katayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukiyasu Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masatsugu Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshinobu Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tetsuya Eto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Satoru Takada
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shinichi Kako
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Naoyuki Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Toshiro Kawakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hashii Yoshiko
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tatsuo Ichinohe
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yoshiko Atsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Seitaro Terakura
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation

Contributions

MW designed the research, analyzed the data, and wrote the manuscript; ST analyzed the data and helped write the manuscript; TF, ND, YK, YO, MT, YK, TE, ST, SK, NU, and TK contributed to data collection; YH, TI and YA supervised data management; KF, MM, and JK designed and supervised the research; and all authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Manabu Wakamatsu or Seitaro Terakura.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 213 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wakamatsu, M., Murata, M., Kanda, J. et al. Different effects of thymoglobulin on acute leukemia with pre-transplant residual blasts in HLA mismatch transplantation. Int J Hematol 117, 889–899 (2023). https://doi.org/10.1007/s12185-023-03563-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-023-03563-5

Keywords

Search

Navigation