Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Host Disease

Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for GvHD prevention

Bone Marrow Transplantation volume 52, pages 1304–1310 (2017)Cite this article

Subjects

Abstract

Chronic GvHD (cGvHD) is the leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic stem cell transplant (AHSCT). We analyzed the late effects of a phase II trial testing the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymoglobulin Thymo) in combination with tacrolimus and sirolimus (TTS) in 47 patients (pts) for the prevention of acute and chronic GvHD after unrelated AHSCT. The median follow-up was 45.2 months. The cumulative incidence of NIH severe cGvHD at 48 months was 6.4% with no new occurrences past 6 months for the entire follow-up period. The overall cumulative incidence of cGvHD was 44.7%. Out of 20 pts who are alive and disease-free at the last follow-up, only 4 pts continue to need systemic immune suppression. We observed low late NRM with only 3 transplant-related deaths after 6 months post transplant. At 4 years of follow-up, the overall cumulative incidence of NRM and disease relapse was 27.7% and 30.0%, respectively. PFS and overall survival (OS) at 4 years were 42 and 47%. At long term follow-up, TTS was associated with low incidence of severe cGvHD and late NRM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Graze PR, Gale RP . Chronic graft versus host disease: a syndrome of disordered immunity. Am J Med 1979; 66: 611–620.

    Article  CAS  PubMed  Google Scholar 

  2. Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012; 367: 1487–1496.

    Article  CAS  PubMed  Google Scholar 

  3. Socie G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 2011; 117: 6375–6382.

    Article  CAS  PubMed  Google Scholar 

  4. 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: 2230–2239.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Boyiadzis M, Arora M, Klein JP, Hassebroek A, Hemmer M, Urbano-Ispizua A et al. Impact of chronic graft-versus-host disease on late relapse and survival on 7,489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia. Clin Cancer Res 2015; 21: 2020–2028.

    Article  PubMed  Google Scholar 

  6. Socie G, Stone JV, Wingard JR, Weisdorf D, Henslee-Downey PJ, Bredeson C et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med 1999; 341: 14–21.

    Article  CAS  PubMed  Google Scholar 

  7. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  PubMed  Google Scholar 

  8. Moon JH, Sohn SK, Lambie A, Ellis L, Hamad N, Uhm J et al. Validation of National Institutes of Health global scoring system for chronic graft-versus-host disease (GVHD) according to overall and GVHD-specific survival. Biol Blood Marrow Transplant 2014; 20: 556–563.

    Article  PubMed  Google Scholar 

  9. Saillard C, Crocchiolo R, Furst S, El-Cheikh J, Castagna L, Signori A et al. National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine-busulfan-antithymocyte globulin conditioning regimen. Leuk Lymphoma 2014; 55: 1106–1112.

    Article  CAS  PubMed  Google Scholar 

  10. Perez-Simon JA, Encinas C, Silva F, Arcos MJ, Diez-Campelo M, Sanchez-Guijo FM et al. Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the national institutes health scale plus the type of onset can predict survival rates and the duration of immunosuppressive therapy. Biol Blood Marrow Transplant 2008; 14: 1163–1171.

    Article  PubMed  Google Scholar 

  11. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.

    CAS  PubMed  Google Scholar 

  12. Ringden O, Labopin M, Gluckman E, Reiffers J, Vernant JP, Jouet JP et al. Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin A combined with methotrexate as prophylaxis. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1996; 18: 921–929.

    CAS  PubMed  Google Scholar 

  13. Weiden PL, Flournoy N, Sanders JE, Sullivan KM, Thomas ED . Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplant Proc 1981; 13: 248–251.

    CAS  PubMed  Google Scholar 

  14. Bhatia S . Long-term health impacts of hematopoietic stem cell transplantation inform recommendations for follow-up. Expert Rev Hematol 2011; 4: 437–452 quiz 453-434.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mitchell SA, Leidy NK, Mooney KH, Dudley WN, Beck SL, LaStayo PC et al. Determinants of functional performance in long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD). Bone Marrow Transplant 2010; 45: 762–769.

    Article  CAS  PubMed  Google Scholar 

  16. Atkinson K, Horowitz MM, Gale RP, van Bekkum DW, Gluckman E, Good RA et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood 1990; 75: 2459–2464.

    CAS  PubMed  Google Scholar 

  17. Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2015; 21: 266–274.

    Article  PubMed  Google Scholar 

  18. Cutler C, Kim HT, Hochberg E, Ho V, Alyea E, Lee SJ et al. Sirolimus and tacrolimus without methotrexate as graft-versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2004; 10: 328–336.

    Article  CAS  PubMed  Google Scholar 

  19. Cutler C, Li S, Ho VT, Koreth J, Alyea E, Soiffer RJ et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood 2007; 109: 3108–3114.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood 2014; 124: 1372–1377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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: 2942–2947.

    Article  CAS  PubMed  Google Scholar 

  22. Bacigalupo A, Lamparelli T, Barisione G, Bruzzi P, Guidi S, Alessandrino PE et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant 2006; 12: 560–565.

    Article  PubMed  Google Scholar 

  23. 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: 43–53.

    Article  PubMed  Google Scholar 

  24. Robert J, Soiffer M, Haesook TK, McGuirk J, Horwitz ME, Johnston L et al. A Prospective Randomized Double Blind Phase 3 Clinical Trial of Anti- T Lymphocyte Globulin (ATLG) to Assess Impact on Chronic Graft-Versus-Host Disease (cGVHD) Free Survival in Patients Undergoing HLA Matched Unrelated Myeloablative Hematopoietic Cell Transplantation (HCT), In: American Society of Hematology: San Diego, CA, 2016.

    Google Scholar 

  25. Al-Kadhimi Z, Gul Z, Rodriguez R, Chen W, Smith D, Mitchell A et al. Anti-thymocyte globulin (thymoglobulin), tacrolimus, and sirolimus as acute graft-versus-host disease prophylaxis for unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012; 18: 1734–1744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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: 825–828.

  27. Al-Kadhimi Z, Gul Z, Chen W, Smith D, Abidi M, Deol A et al. High incidence of severe acute graft-versus-host disease with tacrolimus and mycophenolate mofetil in a large cohort of related and unrelated allogeneic transplantation patients. Biol Blood Marrow Transplant 2014; 20: 979–985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000; 96: 2062–2068.

    CAS  PubMed  Google Scholar 

  29. Shayani S, Palmer J, Stiller T, Liu X, Thomas SH, Khuu T et al. Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant 2013; 19: 298–304.

    Article  PubMed  Google Scholar 

  30. Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood 2011; 118: 1402–1412.

    Article  CAS  PubMed  Google Scholar 

  31. Jacobsen N, Lonnqvist B, Ringden O, Rajantie J, Siimes MA, Volin L et al. Graft-versus-leukaemia activity associated with cytomegalovirus seropositive bone marrow donors but separated from graft-versus-host disease in allograft recipients with AML. Eur J Haematol 1987; 38: 350–355.

    Article  CAS  PubMed  Google Scholar 

  32. Behrendt CE, Rosenthal J, Bolotin E, Nakamura R, Zaia J, Forman SJ . Donor and recipient CMV serostatus and outcome of pediatric allogeneic HSCT for acute leukemia in the era of CMV-preemptive therapy. Biol Blood Marrow Transplant 2009; 15: 54–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nachbaur D, Clausen J, Kircher B . Donor cytomegalovirus seropositivity and the risk of leukemic relapse after reduced-intensity transplants. Eur J Haematol 2006; 76: 414–419.

    Article  PubMed  Google Scholar 

  34. Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 2012; 14: 1258–1275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pical-Izard C, Crocchiolo R, Granjeaud S, Kochbati E, Just-Landi S, Chabannon C et al. Reconstitution of natural killer cells in HLA-matched HSCT after reduced-intensity conditioning: impact on clinical outcome. Biol Blood Marrow Transplant 2015; 21: 429–439.

    Article  CAS  PubMed  Google Scholar 

  36. Wai LE, Fujiki M, Takeda S, Martinez OM, Krams SM . Rapamycin, but not cyclosporine or FK506, alters natural killer cell function. Transplantation 2008; 85: 145–149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Buhlmann L, Buser AS, Cantoni N, Gerull S, Tichelli A, Gratwohl A et al. Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT. Bone Marrow Transplant 2011; 46: 1357–1362.

    Article  CAS  PubMed  Google Scholar 

  38. Gul Z, Van Meter E, Abidi M, Ditah I, Abdul-Hussein M, Deol A et al. Low blood lymphocyte count at 30 days post transplant predicts worse acute GVHD and survival but not relapse in a large retrospective cohort. Bone Marrow Transplant 2015; 50: 432–437.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology, Winship Cancer Center/Emory University, Atlanta, GA, USA

    Z Al-Kadhimi, A Langston & E Waller

  2. Department of Hematology/Oncology, University of Cincinnati, Cincinnati, OH, USA

    Z Gul

  3. Department of Hematology/Oncology, Spectrum Health Institute, Grand Rapids, MI, USA

    M Abidi

  4. Department of Hematology/Oncology, University of Virginia, Charlottesville, VA, USA

    L G Lum

  5. Department of Hematology/Oncology, Wayne State University, Detroit, MI, USA

    A Deol, W Chen, H Jang & J Uberti

  6. Diagnostic Laboratory, Infinity primary care, Novi, MI, USA

    C Ozust

Authors
  1. Z Al-Kadhimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Z Gul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Abidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L G Lum
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Deol
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C Ozust
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Langston
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E Waller
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J Uberti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Z Al-Kadhimi.

Ethics declarations

Competing interests

Z Al-K has received a research grant support from Genzyme pharmaceuticals. The remaining authors declare no conflicts of interest.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Kadhimi, Z., Gul, Z., Abidi, M. et al. Low incidence of severe cGvHD and late NRM in a phase II trial of thymoglobulin, tacrolimus and sirolimus for GvHD prevention. Bone Marrow Transplant 52, 1304–1310 (2017). https://doi.org/10.1038/bmt.2017.95

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2017.95

This article is cited by

Search

Advanced search

Quick links