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.

  • Letter to the Editor
  • Published:

Sirolimus, tacrolimus and antithymocyte globulin as GVHD prophylaxis in HLA-mismatched unrelated donor hematopoietic cell transplantation: a single institution experience

Bone Marrow Transplantation volume 50, pages 1487–1489 (2015)Cite this article

Subjects

Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for various hematological malignancies with improved outcomes observed over the past years.1, 2 Offering a HLA-mismatched allo-HCT to patients lacking a suitable HLA-matched related (MRD) or unrelated donor (MUD) is feasible, but results in high non-relapse mortality (NRM) and inferior overall survival (OS).3 Adding antithymocyte globulin (ATG) improves post-allograft outcomes by reducing incidence and severity of acute (aGVHD) and chronic GVHD (cGVHD).4 Accordingly, ATG has become essential for aGVHD prophylaxis in mismatched unrelated donor (MMUD) allo-HCT.5, 6 No consensus exists on a uniformly accepted standard GVHD prophylaxis regimen for MMUD allografting. Regimen choice is generally based on physician and/or center preference. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is used in combination with tacrolimus for aGVHD prophylaxis. A randomized phase 2 study comparing tacrolimus plus sirolimus (TAC–SIR) or methotrexate (TAC–MTX) in 74 patients receiving an allograft from a MRD (SIR=17, TAC=18) or a MUD (SIR=20, TAC=19) donor showed lower incidence of grade II–IV aGVHD with TAC–SIR but no difference in OS.7 A larger multicenter phase 3 trial comparing TAC–SIR to TAC–MTX failed to show a difference in incidence of grade II–IV aGVHD or OS, though a trend toward less clinically severe grade III–IV aGVHD was described with TAC–SIR.8 TAC–SIR showed faster neutrophil and platelet engraftment and less severe oropharyngeal mucositis.8 Adding ATG to TAC–SIR is feasible. Al-Kadhimi et al.9 evaluated TAC–SIR–ATG in a single-arm phase 2 study of 47 unrelated donor allo-HCT (HLA 8/8 match=47%, HLA 7/8 match=53%) showing an incidence of grade II–IV aGVHD of 23%, cGVHD 33%, 2-year NRM 32% and 1-year OS of 65%. Another phase 2 trial using TAC–SIR–ATG9 was prematurely discontinued after enrolling 32 of 60 intended patients owing to graft failure (12.5%) and 3 associated deaths.10 We report our experience using TAC–SIR–ATG in MMUD allo-HCT recipients at our institution.

This retrospective study evaluated 27 consecutive patients who received TAC–SIR–ATG as GVHD prophylaxis for MMUD allo-HCT between August 2008 and September 2013. This study was approved by the Institutional Review Board of University of South Florida, and patients provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki. Patients were ⩾18 years of age and received a MMUD allograft defined as ⩽7/8 HLA-matching at antigen(s) or allele(s) levels. All received G-CSF mobilized PBSCs. Patients receiving umbilical cord blood transplantation or GVHD prophylaxis other than TAC–SIR–ATG were excluded.

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

References

  1. 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: 2091–2101.

    Article  CAS  Google Scholar 

  2. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M . Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1006–1012.

    Article  CAS  Google Scholar 

  3. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576–4583.

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. Ayuk F, Diyachenko G, Zabelina T, Panse J, Wolschke C, Eiermann T et al. Anti-thymocyte globulin overcomes the negative impact of HLA mismatching in transplantation from unrelated donors. Exp Hematol 2008; 36: 1047–1054.

    Article  CAS  Google Scholar 

  6. Kroger N, Zabelina T, Binder T, Ayuk F, Bacher U, Amtsfeld G 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: 454–462.

    Article  Google Scholar 

  7. Pidala J, Kim J, Jim H, Kharfan-Dabaja MA, Nishihori T, Fernandez HF et al. A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation. Haematologica 2012; 97: 1882–1889.

    Article  CAS  Google Scholar 

  8. 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  Google Scholar 

  9. 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  Google Scholar 

  10. Khaled SK, Palmer J, Stiller T, Senitzer D, Maegawa R, Rodriguez R et al. A phase II study of sirolimus, tacrolimus and rabbit anti-thymocyte globulin as GVHD prophylaxis after unrelated-donor PBSC transplant. Bone Marrow Transplant 2013; 48: 278–283.

    Article  CAS  Google Scholar 

  11. Gray RJ . A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  12. 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.

    CAS  Google Scholar 

  13. 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  Google Scholar 

  14. Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 571–575.

    Article  Google Scholar 

  15. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms Diane Coyle and Mr Ryan Hillgruber for their assistance on data management.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Moffitt Cancer Center, Tampa, FL, USA

    R Nelson & J F Shapiro

  2. Department of Pharmacotherapy and Clinical Research, College of Pharmacy, University of South Florida, Tampa, FL, USA

    J B Perkins

  3. Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA

    J Kim & B Yue

  4. Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, FL, USA

    J Kim, T Nishihori, J Pidala, E Ayala, F L Locke, T Field, A Mishra, M Riches, B Betts, L Perez, J L Ochoa-Bayona, M Alsina, H Fernandez, C Anasetti & M A Kharfan-Dabaja

  5. Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA

    T Nishihori, J Pidala, E Ayala, F L Locke, T Field, A Mishra, M Riches, B Betts, L Perez, J L Ochoa-Bayona, M Alsina, H Fernandez, C Anasetti & M A Kharfan-Dabaja

Authors
  1. R Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J F Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J B Perkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Nishihori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Pidala
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Ayala
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F L Locke
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T Field
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Riches
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. B Betts
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. L Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. B Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J L Ochoa-Bayona
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M Alsina
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. H Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. C Anasetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M A Kharfan-Dabaja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Kharfan-Dabaja.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

This work was presented in part at the Annual Meeting of the American Society of Hematology in December 2014 in San Francisco, CA, USA (poster presentation 2553).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nelson, R., Shapiro, J., Perkins, J. et al. Sirolimus, tacrolimus and antithymocyte globulin as GVHD prophylaxis in HLA-mismatched unrelated donor hematopoietic cell transplantation: a single institution experience. Bone Marrow Transplant 50, 1487–1489 (2015). https://doi.org/10.1038/bmt.2015.192

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.192

This article is cited by

Search

Advanced search

Quick links