Abstract
Acute GVHD (aGVHD) is a major cause of morbidity and mortality in hematopoietic allograft recipients. The best therapy for patients failing to respond, or not tolerating, systemic glucocorticoids remains undefined. We evaluated the efficacy of sirolimus in 34 patients, median age of 49 (23–67) years, with steroid-refractory (n=31) or steroid-intolerant (n=3) aGVHD. aGVHD was diagnosed at a median of 34 (7–1042) days post allografting, and confirmed by biopsy in all cases. Initial aGVHD treatment consisted of prednisone up to 2 mg/kg. Sirolimus was initiated at a median of 9 (1–255) days after glucocorticoid initiation. A sirolimus loading dose was administered to 19 (56%) of 34 patients, median 6 (3–8) mg, followed by maintenance of 1–2 mg/day to target therapeutic trough levels between 4 and 12 ng/ml. Overall response rate was 76%. Fifteen (44%) of 34 patients achieved CR, defined as complete resolution of aGVHD sustained for at least 1 month, after sirolimus initiation without additional immunosuppressive agents. CR was achieved in 11 (42%) of 31 steroid-refractory and 2 (67%) of 3 steroid-intolerant patients. Median OS after initiation of sirolimus was 5.6 months, and 1-year OS was 44% (95% CI: 27–60%). Sirolimus is effective in controlling steroid-refractory aGVHD.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ferrara JL, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550–1561.
MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant 2002; 8: 387–394.
Martin PJ, Schoch G, Fisher L, Byers V, Anasetti C, Appelbaum FR et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood 1990; 76: 1464–1472.
Weisdorf D, Haake R, Blazar B, Miller W, McGlave P, Ramsay N et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood 1990; 75: 1024–1030.
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.
Pidala J, Kim J, Anasetti C . Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009; 15: 881–885.
Benito AI, Furlong T, Martin PJ, Anasetti C, Appelbaum FR, Doney K et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation 2001; 72: 1924–1929.
Furlong T, Kiem HP, Appelbaum FR, Carpenter PA, Deeg HJ, Doney K et al. Sirolimus in combination with cyclosporine or tacrolimus plus methotrexate for prevention of graft-versus-host disease following hematopoietic cell transplantation from unrelated donors. Biol Blood Marrow Transplant 2008; 14: 531–537.
Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB et al. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood 2003; 102: 1601–1605.
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.
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.
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.
Basara N, Blau WI, Romer E, Rudolphi M, Bischoff M, Kirsten D et al. Mycophenolate mofetil for the treatment of acute and chronic GVHD in bone marrow transplant patients. Bone Marrow Transplant 1998; 22: 61–65.
Kim JG, Sohn SK, Kim DH, Lee NY, Suh JS, Lee KS et al. Different efficacy of mycophenolate mofetil as salvage treatment for acute and chronic GVHD after allogeneic stem cell transplant. Eur J Haematol 2004; 73: 56–61.
Krejci M, Doubek M, Buchler T, Brychtova Y, Vorlicek J, Mayer J . Mycophenolate mofetil for the treatment of acute and chronic steroid-refractory graft-versus-host disease. Ann Hematol 2005; 84: 681–685.
Takami A, Mochizuki K, Okumura H, Ito S, Suga Y, Yamazaki H et al. Mycophenolate mofetil is effective and well tolerated in the treatment of refractory acute and chronic graft-versus-host disease. Int J Hematol 2006; 83: 80–85.
MacMillan ML, Weisdorf DJ, Davies SM, DeFor TE, Burns LJ, Ramsay NK et al. Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8: 40–46.
Couriel D, Saliba R, Hicks K, Ippoliti C, de Lima M, Hosing C et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 2004; 104: 649–654.
Patriarca F, Sperotto A, Damiani D, Morreale G, Bonifazi F, Olivieri A et al. Infliximab treatment for steroid-refractory acute graft-versus-host disease. Haematologica 2004; 89: 1352–1359.
Bolanos-Meade J, Jacobsohn DA, Margolis J, Ogden A, Wientjes MG, Byrd JC et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol 2005; 23: 2661–2668.
Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L, Gonzalez-Llano O, Gutierrez-Aguirre H, Cantu-Rodriguez O et al. Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2008; 14: 10–15.
Carpenter PA, Appelbaum FR, Corey L, Deeg HJ, Doney K, Gooley T et al. A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood 2002; 99: 2712–2719.
Ho VT, Zahrieh D, Hochberg E, Micale E, Levin J, Reynolds C et al. Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood 2004; 104: 1224–1226.
Greinix HT, Socie G, Bacigalupo A, Holler E, Edinger MG, Apperley JF et al. Assessing the potential role of photopheresis in hematopoietic stem cell transplant. Bone Marrow Transplant 2006; 38: 265–273.
Greinix HT, Volc-Platzer B, Knobler RM . Extracorporeal photochemotherapy in the treatment of severe graft-versus-host disease. Leuk Lymphoma 2000; 36: 425–434.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371: 1579–1586.
Mielcarek M, Storer BE, Boeckh M, Carpenter PA, McDonald GB, Deeg HJ et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood 2009; 113: 2888–2894.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Hoda, D., Pidala, J., Salgado-Vila, N. et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant 45, 1347–1351 (2010). https://doi.org/10.1038/bmt.2009.343
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2009.343
Keywords
This article is cited by
-
A prospective single-center study on CNI-free GVHD prophylaxis with everolimus plus mycophenolate mofetil in allogeneic HCT
Annals of Hematology (2021)
-
A monocentric study of steroid-refractory acute graft-versus-host disease treatment with tacrolimus and mTOR inhibitor
Bone Marrow Transplantation (2020)
-
Ruxolitinib treatment for SR-aGVHD in patients with EBV-HLH undergoing allo-HSCT
Annals of Hematology (2020)
-
Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study
Bone Marrow Transplantation (2020)
-
Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation
Bone Marrow Transplantation (2019)