Abstract
GvHD results in death in the majority of steroid-resistant patients. This report assesses the safety and efficacy of two regional intra-arterial steroid (IAS) treatment protocols in the largest published cohort of patients with resistant/dependent hepatic and/or gastrointestinal GvHD, as well as identification of predictors of response to IAS and survival. One hundred and twenty patients with hepatic, gastrointestinal GvHD or both were given IAS. Gastrointestinal initial response (IR) and complete response (CR) were documented in 67.9% and 47.6%, respectively, whereas hepatic IR/CR in 54.9% and 33.3%, respectively. The predictors of gastrointestinal CR were lower peak GvHD and steroid-dependent (SD) GvHD. The predictors for hepatic CR were male patient, reduced intensity conditioning and SD GvHD. Twenty-six of the 120 patients (21.6%) are currently alive (median follow-up for the survivors 91.5 months). The 12 months’ overall survival is 30% with no treatment-associated deaths. Predictors of 12 months’ survival were as follows: first transplant, age<20 years, non-TBI regimen and GvHD CR. Shorter time to gastrointestinal IR but not time to hepatic IR was associated with improved 12 months’ survival. IAS appears to be safe and effective. Gastrointestinal treatment is more effective than hepatic treatment. In our study, we conclude our current recommendations for IAS treatment.
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Change history
20 October 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41409-021-01504-6
References
Berger M, Biasin E, Saglio F, Fagioli F . Innovative approaches to treat steroid-resistant or steroid refractory GVHD. Bone Marrow Transplant 2008; 42: S101–S105.
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.
Martin PJ, Schoch G, Fisher L, Byers V, Appelbaum FR, McDonald GB et al. A retrospective analysis of therapy of acute graft-versus-host- disease: secondary treatment. Blood 1991; 77: 1821–1828.
Shapira MY, Bloom AI, Or R, Sasson T, Nagler A, Resnick IB et al. Intra-arterial catheter directed therapy for severe graft-versus-host disease. Br J Haematol 2002; 119: 760–764.
Sato T, Sakamaki S, Nagaoka Y, Kuribayashi K, Nagamachi Y, Morii K et al. Intra-mesenteric artery steroid administration relieved severe refractory gastro-intestinal graft vs. host disease in an allogeneic bone marrow transplantation patient. Am J Hematol 1997; 56: 277–280.
Nakai K, Tajima K, Tanigawa N, Matsumoto N, Zen K, Nomura S et al. Intra-arterial steroid-injection therapy for steroid-refractory acute graft-versus-host disease with the evaluation of angiography. Bone Marrow Transplant 2004; 33: 1231–1233.
Martino R, Romero P, Subira M, Bellido M, Altés A, Sureda A et al. Comparison of the classic Glucksberg criteria and the IBMTR severity index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow Transplant Registry. Bone Marrow Transplant 1999; 24: 283–287.
Storb R, Kolb HJ, Graham TC, Kolb H, Weiden PL, Thomas ED . Treatment of established graft-versus-host disease in dogs by antithymocyte serum or prednisone. Blood 1973; 42: 601–609.
Martin PJ, Rizzo D, 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: 1150–1163.
Lee SJ, Zahrieh D, Agura E, MacMillan ML, Maziarz RT, McCarthy PL Jr et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft versus-host disease: results of a randomized trial. Blood 2004; 104: 1559–1564.
Cragg L, Blazar BR, Defor T, Kolatker N, Miller W, Kersey J et al. A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. Biol Blood Marrow Transplant 2000; 6: 441–447.
Levine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood 2008; 111: 2470–2475.
Westin JR, Saliba RM, De Lima M, Alousi A, Hosing C, Qazilbash MH et al. Steroid-refractory acute GVHD: predictors and outcomes. Adv Hematol 2011; 2011: 601953.
Khoury H, Kashyap A, Adkins DR, Brown RA, Miller G, Vij R et al. Treatment of steroid resistant acute graft-versus-host disease with anti-thymocyte globulin. Bone Marrow Transplant 2001; 27: 1059–1064.
Perales MA, Ishill N, Lomazow WA, Weinstock DM, Papadopoulos EB, Dastigir H et al. Long-term follow-up of patients treated with daclizumab for steroid-refractory acute graft-vs-host disease. Bone Marrow Transplant 2007; 40: 481–486.
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.
Macmillan ML, Couriel D, Weisdorf DJ, Schwab G, Havrilla N, Fleming TR et al. A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute graft-versus-host disease. Blood 2007; 109: 2657–2662.
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.
Furlong T, Martin P, Flowers ME, Carnevale-Schianca F, Yatscoff R, Chauncey T et al. Therapy with mycophenolate mofetil for refractory acute and chronic GVHD. Bone Marrow Transplant 2009; 44: 739–748.
Hoda D, Pidala J, Salgado-Vila N, Kim J, Perkins J, Bookout R et al. Sirolimus for treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant 2010; 45: 1347–1351.
Messina C, Locatelli F, Lanino E, Uderzo C, Zacchello G, Cesaro S et al. Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol 2003; 122: 118–127.
Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lönnies H et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81: 1390–1397.
Xhaard A, Rocha V, Bueno B, de Latour RP, Lenglet J, Petropoulou A et al. Steroid-refractory acute GVHD: lack of long-term improved survival using new generation anticytokine treatment. Biol Blood Marrow Transplant 2012; 18: 406–413.
Martin PJ . Study design and endpoints in graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21: 357–372.
Shields CL, Lally SE, Leahey AM, Jabbour PM, Caywood EH, Schwendeman R et al. Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Curr Opin Ophthalmol 2014; 25: 374–385.
Allard MA, Malka D . Place of hepatic intra-arterial chemotherapy in the treatment of colorectal liver metastases. J Visc Surg 2014; 151: S21–S24.
Theodotou C, Shah AH, Hayes S, Bregy A, Johnson JN, Aziz-Sultan MA et al. The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma. Br J Neurosurg 2014; 28: 438–446.
Amsterdam A, Sasson R . The anti-inflammatory action of glucocorticoids is mediated by cell type specific regulation of apoptosis. Mol Cell Endocrinol 2002; 189: 1–9.
Bladh LG, Liden J, Pazirandeh A, Rafter I, Dahlman-Wright K, Nilsson S et al. Identification of target genes involved in the antiproliferative effect of glucocorticoids reveals a role for nuclear factor-(kappa)B repression. Mol Endocrinol 2005; 19: 632–643.
Bouazzaoui A, Spacenko E, Mueller G, Huberb E, Schubertc T, Holler E et al. Steroid treatment alters adhesion molecule and chemokine expression in experimental acute graft-vs.-host disease of the intestinal tract. Exp Hematol 2011; 39: 238–249.
Murai M, Yoneyama H, Ezaki T, Suematsu M, Terashima Y, Harada A et al. Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol 2003; 4: 154–160.
Silva IA, Olkiewicz K, Askew D, Fisher JM, Chaudhary MN, Vannella KM et al. Secondary lymphoid organs contribute to, but are not required for the induction of graft-versus-host responses following allogeneic bone marrow transplantation: a shifting paradigm for T cell allo-activation. Biol Blood Marrow Transplant 2010; 16: 598–611.
Weintraub JL, Belanger AR, Sung CC, Stangl PA, Nowakowski FS, Lookstein RL . Intra-arterial methylprednisolone infusion in treatment-resistant graft-versus-host disease. Cardiovasc Intervent Radiol 2010; 33: 509–512.
Bürgler D, Medinger M, Passweg J, Fischmann A, Bucher C . Intra-arterial catheter guided steroid administration for the treatment of steroid-refractory intestinal GvHD. Leuk Res 2014; 38: 184–187.
Nishimoto M, Koh H, Hirose A, Nakamae M, Nakane T, Hayashi Y et al. Efficacy and safety of intra-arterial steroid infusions in patients with steroid-resistant gastrointestinal acute graft-versus-host disease. Exp Hematol 2015; 43: 995–1000.
Arima N, Nakamura F, Fukunaga A, Hirata H, Machida H, Kouno S et al. Single intra-arterial injection of mesenchymal stromal cells for treatment of steroid-refractory acute graft-versus-host disease: a pilot study. Cytotherapy 2010; 12: 265–268.
Kably IM, Ziga ED, Andreansky M . Intra-arterial platelet infusion for intractable hemorrhage and refractory thrombocytopenia in children with gastrointestinal graft-versus-host disease. Pediatr Blood Cancer 2015; 62: 2226–2228.
Socié G, Vigouroux S, Yakoub-Agha I, Bay JO, Fürst S, Bilger K et al. A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD. Blood 2017; 129: 643–649.
García-Cadenas I, Valcárcel D, Martino R, Piñana JL, Novelli S, Esquirol A et al. Updated experience with inolimomab as treatment for corticosteroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2013; 19: 435–439.
Busca A, Locatelli F, Marmont F, Ceretto C, Falda M . Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007; 82: 45–52.
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Author contributions
SMY designed treatment, conducted the trial, collected data, performed statistical analysis and wrote the paper. KA, GS and ABR treated patients. VS treated patients and collected data. RO helped design treatment and treated patients. BAI helped design and conduct the treatment, treated patients and helped write the paper.
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The original online version of this article was revised: In this article the author name V Sheth was incorrectly written as S Vipul.
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Shapira, M., Klimov, A., Sheth, V. et al. Regional intra-arterial steroid treatment in 120 patients with steroid-resistant or -dependent GvHD. Bone Marrow Transplant 52, 1416–1422 (2017). https://doi.org/10.1038/bmt.2017.120
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DOI: https://doi.org/10.1038/bmt.2017.120
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