Abstract
Acute corticosteroid refractory GVHD (aGVHD) remains a challenging problem after allogeneic hematopoietic SCT. Even though immunosuppressive therapies may achieve a response, unsatisfactory aGVHD control and toxicity of high cumulative doses of corticosteroids are frequent, notably with an increased infection rate. We report long-term follow-up of 33 consecutive patients who developed corticosteroid refractory aGVHD in our institution, treated homogeneously according to a unique algorithm combining an induction treatment (Inolimomab, 0.3 mg/kg per day), an associated immunosuppression (Mycophenolate Mofetil) and a predefined management of partial responses (PR) by the switch from Cyclosporin to Tacrolimus, together with an intensive infectious monitoring and supportive care. In this cohort, 17 patients (52%) achieved a complete response (CR) and 14 patients (42%) a PR, which converted to CR for 12 patients after Tacrolimus introduction. Transplant related mortality (TRM) was 15.5% and 29.7% at 1 and 3 years, respectively. OS was 54.5% at 3 years. Multivariate analysis identified CR after Inolimomab therapy as the unique prognostic factor on OS. Among the 30 evaluable patients, 19 (63%) developed extensive chronic GVHD. This Inolimomab-based algorithm allows for an efficient control of corticosteroid refractory aGVHD in a high proportion of patients with low toxicity, and deserves further investigation.
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
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. New Engl J Med 2010; 363: 2091–2101.
Deeg HJ . How I treat acute GVHD. Blood 2007; 109: 4119–4126.
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.
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.
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.
Bay JO, Peffault de Latour R . Place des anticorps monoclonaux dans le traitement de la maladie aiguë du greffon contre l′hôte. Hématologie 2009; 15: 61–71.
Bay JO, Cabrespine A, Peffault de Latour R . Place des anticorps monoclonaux dans le traitement de la maladie aiguë du greffon contre l′hôte en 2006. Bull Cancer 2007; 94: 33–41.
Von Bonin M, Wermke M, Platzbecker U, Radke J, Shayegi N, Gretzinger S et al. Therapy of acute graft-versus-host disease. Cell Therapy Transplant 2010; 2: 1–4.
Kim SS . Treatment options in steroid-refractory acute graft-versus-host disease following hematopoietic stem cell transplantation. Ann Pharmacother 2007; 41: 1436–1444.
Bolaños-Meadea J, Vogelsang GB . Novel strategies for steroid-refractory acute graft-versus-host disease. Curr Opin Hematol 2005; 12: 40–44.
Bay JO, Dhedin N, Goerner M, Vannier JP, Marie-Cardine A, Stametoullas A et al. Inolimomab in steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: retrospective analysis and comparison with other interleukin-2 receptor antibodies. Transplantation 2005; 80: 782–788.
Cahn JY, Bordigoni P, Tiberghien P, Milpied N, Brion A, Widjenes J et al. Treatment of acute graft-versus-host disease with methylprednisolone and cyclosporine with or without an anti-interleukin-2 receptor monoclonal antibody. A multicenter phase III study. Transplantation 1995; 60: 939–942.
Hervé P, Wijdenes J, Bergerat JP, Bordigoni P, Milpied N, Cahn JY et al. Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10). Blood 1990; 75: 1017–1023.
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.
Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmuller W, Thiel E et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol 2005; 130: 568–574.
Massenkeil G, Rackwitz S, Genvresse I, Rosen O, Dörken B, Arnold R . Basiliximab is well tolerated and effective in the treatment of steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 30: 899–903.
Przepiorka D, Kernan NA, Ippoliti C, Papadopoulos EB, Giralt S, Khouri I et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 2000; 95: 83–89.
Schub N, Günther A, Schrauder A, Claviez A, Ehlert C, Gramatzki M et al. Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective. Bone Marrow Transplant 2011; 46: 143–147.
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.
Piñana JL, Valcárcel D, Martino R, Moreno ME, Sureda A, Briones J et al. Encouraging results with inolimomab (anti-IL-2 receptor) as treatment for refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2006; 12: 1135–1141.
Socié G, Blazar BR . Acute graft-versus-host disease: from the bench to the bedsite. Blood 2009; 114: 4327–4336.
Rager A, Frey N, Goldstein SC, Reshef R, Hexner EO, Loren A et al. Inflammatory cytokine inhibition with combination daclizumab and infliximab for steroid-refractory acute GVHD. Bone Marrow Transplant 2011; 46: 430–435.
MacMillian ML, DeFor TE, Weisdorf DJ . The best endpoint for acute GVHD treatment trials. Blood 2010; 115: 5412–5417.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestation of graft-versus-host disease in human recipients of marrow from HLA matched sibling donors. Transplantation 1974; 18: 295–304.
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.
Van Lint MT, Uderzo C, Locasciulli A, Majolino R, Scimé R, Locatelli F et al. Early treatment of acute graft-versus-host disease with high- or low-dose methylprednisolone: a multicenter randomized trial for bone marrow transplantation for the Italian Group for Bone Marrow Transplantation. Blood 1998; 92: 2288–2293.
Van Lint MT, Milone G, Leotta S, Uderzo C, Scimè R, Dallorso S et al. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day+5 responders and no advantage for non responders receiving anti-thymocyte globulin. Blood 2006; 107: 4177–4181.
Couriel D, Caldera H, Champlin R, Komanduri K . Acute graft-versus-host disease: pathology, clinical manifestations, and management. Cancer 2004; 101: 1936–1946.
Dartois C, Freyer G, Michallet M, Henin E, You B, Darlavoix I et al. Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease. Clin Pharmacokinet 2007; 46: 417–432.
Koehler MT, Howrie D, Mirro J, Neudorf S, Blatt J, Corey S et al. FK506 (tacrolimus) in the treatment of steroid-resistant acute graft-versus-host disease in children undergoing bone marrow transplantation. Bone Marrow Transplant 1995; 15: 895–899.
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.
Saliba RM, Couriel DR, Giralt S, Rondon G, Okoroji G-J, Rashid A et al. Prognostic value of response after upfront therapy for acute GVHD. Bone Marrow Transplant 2012; 47: 125–131.
Martin PJ, Bachier CR, Klingemann HG, McCarthy PL, Szabolcs P, Uberti JP et al. Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transplant 2009; 15: 777–784.
Martin PJ . Study design and endpoints in graft-versus-host disease. Best Prac & Res Clin Hematol 2008; 21: 357–372.
Pallua S, Giesinger J, Oberguggenberger A, Kemmler G, Nachbaur D, Clausen J et al. Impact of GvHD on quality of life in long-term survivors of haematopoietic transplantation. Bone Marrow Transplant 2010; 45: 1534–1539.
Bevans M . Health-related quality of life following allogeneic hematopoietic stem cell transplantation. Hematology Am Soc Hematol Educ Program 2010; 2010: 248–254.
Hervé P, Bordigoni P, Cahn JY, Flesh M, Tiberghien P, Racadot E et al. Use of monoclonal antibodies in vivo as a therapeutic strategy for acute GvHD in matched and mismatched bone marrow transplantation. Transplant Proc 1991; 23: 1692–1694.
Ferrara JLM, Levine JE, Reddy P, Holler E . Graft-versus-host disease. Lancet 2009; 373: 1550–1561.
Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S et al. Patient reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood 2011; 117: 4651–4657.
Acknowledgements
We thank Dr Emmanuel GYAN (Department of Hematology and Cellular Therapy, Hôpital Bretonneau, Tours) and Dr Régis PEFFAULT de la TOUR (Hematology-BMT, Hôpital Saint Louis, Paris) for their critical reading of the manuscript. We are grateful to EUSA Pharma for computer support and to Association Pictave pour l′ Etude des Maladies du Sang (APEMSA) for financial support.
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
Girerd, S., Renaud, M., Guilhot, J. et al. Long-term follow-up of corticosteroid refractory acute GVHD treated with an Inolimomab-based algorithm: a single center experience. Bone Marrow Transplant 48, 1243–1248 (2013). https://doi.org/10.1038/bmt.2013.16
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2013.16