Abstract
We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD—22% had stage 3–4 liver GVHD and 51% had stage 3–4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1–9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61–84%) and overall survival (OS) was 21% (95% CI 12–32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01–3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5–3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2–0.8, p = 0.01). On stratified analysis, patients <60 years with isolated LGI GVHD had the best outcomes with an ORR of 48% and OS of 42% at 18 months. Among older patients, OS was 14% in those with isolated LGI aGVHD and 0% in others. Pentostatin remains a viable treatment option for SR-aGVHD, especially in patients 60 years or younger with isolated LGI involvement.
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References
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;113:2888–94. https://doi.org/10.1182/blood-2008-07-168401.
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;8:387–94.
Weisdorf D, Hakke R, Blazar B, Miller W, McGlave P, Ramsay N, et al. Risk factors for acute graft-versus-host disease in histocompatible donor bone marrow transplantation. Transplantation. 1991;51:1197–203.
Hings IM, Severson R, Filipovich AH, Blazar BR, Kersey JH, Ramsay NK, et al. Treatment of moderate and severe acute GVHD after allogeneic bone marrow transplantation. Transplantation. 1994;58:437–42.
Martin PJ, Schoch G, Fisher L, Byers V, Appelbaum FR, McDonald GB, et al. A retrospective analysis of therapy for acute graft-versus-host disease: secondary treatment. Blood. 1991;77: 1821–8.
Martin PJ, Rizzo JD, 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;18:1150–63. https://doi.org/10.1016/j.bbmt.2012.04.005.
Alousi AM, Weisdorf DJ, Logan BR, Bolanos-Meade J, Carter S, Difronzo N, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the blood and marrow transplant clinical trials network. Blood. 2009;114:511–7. https://doi.org/10.1182/blood-2009-03-212290.
Parmar S, Andersson BS, Couriel D, Munsell MF, Fernandez-Vina M, Jones RB, et al. Prophylaxis of graft-versus-host disease in unrelated donor transplantation with pentostatin, tacrolimus, and mini-methotrexate: a phase I/II controlled, adaptively randomized study. J Clin Oncol. 2011;29:294–302. https://doi.org/10.1200/JCO.2010.30.6357.
Jacobsohn DA, Chen AR, Zahurak M, Piantadosi S, Anders V, Bolanos-Meade J, et al. Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease. J Clin Oncol. 2007;25:4255–61. https://doi.org/10.1200/JCO.2007.10.8456.
Bolaños-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;23:2661–8. https://doi.org/10.1200/jco.2005.06.130.
Jacobsohn DA, Gilman AL, Rademaker A, Browning B, Grimley M, Lehmann L, et al. Evaluation of pentostatin in corticosteroid-refractory chronic graft-versus-host disease in children: a pediatric blood and marrow transplant consortium study. Blood. 2009; 114:4354–60. https://doi.org/10.1182/blood-2009-05-224840.
Klein SMS, Bug G, Wassmann B, Martin H. Long-term follow up of a phase II study of pentostatin in patients with steroid refractory acute intestinal graft-versus-host disease. Bone Marrow Transplant. 2008;41:S222.
Pidala J, Kim J, Roman-Diaz J, Shapiro J, Nishihori T, Bookout R, et al. Pentostatin as rescue therapy for glucocorticoid-refractory acute and chronic graft-versus-host disease. Ann Transplant. 2010;15:21–29.
Schmitt T, Luft T, Hegenbart U, Tran TH, Ho AD, Dreger P. Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis. Bone Marrow Transplant. 2011;46:580–5. https://doi.org/10.1038/bmt.2010.146.
Alam N, Atenafu EG, Tse G, Viswabandya A, Gupta V, Kim D, et al. Limited benefit of pentostatin salvage therapy for steroid-refractory grade III-IV acute graft-versus-host disease. Clin Transplant. 2013;27:930–7. https://doi.org/10.1111/ctr.12268.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.
Arai S, Margolis J, Zahurak M, Anders V, Vogelsang GB. Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment. Biol Blood Marrow Transplant. 2002;8:155–60. https://doi.org/10.1053/bbmt.2002.v8.pm11939605.
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;8:40–6.
Van Lint MT, Milone G, Leotta S, Uderzo C, Scime 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 nonresponders receiving anti-thymocyte globulin. Blood. 2006;107:4177–81. https://doi.org/10.1182/blood-2005-12-4851.
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;27:1059–64. https://doi.org/10.1038/sj.bmt.1703032.
Roy J, McGlave PB, Filipovich AH, Miller WJ, Blazar BR, Ramsay NK, et al. Acute graft-versus-host disease following unrelated donor marrow transplantation: failure of conventional therapy. Bone Marrow Transplant. 1992;10:77–82.
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: 2657–62. https://doi.org/10.1182/blood-2006-08-013995.
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;95:83–9.
Massenkeil G, Rackwitz S, Genvresse I, Rosen O, Dorken 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. https://doi.org/10.1038/sj.bmt.1703737.
Nadeau M, Perreault S, Seropian S, Foss F, Isufi I, Cooper DL. The use of basiliximab-infliximab combination for the treatment of severe gastrointestinal acute GvHD. Bone Marrow Transplant. 2016;51:273–6. https://doi.org/10.1038/bmt.2015.247.
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;40:481–6. https://doi.org/10.1038/sj.bmt.1705762.
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;130:568–74. https://doi.org/10.1111/j.1365-2141.2005.05631.x.
Socie G, Vigouroux S, Yakoub-Agha I, Bay JO, Furst S, Bilger K, et al. A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD. Blood. 2017;129:643–9. https://doi.org/10.1182/blood-2016-09-738625.
Wang JZ, Liu KY, Xu LP, Liu DH, Han W, Chen H, et al. Basiliximab for the treatment of steroid-refractory acute graft-versus-host disease after unmanipulated HLA-mismatched/haploidentical hematopoietic stem cell transplantation. Transplant Proc. 2011;43:1928–33. https://doi.org/10.1016/j.transproceed.2011.03.044.
Willenbacher W, Basara N, Blau IW, Fauser AA, Kiehl MG. Treatment of steroid refractory acute and chronic graft-versus-host disease with daclizumab. Br J Haematol. 2001;112:820–3.
Rao K, Rao A, Karlsson H, Jagani M, Veys P, Amrolia PJ. Improved survival and preserved antiviral responses after combination therapy with daclizumab and infliximab in steroid-refractory graft-versus-host disease. J Pediatr Hematol Oncol. 2009;31:456–61. https://doi.org/10.1097/MPH.0b013e31819daf60.
Bay JO, Dhedin N, Goerner M, Vannier JP, Marie-Cardine A, Stamatoullas 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: 782–8.
Shaughnessy PJ, Bachier C, Grimley M, Freytes CO, Callander NS, Essell JH, et al. Denileukin diftitox for the treatment of steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant. 2005;11:188–93. https://doi.org/10.1016/j.bbmt.2004.11.022.
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;104:1224–6. https://doi.org/10.1182/blood-2004-01-0028.
van Groningen LF, Liefferink AM, de Haan AF, Schaap NP, Donnelly JP, Blijlevens NM, et al. Combination therapy with inolimomab and etanercept for severe steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2016;22:179–82. https://doi.org/10.1016/j.bbmt.2015.08.039.
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. https://doi.org/10.1002/ajh.20752.
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;89:1352–9.
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;104:649–54. https://doi.org/10.1182/blood-2003-12-4241.
Jacobsohn DA, Hallick J, Anders V, McMillan S, Morris L, Vogelsang GB. Infliximab for steroid-refractory acute GVHD: a case series. Am J Hematol. 2003;74:119–24. https://doi.org/10.1002/ajh.10392.
Kennedy GA, Butler J, Western R, Morton J, Durrant S, Hill GR. Combination antithymocyte globulin and soluble TNFalpha inhibitor (etanercept) +/− mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease. Bone Marrow Transplant. 2006;37:1143–7. https://doi.org/10.1038/sj.bmt.1705380.
Meunier M, Bulabois CE, Thiebaut-Bertrand A, Itzykson R, Carre M, Carras S, et al. Alemtuzumab for severe steroid-refractory gastrointestinal acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1451–4. https://doi.org/10.1016/j.bbmt.2014.05.031.
Khandelwal P, Lawrence J, Filipovich AH, Davies SM, Bleesing JJ, Jordan MB, et al. The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients. Pediatr Transplant. 2014;18:94–102. https://doi.org/10.1111/petr.12183.
Schub N, Gunther 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;46:143–7. https://doi.org/10.1038/bmt.2010.68.
Martinez C, Solano C, Ferra C, Sampol A, Valcarcel D, Perez-Simon JA, et al. Alemtuzumab as treatment of steroid-refractory acute graft-versus-host disease: results of a phase II study. Biol Blood Marrow Transplant. 2009;15:639–42. https://doi.org/10.1016/j.bbmt.2009.01.014.
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;14:10–5. https://doi.org/10.1016/j.bbmt.2007.08.052.
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;72:1924–9.
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;45:1347–51. https://doi.org/10.1038/bmt.2009.343.
Pierelli L, Perseghin P, Marchetti M, Messina C, Perotti C, Mazzoni A, et al. Extracorporeal photopheresis for the treatment of acute and chronic graft-versus-host disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Transplantation (GITMO) consensus process. Transfus. 2013;53:2340–52. https://doi.org/10.1111/trf.12059.
Kitko CL, Braun T, Couriel DR, Choi SW, Connelly J, Hoffmann S, et al. Combination therapy for graft-versus-host disease prophylaxis with etanercept and extracorporeal photopheresis: results of a phase II clinical trial. Biol Blood Marrow Transplant. 2016;22:862–8. https://doi.org/10.1016/j.bbmt.2015.11.002.
Malagola M, Cancelli V, Skert C, Leali PF, Ferrari E, Tiburzi A, et al. Extracorporeal photopheresis for treatment of acute and chronic graft versus host disease: an italian multicentric retrospective analysis on 94 patients on behalf of the Gruppo Italiano Trapianto di Midollo Osseo. Transplantation. 2016;100:e147–55. https://doi.org/10.1097/TP.0000000000001466.
Abu-Dalle I, Reljic T, Nishihori T, Antar A, Bazarbachi A, Djulbegovic B, et al. Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies. Biol Blood Marrow Transplant. 2014;20:1677–86. https://doi.org/10.1016/j.bbmt.2014.05.017.
Jagasia M, Greinix H, Robin M, Das-Gupta E, Jacobs R, Savani BN, et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant. 2013;19:1129–33. https://doi.org/10.1016/j.bbmt.2013.04.018.
Perfetti P, Carlier P, Strada P, Gualandi F, Occhini D, Van Lint MT, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. 2008;42:609–17. https://doi.org/10.1038/bmt.2008.221.
Pidala J, Kim J, Perkins J, Field T, Fernandez H, Perez L, et al. Mycophenolate mofetil for the management of steroid-refractory acute graft vs host disease. Bone Marrow Transplant. 2010;45:919–24. https://doi.org/10.1038/bmt.2009.252.
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;44:739–48. https://doi.org/10.1038/bmt.2009.76.
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;84:681–5. https://doi.org/10.1007/s00277-005-1070-0.
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. https://doi.org/10.1111/j.1600-0609.2004.00247.x.
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;23:2661–8. https://doi.org/10.1200/JCO.2005.06.130.
Thaler J, Grunewald K, Gattringer C, Ho AD, Weyrer K, Dietze O, et al. Long-term follow-up of patients with hairy cell leukaemia treated with pentostatin: lymphocyte subpopulations and residual bone marrow infiltration. Br J Haematol. 1993;84: 75–82.
Bagasra O, Howeedy A, Pomerantz RJ. Adenosine-deaminase-associated immunodeficiency. I. Differential sensitivities of lymphocyte subpopulations exposed to 2-deoxycoformycin in vivo. Clin Exp Immunol. 1992;88:383–8.
Kraut EH, Neff JC, Bouroncle BA, Gochnour D, Grever MR. Immunosuppressive effects of pentostatin. J Clin Oncol. 1990;8:848–55. https://doi.org/10.1200/JCO.1990.8.5.848.
Luebke RW, Lawson LD, Rogers RR, Riddle MM, Rowe DG, Smialowicz RJ. Selective immunotoxic effects in mice treated with the adenosine deaminase inhibitor 2’-deoxycoformycin. Immunopharmacology. 1987;13:25–35.
Nicholson JK, Gordon DS, McDougal JS. Inhibition of adenosine deaminase leads to enhanced antibody responses in the mouse. Cell Immunol. 1983;79:320–33.
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29:2062–8. https://doi.org/10.1038/leu.2015.212.
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Brittany Knick Ragon and Rohtesh S. Mehta contributed equally to this work.
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Ragon, B.K., Mehta, R.S., Gulbis, A.M. et al. Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit. Bone Marrow Transplant 53, 315–325 (2018). https://doi.org/10.1038/s41409-017-0034-z
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DOI: https://doi.org/10.1038/s41409-017-0034-z
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