Abstract：Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative disease (EBV-PTLD) is a potentially life-threatening complication after hematopoietic stem cell transplantation or solid organ transplantation. In the last decade, the survival of patients with EBV-PTLD has been significantly improved by immunotherapeutic interventions among high-risk patients. The immunotherapeutic interventions for EBV-PTLD include reduction in immunosuppression, CD20 monoclonal antibodies (rituximab) as monotherapy or in combination with chemotherapy, and adoptive immunotherapy with EBV-specific T cells. This paper reviews the latest update on the high-risk factors, clinical manifestations and immunotherapy of EBV-PTLD.
Swerdlow SH, Campo E. WHO Classification of Tumours of haematopoietic and lymphoid tissues[M]. Lyon: IARC Press, 2008: 233-268.
[2]
Bordon V, Padalko E, Benoit Y, Dhooge C, Laureys G. Incidence, kinetics, and risk factors of Epstein-Barr virus viremia in pediatric patients after allogeneic stem cell transplantation[J]. Pediatr Transplant, 2012, 16(2): 144-150.
Xing Y, Song HM, Wei M, Liu Y, Zhang YH, Gao L. Clinical significance of variations in levels of Epstein-Barr Virus (EBV) antigen and adaptive immune response during chronic active EBV infection in children[J]. J Immunotoxicol, 2013.[Epub ahead of print]
[5]
Capello D, Gaidano G. Post-transplant lymphoproliferative disorders: role of viral infection, genetic lesions and antigen stimulation in the pathogenesis of the disease[J]. Mediterr J Hematol Infect Dis, 2009, 1(2): e2009018.
[6]
Kuppers R. Mechanisms of B-cell lymphoma pathogenesis[J]. Nat Rev Cancer, 2005, 5(4): 251-262.
[7]
Cruz RJ, Ramachandra S, Sasatomi E, DiMartini A, de Vera M, Fontes P, et al. Surgical management of gastrointestinal posttransplant lymphoproliferative disorders in liver transplant recipients[J]. Transplantation, 2012, 94(4): 417-423.
[8]
Izadi M, Taheri S. Allograft involvement by lymphoproliferative disorders after lung transplantation: report from the PTLD. Int survey[J]. Prog Transplant, 2011, 21(4): 353-359.
[9]
Khedmat H, Taheri S. Lymphoproliferative disorders in pediatric liver allograft recipients: a review of 212 cases[J]. Hematol Oncol Stem Cell Ther, 2012, 5(2): 84-90.
[10]
Caillard S, Porcher R, Provot F, Dantal J, Choquet S, Durrbach A, et al. Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide french registry and the development of a new prognostic score[J]. J Clin Oncol, 2013, 31(10): 1302-1309.
[11]
Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era[J]. J Clin Oncol, 2010, 28(6): 1038-1046.
[12]
Curtis RE, Travis LB, Rowlings PA, Socie G, Kingma DW, Banks PM, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study[J]. Blood, 1999, 94(7): 2208-2216.
[13]
Nash RA, Dansey R, Storek J, Georges GE, Bowen JD, Holmberg LA, et al. Epstein-Barr virus-associated post-transplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases[J]. Biol Blood Marrow Transplant, 2003, 9(9): 583-591.
[14]
Rizzi R, Curci P, Delia M, Rinaldi E, Chiefa A, Specchia G, et al. Spontaneous remission of "methotrexate-associated lymphoproliferative disorders" after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature[J]. Med Oncol, 2009, 26(1):1-9.
[15]
Herreman A, Dierickx D, Morscio J, Camps J, Bittoun E, Verhoef G, et al. Clinicopathological characteristics of posttransplant lymphoproliferative disorders of T-cell origin: single center series of 9 cases and meta-analysis of 147 reported cases[J]. Leuk Lymphoma, 2013.[Epub ahead of print]
[16]
Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, et al. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinico-pathological characteristics and prognostic factors[J]. Leuk Lymphoma, 2013.[Epub ahead of print]
Patriarca F, Medeot M, Isola M, Battista ML, Sperotto A, Pipan C, et al. Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab[J]. Transpl Infect Dis, 2013, 15(3): 259-267.
[19]
Green M, Michaels MG. Epstein-Barr virus infection and posttransplant lymphoproliferative disorder[J]. Am J Transplant,2013, 13 Suppl 3:41-54.
[20]
Gallego S, Llort A, Gros L, Sanchez de Toledo J Jr, Bueno J, Moreno A, et al. Post-transplant lymphoproliferative disorders in children: the role of chemotherapy in the era of rituximab[J]. Pediatr Transplant, 2010, 14(1): 61-66.
[21]
Fischer A, Blanche S, Le Bidois J, Bordigoni P, Garnier JL, Niaudet P, et al. Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation[J]. N Engl J Med, 1991, 324(21): 1451-1456.
[22]
Coppoletta S, Tedone E, Galano B, Soracco M, Raiola AM, Lamparelli T, et al. Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation[J]. Biol Blood Marrow Transplant, 2011, 17(6): 901-907.
[23]
Styczynski J, Einsele H, Gil L, Ljungman P. Outcome of treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a comprehensive review of reported cases[J]. Transpl Infect Dis, 2009, 11(5): 383-392.
[24]
Choquet S, Oertel S, LeBlond V, Riess H, Varoqueaux N, Dorken B, et al. Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution[J]. Ann Hematol, 2007, 86(8): 599-607.
[25]
Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder[J]. N Engl J Med, 2001, 345(13): 1000.
[26]
Verschuuren EA, Stevens SJ, van Imhoff GW, Middeldorp JM, de Boer C, Koeter G, et al. Treatment of posttransplant lymphoproliferative disease with rituximab: the remission, the relapse, and the complication[J]. Transplantation, 2002, 73(1):100-104.
[27]
Heslop HE, Brenner MK, Rooney CM. Donor T cells to treat EBV-associated lymphoma[J]. N Engl J Med, 1994, 331(10):679-680.
[28]
Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study[J]. Lancet Oncol, 2009, 10(5): 489-500.
[29]
Hoyos V, Savoldo B, Dotti G. Genetic modification of human T lymphocytes for the treatment of hematologic malignancies[J]. Haematologica, 2012, 97(11): 1622-1631.
[30]
Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients[J]. Blood, 2010, 115(5): 925-935.
[31]
Heslop HE. How I treat EBV lymphoproliferation[J]. Blood, 2009, 114(19): 4002-4008.
[32]
Cooper LJ, Al-Kadhimi Z, Serrano LM, Pfeiffer T, Olivares S, Castro A, et al. Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1[J]. Blood, 2005, 105(4): 1622-1631.
[33]
Foster AE, Dotti G, Lu A, Khalil M, Brenner MK, Heslop HE, et al. Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor[J]. J Immunother, 2008, 31(5):500-505.
[34]
Comoli P, Maccario R, Locatelli F, Valente U, Basso S, Garaventa A, et al. Treatment of EBV-related post-renal transplant lymphoproliferative disease with a tailored regimen including EBV-specific T cells[J]. Am J Transplant, 2005, 5(6):1415-1422.
[35]
McAulay KA, Haque T, Urquhart G, Bellamy C, Guiretti D, Crawford DH. Epitope specificity and clonality of EBV-specific CTLs used to treat posttransplant lymphoproliferative disease[J]. J Immunol, 2009, 182(6):3892-3901.
[36]
De Angelis B, Dotti G, Quintarelli C, Huye LE, Zhang L, Zhang M, et al. Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506)[J]. Blood, 2009, 114(23):4784-4791.
[37]
Brewin J, Mancao C, Straathof K, Karlsson H, Samarasinghe S, Amrolia PJ, et al. Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease[J]. Blood, 2009, 114(23):4792-4803.
[38]
Haque T, McAulay KA, Kelly D, Crawford DH. Allogeneic T-cell therapy for Epstein-Barr virus-positive posttransplant lymphoproliferative disease: long-term follow-up[J]. Transplantation, 2010, 90(1):93-94.
[39]
Moosmann A, Bigalke I, Tischer J, Schirrmann L, Kasten J, Tippmer S, et al. Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells[J]. Blood, 2010, 115(14):2960-2970.
[40]
Gerdemann U, Christin AS, Vera JF, Ramos CA, Fujita Y, Liu H, et al. Nucleofection of DCs to generate Multivirus-specific T cells for prevention or treatment of viral infections in the immunocompromised host[J]. Mol Ther, 2009, 17(9):1616-1625.
[41]
Swinnen LJ, LeBlanc M, Grogan TM, Gordon LI, Stiff PJ, Miller AM, et al. Prospective study of sequential reduction in immunosuppression, interferon alpha-2B, and chemotherapy for posttransplantation lymphoproliferative disorder[J]. Transplantation, 2008, 86(2):215-222.
[42]
Haddad E, Paczesny S, Leblond V, Seigneurin JM, Stern M, Achkar A, et al. Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial[J]. Blood, 2001, 97(6):1590-1597.
[43]
Ogawa J, Harigai M, Akashi T, Nagasaka K, Suzuki F, Tominaga S, et al. Exacerbation of chronic active Epstein-Barr virus infection in a patient with rheumatoid arthritis receiving humanised anti-interleukin-6 receptor monoclonal antibody[J]. Ann Rheum Dis, 2006, 65(12):1667-1669.
