Review Article | Published:

Epstein-Barr virus-related post-transplant lymphoproliferative disease (EBV-PTLD) in the setting of allogeneic stem cell transplantation: a comprehensive review from pathogenesis to forthcoming treatment modalities

Bone Marrow Transplantation (2019) | Download Citation

Abstract

Epstein-Barr virus (EBV) is a ubiquitous herpes virus that infects the majority of the population worldwide. The virus can establish a lifelong latent infection in host B-lymphocytes. In the setting of immunocompromise as is the case post transplantation, the virus can reactivate and cause one of the deadliest complications post hematopoietic stem cell transplantation (HSCT), post-lymphoproliferative disease (PTLD), the incidence of which has been increasing. Multiple risk factors have been associated with the onset of PTLD such as age, reduced intensity conditioning, EBV serology mismatch and cytomegalovirus (CMV) reactivation. The rarity of clinical trials involving PTLD and the lack of approved treatment modalities renders the management of PTLD challenging. While the first-line treatment involves weekly administration of rituximab, there is no consensus when treating rituximab-refractory PTLD. There is a handful of clinical trials that investigate the role of EBV-specific cytotoxic T-lymphocytes (CTLs) and novel agents, such as bortezomib, lenalidomide, everolimus, panobinostat, and brentuximab. This article aims to explore the entity of EBV-PTLD in HSCT recipients, expanding on clinical presentation, risk factors, modes of monitoring and treatment, and so highlighting the gaps in knowledge that are needed in order to build a treatment paradigm suitable for all patients at risk.

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References

  1. 1.

    Balfour HH Jr., Dunmire SK, Hogquist KA. Infectious mononucleosis. Clin Transl Immunology. 2015;4:e33.

  2. 2.

    Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343:481–92.

  3. 3.

    Comoli P, Basso S, Zecca M, Pagliara D, Baldanti F, Bernardo ME, et al. Preemptive therapy of EBV-related lymphoproliferative disease after pediatric haploidentical stem cell transplantation. Am J Transplant. 2007;7:1648–55.

  4. 4.

    Yates J, Warren N, Reisman D, Sugden B. A cis-acting element from the Epstein-Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells. Proc Natl Acad Sci USA. 1984;81:3806–10.

  5. 5.

    Shannon-Lowe C, Rickinson AB, Bell AI. Epstein-Barr virus-associated lymphomas. Philos Trans R Soc Lond B Biol Sci. 2017;372:1732.

  6. 6.

    Kalinova L, Indrakova J, Bachleda P. Post-transplant lymphoproliferative disorder. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2009;153:251–7.

  7. 7.

    Ferreiro JF, Morscio J, Dierickx D, Vandenberghe P, Gheysens O, Verhoef G, et al. EBV-positive and EBV-negative posttransplant diffuse large B cell lymphomas have distinct genomic and transcriptomic features. Am J Transplant. 2016;16:414–25.

  8. 8.

    Quinn LL, Williams LR, White C, Forrest C, Zuo J, Rowe M. The missing link in epstein-barr virus immune evasion: the BDLF3 gene induces ubiquitination and downregulation of major histocompatibility complex class I (MHC-I) and MHC-II. J Virol. 2016;90:356–67.

  9. 9.

    Ressing ME, Keating SE, van Leeuwen D, Koppers-Lalic D, Pappworth IY, Wiertz EJ, et al. Impaired transporter associated with antigen processing-dependent peptide transport during productive EBV infection. J Immunol. 2005;174:6829–38.

  10. 10.

    Djaoud Z, Guethlein LA, Horowitz A, Azzi T, Nemat-Gorgani N, Olive D, et al. Two alternate strategies for innate immunity to Epstein-Barr virus: One using NK cells and the other NK cells and gammadelta T cells. J Exp Med. 2017;214:1827–41.

  11. 11.

    Kanakry JA, Ambinder RF. EBV-related lymphomas: new approaches to treatment. Curr Treat Options Oncol. 2013;14:224–36.

  12. 12.

    Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, et al. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991;65:1107–15.

  13. 13.

    Capello D, Rossi D, Gaidano G. Post-transplant lymphoproliferative disorders: molecular basis of disease histogenesis and pathogenesis. Hematol Oncol. 2005;23:61–7.

  14. 14.

    Krams SM, Martinez OM. Epstein-Barr virus, rapamycin, and host immune responses. Curr Opin Organ Transplant. 2008;13:563–8.

  15. 15.

    Vereide DT, Sugden B. Lymphomas differ in their dependence on Epstein-Barr virus. Blood. 2011;117:1977–85.

  16. 16.

    Burns DM, Tierney R, Shannon-Lowe C, Croudace J, Inman C, Abbotts B, et al. Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event. Blood. 2015;126:2665–75.

  17. 17.

    Friedberg JW, Swinnen L. Post-transplant lymphoproliferative disease in the lymphomas. 2nd ed. Philadelphia, PA, USA: Elsevier; 2006.

  18. 18.

    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO classification of tumors of haemotopoietic and lymphoid tissue. 4th ed. Lyon: IARC; 2008.

  19. 19.

    Ruf S, Moser O, Wossmann W, Kreyenberg H, Wagner HJ. Examining the origin of posttransplant lymphoproliferative disorder in a patient after a second allogeneic hematopoeitic stem cell transplantation for relapsed BCR-ABL positive acute lymphoblastic leukemia. J Pedia Hematol Oncol. 2011;33:50–4.

  20. 20.

    Landgren O, Gilbert ES, Rizzo JD, Socie G, Banks PM, Sobocinski KA, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113:4992–5001.

  21. 21.

    Luskin MR, Heil DS, Tan KS, Choi S, Stadtmauer EA, Schuster SJ, et al. The impact of EBV status on characteristics and outcomes of posttransplantation lymphoproliferative disorder. Am J Transplant. 2015;15:2665–73.

  22. 22.

    Johansson JE, Remberger M, Lazarevic V, Hallbook H, Wahlin A, Kimby E, et al. Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage Hodgkin’s lymphoma in Sweden: high incidence of post transplant lymphoproliferative disorder. Bone Marrow Transplant. 2011;46:870–5.

  23. 23.

    Hou HA, Yao M, Tang JL, Chen YK, Ko BS, Huang SY, et al. Poor outcome in post transplant lymphoproliferative disorder with pulmonary involvement after allogeneic hematopoietic SCT: 13 years’ experience in a single institute. Bone Marrow Transplant. 2009;43:315–21.

  24. 24.

    Buyck HC, Ball S, Junagade P, Marsh J, Chakrabarti S. Prior immunosuppressive therapy with antithymocyte globulin increases the risk of EBV-related lymphoproliferative disorder following allo-SCT for acquired aplastic anemia. Bone Marrow Transplant. 2009;43:813–6.

  25. 25.

    Ocheni S, Kroeger N, Zabelina T, Sobottka I, Ayuk F, Wolschke C, et al. EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT. Bone Marrow Transplant. 2008;42:181–6.

  26. 26.

    Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Engl J Med. 2018;378:549–62.

  27. 27.

    Gu B, Chen GH, Wu DP. [Recent advances on diagnosis and therapy of lymphoproliferative disorders after allo-HSCT]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014;22:538–42.

  28. 28.

    Deeg HJ, Socie G. Malignancies after hematopoietic stem cell transplantation: many questions, some answers. Blood. 1998;91:1833–44.

  29. 29.

    Tamaru JI. 2016 revision of the WHO classification of lymphoid neoplasms. Rinsho Ketsueki. 2017;58:2188–93.

  30. 30.

    Rasche L, Kapp M, Einsele H, Mielke S. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT. Bone Marrow Transplant. 2014;49:163–7.

  31. 31.

    Zimmermann H, Trappe RU. Therapeutic options in post-transplant lymphoproliferative disorders. Ther Adv Hematol. 2011;2:393–407.

  32. 32.

    Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013;8:173–83.

  33. 33.

    Uhlin M, Wikell H, Sundin M, Blennow O, Maeurer M, Ringden O, et al. Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99:346–52.

  34. 34.

    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. Blood. 1999;94:2208–16.

  35. 35.

    Styczynski J, Reusser P, Einsele H, de la Camara R, Cordonnier C, Ward KN, et al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant. 2009;43:757–70.

  36. 36.

    Styczynski J, Gil L, Tridello G, Ljungman P, Donnelly JP, van der Velden W, et al. Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis. 2013;57:794–802.

  37. 37.

    DeStefano CB, Desai SH, Shenoy AG, Catlett JP Management of post-transplant lymphoproliferative disorders. Br J Haematol. 2018;182:330–343.

  38. 38.

    Garcia-Cadenas I, Yanez L, Jarque I, Martino R, Perez-Simon JA, Valcarcel D, et al. Frequency, characteristics and outcome of PTLD after allo-SCT: a multicenter study from the Spanish group of blood and marrow transplantation (GETH). Eur J Haematol. 2019;00:1–7.

  39. 39.

    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 Clin Oncol. 2010;28:1038–46.

  40. 40.

    Chakrabarti S, Milligan DW, Pillay D, Mackinnon S, Holder K, Kaur N, et al. Reconstitution of the Epstein-Barr virus-specific cytotoxic T-lymphocyte response following T-cell-depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation. Blood. 2003;102:839–42.

  41. 41.

    Saito T, Kanda Y, Nakai K, Kim SW, Arima F, Kami M, et al. Immune reconstitution following reduced-intensity transplantation with cladribine, busulfan, and antithymocyte globulin: serial comparison with conventional myeloablative transplantation. Bone Marrow Transplant. 2003;32:601–8.

  42. 42.

    Reshef R, Luskin MR, Kamoun M, Vardhanabhuti S, Tomaszewski JE, Stadtmauer EA, et al. Association of HLA polymorphisms with post-transplant lymphoproliferative disorder in solid-organ transplant recipients. Am J Transplant. 2011;11:817–25.

  43. 43.

    Pourfarziani V, Einollahi B, Taheri S, Nemati E, Nafar M, Kalantar E. Associations of Human Leukocyte Antigen (HLA) haplotypes with risk of developing lymphoproliferative disorders after renal transplantation. Ann Transplant. 2007;12:16–22.

  44. 44.

    Subklewe M, Marquis R, Choquet S, Leblond V, Garnier JL, Hetzer R, et al. Association of human leukocyte antigen haplotypes with posttransplant lymphoproliferative disease after solid organ transplantation. Transplantation. 2006;82:1093–100.

  45. 45.

    Wheless SA, Gulley ML, Raab-Traub N, McNeillie P, Neuringer IP, Ford HJ, et al. Post-transplantation lymphoproliferative disease: Epstein-Barr virus DNA levels, HLA-A3, and survival. Am J Respir Crit Care Med. 2008;178:1060–5.

  46. 46.

    Lustberg ME, Pelletier RP, Porcu P, Martin SI, Quinion CD, Geyer SM, et al. Human leukocyte antigen type and posttransplant lymphoproliferative disorder. Transplantation. 2015;99:1220–5.

  47. 47.

    Jones K, Wockner L, Thornton A, Gottlieb D, Ritchie DS, Seymour JF, et al. HLA class I associations with EBV+post-transplant lymphoproliferative disorder. Transpl Immunol. 2015;32:126–30.

  48. 48.

    Walker RC, Marshall WF, Strickler JG, Wiesner RH, Velosa JA, Habermann TM, et al. Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis. 1995;20:1346–53.

  49. 49.

    Sundin M, Le Blanc K, Ringden O, Barkholt L, Omazic B, Lergin C, et al. The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation. Haematologica. 2006;91:1059–67.

  50. 50.

    Hoegh-Petersen M, Goodyear D, Geddes MN, Liu S, Ugarte-Torres A, Liu Y, et al. High incidence of post transplant lymphoproliferative disorder after antithymocyte globulin-based conditioning and ineffective prediction by day 28 EBV-specific T lymphocyte counts. Bone Marrow Transplant. 2011;46:1104–12.

  51. 51.

    Kelly SS, Parmar S, De Lima M, Robinson S, Shpall E. Overcoming the barriers to umbilical cord blood transplantation. Cytotherapy. 2010;12:121–30.

  52. 52.

    Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, Weisdorf DJ. Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant. 2002;8:257–60.

  53. 53.

    Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003;101:4233–44.

  54. 54.

    Barker JN, Martin PL, Coad JE, DeFor T, Trigg ME, Kurtzberg J, et al. Low incidence of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorders in 272 unrelated-donor umbilical cord blood transplant recipients. Biol Blood Marrow Transplant. 2001;7:395–9.

  55. 55.

    Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JA, et al. Marked increased risk of Epstein-Barr virus-related complications with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood. 2006;108:2874–80.

  56. 56.

    Peric Z, Cahu X, Chevallier P, Brissot E, Malard F, Guillaume T, et al. Features of EBV reactivation after reduced intensity conditioning unrelated umbilical cord blood transplantation. Bone Marrow Transplant. 2012;47:251–7.

  57. 57.

    Vantourout P, Hayday A. Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat Rev Immunol. 2013;13:88–100.

  58. 58.

    Knight A, Madrigal AJ, Grace S, Sivakumaran J, Kottaridis P, Mackinnon S, et al. The role of Vdelta2-negative gammadelta T cells during cytomegalovirus reactivation in recipients of allogeneic stem cell transplantation. Blood. 2010;116:2164–72.

  59. 59.

    Liu J, Bian Z, Wang X, Xu LP, Fu Q, Wang C, et al. Inverse correlation of Vdelta2(+) T-cell recovery with EBV reactivation after haematopoietic stem cell transplantation. Br J Haematol. 2018;180:276–85.

  60. 60.

    Laberko A, Bogoyavlenskaya A, Shelikhova L, Shekhovtsova Z, Balashov D, Voronin K, et al. Risk factors for and the clinical impact of cytomegalovirus and Epstein-Barr virus infections in pediatric recipients of TCR-alpha/beta- and CD19-depleted grafts. Biol Blood Marrow Transplant. 2017;23:483–90.

  61. 61.

    Lang PJ, Schlegel PG, Roland M, Schulz AS, Greil J, Bader P, et al. Safety and efficacy of Tcralpha/beta and CD19 depleted haploidentical stem cell transplantation following reduced intensity conditioning in children: Results of a prospective multicenter phase I/II clinical trial. Blood. 2017;130(Suppl 1):214

  62. 62.

    Rooney CM, Loftin SK, Holladay MS, Brenner MK, Krance RA, Heslop HE. Early identification of Epstein-Barr virus-associated post-transplantation lymphoproliferative disease. Br J Haematol. 1995;89:98–103.

  63. 63.

    van Esser JW, van der Holt B, Meijer E, Niesters HG, Trenschel R, Thijsen SF, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT. Blood. 2001;98:972–8.

  64. 64.

    Mensen A, Na IK, Hafer R, Meerbach A, Schlecht M, Pietschmann ML, et al. Comparison of different rabbit ATG preparation effects on early lymphocyte subset recovery after allogeneic HSCT and its association with EBV-mediated PTLD. J Cancer Res Clin Oncol. 2014;140:1971–80.

  65. 65.

    Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Biancotto A, Wu CO, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365:430–8.

  66. 66.

    Burns DM, Rana S, Martin E, Nagra S, Ward J, Osman H, et al. Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab-conditioned allogeneic HSCT. Bone Marrow Transplant. 2016;51:825–32.

  67. 67.

    Sica S, Metafuni E, Bellesi S, Chiusolo P. Epstein-barr virus related lymphoproliferations after stem cell transplantation. Mediterr J Hematol Infect Dis. 2009;1:e2009019.

  68. 68.

    Scheinberg P, Fischer SH, Li L, Nunez O, Wu CO, Sloand EM, et al. Distinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia. Blood. 2007;109:3219–24.

  69. 69.

    Nijland ML, Kersten MJ, Pals ST, Bemelman FJ, Ten Berge IJ. Epstein-Barr virus-positive posttransplant lymphoproliferative disease after solid organ transplantation: pathogenesis, clinical manifestations, diagnosis, and management. Transpl Direct. 2016;2:e48.

  70. 70.

    Kanakry JA, Kasamon YL, Bolanos-Meade J, Borrello IM, Brodsky RA, Fuchs EJ, et al. Absence of post-transplantation lymphoproliferative disorder after allogeneic blood or marrow transplantation using post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2013;19:1514–7.

  71. 71.

    Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, et al. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:1835–44.

  72. 72.

    Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, et al. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013;19:117–22.

  73. 73.

    Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK, et al. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012;18:1859–66.

  74. 74.

    Bilmon IA, Kwan J, Gottlieb D, Kerridge I, McGurgan M, Huang G, et al. Haploidentical bone marrow transplants for haematological malignancies using non-myeloablative conditioning therapy and post-transplant immunosuppression with cyclophosphamide: results from a single Australian centre. Intern Med J. 2013;43:191–6.

  75. 75.

    Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013;31:1310–6.

  76. 76.

    Retiere C, Willem C, Guillaume T, Vie H, Gautreau-Rolland L, Scotet E, et al. Impact on early outcomes and immune reconstitution of high-dose post-transplant cyclophosphamide vs anti-thymocyte globulin after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation. Oncotarget. 2018;9:11451–64.

  77. 77.

    Zhang Q, Zou BH, Lou X, Liu H, Zhang B, Chen H. [An analysis of risk factors and prognosis of Epstein-Barr virus infection after allogeneic hematopoietic stem cell transplantation]. Zhonghua Nei Ke Za Zhi. 2016;55:619–23.

  78. 78.

    Zallio F, Primon V, Tamiazzo S, Pini M, Baraldi A, Corsetti MT, et al. Epstein-Barr virus reactivation in allogeneic stem cell transplantation is highly related to cytomegalovirus reactivation. Clin Transplant. 2013;27:E491–7.

  79. 79.

    Bao X, Zhu Q, Qiu H, Chen F, Xue S, Ma X, et al. [Clinical risks analysis of EBV infection in patients with allogeneic hematopoietic stem cell transplantation]. Zhonghua Xue Ye Xue Za Zhi. 2016;37:138–43.

  80. 80.

    Abedi MR, Linde A, Christensson B, Mackett M, Hammarstrom L, Smith CI. Preventive effect of IgG from EBV-seropositive donors on the development of human lympho-proliferative disease in SCID mice. Int J Cancer. 1997;71:624–9.

  81. 81.

    Gary-Gouy H, Harriague J, Bismuth G, Platzer C, Schmitt C, Dalloul AH. Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production. Blood . 2002;100:4537–43.

  82. 82.

    Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143–238.

  83. 83.

    Styczynski J, van der Velden W, Fox CP, Engelhard D, de la Camara R, Cordonnier C, et al. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica. 2016;101:803–11.

  84. 84.

    Jones K, Nourse JP, Keane C, Crooks P, Gottlieb D, Ritchie DS, et al. Tumor-specific but not nonspecific cell-free circulating DNA can be used to monitor disease response in lymphoma. Am J Hematol. 2012;87:258–65.

  85. 85.

    Wang ZY, Liu QF, Wang H, Jin J, Wang WH, Wang SL, et al. Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy. Blood. 2012;120:2003–10.

  86. 86.

    Gandhi MK, Lambley E, Burrows J, Dua U, Elliott S, Shaw PJ, et al. Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive Hodgkin’s lymphoma. Clin Cancer Res. 2006;12:460–4.

  87. 87.

    Hohaus S, Santangelo R, Giachelia M, Vannata B, Massini G, Cuccaro A, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17:2885–92.

  88. 88.

    Hakim H, Gibson C, Pan J, Srivastava K, Gu Z, Bankowski MJ, et al. Comparison of various blood compartments and reporting units for the detection and quantification of Epstein-Barr virus in peripheral blood. J Clin Microbiol. 2007;45:2151–5.

  89. 89.

    Ruf S, Behnke-Hall K, Gruhn B, Bauer J, Horn M, Beck J, et al. Comparison of six different specimen types for Epstein-Barr viral load quantification in peripheral blood of pediatric patients after heart transplantation or after allogeneic hematopoietic stem cell transplantation. J Clin Virol. 2012;53:186–94.

  90. 90.

    Ito Y, Kimura H, Maeda Y, Hashimoto C, Ishida F, Izutsu K, et al. Pretreatment EBV-DNA copy number is predictive of response and toxicities to SMILE chemotherapy for extranodal NK/T-cell lymphoma, nasal type. Clin Cancer Res. 2012;18:4183–90.

  91. 91.

    Kanakry JA, Li H, Gellert LL, Lemas MV, Hsieh WS, Hong F, et al. Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood. 2013;121:3547–53.

  92. 92.

    Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena SC, et al. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant. 2006;6:569–76.

  93. 93.

    Ghobrial IM, Habermann TM, Maurer MJ, Geyer SM, Ristow KM, Larson TS, et al. Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol. 2005;23:7574–82.

  94. 94.

    Ghobrial IM, Habermann TM, Ristow KM, Ansell SM, Macon W, Geyer SM, et al. Prognostic factors in patients with post-transplant lymphoproliferative disorders (PTLD) in the rituximab era. Leuk Lymphoma. 2005;46:191–6.

  95. 95.

    Swinnen LJ, Mullen GM, Carr TJ, Costanzo MR, Fisher RI. Aggressive treatment for postcardiac transplant lymphoproliferation. Blood. 1995;86:3333–40.

  96. 96.

    Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW. Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol. 2009;27:3354–62.

  97. 97.

    Jagadeesh D, Woda BA, Draper J, Evens AM. Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options Oncol. 2012;13:122–36.

  98. 98.

    Oton AB, Wang H, Leleu X, Melhem MF, George D, Lacasce A, et al. Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders in solid transplant. Leuk Lymphoma. 2008;49:1738–44.

  99. 99.

    Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005;80:1233–43.

  100. 100.

    Maecker B, Jack T, Zimmermann M, Abdul-Khaliq H, Burdelski M, Fuchs A, et al. CNS or bone marrow involvement as risk factors for poor survival in post-transplantation lymphoproliferative disorders in children after solid organ transplantation. J Clin Oncol. 2007;25:4902–8.

  101. 101.

    Franke AJ, Bishnoi R, Bajwa R, Skelton WP, Patel N, Slayton WB, et al. Association of allograft rejection with reduction of immunosuppression for post-transplant lymphoproliferative disorder: Analysis of a 20-year single-institutional experience. J Clin Oncol. 2017;35(15suppl):19047. Abstract

  102. 102.

    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. Transplantation. 2008;86:215–22.

  103. 103.

    Nelson BP, Wolniak KL, Evens A, Chenn A, Maddalozzo J, Proytcheva M. Early posttransplant lymphoproliferative disease: clinicopathologic features and correlation with mTOR signaling pathway activation. Am J Clin Pathol. 2012;138:568–78.

  104. 104.

    El-Salem M, Raghunath PN, Marzec M, Wlodarski P, Tsai D, Hsi E, et al. Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders. Lab Invest. 2007;87:29–39.

  105. 105.

    Garcia VD, Bonamigo Filho JL, Neumann J, Fogliatto L, Geiger AM, Garcia CD, et al. Rituximab in association with rapamycin for post-transplant lymphoproliferative disease treatment. Transpl Int. 2003;16:202–6.

  106. 106.

    Gibelli NE, Tannuri U, Pinho-Apezzato ML, Tannuri AC, Maksoud-Filho JG, Andrade WC, et al. Sirolimus in pediatric liver transplantation: a single-center experience. Transpl Proc. 2009;41:901–3.

  107. 107.

    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. Transpl Infect Dis. 2009;11:383–92.

  108. 108.

    Xu LP, Zhang CL, Mo XD, Zhang XH, Chen H, Han W, et al. Epstein-Barr virus-related post-transplantation lymphoproliferative disorder after unmanipulated human leukocyte antigen haploidentical hematopoietic stem cell transplantation: Incidence, risk factors, treatment, and clinical outcomes. Biol Blood Marrow Transplant. 2015;21:2185–91.

  109. 109.

    Gonzalez-Barca E, Domingo-Domenech E, Capote FJ, Gomez-Codina J, Salar A, Bailen A, et al. Prospective phase II trial of extended treatment with rituximab in patients with B-cell post-transplant lymphoproliferative disease. Haematologica. 2007;92:1489–94.

  110. 110.

    Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, Mollee P, Zaucha JM, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol. 2017;35:536–43.

  111. 111.

    Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Vary M, Babel N, et al. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant. 2005;5:2901–6.

  112. 112.

    Blaes AH, Peterson BA, Bartlett N, Dunn DL, Morrison VA. Rituximab therapy is effective for posttransplant lymphoproliferative disorders after solid organ transplantation: results of a phase II trial. Cancer. 2005;104:1661–7.

  113. 113.

    Choquet S, Leblond V, Herbrecht R, Socie G, Stoppa AM, Vandenberghe P, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood. 2006;107:3053–7.

  114. 114.

    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. Ann Hematol. 2007;86:599–607.

  115. 115.

    Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. 2012;13:196–206.

  116. 116.

    van Esser JW, Niesters HG, van der Holt B, Meijer E, Osterhaus AD, Gratama JW, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood . 2002;99:4364–9.

  117. 117.

    Delapierre B, Reman O, Dina J, Breuil C, Bellal M, Johnson-Ansah H, et al. Low dose rituximab for pre-emptive treatment of Epstein Barr virus reactivation after allogenic hematopoietic stem cell transplantation. Curr Res Transl Med. 2019. https://doi.org/10.1016/j.retram.2019.03.001.

  118. 118.

    Van Besien K, Bachier-Rodriguez L, Satlin M, Brown MA, Gergis U, Guarneri D, et al. Prophylactic rituximab prevents EBV PTLD in haplo-cord transplant recipients at high risk. Leuk Lymphoma. 2019. https://doi.org/10.1080/10428194.2018.1543877.

  119. 119.

    Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, et al. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance. Blood. 2009;113:4885–93.

  120. 120.

    Tsai PC, Hernandez-Ilizaliturri FJ, Bangia N, Olejniczak SH, Czuczman MS. Regulation of CD20 in rituximab-resistant cell lines and B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2012;18:1039–50.

  121. 121.

    McIver Z, Stephens N, Grim A, Barrett AJ. Rituximab administration within 6 months of T cell-depleted allogeneic SCT is associated with prolonged life-threatening cytopenias. Biol Blood Marrow Transplant. 2010;16:1549–56.

  122. 122.

    Petropoulou AD, Porcher R, Peffault de Latour R, Xhaard A, Weisdorf D, Ribaud P, et al. Increased infection rate after preemptive rituximab treatment for Epstein-Barr virus reactivation after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2012;94:879–83.

  123. 123.

    Teeling JL, Mackus WJ, Wiegman LJ, van den Brakel JH, Beers SA, French RR, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006;177:362–71.

  124. 124.

    Herter S, Herting F, Mundigl O, Waldhauer I, Weinzierl T, Fauti T, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12:2031–42.

  125. 125.

    Vitolo U, Trneny M, Belada D, Burke JM, Carella AM, Chua N, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35:3529–37.

  126. 126.

    Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377:1331–44.

  127. 127.

    Sehn LH, Chua N, Mayer J, Dueck G, Trneny M, Bouabdallah K, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17:1081–93.

  128. 128.

    Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+indolent B-cell non-Hodgkin lymphoma: Final analysis of the GAUSS study. J Clin Oncol. 2015;33:3467–74.

  129. 129.

    Tang T, Lim C, Tao M, Quek R, Farid M, Kim WS, et al . A multi-center, non-randomized phase 2 study of ofatumumab in combination with ICE-chemotherapy (O-ICE) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) [abstract]. Blood. 2014;124:5645.

  130. 130.

    van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, et al. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: The ORCHARRD Study. J Clin Oncol. 2017;35:544–51.

  131. 131.

    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. Blood. 2010;115:925–35.

  132. 132.

    Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet. 1995;345:9–13.

  133. 133.

    Vickers MA, Wilkie GM, Robinson N, Rivera N, Haque T, Crawford DH, et al. Establishment and operation of a Good Manufacturing Practice-compliant allogeneic Epstein-Barr virus (EBV)-specific cytotoxic cell bank for the treatment of EBV-associated lymphoproliferative disease. Br J Haematol. 2014;167:402–10.

  134. 134.

    Prockop SE, Doubrovina E, Baroudy K, Boulad F, Khalaf R, Papadopoulose EB, et al. Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (EBV-CTLs) for treatment of rituximab-refractory EBV-associated lymphoproliferative disorder (EBV-LPD). Presented at: 2015 AACR Annual Meeting; April 18–22, Philadelphia, PA: 2015. Abstract 8841.

  135. 135.

    Doubrovina E, Oflaz-Sozmen B, Prockop SE, Kernan NA, Abramson S, Teruya-Feldstein J, et al. Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+lymphomas after allogeneic hematopoietic cell transplantation. Blood. 2012;119:2644–56.

  136. 136.

    Quintarelli C, Savoldo B, Dotti G. Gene therapy to improve function of T cells for adoptive immunotherapy. Methods Mol Biol. 2010;651:119–30.

  137. 137.

    Marin V, Cribioli E, Philip B, Tettamanti S, Pizzitola I, Biondi A, et al. Comparison of different suicide-gene strategies for the safety improvement of genetically manipulated T cells. Hum Gene Ther Methods. 2012;23:376–86.

  138. 138.

    Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33:540–9.

  139. 139.

    Fox CP, Burns D, Parker AN, Peggs KS, Harvey CM, Natarajan S, et al. EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era. Bone Marrow Transplant. 2014;49:280–6.

  140. 140.

    Dotti G, Fiocchi R, Motta T, Mammana C, Gotti E, Riva S, et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation. 2002;74:1095–102.

  141. 141.

    Gershburg E, Marschall M, Hong K, Pagano JS. Expression and localization of the Epstein-Barr virus-encoded protein kinase. J Virol. 2004;78:12140–6.

  142. 142.

    AlDabbagh MA, Gitman MR, Kumar D, Humar A, Rotstein C, Husain S. The role of antiviral prophylaxis for the prevention of Epstein-Barr virus-associated posttransplant lymphoproliferative disease in solid organ transplant recipients: A systematic review. Am J Transplant. 2017;17:770–81.

  143. 143.

    Portell C, Nand S. Single agent lenalidomide induces a response in refractory T-cell posttransplantation lymphoproliferative disorder. Blood. 2008;111:4416–7.

  144. 144.

    Laubli H, Tzankov A, Juskevicius D, Degen L, Rochlitz C, Stenner-Liewen F. Lenalidomide monotherapy leads to a complete remission in refractory B-cell post-transplant lymphoproliferative disorder. Leuk Lymphoma. 2016;57:945–8.

  145. 145.

    Haque T, Chaggar T, Schafers J, Atkinson C, McAulay KA, Crawford DH. Soluble CD30: a serum marker for Epstein-Barr virus-associated lymphoproliferative diseases. J Med Virol. 2011;83:311–6.

  146. 146.

    Gandhi M, Ma S, Smith SM, Nabhan C, Evens AM, Winter JN et al. Brentuximab vedotin (BV) plus rituximab (R) as frontline therapy for patients (Pts) with Epstein Barr Virus (EBV)+and/or CD30+lymphoma: phase I results of an ongoing phase I-II study. Blood. 2014;124:3096.

  147. 147.

    Massachusetts General Hospital, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Millennium Pharmaceuticals, Inc. Bortezomib plus rituximab for EBV+PTLD. https://ClinicalTrials.gov/show/NCT01058239; 2011.

  148. 148.

    Noy A, de Vos S, Thieblemont C, Martin P, Flowers CR, Morschhauser F, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129:2224–32.

  149. 149.

    Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.

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  1. These authors contributed equally: Rama Al Hamed, Abdul Hamid Bazarbachi

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  1. Service d’hématologie clinique et thérapie cellulaire, Hôpital Saint-Antoine, INSERM UMRs 938, and Université Sorbonne, Paris, France

    • Rama Al Hamed
    • , Abdul Hamid Bazarbachi
    •  & Mohamad Mohty

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https://doi.org/10.1038/s41409-019-0548-7