Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT

Bone Marrow Transplantation volume 49, pages 163–167 (2014)Cite this article

Subjects

Abstract

EBV-induced post transplantation lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after allogeneic hematopoietic cell transplantation. Profound T-cell depletion of the allograft represents a major risk factor for EBV-PTLD. With regard to the increasing use of alternative stem cell sources such as cord blood or purified haploidentical stem cell grafts both associated with impaired immune reconstitution, the frequent occurrence of EBV-PTLD demands particular vigilance on laboratory changes and early symptoms. Here we have summarized today’s knowledge about EBV-PTLD in a comprehensive review explaining the underlying mechanisms of EBV-based transformation, EBV-PTLD development, clinical presentation, incidence, diagnosis, screening, therapy and prognosis. In this context, we emphasize on the necessity of regularly applied screening tools and pre-emptive treatment strategies including anti-CD20 Abs particularly in high-risk patients to avoid disease progression to malignant lymphoma. Although EBV-PTLD has always been associated with a high mortality rate, novel immunotherapeutic approaches such as the transfer of EBV-specific T cells nowadays offer improved chances of disease control even at late stages.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Ruf S, Moser O, Wössmann 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 Pediatr Hematol Oncol 2011; 33: 50–54.

    Article  PubMed  Google Scholar 

  2. Reddiconto G, Chiusolo P, Fiorini A, Farina G, Laurenti L, Martini M et al. Assessment of cellular origin and EBV status in a PTLD after double cord blood transplantation. Leukemia 2007; 21: 2552–2554.

    Article  CAS  PubMed  Google Scholar 

  3. Gong JZ, Bayerl MG, Sandhaus LM, Sebastian S, Rehder CW, Routbort M et al. Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children. Am J Surg Pathol 2006; 30: 328–336.

    Article  PubMed  Google Scholar 

  4. Johansson JE, Remberger M, Lazarevic VLj, Hallböök 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: 870–875.

    Article  CAS  PubMed  Google Scholar 

  5. 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: 315–321.

    Article  PubMed  Google Scholar 

  6. 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 anaemia. Bone Marrow Transplant 2009; 43: 813–816.

    Article  CAS  PubMed  Google Scholar 

  7. 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: 181–186.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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: 383–392.

    Article  CAS  PubMed  Google Scholar 

  10. Omar H, Hägglund H, Gustafsson-Jernberg A, LeBlanc K, Mattsson J, Remberger M et al. Targeted monitoring of patients at high risk of post-transplant lymphoproliferative disease by quantitative Epstein-Barr virus polymerase chain reaction. Transpl Infect Dis 2009; 11: 393–399.

    Article  CAS  PubMed  Google Scholar 

  11. Sundin M, Le Blanc K, Ringdén 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: 1059–1067.

    PubMed  Google Scholar 

  12. Agbalika F, Larghero J, Esperou H, Marais D, Robin M, Foïs E et al. Epstein-Barr virus early-antigen antibodies before allogeneic haematopoietic stem cell transplantation as a marker of risk of post-transplant lymphoproliferative disorders. Br J Haematol 2007; 136: 305–308.

    Article  CAS  PubMed  Google Scholar 

  13. Islam MS, Anoop P, Gordon-Smith EC, Rice P, Datta-Nemdharry P, Marsh JC . Epstein-Barr virus infections after allogeneic stem cell transplantation: a comparison between non-malignant and malignant hematological disorders. Hematology 2010; 15: 344–350.

    Article  CAS  PubMed  Google Scholar 

  14. Carpenter B, Haque T, Dimopoulou M, Atkinson C, Roughton M, Grace S et al. Incidence and dynamics of Epstein-Barr virus reactivation after alemtuzumab-based conditioning for allogeneic hematopoietic stem-cell transplantation. Transplantation 2010; 90: 564–570.

    Article  CAS  PubMed  Google Scholar 

  15. Chiusolo P, Metafuni E, Cattani P, Piccirillo N, Santangelo R, Manzara S et al. Prospective evaluation of epstein-barr virus reactivation after stem cell transplantation: association with monoclonal gammopathy. J Clin Immunol 2010; 30: 894–902.

    Article  PubMed  Google Scholar 

  16. Cohen JI . Epstein-Barr virus infection. N Engl J Med 2000; 343: 481–492.

    Article  CAS  PubMed  Google Scholar 

  17. 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: 3806–3810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kalinova L, Indrakova J, Bachleda P . Post-transplant lymphoproliferative disorder. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009; 153: 251–257.

    Article  CAS  PubMed  Google Scholar 

  19. Friedberg JW, Swinnen LJ . Post-Transplant Lymphproliferative Disease in The Lymphomas Second Edition Elsevier: Philadelphia, PA, USA, 2006.

    Google Scholar 

  20. Diekmann J, Adamopoulou E, Beck O, Rauser G, Lurati S, Tenzer S et al. Processing of two latent membrane protein 1 MHC class I epitopes requires tripeptidyl peptidase II involvement. J Immunol 2009; 183: 1587–1597.

    Article  CAS  PubMed  Google Scholar 

  21. Wang D, Liebowitz D, Kieff E, An EBV . membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 1985; 43 (3 Pt 2): 831–840.

    Article  CAS  PubMed  Google Scholar 

  22. Henderson S, Huen D, Rowe M, Dawson C, Johnson G, Rickinson A . Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci USA 1993; 90: 8479–8483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Swerdlow SH, Webber SA, Chadbrun A, Ferry JA . WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, France, 2008.

    Google Scholar 

  24. Knowles DM, Cesarman E, Chadburn A, Frizzera G, Chen J, Rose EA et al. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 1995; 85: 552–565.

    CAS  PubMed  Google Scholar 

  25. 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: 1648–1655.

    Article  CAS  PubMed  Google Scholar 

  26. Muramatsu H, Takahashi Y, Shimoyama Y, Doisaki S, Nishio N, Ito Y et al. CD20-negative Epstein-Barr virus-associated post-transplant lymphoproliferative disease refractory to rituximab in a patient with severe aplastic anemia. Int J Hematol 2011; 93: 779–781.

    Article  PubMed  Google Scholar 

  27. Deeg HJ, Socie G . Malignancies after hematopoietic stem cell transplantation: many questions, some answers. Blood 1998; 91: 1833–1844.

    CAS  PubMed  Google Scholar 

  28. 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: 1143–1238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ahmad I, Cau NV, Kwan J, Maaroufi Y, Meuleman N, Aoun M et al. Preemptive management of Epstein-Barr virus reactivation after hematopoietic stem-cell transplantation. Transplantation 2009; 87: 1240–1245.

    Article  CAS  PubMed  Google Scholar 

  30. Blaes AH, Cao Q, Wagner JE, Young JA, Weisdorf DJ, Brunstein CG . Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation. Biol Blood Marrow Transplant 2010; 16: 287–291.

    Article  CAS  PubMed  Google Scholar 

  31. Weinstock DM, Ambrossi GG, Brennan C, Kiehn TE, Jakubowski A . Preemptive diagnosis and treatment of Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development. Bone Marrow Transplant 2006; 37: 539–546.

    Article  CAS  PubMed  Google Scholar 

  32. Rowe DT, Webber S, Schauer EM, Reyes J, Green M . Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease. Transpl Infect Dis 2001; 3: 79–87.

    Article  CAS  PubMed  Google Scholar 

  33. Meijer E, Cornelissen JJ . Epstein-Barr virus-associated lymphoproliferative disease after allogeneic haematopoietic stem cell transplantation: molecular monitoring and early treatment of high-risk patients. Curr Opin Hematol 2008; 15: 576–585.

    Article  PubMed  Google Scholar 

  34. Beck R, Westdörp I, Jahn G, Schäfer H, Kanz L, Einsele H . Detection of Epstein-Barr virus DNA in plasma from patients with lymphoproliferative disease after allogeneic bone marrow or peripheral blood stem cell transplantation. J Clin Microbiol 1999; 37: 3430–3431.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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: 1549–1556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stuhler G, Knop S, Topp MS, Kröber SM, Ernemann U, Herrlinger U et al. Intravenously administered rituximab induces remission of EBV associated non Hodgkin lymphoma confined to the brain in a patient after allogeneic stem cell transplantation. Haematologica 2006; 91: ECR01.

    CAS  PubMed  Google Scholar 

  37. Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA . Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 2010; 115: 925–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rooney CM, Smith CA, Ng CY, Loftin SK, Sixbey JW, Gan Y et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 1998; 92: 1549–1555.

    CAS  PubMed  Google Scholar 

  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. Blood 2010; 115: 2960–2970.

    Article  CAS  PubMed  Google Scholar 

  40. Uhlin M, Okas M, Gertow J, Uzunel M, Brismar TB, Mattsson J . A novel haplo-identical adoptive CTL therapy as a treatment for EBV-associated lymphoma after stem cell transplantation. Cancer Immunol Immunother 2010; 59: 473–477.

    Article  PubMed  Google Scholar 

  41. Barker JN, Doubrovina E, Sauter C, Jaroscak JJ, Perales MA, Doubrovin M et al. Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes. Blood 2010; 116: 5045–5049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Reisner Y, Hagin D, Martelli MF . Haploidentical hematopoietic transplantation: current status and future perspectives. Blood 2011; 118: 6006–6017.

    Article  CAS  PubMed  Google Scholar 

  43. Mielke S, McIver ZA, Shenoy A, Fellowes V, Khuu H, Stroncek DF et al. Selectively T cell-depleted allografts from HLA-matched sibling donors followed by low-dose posttransplantation immunosuppression to improve transplantation outcome in patients with hematologic malignancies. Biol Blood Marrow Transplant 2011; 17: 1855–1861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Savani BN, Mielke S, Rezvani K, Montero A, Yong AS, Wish L et al. Absolute lymphocyte count on day 30 is a surrogate for robust hematopoietic recovery and strongly predicts outcome after T cell-depleted allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2007; 13: 1216–1223.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Leen AM, Bollard CM, Mendizabal AM, Shpall EJ, Szabolcs P, Antin JH et al. Multicenter study of banked third party virus-specific T-cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood, (e-pub ahead of print 22 April 2013).

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine II, Allogeneic Stem Cell Transplantation Center, Würzburg University Medical Center, Würzburg, Germany

    L Rasche, M Kapp, H Einsele & S Mielke

Authors
  1. L Rasche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Kapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Einsele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Mielke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Mielke.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rasche, L., Kapp, M., Einsele, H. et al. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoetic SCT. Bone Marrow Transplant 49, 163–167 (2014). https://doi.org/10.1038/bmt.2013.96

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2013.96

Keywords

This article is cited by

Search

Advanced search

Quick links