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.

  • Original Article
  • Published:

Infectious Medicine

Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation

Abstract

This single centre study assessed the incidence, kinetics and predictive factors of Epstein-Barr Virus (EBV) reactivation and EBV-related lymphoproliferative diseases (LPDs) in 175 consecutive patients who received a reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT). The cumulative incidence of EBV reactivation at 6 months after allo-HSCT defined as an EBV PCR load above 1000 copies of EBV DNA/105 cells was 15%, and none of these patients experienced any sign or symptom of LPD. A total of 17 patients, who had EBV DNA levels exceeding 1000 copies/105 cells on two or more occasions, were pre-emptively treated with rituximab. With a median follow-up of 655 (range, 92–1542) days post allo-HSCT, there was no statistically significant difference in term of outcome between those patients who experienced an EBV reactivation and those who did not. In multivariate analysis, the use of antithymocyte globulin as part of the RIC regimen was the only independent risk factor associated with EBV reactivation (relative risk=4.9; 95% confidence interval, 1.1–21.0; P=0.03). We conclude that patients undergoing RIC allo-HSCT using anti-thymocyte globulin as part of the preparative regimen are at higher risk for EBV reactivation. However, this did not impact on outcome, as quantitative monitoring of EBV viral load by PCR and preemptive rituximab therapy allowed for significantly reducing the risk of EBV-related LPD.

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

Access options

Buy this article

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

Figure 1

Similar content being viewed by others

References

  1. Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531–4536.

    CAS  Google Scholar 

  2. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  Google Scholar 

  3. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  Google Scholar 

  4. Storb R . Reduced-intensity conditioning transplantation in myeloid malignancies. Curr Opin Oncol 2009; 21 (Suppl 1): S3–S5.

    Article  Google Scholar 

  5. Mohty M, Rocha V, Chevallier P, Harousseau JL, Nagler A . Reduced-intensity conditioning for allogeneic stem cell transplantation: 10 years later. Curr Opin Oncol 2009; 21 (Suppl 1): S1.

    Article  Google Scholar 

  6. Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997; 89: 3048–3054.

    CAS  PubMed  Google Scholar 

  7. Shapiro RS, McClain K, Frizzera G, Gajl-Peczalska KJ, Kersey JH, Blazar BR et al. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 1988; 71: 1234–1243.

    CAS  PubMed  Google Scholar 

  8. Micallef IN, Chhanabhai M, Gascoyne RD, Shepherd JD, Fung HC, Nantel SH et al. Lymphoproliferative disorders following allogeneic bone marrow transplantation: the Vancouver experience. Bone Marrow Transplant 1998; 22: 981–987.

    Article  CAS  Google Scholar 

  9. Hale G, Waldmann H . Risks of developing Epstein-Barr virus-related lymphoproliferative disorders after T-cell-depleted marrow transplants. CAMPATH Users. Blood 1998; 91: 3079–3083.

    CAS  PubMed  Google Scholar 

  10. 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: 2208–2216.

    CAS  Google Scholar 

  11. Gross TG, Steinbuch M, DeFor T, Shapiro RS, McGlave P, Ramsay NK et al. B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome. Bone Marrow Transplant 1999; 23: 251–258.

    Article  CAS  Google Scholar 

  12. Juvonen E, Aalto SM, Tarkkanen J, Volin L, Mattila PS, Knuutila S et al. High incidence of PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a consequence of intensive immunosuppressive treatment. Bone Marrow Transplant 2003; 32: 97–102.

    Article  CAS  Google Scholar 

  13. Heslop HE . How I treat EBV lymphoproliferation. Blood 2009; 114: 4002–4008.

    Article  CAS  Google Scholar 

  14. Gottschalk S, Rooney CM, Heslop HE . Post-transplant lymphoproliferative disorders. Annu Rev Med 2005; 56: 29–44.

    Article  CAS  Google Scholar 

  15. Lucas KG, Burton RL, Zimmerman SE, Wang J, Cornetta KG, Robertson KA et al. Semiquantitative Epstein-Barr virus (EBV) polymerase chain reaction for the determination of patients at risk for EBV-induced lymphoproliferative disease after stem cell transplantation. Blood 1998; 91: 3654–3661.

    CAS  PubMed  Google Scholar 

  16. Hoshino Y, Kimura H, Tanaka N, Tsuge I, Kudo K, Horibe K et al. Prospective monitoring of the Epstein-Barr virus DNA by a real-time quantitative polymerase chain reaction after allogenic stem cell transplantation. Br J Haematol 2001; 115: 105–111.

    Article  CAS  Google Scholar 

  17. Gartner BC, Schafer H, Marggraff K, Eisele G, Schafer M, Dilloo D et al. Evaluation of use of Epstein-Barr viral load in patients after allogeneic stem cell transplantation to diagnose and monitor posttransplant lymphoproliferative disease. J Clin Microbiol 2002; 40: 351–358.

    Article  Google Scholar 

  18. 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: 972–978.

    Article  CAS  Google Scholar 

  19. Lankester AC, van Tol MJ, Vossen JM, Kroes AC, Claas E . Epstein-Barr virus (EBV)-DNA quantification in pediatric allogenic stem cell recipients: prediction of EBV-associated lymphoproliferative disease. Blood 2002; 99: 2630–2631.

    Article  CAS  Google Scholar 

  20. Wagner HJ, Cheng YC, Huls MH, Gee AP, Kuehnle I, Krance RA et al. Prompt versus preemptive intervention for EBV lymphoproliferative disease. Blood 2004; 103: 3979–3981.

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Cohen J, Gandhi M, Naik P, Cubitt D, Rao K, Thaker U et al. Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning. Br J Haematol 2005; 129: 229–239.

    Article  Google Scholar 

  23. 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: 2874–2880.

    Article  CAS  Google Scholar 

  24. Cahu X, Rialland F, Touzeau C, Chevallier P, Guillaume T, Delaunay J et al. Infectious complications after unrelated umbilical cord blood transplantation in adult patients with hematologic malignancies. Biol Blood Marrow Transplant 2009; 15: 1531–1537.

    Article  Google Scholar 

  25. Mohty M, Bay JO, Faucher C, Choufi B, Bilger K, Tournilhac O et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood 2003; 102: 470–476.

    Article  CAS  Google Scholar 

  26. Malard F, Szydlo RM, Brissot E, Chevallier P, Guillaume T, Delaunay J et al. Impact of cyclosporine-A concentration on the incidence of severe acute graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16: 28–34.

    Article  CAS  Google Scholar 

  27. Mohty M, Jacot W, Faucher C, Bay JO, Zandotti C, Collet L et al. Infectious complications following allogeneic HLA-identical sibling transplantation with antithymocyte globulin-based reduced intensity preparative regimen. Leukemia 2003; 17: 2168–2177.

    Article  CAS  Google Scholar 

  28. Chevallier P, Hebia-Fellah I, Planche L, Guillaume T, Bressolette-Bodin C, Coste-Burel M et al. Human herpes virus 6 infection is a hallmark of cord blood transplant in adults and may participate to delayed engraftment: a comparison with matched unrelated donors as stem cell source. Bone Marrow Transplant 2010; 45: 1204–1211.

    Article  CAS  Google Scholar 

  29. Bressollette-Bodin C, Coste-Burel M, Besse B, Andre-Garnier E, Ferre V, Imbert-Marcille BM . Cellular normalization of viral DNA loads on whole blood improves the clinical management of cytomegalovirus or Epstein Barr virus infections in the setting of pre-emptive therapy. J Med Virol 2009; 81: 90–98.

    Article  Google Scholar 

  30. Klein JP, Rizzo JD, Zhang MJ, Keiding N . Statistical methods for the analysis and presentation of the results of bone marrow transplants. Part I: unadjusted analysis. Bone Marrow Transplant 2001; 28: 909–915.

    Article  CAS  Google Scholar 

  31. Fine JP, Gray RJ . A proportional hazards model for subdistribution of a competing risk. JASA 1999; 94: 496–509.

    Article  Google Scholar 

  32. Scrucca L, Santucci A, Aversa F . Regression modeling of competing risk using R: an in depth guide for clinicians. Bone Marrow Transplant 2010; 45: 1388–1395.

    Article  CAS  Google Scholar 

  33. Antin JH, Bierer BE, Smith BR, Ferrara J, Guinan EC, Sieff C et al. Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies. Blood 1991; 78: 2139–2149.

    CAS  PubMed  Google Scholar 

  34. Wagner JE, Thompson JS, Carter SL, Kernan NA . Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell depletion trial): a multi-centre, randomised phase II-III trial. Lancet 2005; 366: 733–741.

    Article  CAS  Google Scholar 

  35. Paya CV, Fung JJ, Nalesnik MA, Kieff E, Green M, Gores G et al. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD task force and the mayo clinic organized international consensus development meeting. Transplantation 1999; 68: 1517–1525.

    Article  CAS  Google Scholar 

  36. van Esser JW, Niesters HG, Thijsen SF, Meijer E, Osterhaus AD, Wolthers KC et al. Molecular quantification of viral load in plasma allows for fast and accurate prediction of response to therapy of Epstein-Barr virus-associated lymphoproliferative disease after allogeneic stem cell transplantation. Br J Haematol 2001; 113: 814–821.

    Article  CAS  Google Scholar 

  37. Clave E, Agbalika F, Bajzik V, Peffault de Latour R, Trillard M, Rabian C et al. Epstein-Barr virus (EBV) reactivation in allogeneic stem-cell transplantation: relationship between viral load, EBV-specific T-cell reconstitution and rituximab therapy. Transplantation 2004; 77: 76–84.

    Article  CAS  Google Scholar 

  38. Stevens SJ, Verschuuren EA, Verkuujlen SA, Van Den Brule AJ, Meijer CJ, Middeldorp JM . Role of Epstein-Barr virus DNA load monitoring in prevention and early detection of post-transplant lymphoproliferative disease. Leuk Lymphoma 2002; 43: 831–840.

    Article  Google Scholar 

  39. 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: 757–770.

    Article  CAS  Google Scholar 

  40. Faye A, Quartier P, Reguerre Y, Lutz P, Carret AS, Dehee A et al. Chimaeric anti-CD20 monoclonal antibody (rituximab) in post-transplant B-lymphoproliferative disorder following stem cell transplantation in children. Br J Haematol 2001; 115: 112–118.

    Article  CAS  Google Scholar 

  41. Kuehnle I, Huls MH, Liu Z, Semmelmann M, Krance RA, Brenner MK et al. CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 2000; 95: 1502–1505.

    CAS  PubMed  Google Scholar 

  42. Suzan F, Ammor M, Ribrag V . Fatal reactivation of cytomegalovirus infection after use of rituximab for a post-transplantation lymphoproliferative disorder. N Engl J Med 2001; 345: 1000.

    Article  CAS  Google Scholar 

  43. Choquet S, Trappe R, Leblond V, Jager U, Davi F, Oertel S . CHOP-21 for the treatment of post-transplant lymphoproliferative disorders (PTLD) following solid organ transplantation. Haematologica 2007; 92: 273–274.

    Article  Google Scholar 

  44. 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: 925–935.

    Article  CAS  Google Scholar 

  45. Savani BN, Pohlmann PR, Jagasia M, Chinratanalab W, Kassim A, Engelhardt B et al. Does peritransplantation use of rituximab reduce the risk of EBV reactivation and PTLPD? Blood 2009; 113: 6263–6264.

    Article  CAS  Google Scholar 

  46. Mohty M . Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia 2007; 21: 1387–1394.

    Article  CAS  Google Scholar 

  47. Mohty M, Mohty AM, Blaise D, Faucher C, Bilger K, Isnardon D et al. Cytomegalovirus-specific immune recovery following allogeneic HLA-identical sibling transplantation with reduced-intensity preparative regimen. Bone Marrow Transplant 2004; 33: 839–846.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the nursing staff for providing excellent care for our patients. We also thank the ‘Région Pays de Loire’, the ‘Association pour la Recherche sur le Cancer (ARC)’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’ and the ‘Association Laurette Fuguain’, for their generous and continuous support for our clinical and basic research work. Our group is supported by several grants from the French national cancer institute (PHRC, INCa). The authors would like to acknowledge the continuous support of the cell banking facility (‘tumurotheque’) of the CHU de Nantes.

Author contributions

Z Peric: collected and assembled and analyzed data, wrote and revised the manuscript; X Cahu: collected data, performed statistical analysis, and helped writing and revising the manuscript; E Brissot, F Malard: collected and assembled data; T Guillaume, J Delaunay, P Chevallier, S Ayari, V Dubruille, S Le Gouill, B Mahe, T Gastinne, N Blin, JL Harousseau, P Moreau, N Milpied: recruited patients, and commented on the manuscript; B Saulquin: collected and assembled data; M Coste-Burel, BM Imbert-Marcille: performed viral monitoring and commented on the manuscript; M Mohty: supervised research, analyzed data, performed statistical analysis, wrote and revised the manuscript; All authors approved submission of the manuscript for publication purposes.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Mohty.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peric, Z., Cahu, X., Chevallier, P. et al. Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia 25, 932–938 (2011). https://doi.org/10.1038/leu.2011.26

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.26

Keywords

This article is cited by

Search

Quick links