Advertisement

Incidence, risk factors, and clinical significance of Epstein–Barr virus reactivation in myelodysplastic syndrome after allogeneic haematopoietic stem cell transplantation

  • Hong Wang
  • Tong-Tong Zhang
  • Jia-Qian Qi
  • Tian-Tian Chu
  • Miao Miao
  • Hui-Ying Qiu
  • Cheng-Cheng Fu
  • Xiao-Wen Tang
  • Chang-Geng Ruan
  • De-Pei WuEmail author
  • Yue HanEmail author
Original Article
  • 20 Downloads

Abstract

Epstein–Barr virus (EBV) reactivation is a life-threatening complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT). In this study, we investigated the characteristics of EBV reactivation in 186 consecutive myelodysplastic (MDS) patients who underwent allo-HSCT in our centre. In 35 patients (18.8%) who experienced EBV reactivation after allo-HSCT, the median onset was 53 days (range 4–381 days). The cumulative incidence of EBV reactivation at the first, sixth, and twelfth month after allo-HSCT was 10.7%, 15.1%, and 17.9%, respectively. Twenty-five patients (71.4%) received pre-emptive rituximab therapy, and no patients developed post-transplant lymphoproliferative disorders. Stem cell source was proven to be a risk factor correlated with EBV reactivation. The cumulative incidence of relapse in the EBV-positive group was 11.4%, 25.2%, and 31.0% at the first, second, and third year after transplantation, respectively, being significantly higher than the corresponding 6.8%, 10.2%, and 10.2%, in the EBV-negative group (P = 0.014). Prognostic analysis showed that EBV reactivation was an independent risk factor for relapse-free survival (RFS). Patients in the EBV-positive group showed obviously shorter RFS than those in the EBV-negative group, with 3-year RFS of 62% and 85%, respectively (P = 0.017).

Keywords

Epstein–Barr virus Myelodysplastic syndrome Stem cell transplantation Relapse Prognosis 

Notes

Acknowledgements

We would like to thank the patients and the physicians from the Department of Hematology, the First Affiliated Hospital of Soochow University.

Financial disclosures

This study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81100342, 81270591, 81270617, 81470346, 81670132), Jiangsu Province of China (BE2016665, BRA2011218), Jiangsu Provincial Special Program of Medical Science (BL2012005), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), National Key Research and Development Program (2016YFC0902800), and Innovation Capability Development Project of Jiangsu Province (BM2015004).

Compliance with ethical standards

The study was performed in accordance with institutional guidelines and was approved by the Committees for the Ethical Review of Research at the First Affiliated Hospital of Suchow University. Informed consent was obtained from the patients before data collection.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Pérez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy P, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM (2004) A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104:579–585CrossRefGoogle Scholar
  2. 2.
    Sierra J, Perez WS, Rozman C et al (2002) Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100:1997–2004Google Scholar
  3. 3.
    Martin PJ, Counts GW Jr, Appelbaum FR, Lee SJ, Sanders JE, Deeg HJ, Flowers MED, Syrjala KL, Hansen JA, Storb RF, Storer BE (2010) Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol 28:1011–1016CrossRefGoogle Scholar
  4. 4.
    Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, Socié G (2011) Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 29:2230–2239CrossRefGoogle Scholar
  5. 5.
    Styczynski J, van der Velden W, Fox CP, Engelhard D, de la Camara R, Cordonnier C, Ljungman P, on behalf of the Sixth European Conference on Infections in Leukemia, a joint venture of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation (EBMT-IDWP), the Infectious Diseases Group of the European Organizat (2016) 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 101:803–811CrossRefGoogle Scholar
  6. 6.
    Styczynski J, Gil L, Tridello G, Ljungman P, Donnelly JP, van der Velden W, Omar H, Martino R, Halkes C, Faraci M, Theunissen K, Kalwak K, Hubacek P, Sica S, Nozzoli C, Fagioli F, Matthes S, Diaz MA, Migliavacca M, Balduzzi A, Tomaszewska A, Camara Rde L, van Biezen A, Hoek J, Iacobelli S, Einsele H, Cesaro S, Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation (2013) 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 57:794–802CrossRefGoogle Scholar
  7. 7.
    Sanz J, Arango M, Senent L, Jarque I, Montesinos P, Sempere A, Lorenzo I, Martín G, Moscardó F, Mayordomo E, Salavert M, Cañigral C, Boluda B, Salazar C, López-Hontangas JL, Sanz MA, Sanz GF (2014) EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases. Bone Marrow Transplant 49:397–402CrossRefGoogle Scholar
  8. 8.
    Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JAH, Wagner JE (2006) 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 108:2874–2880CrossRefGoogle Scholar
  9. 9.
    Sundin M, Le Blanc K, Ringden O et al (2006) 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 91:1059–1067Google Scholar
  10. 10.
    van Esser JW, van der Holt B, Meijer E et al (2001) 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 98:972–978CrossRefGoogle Scholar
  11. 11.
    Styczynski J, Einsele H, Gil L, Ljungman P (2009) 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 11:383–392CrossRefGoogle Scholar
  12. 12.
    Styczynski J, Reusser P, Einsele H et al (2009) 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 43:757–770CrossRefGoogle Scholar
  13. 13.
    Mautner J, Bornkamm GW (2012) The role of virus-specific CD4+ T cells in the control of Epstein-Barr virus infection. Eur J Cell Biol 91:31–35CrossRefGoogle Scholar
  14. 14.
    Cohen JM, Sebire NJ, Harvey J, Gaspar HB, Cathy C, Jones A, Rao K, Cubitt D, Amrolia PJ, Davies EG, Veys P (2007) Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation. Blood 110:2209–2214CrossRefGoogle Scholar
  15. 15.
    Gottschalk S, Rooney CM, Heslop HE (2005) Post-transplant lymphoproliferative disorders. Annu Rev Med 56:29–44CrossRefGoogle Scholar
  16. 16.
    Glucksberg H, Storb R, Fefer A et al (1974) Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18:295–304CrossRefGoogle Scholar
  17. 17.
    Scrucca L, Santucci A, Aversa F (2007) Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant 40:381–387CrossRefGoogle Scholar
  18. 18.
    Scrucca L, Santucci A, Aversa F (2010) Regression modeling of competing risk using R: an in depth guide for clinicians. Bone Marrow Transplant 45:1388–1395CrossRefGoogle Scholar
  19. 19.
    Bian Z, Liu J, Xu LP, Chang YJ, Wang Y, Zhang XH, Huang XJ (2017) Association of Epstein-Barr virus reactivation with the recovery of CD4/CD8 double-negative T lymphocytes after haploidentical hematopoietic stem cell transplantation. Bone Marrow Transplant 52:264–269CrossRefGoogle Scholar
  20. 20.
    Han TT, Xu LP, Liu DH et al (2013) Prevalence of EBV infection in patients with allogeneic hematopoietic stem cell transplantation. Zhonghua Xue Ye Xue Za Zhi 34:651–654Google Scholar
  21. 21.
    Peric Z, Cahu X, Chevallier P, Brissot E, Malard F, Guillaume T, Delaunay J, Ayari S, Dubruille V, le Gouill S, Mahe B, Gastinne T, Blin N, Saulquin B, Harousseau JL, Moreau P, Milpied N, Coste-Burel M, Imbert-Marcille BM, Mohty M (2011) Features of Epstein-Barr virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia 25:932–938CrossRefGoogle Scholar
  22. 22.
    Cohen J, Gandhi M, Naik P, Cubitt D, Rao K, Thaker U, Graham Davies E, Bobby Gaspar H, Amrolia PJ, Veys P (2005) Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning. Br J Haematol 129:229–239CrossRefGoogle Scholar
  23. 23.
    Curtis RE, Travis LB, Rowlings PA, Socié G, Kingma DW, Banks PM, Jaffe ES, Sale GE, Horowitz MM, Witherspoon RP, Shriner DA, Weisdorf DJ, Kolb HJ, Sullivan KM, Sobocinski KA, Gale RP, Hoover RN, Fraumeni JF Jr, Deeg HJ (1999) Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 94:2208–2216Google Scholar
  24. 24.
    Omar H, Hagglund H, Gustafsson-Jernberg A et al (2009) Targeted monitoring of patients at high risk of post-transplant lymphoproliferative disease by quantitative Epstein-Barr virus polymerase chain reaction. Transpl Infect Dis 11:393–399CrossRefGoogle Scholar
  25. 25.
    Gartner BC, Schafer H, Marggraff K et al (2002) 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 40:351–358CrossRefGoogle Scholar
  26. 26.
    Hoshino Y, Kimura H, Tanaka N, Tsuge I, Kudo K, Horibe K, Kato K, Matsuyama T, Kikuta A, Kojima S, Morishima T (2001) Prospective monitoring of the Epstein-Barr virus DNA by a real-time quantitative polymerase chain reaction after allogenic stem cell transplantation. Br J Haematol 115:105–111CrossRefGoogle Scholar
  27. 27.
    Lucas KG, Burton RL, Zimmerman SE, Wang J, Cornetta KG, Robertson KA, Lee CH, Emanuel DJ (1998) 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 91:3654–3661Google Scholar
  28. 28.
    Wagner HJ, Cheng YC, Huls MH et al (2004) Prompt versus preemptive intervention for EBV lymphoproliferative disease. Blood 103:3979–3981CrossRefGoogle Scholar
  29. 29.
    Lankester AC, van Tol MJ, Vossen JM et al (2002) Epstein-Barr virus (EBV)-DNA quantification in pediatric allogenic stem cell recipients: prediction of EBV-associated lymphoproliferative disease. Blood 99:2630–2631CrossRefGoogle Scholar
  30. 30.
    Blaes AH, Cao Q, Wagner JE, Young JAH, Weisdorf DJ, Brunstein CG (2010) 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 16:287–291CrossRefGoogle Scholar
  31. 31.
    Ringden O, Karlsson H, Olsson R et al (2009) The allogeneic graft-versus-cancer effect. Br J Haematol 147:614–633CrossRefGoogle Scholar
  32. 32.
    Kapp M, Stevanovic S, Fick K et al (2009) CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT. Bone Marrow Transplant 43:399–410CrossRefGoogle Scholar
  33. 33.
    Hoegh-Petersen M, Sy S, Ugarte-Torres A, Williamson TS, Eliasziw M, Mansoor A, Liu Y, Liu S, Podgorny P, Khan F, Duggan PR, Stewart DA, Russell JA, Storek J (2012) High Epstein-Barr virus-specific T-cell counts are associated with near-zero likelihood of acute myeloid leukemia relapse after hematopoietic cell transplantation. Leukemia 26:359–362CrossRefGoogle Scholar
  34. 34.
    Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T, Stern M, Pende D, Perruccio K, Burchielli E, Topini F, Bianchi E, Aversa F, Martelli MF, Velardi A (2007) Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 110:433–440CrossRefGoogle Scholar
  35. 35.
    Bakker NA, Verschuuren EA, Erasmus ME et al (2007) Epstein-Barr virus-DNA load monitoring late after lung transplantation: a surrogate marker of the degree of immunosuppression and a safe guide to reduce immunosuppression. Transplantation 83:433–438CrossRefGoogle Scholar
  36. 36.
    Choquet S, Varnous S, Deback C, Golmard JL, Leblond V (2014) Adapted treatment of Epstein-Barr virus infection to prevent posttransplant lymphoproliferative disorder after heart transplantation. Am J Transplant 14:857–866CrossRefGoogle Scholar
  37. 37.
    Merlo A, Turrini R, Dolcetti R, Martorelli D, Muraro E, Comoli P, Rosato A (2010) The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders. Haematologica 95:1769–1777CrossRefGoogle Scholar
  38. 38.
    Green M, Cacciarelli TV, Mazariegos GV, Sigurdsson L, Qu L, Rowe DT, Reyes J (1998) Serial measurement of Epstein-Barr viral load in peripheral blood in pediatric liver transplant recipients during treatment for posttransplant lymphoproliferative disease. Transplantation 66:1641–1644CrossRefGoogle Scholar
  39. 39.
    Lee TC, Savoldo B, Rooney CM, Heslop HE, Gee AP, Caldwell Y, Barshes NR, Scott JD, Bristow LJ, O’Mahony CA, Goss JA (2005) Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients. Am J Transplant 5:2222–2228CrossRefGoogle Scholar
  40. 40.
    Hill JA, Mayer BT, Xie H, Leisenring WM, Huang ML, Stevens-Ayers T, Milano F, Delaney C, Sorror ML, Sandmaier BM, Nichols G, Zerr DM, Jerome KR, Schiffer JT, Boeckh M (2017) The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood 129:2316–2325CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hong Wang
    • 1
    • 2
    • 3
  • Tong-Tong Zhang
    • 1
    • 2
    • 3
  • Jia-Qian Qi
    • 1
    • 2
    • 3
  • Tian-Tian Chu
    • 1
  • Miao Miao
    • 1
    • 2
    • 3
    • 4
  • Hui-Ying Qiu
    • 1
    • 2
    • 3
    • 4
  • Cheng-Cheng Fu
    • 1
    • 2
    • 3
    • 4
  • Xiao-Wen Tang
    • 1
    • 2
    • 3
    • 4
  • Chang-Geng Ruan
    • 1
    • 2
    • 3
    • 4
  • De-Pei Wu
    • 1
    • 2
    • 3
    • 4
    Email author
  • Yue Han
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Jiangsu Institute of HaematologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Institute of Blood and Marrow TransplantationSuzhouChina
  3. 3.Key Laboratory of Thrombosis and Haemostasis of Ministry of HealthSuzhouChina
  4. 4.Collaborative Innovation Centre of HaematologySoochow UniversitySuzhouChina

Personalised recommendations