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Post-transplant lymphoproliferative disorder: a review

Summary:

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein–Barr virus-related (EBV) clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. In the setting of hematopoietic stem cell transplantation, PTLD is an often-fatal complication occurring relatively early after transplant. Risk factors for the development of PTLD are well established, and include HLA-mismatching, T-cell depletion, and the use of antilymphocyte antibodies as conditioning or treatment of graft-versus-host disease. Early recognition of PTLD is particularly important in the SCT setting, because PTLD in these patients tends to be rapidly progressive. Familiarity with the clinical features of PTLD and a heightened level of suspicion are critical for making the diagnosis. Surveillance techniques with EBV antibody titers and/or polymerase chain raction (PCR) may have a role in some high-risk settings. Immune-based therapies such as monoclonal anti-B-cell antibodies, interferon-α, and EBV-specific donor T cells, either as treatment for PTLD or as prophylaxis in high-risk patients, represent promising new directions in the treatment of this disease.

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References

  1. Starzl TE . Discussion of Murray JE, Wilson RE, Tilney NL et al: Five years' experience in renal transplantation with immunosuppressive drugs: survival, function, complications and the role of lymphocyte depletion by thoracic duct fistula. Ann Surg 1968; 168: 416–435.

    Article  Google Scholar 

  2. Penn I, Hammond W, Brettschneider L et al. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 1: 106–112.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bhatia S, Ramsay NK, Steinbuch M et al. Malignant neoplasms following bone marrow transplantation. Blood 1996; 87: 3633–3639.

    CAS  PubMed  Google Scholar 

  4. Nalesnik MA . Posttransplantation lymphoproliferative disorders (PTLD): current perspectives. Semin Thorac Cardiovasc Surg 1996; 8: 139–148.

    CAS  PubMed  Google Scholar 

  5. Paya CV, Fung JJ, Nalesnik MA 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  PubMed  Google Scholar 

  6. Harris NL, Ferry JA, Swerdlow SH . Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol 1997; 14: 8–14.

    CAS  PubMed  Google Scholar 

  7. Harris NL, Jaffe ES, Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835–3849.

    Article  CAS  PubMed  Google Scholar 

  8. Harris NL, Jaffe ES, Stein H et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–1392.

    CAS  PubMed  Google Scholar 

  9. Epstein MA, Achong BG, Barr YM . Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1964; 1: 702–703.

    Article  CAS  PubMed  Google Scholar 

  10. Cohen JI . Epstein–Barr virus infection. New Engl J Med 2000; 343: 481–492.

    Article  CAS  PubMed  Google Scholar 

  11. Zutter MM, Martin PJ, Sale GE et al. Epstein–Barr virus lymphoproliferation after bone marrow transplantation. Blood 1988; 72: 520–529.

    CAS  PubMed  Google Scholar 

  12. Shapiro RS, McClain K, Frizzera G et al. Epstein–Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 1988; 71: 1234–1243.

    CAS  PubMed  Google Scholar 

  13. Parry-Jones N, Haque T, Ismail M et al. Epstein–Barr virus (EBV) associated B-cell lymphoproliferative disease following HLA identical sibling marrow transplantation for aplastic anaemia in a patient with an EBV seronegative donor. Transplantation 1999; 67: 1373–1375.

    Article  CAS  PubMed  Google Scholar 

  14. Nalesnik MA, Makowka L, Starzl TE . The diagnosis and treatment of posttransplant lymphoproliferative disorders. Curr Probl Surg 1988; 25: 367–472.

    Article  CAS  PubMed  Google Scholar 

  15. Armitage JM, Kormos RL, Stuart RS et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 1991; 10: 877–886; discussion 886–877.

    CAS  PubMed  Google Scholar 

  16. Tsai DE, Hardy CL, Tomaszewski JE et al. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long- term follow-up of 42 adult patients. Transplantation 2001; 71: 1076–1088.

    Article  CAS  PubMed  Google Scholar 

  17. Crawford DH, Mulholland N, Iliescu V et al. Epstein–Barr virus infection and immunity in bone marrow transplant recipients. Transplantation 1986; 42: 50–54.

    Article  CAS  PubMed  Google Scholar 

  18. Lucas KG, Small TN, Heller G et al. The development of cellular immunity to Epstein–Barr virus after allogeneic bone marrow transplantation. Blood 1996; 87: 2594–2603.

    CAS  PubMed  Google Scholar 

  19. Marshall NA, Howe JG, Formica R et al. Rapid reconstitution of Epstein–Barr virus-specific T lymphocytes following allogeneic stem cell transplantation. Blood 2000; 96: 2814–2821.

    CAS  PubMed  Google Scholar 

  20. Small TN, Papadopoulos EB, Boulad F et al. Comparison of immune reconstitution after unrelated and related T-cell- depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 1999; 93: 467–480.

    CAS  PubMed  Google Scholar 

  21. Gross TG, Steinbuch M, DeFor T 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Curtis RE, Travis LB, Rowlings PA et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 1999; 94: 2208–2216.

    CAS  PubMed  Google Scholar 

  24. Chiang KY, Hazlett LJ, Godder KT et al. Epstein–Barr virus-associated B cell lymphoproliferative disorder following mismatched related T cell-depleted bone marrow transplantation. Bone Marrow Transplant 2001; 28: 1117–1123.

    Article  CAS  PubMed  Google Scholar 

  25. Hauke RJ, Greiner TC, Smir BN et al. Epstein–Barr virus-associated lymphoproliferative disorder after autologous bone marrow transplantation: report of two cases. Bone Marrow Transplant 1998; 21: 1271–1274.

    Article  CAS  PubMed  Google Scholar 

  26. Shepherd JD, Gascoyne RD, Barnett MJ et al. Polyclonal Epstein–Barr virus-associated lymphoproliferative disorder following autografting for chronic myeloid leukemia. Bone Marrow Transplant 1995; 15: 639–641.

    CAS  PubMed  Google Scholar 

  27. Lones MA, Kirov I, Said JW et al. Post-transplant lymphoproliferative disorder after autologous peripheral stem cell transplantation in a pediatric patient. Bone Marrow Transplant 2000; 26: 1021–1024.

    Article  CAS  PubMed  Google Scholar 

  28. Leblond V, Davi F, Charlotte F et al. Posttrans-plant lymphoproliferative disorders not associated with Epstein–Barr virus: a distinct entity? J Clin Oncol 1998; 16: 2052–2059.

    Article  CAS  PubMed  Google Scholar 

  29. Nelson BP, Nalesnik MA, Bahler DW et al. Epstein–Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol 2000; 24: 375–385.

    Article  CAS  PubMed  Google Scholar 

  30. Benkerrou M, Durandy A, Fischer A . Therapy for transplant-related lymphoproliferative diseases. Hematol Oncol Clin North Am 1993; 7: 467–475.

    Article  CAS  PubMed  Google Scholar 

  31. Benkerrou M, Jais JP, Leblond V et al. Anti-B-cell monoclonal antibody treatment of severe posttransplant B- lymphoproliferative disorder: prognostic factors and long-term outcome. Blood 1998; 92: 3137–3147.

    CAS  PubMed  Google Scholar 

  32. Riddler SA, Breinig MC, McKnight JL . Increased levels of circulating Epstein–Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients. Blood 1994; 84: 972–984.

    CAS  PubMed  Google Scholar 

  33. Savoie A, Perpete C, Carpentier L et al. Direct correlation between the load of Epstein–Barr virus-infected lymphocytes in the peripheral blood of pediatric transplant patients and risk of lymphoproliferative disease. Blood 1994; 83: 2715–2722.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Kenagy DN, Schlesinger Y, Weck K et al. Epstein–Barr virus DNA in peripheral blood leukocytes of patients with posttransplant lymphoproliferative disease. Transplantation 1995; 60: 547–554.

    Article  CAS  PubMed  Google Scholar 

  36. Lucas KG, Burton RL, Zimmerman SE 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 

  37. McDiarmid SV, Jordan S, Kim GS et al. Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients. Transplantation 1998; 66: 1604–1611.

    Article  CAS  PubMed  Google Scholar 

  38. Rooney CM, Loftin SK, Holladay MS et al. Early identification of Epstein–Barr virus-associated post-transplantation lymphoproliferative disease. Br J Haematol 1995; 89: 98–103.

    Article  CAS  PubMed  Google Scholar 

  39. Green M, Bueno J, Rowe D et al. Predictive negative value of persistent low Epstein–Barr virus viral load after intestinal transplantation in children. Transplantation 2000; 70: 593–596.

    Article  CAS  PubMed  Google Scholar 

  40. Yang J, Tao Q, Flinn IW et al. Characterization of Epstein–Barr virus-infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response. Blood 2000; 96: 4055–4063.

    CAS  PubMed  Google Scholar 

  41. Colby BM, Shaw JE, Elion GB et al. Effect of acyclovir [9-(2-hydroxyethoxymethyl)guanine] on Epstein–Barr virus DNA replication. J Virol 1980; 34: 560–568.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Crumpacker CS . Ganciclovir. New Engl J Med 1996; 335: 721–729.

    Article  CAS  PubMed  Google Scholar 

  43. Faller DV, Mentzer SJ, Perrine SP . Induction of the Epstein–Barr virus thymidine kinase gene with concomitant nucleoside antivirals as a therapeutic strategy for Epstein–Barr virus-associated malignancies. Curr Opin Oncol 2001; 13: 360–367.

    Article  CAS  PubMed  Google Scholar 

  44. Starzl TE, Nalesnik MA, Porter KA et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984; 1: 583–587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Davis CL, Wood BL, Sabath DE . Interferon-alpha treatment of posttransplant lymphoproliferative disorder in recipients of solid organ transplants. Transplantation 1998; 66: 1770–1779.

    Article  CAS  PubMed  Google Scholar 

  46. Faro A, Kurland G, Michaels MG et al. Interferon-alpha affects the immune response in post-transplant lymphoproliferative disorder. Am J Respir Crit Care Med 1996; 153: 1442–1447.

    Article  CAS  PubMed  Google Scholar 

  47. Haddad E, Paczesny S, Leblond V et al. Treatment of B-lymphoproliferative disorder with a monoclonal anti-interleukin-6 antibody in 12 patients: a multicenter phase 1-2 clinical trial. Blood 2001; 97: 1590–1597.

    Article  CAS  PubMed  Google Scholar 

  48. Swinnen LJ, Mullen GM, Carr TJ et al. Aggressive treatment for postcardiac transplant lymphoproliferation. Blood 1995; 86: 3333–3340.

    CAS  PubMed  Google Scholar 

  49. Mamzer-Bruneel MF, Lome C, Morelon E et al. Durable remission after aggressive chemotherapy for very late post- kidney transplant lymphoproliferation: a report of 16 cases observed in a single center. J Clin Oncol 2000; 18: 3622–3632.

    Article  CAS  PubMed  Google Scholar 

  50. Kook H, Goldman F, Padley D et al. Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery. Blood 1996; 88: 1089–1097.

    CAS  PubMed  Google Scholar 

  51. Kuzushima K, Kimura H, Hoshino Y et al. Longitudinal dynamics of Epstein–Barr virus-specific cytotoxic T lymphocytes during posttransplant lymphoproliferative disorder. J Infect Dis 2000; 182: 937–940.

    Article  CAS  PubMed  Google Scholar 

  52. Khatri VP, Baiocchi RA, Peng R et al. Endogenous CD8+ T cell expansion during regression of monoclonal EBV- associated posttransplant lymphoproliferative disorder. J Immunol 1999; 163: 500–506.

    CAS  PubMed  Google Scholar 

  53. Porter DL, Orloff GJ, Antin JH . Donor mononuclear cell infusions as therapy for B-cell lymphoproliferative disorder following allogeneic bone marrow transplant. Transplant Sci 1994; 4: 12–14; discussion 14–16.

    CAS  PubMed  Google Scholar 

  54. Papadopoulos EB, Ladanyi M, Emanuel D et al. Infusions of donor leukocytes to treat Epstein–Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. New Engl J Med 1994; 330: 1185–1191.

    Article  CAS  PubMed  Google Scholar 

  55. Gustafsson A, Levitsky V, Zou JZ et al. Epstein–Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 2000; 95: 807–814.

    CAS  PubMed  Google Scholar 

  56. Rooney CM, Smith CA, Ng CY 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 

  57. Wagner HJ, Rooney CM, Heslop HE . Diagnosis and treatment of posttransplantation lymphoproliferative disease after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 1–8.

    Article  CAS  PubMed  Google Scholar 

  58. Emanuel DJ, Lucas KG, Mallory Jr GB et al. Treatment of posttransplant lymphoproliferative disease in the central nervous system of a lung transplant recipient using allogeneic leukocytes. Transplantation 1997; 63: 1691–1694.

    Article  CAS  PubMed  Google Scholar 

  59. Gottschalk S, Ng CY, Perez M et al. An Epstein–Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. Blood 2001; 97: 835–843.

    Article  CAS  PubMed  Google Scholar 

  60. Nalesnik MA, Rao AS, Zeevi A et al. Autologous lymphokine-activated killer cell therapy of lymphoproliferative disorders arising in organ transplant recipients. Transplant Proc 1997; 29: 1905–1906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Haque T, Amlot PL, Helling N et al. Reconstitution of EBV-specific T cell immunity in solid organ transplant recipients. J Immunol 1998; 160: 6204–6209.

    CAS  PubMed  Google Scholar 

  62. Frizzera G, Hanto DW, Gajl-Peczalska KJ et al. Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 1981; 41: 4262–4279.

    CAS  PubMed  Google Scholar 

  63. Knowles DM, Cesarman E, Chadburn A 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 

  64. Darenkov IA, Marcarelli MA, Basadonna GP et al. Reduced incidence of Epstein–Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy. Transplantation 1997; 64: 848–852.

    Article  CAS  PubMed  Google Scholar 

  65. Davis CL, Harrison KL, McVicar JP et al. Antiviral prophylaxis and the Epstein Barr virus-related post- transplant lymphoproliferative disorder. Clin Transplant 1995; 9: 53–59.

    CAS  PubMed  Google Scholar 

  66. Fischer A, Blanche S, Le Bidois J et al. Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation. N Engl J Med 1991; 324: 1451–1456.

    Article  CAS  PubMed  Google Scholar 

  67. Faye A, Van Den Abeele T, Peuchmaur M et al. Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders. Lancet 1998; 352: 1285.

    Article  CAS  PubMed  Google Scholar 

  68. Kuehnle I, Huls MH, Liu Z 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 

  69. Horowitz SM, Tsai DE, Twist C et al. Rituximab is effective therapy for post transplant lymphoproliferative disorder (PTLD) not responding to reduction in immunosuppression: a prospective trial in adults and children. Proceedings of ASCO 2001; 20: 284a.

    Google Scholar 

  70. Bonini C, Ferrari G, Verzeletti S et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1727.

    Article  CAS  PubMed  Google Scholar 

  71. McGuirk JP, Seropian S, Howe G et al. Use of rituximab and irradiated donor-derived lymphocytes to control Epstern-Barr virus-associated lymphoproliferation in patients undergoing related haplo-identical stem cell transplantation. Bone Marrow Transplant 1999; 24: 1253–1258.

    Article  CAS  PubMed  Google Scholar 

  72. Haque T, Taylor C, Wilkie GM et al. Complete regression of post transplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells. Transplantation 2001; 72: 1399–1402.

    Article  CAS  PubMed  Google Scholar 

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Loren, A., Porter, D., Stadtmauer, E. et al. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31, 145–155 (2003). https://doi.org/10.1038/sj.bmt.1703806

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