Medical Oncology

, Volume 24, Issue 2, pp 125–136 | Cite as

The management of posttransplant lymphoproliferative disorder

Review

Abstract

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication of allogeneic hematopoietic stem cell and solid organ transplantation. Most cases are EBV-positive B-cell neoplasms, which occur in the setting of pharmacologically impaired cellular immunity. Several different treatment strategies including cytotoxic antitumor therapy, anti-B-cell monoclonal antibody therapy, antiviral therapy, and modalities aimed at restoration of EBV-specific cellular immunity have been employed. In addition, efforts to identify patients at high risk for PTLD have resulted in attempts at prophylactic and preemptive therapies. In this review we discuss the available literature on differing approaches to PTLD management, identify areas in need of further investigation, and, when possible, make general recommendations. Reduction of immunosuppression remains the mainstay of first-line treatment. Accumulating evidence supports the role of rituximab as second-line therapy with cytotoxic chemotherapy reserved for specific circumstances. Further investigations are needed to better define the role of more novel and less widely available therapies such as the adoptive transfer of EBV-specific T cells and optimization of antiviral therapies.

Key words

PTLD rituximab transplantation lymphoma chemotherapy EBV 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Harris NL SS, Frizzera G, Knowles DM. Post-transplant lymphoproliferative disorders. In:World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001, pp 264–269.Google Scholar
  2. 2.
    Paya CV, 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Yang J, et al. Characterization of Epstein-Barr virusinfected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response.Blood 2000;96:4055–4063.PubMedGoogle Scholar
  4. 4.
    Gulley ML, et al. Tumor origin and CD20 expression in posttransplant lymphoproliferative disorder occurring in solid organ transplant recipients: implications for immunebased therapy.Transplantation 2003;76:959–964.PubMedCrossRefGoogle Scholar
  5. 5.
    Cohen JI. Epstein-Barr virus infection.N Engl J Med 2000;343:481–492.PubMedCrossRefGoogle Scholar
  6. 6.
    Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas.N Engl J Med 2004;350:1328–1337.PubMedCrossRefGoogle Scholar
  7. 7.
    Khanna R, Moss DJ, Burrows SR. Vaccine strategies against Epstein-Barr virus-associated diseases: lessons from studies on cytotoxic T-cell-mediated immune regulation.Immunol Rev 1999;170:49–64.PubMedCrossRefGoogle Scholar
  8. 8.
    Callan MF, et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo.J Exp Med 1998;187:1395–1402.PubMedCrossRefGoogle Scholar
  9. 9.
    Epstein MA, Achong BG, Pope JH. Virus in cultured lymphoblasts from a New Guinea Burkitt lymphoma.Br Med J 1967;2:290–291.PubMedCrossRefGoogle Scholar
  10. 10.
    Weiss LM, Movahed LA, Warnke RA, Sklar J. Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin’s disease.N Engl J Med 1989;320:502–506.PubMedCrossRefGoogle Scholar
  11. 11.
    Curtis RE, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study.Blood 1999;94:2208–2216.PubMedGoogle Scholar
  12. 12.
    Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report.Am J Transplant 2004;4:222–230.PubMedCrossRefGoogle Scholar
  13. 13.
    Herzig KA, et al. A single-centre experience of post-renal transplant lymphoproliferative disorder.Transpl Int 2003;16:529–536.PubMedCrossRefGoogle Scholar
  14. 14.
    Tsai DE, 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Finn L, Reyes J, Bueno J, Yunis E. Epstein-Barr virus infections in children after transplantation of the small intestine.Am J Surg Pathol 1998;22:299–309.PubMedCrossRefGoogle Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    Shapiro RS, et al. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation.Blood 1988;71:1234–1243.PubMedGoogle Scholar
  18. 18.
    Darenkov IA, et al. Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy.Transplantation 1997;64:848–852.PubMedCrossRefGoogle Scholar
  19. 19.
    Davis CL, et al. Antiviral prophylaxis and the Epstein Barr virus-related post-transplant lymphoproliferative disorder.Clin Transplant 1995;9:53–59.PubMedGoogle Scholar
  20. 20.
    Gross TG, et al. B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome.Bone Marrow Transplant 1999;23:251–258.PubMedCrossRefGoogle Scholar
  21. 21.
    Green M, et al. Predictive negative value of persistent low Epstein-Barr virus viral load after intestinal transplantation in children.Transplantation 2000;70:593–596.PubMedCrossRefGoogle Scholar
  22. 22.
    McDiarmid SV, et al. Prevention and preemptive therapy of postransplant lymphoproliferative disease in pediatric liver recipients.Transplantation 1998;66:1604–1611.PubMedCrossRefGoogle Scholar
  23. 23.
    Malouf MA, et al. Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients.J Heart Lung Transplant 2002;21:547–554.PubMedCrossRefGoogle Scholar
  24. 24.
    Starzl TE, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy.Lancet 1984;1:583–587.PubMedCrossRefGoogle Scholar
  25. 25.
    Loren AW, Tsai DE. Post-transplant lymphoproliferative disorder.Clin Chest Med 2005;26:631–645, vii.PubMedCrossRefGoogle Scholar
  26. 26.
    Taylor AL, Marcus R, Bradley JA. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation.Crit Rev Oncol Hematol 2005;56:155–167.PubMedCrossRefGoogle Scholar
  27. 27.
    Hurwitz M, et al. Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation.Pediatr Transplant 2004;8:267–272.PubMedCrossRefGoogle Scholar
  28. 28.
    Green M. Management of Epstein-Barr virus-induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation.Am J Transplant 2001;1:103–108.PubMedGoogle Scholar
  29. 29.
    Pasquale MA, et al. Burkitt’s lymphoma variant of posttransplant lymphoproliferative disease (PTLD).Pathol Oncol Res 2002;8:105–108.PubMedCrossRefGoogle Scholar
  30. 30.
    Dotti G, et al. Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant.Transplantation 2000;69:827–833.PubMedCrossRefGoogle Scholar
  31. 31.
    Leblond V, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity?J Clin Oncol 1998;16:2052–2059.PubMedGoogle Scholar
  32. 32.
    Nelson BP, et al. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity?Am J Surg Pathol 2000;24:375–385.PubMedCrossRefGoogle Scholar
  33. 33.
    Dotti G, et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome.Transplantation 2002;74:1095–1102.PubMedCrossRefGoogle Scholar
  34. 34.
    Hauke R, et al. Clinical and pathological features of posttransplant lymphoproliferative disorders: influence on survival and response to treatment.Ann Oncol 2001;12: 831–834.PubMedCrossRefGoogle Scholar
  35. 35.
    Koffman BH, Kennedy AS, Heyman M, Colonna J, Howell C. Use of radiation therapy in posttransplant lymphoproliferative disorder (PTLD) after liver transplantation.Int J Cancer 2000;90:104–109.PubMedCrossRefGoogle Scholar
  36. 36.
    Elstrom RL, et al. Treatment of PTLD with rituximab or chemotherapy.Am J Transplant 2006;6:569–576.PubMedCrossRefGoogle Scholar
  37. 37.
    Karras A, et al. Successful renal retransplantation after posttransplant lymphoproliferative disease.Am J Transplant 2004;4:1904–1909.PubMedCrossRefGoogle Scholar
  38. 38.
    Kang SK, Kirkpatrick JP, Halperin EC. Low-dose radiation for posttransplant lymphoproliferative disorder.Am J Clin Oncol 2003;26:210–214.PubMedCrossRefGoogle Scholar
  39. 39.
    Swinnen LJ. Durable remission after aggressive chemotherapy for post-cardiac transplant lymphoproliferation.Leuk Lymphoma 1997;28:89–101.PubMedGoogle Scholar
  40. 40.
    Mamzer-Bruneel MF, 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.PubMedGoogle Scholar
  41. 41.
    Buell JF, et al. Chemotherapy for posttransplant lymphoproliferative disorder: the Israel Penn International Transplant Tumor Registry experience.Transplant Proc 2005;37: 956–957.PubMedCrossRefGoogle Scholar
  42. 42.
    Orjuela M, et al. A pilot study of chemoimmunotherapy (cyclophosphamide, prednisone, and rituximab) in patients with post-transplant lymphoproliferative disorder following solid organ transplantation.Clin Cancer Res 2003;9:3945S-3952S.PubMedGoogle Scholar
  43. 43.
    Gross TG. Low-dose chemotherapy for children with posttransplant lymphoproliferative disease.Recent Results Cancer Res 2002;159:96–103.PubMedGoogle Scholar
  44. 44.
    Gross TG, et al. Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation.J Clin Oncol 2005;23:6481–6488.PubMedCrossRefGoogle Scholar
  45. 45.
    Oertel SH, et al. Salvage chemotherapy for refractory or relapsed post-transplant lymphoproliferative disorder in patients after solid organ transplantation with a combination of carboplatin and etoposide.Br J Haematol 2003;123:830–835.PubMedCrossRefGoogle Scholar
  46. 46.
    Komrokji RS, Oliva JL, Zand M, Felgar R, Abboud CN. Mini-BEAM and autologous hematopoietic stem-cell transplant for treatment of post-transplant lymphoproliferative disorders.Am J Hematol 2005;79:211–215.PubMedCrossRefGoogle Scholar
  47. 47.
    Bobey NA, Stewart DA, Woodman RC. Successful treatment of posttransplant lymphoproliferative disorder in a renal transplant patient by autologous peripheral blood stem cell transplantation.Leuk Lymphoma 2002;43:2421–2423.PubMedCrossRefGoogle Scholar
  48. 48.
    Au WY, et al. Treatment of postrenal transplantation lymphoproliferative disease manifesting as plasmacytoma with nonmyeloablative hematopoietic stem cell transplantation from the same kidney donor.Am J Hematol 2003;74: 283–286.PubMedCrossRefGoogle Scholar
  49. 49.
    Faro A, et al. Interferon-alpha affects the immune response in post-transplant lymphoproliferative disorder.Am J Respir Crit Care Med 1996;153:1442–1447.PubMedGoogle Scholar
  50. 50.
    Davis CL et al. Interferon-alpha treatment of posttransplant lymphoproliferative disorder in recipients of solid organ transplants.Transplantation 1998;66:1770–1779.PubMedCrossRefGoogle Scholar
  51. 51.
    Tosato G, Tanner J, Jones KD, Revel M, Pike SE. Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells.J Virol 1990;64:3033–3041.PubMedGoogle Scholar
  52. 52.
    Tosato G, Jones K, Breinig MK, McWilliams HP, McKnight JL. Interleukin-6 production in posttransplant lymphoproliferative disease.J Clin Invest 1993;91:2806–2814.PubMedCrossRefGoogle Scholar
  53. 53.
    Haddad E, 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.PubMedCrossRefGoogle Scholar
  54. 54.
    Shan D, Ledbetter JA, Press OW. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies.Blood 1998;91:1644–1652.PubMedGoogle Scholar
  55. 55.
    Di Gaetano N, et al. Complement activation determines the therapeutic activity of rituximab in vivo.J Immunol 2003;171:1581–1587.PubMedGoogle Scholar
  56. 56.
    Svoboda J, Kotloff R, Tsai DE. Management of patients with post-transplant lymphoproliferative disorder: the role of rituximab.Transpl Int 2006;19:259–269.PubMedCrossRefGoogle Scholar
  57. 57.
    McLaughlin P, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.J Clin Oncol 1998;16:2825–2833.PubMedGoogle Scholar
  58. 58.
    Coiffier B, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study.Blood 1998;92:1927–1932.PubMedGoogle Scholar
  59. 59.
    Feugier P, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte.J Clin Oncol 2005;23:4117–4126.PubMedCrossRefGoogle Scholar
  60. 60.
    Witzig TE, et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin’s lymphoma: a phase II trial in the North Central Cancer Treatment Group.J Clin Oncol 2005;23:1103–1108.PubMedCrossRefGoogle Scholar
  61. 61.
    Hiddemann W, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group.Blood 2005;106:3725–3732.PubMedCrossRefGoogle Scholar
  62. 62.
    Choquet S, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study.Blood 2006;107:3053–3057.PubMedCrossRefGoogle Scholar
  63. 63.
    Milpied N, et al. Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients.Ann Oncol 2000;11 Suppl 1:113–116.PubMedCrossRefGoogle Scholar
  64. 64.
    Oertel SH, et al. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD).Am J Transplant 2005;5:2901–2906.PubMedCrossRefGoogle Scholar
  65. 65.
    Faye 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.PubMedCrossRefGoogle Scholar
  66. 66.
    van Esser 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;99:4364–4369.PubMedCrossRefGoogle Scholar
  67. 67.
    Webber S, et al. Anti-CD20 monoclonal antibody (rituximab) for refractory PTLD after pediatric solid organ transplantation: multicenter experience and from a registry and prospective clinical trial.Blood 2004;104.Google Scholar
  68. 68.
    Gonzalez-Barca E, et al. First-line treatment with rituximab improves survival of patients with post transplant lymphoproliferative disorder.Blood 2004;104.Google Scholar
  69. 69.
    Kimby E. Tolerability and safety of rituximab (MabThera).Cancer Treat Rev 2005;31:456–473.PubMedCrossRefGoogle Scholar
  70. 70.
    Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab.N Engl J Med 2001;344:68–69.PubMedCrossRefGoogle Scholar
  71. 71.
    Sharma VR, Fleming DR, Slone SP. Pure red cell aplasia due to parvovirus B19 in a patient treated with rituximab.Blood 2000;96:1184–1186.PubMedGoogle Scholar
  72. 72.
    Suzan F, Ammor M, Ribrag V. Fatal reactivation of cytomegalovirus infection after use of rituximab for a posttransplantation lymphoproliferative disorder.N Engl J Med 2001;345:1000.PubMedCrossRefGoogle Scholar
  73. 73.
    Savoldo B, et al. Cellular immunity to Epstein-Barr virus in liver transplant recipients treated with rituximab for posttransplant lymphoproliferative disease.Am J Transplant 2005;5:566–572.PubMedCrossRefGoogle Scholar
  74. 74.
    Papadopoulos EB, et al. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.N Engl J Med 1994;330:1185–1191.PubMedCrossRefGoogle Scholar
  75. 75.
    O’Reilly RJ, et al. Biology and adoptive cell therapy of Epstein-Barr virus-associated lymphoproliferative disorders in recipients of marrow allografts.Immunol Rev 1997;157:195–216.PubMedCrossRefGoogle Scholar
  76. 76.
    Rooney CM, 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.PubMedGoogle Scholar
  77. 77.
    Gottschalk S, 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.PubMedCrossRefGoogle Scholar
  78. 78.
    Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders.Annu Rev Med 2005;56:29–44.PubMedCrossRefGoogle Scholar
  79. 79.
    Nalesnik MA, et al. Autologous lymphokine-activated killer cell therapy of Epstein-Barr virus-positive and -negative lymphoproliferative disorders arising in organ transplant recipients.Transplantation 1997;63:1200–1205.PubMedCrossRefGoogle Scholar
  80. 80.
    Comoli P, et al. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBVrelated lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication.Blood 2002;99:2592–2598.PubMedCrossRefGoogle Scholar
  81. 81.
    Comoli P, et al. Treatment of EBV-related post-renal transplant lymphoproliferative disease with a tailored regimen including EBV-specific T cells.Am J Transplant 2005;5: 1415–1422.PubMedCrossRefGoogle Scholar
  82. 82.
    Haque T, et al. Reconstitution of EBV-specific T cell immunity in solid organ transplant recipients.J Immunol 1998;160:6204–6209.PubMedGoogle Scholar
  83. 83.
    Khanna R, et al. Activation and adoptive transfer of Epstein-Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease.Proc Natl Acad Sci USA 1999;96:10391–10396.PubMedCrossRefGoogle Scholar
  84. 84.
    Sherritt MA, et al. Reconstitution of the latent T-lymphocyte response to Epstein-Barr virus is coincident with long-term recovery from posttransplant lymphoma after adoptive immunotherapy.Transplantation 2003;75:1556–1560.PubMedCrossRefGoogle Scholar
  85. 85.
    Metes D, et al. Ex vivo generation of effective Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T lymphocytes from the peripheral blood of immunocompetent Epstein Barr virus-seronegative individuals.Transplantation 2000;70: 1507–1515.PubMedCrossRefGoogle Scholar
  86. 86.
    Popescu I, et al. Ex vivo priming of naive T cells into EBVspecific Th1/Tc1 effector cells by mature autologous DC loaded with apoptotic/necrotic LCL.Am J Transplant 2003;3:1369–1377.PubMedCrossRefGoogle Scholar
  87. 87.
    Haque T, et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells.Lancet 2002;360:436–442.PubMedCrossRefGoogle Scholar
  88. 88.
    Sun Q, Burton R, Reddy V, Lucas KG. Safety of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for patients with refractory EBV-related lymphoma.Br J Haematol 2002;118:799–808.PubMedCrossRefGoogle Scholar
  89. 89.
    Emanuel DJ, 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.PubMedCrossRefGoogle Scholar
  90. 90.
    Restrepo A, et al. Post-liver transplantation lymphoproliferative disorders with and without infusions of donor bone marrow cells.Crit Rev Oncog 1999;10:239–245.PubMedGoogle Scholar
  91. 90.
    Wilkie GM, et al. Establishment and characterization of a bank of cytotoxic T lymphocytes for immunotherapy of epstein-barr virus-associated diseases.J Immunother 2004;27:309–316.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2007

Authors and Affiliations

  1. 1.University of Pennsylvania Cancer CenterPhiladelphia

Personalised recommendations