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Current Hematologic Malignancy Reports

, Volume 8, Issue 3, pp 173–183 | Cite as

Post-Transplant Lymphoproliferative Disease (PTLD): Risk Factors, Diagnosis, and Current Treatment Strategies

  • Zeina Al-Mansour
  • Beverly P. Nelson
  • Andrew M. EvensEmail author
Lymphomas (C Dearden, Section Editor)

Abstract

Post-transplant lymphoproliferative diseases (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that complicate solid organ or hematopoietic transplantation. Risk factors for PTLD include viral infections, degree of immunosuppression, recipient age and race, allograft type, and host genetic variations. Clinically, extra-nodal disease is common including 10–15 % presenting with central nervous system (CNS) disease. Most PTLD cases are B cell (5-10 % T/NK cell or Hodgkin lymphoma), while over one-third are EBV-negative. World Health Organization (WHO) diagnostic categories are: early lesions, polymorphic, and monomorphic PTLD; although in practice, a clear separation is not always possible. Therapeutically, reduction in immunosuppression remains a mainstay, and recent data has documented the importance of rituximab +/- combination chemotherapy. Therapy for primary CNS PTLD should be managed according to immunocompetent CNS paradigms. Finally, novel treatment strategies for PTLD have emerged, including adoptive immunotherapy and rational targeted therapeutics (e.g., anti-CD30 based therapy and downstream signaling pathways of latent membrane protein-2A).

Keywords

Post-transplant lymphoproliferative disease PTLD Lymphoma Non-Hodgkin lymphoma Hodgkin lymphoma Central nervous system CNS Lymphoma Epidemiology Risk factors Diagnosis Pathogenesis Genetic variation EBV LMP2A Prognosis Treatment Rituximab Adoptive immunotherapy Chemotherapy 

Notes

Conflict of Interest

Z. Al-Mansour declares that she has no conflict of interest.

B. Nelson declares that she has no conflict of interest.

A. Evens: Consultant for Seattle Genetics and Millennium.

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Doak PB, Montgomerie JZ, North JD, Smith F. Reticulum cell sarcoma after renal homotransplantation and azathioprine and prednisone therapy. Br Med J. 1968;4(5633):746–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984;1(8377):583–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Bhatia S, Ramsay NK, Steinbuch M, Dusenbery KE, Shapiro RS, Weisdorf DJ, et al. Malignant neoplasms following bone marrow transplantation. Blood. 1996;87(9):3633–9.PubMedGoogle Scholar
  4. 4.
    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(5):1234–43.PubMedGoogle Scholar
  5. 5.
    Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet. 1993;342(8886–8887):1514–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Cockfield SM. Identifying the patient at risk for post-transplant lymphoproliferative disorder. Transpl Infect Dis. 2001;3(2):70–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004;4(2):222–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Caillard S, Lelong C, Pessione F, Moulin B, French PWG. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry. Am J Transplant. 2006;6(11):2735–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Hartmann C, Schuchmann M, Zimmermann T. Posttransplant lymphoproliferative disease in liver transplant patients. Curr Infect Dis Rep. 2011;13(1):53–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Leblond V, Dhedin N, Mamzer Bruneel MF, Choquet S, Hermine O, Porcher R, et al. Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol. 2001;19(3):772–8.PubMedGoogle Scholar
  11. 11.
    Ghobrial IM, Habermann TM, Maurer MJ, Geyer SM, Ristow KM, Larson TS, et al. Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol. 2005;23(30):7574–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Dotti G, Fiocchi R, Motta T, Mammana C, Gotti E, Riva S, et al. Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation. 2002;74(8):1095–102.PubMedCrossRefGoogle Scholar
  13. 13.
    • Evens AM, David KA, Helenowski I, Nelson B, Kaufman D, Kircher SM, et al. Multicenter analysis of 80 solid organ transplantation recipients with post-transplantation lymphoproliferative disease: outcomes and prognostic factors in the modern era. J Clin Oncol. 2010;28(6):1038–46. This was a multicenter retrospective analysis of 80 PTLD patients treated over a recent 10-year period. There appeared to be improved survival among patients treated with rituximab-based therapy. PubMedCrossRefGoogle Scholar
  14. 14.
    •• Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, et al. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. 2012;13(2):196–206. This was the largest prospective PTLD clinical study conducted to date; it showed the feasibility of sequential rituximab therapy followed by CHOP. Outcomes appeared improved compared with historical controls. The study was modified to a 'risk stratified' approach; the results from this treatment strategy are eagerly awaited. PubMedCrossRefGoogle Scholar
  15. 15.
    Ghobrial IM, Habermann TM, Ristow KM, Ansell SM, Macon W, Geyer SM, et al. Prognostic factors in patients with post-transplant lymphoproliferative disorders (PTLD) in the rituximab era. Leuk Lymphoma. 2005;46(2):191–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Swinnen LJ, Mullen GM, Carr TJ, Costanzo MR, Fisher RI. Aggressive treatment for postcardiac transplant lymphoproliferation. Blood. 1995;86(9):3333–40.PubMedGoogle Scholar
  17. 17.
    • Knight JS, Tsodikov A, Cibrik DM, Ross CW, Kaminski MS, Blayney DW. Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol. 2009;27(20):3354–62. The authors examined 7,040 patients who received SOT from 1964 to 2007, from which 78 patients developed PTLD. They assessed risk factors for development of PTLD and compared outcomes with a SEER population sample. PubMedCrossRefGoogle Scholar
  18. 18.
    Jagadeesh D, Woda BA, Draper J, Evens AM. Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options in Oncol. 2012;13(1):122–36.CrossRefGoogle Scholar
  19. 19.
    Zimmermann H, Reinke P, Neuhaus R, Lehmkuhl H, Oertel S, Atta J, et al. Burkitt post-transplantation lymphoma in adult solid organ transplant recipients: sequential immunochemotherapy with rituximab (R) followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or R-CHOP is safe and effective in an analysis of 8 patients. Cancer. 2012;118(19):4715–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Loren AW, Porter DL, Stadtmauer EA, Tsai DE. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant. 2003;31(3):145–55.PubMedCrossRefGoogle Scholar
  21. 21.
    Oton AB, Wang H, Leleu X, Melhem MF, George D, Lacasce A, et al. Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders in solid transplant. Leuk Lymphoma. 2008;49(9):1738–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Johnson LR, Nalesnik MA, Swerdlow SH. Impact of Epstein-Barr virus in monomorphic B cell posttransplant lymphoproliferative disorders: a histogenetic study. Am J Surg Pathol. 2006;30(12):1604–12.PubMedCrossRefGoogle Scholar
  23. 23.
    Novoa-Takara L, Perkins SL, Qi D, Shidham VB, Vesole DH, Hariharan S, et al. Histogenetic phenotypes of B cells in posttransplant lymphoproliferative disorders by immunohistochemical analysis correlate with transplant type: solid organ vs hematopoietic stem cell transplantation. Am J Clin Pathol. 2005;123(1):104–12.PubMedCrossRefGoogle Scholar
  24. 24.
    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(10):1517–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Nourse JP, Jones K, Gandhi MK. Epstein-Barr Virus-related post-transplant lymphoproliferative disorders: pathogenetic insights for targeted therapy. Am J Transplant. 2011;11(5):888–95.PubMedCrossRefGoogle Scholar
  26. 26.
    McDonald RA, Smith JM, Ho M, Lindblad R, Ikle D, Grimm P, et al. Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant. 2008;8(5):984–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Schaffer K, Hassan J, Staines A, Coughlan S, Holder P, Tuite G, et al. Surveillance of Epstein-Barr virus loads in adult liver transplantation: associations with age, sex, posttransplant times, and transplant indications. Liver Transplant. 2011;17(12):1420–6.CrossRefGoogle Scholar
  28. 28.
    Humar A, Michaels M. Monitoring AIWGoID. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006;6(2):262–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Stevens SJ, Verschuuren EA, Pronk I, van Der Bij W, Harmsen MC, The TH, et al. Frequent monitoring of Epstein-Barr virus DNA load in unfractionated whole blood is essential for early detection of posttransplant lymphoproliferative disease in high-risk patients. Blood. 2001;97(5):1165–71.PubMedCrossRefGoogle Scholar
  30. 30.
    Buda A, Caforio A, Calabrese F, Fagiuoli S, Pevere S, Livi U, et al. Lymphoproliferative disorders in heart transplant recipients: role of hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection. Transplant Int. 2000;13 Suppl 1:S402–5.Google Scholar
  31. 31.
    Manez R, Breinig MC, Linden P, Wilson J, Torre-Cisneros J, Kusne S, et al. Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. J Infect Dis. 1997;176(6):1462–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Tsao L, Hsi ED. The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med. 2007;131(8):1209–18.PubMedGoogle Scholar
  33. 33.
    Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. North American Pediatric Renal Transplant Cooperative S. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation. 2001;71(8):1065–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005;80(9):1233–43.PubMedCrossRefGoogle Scholar
  35. 35.
    Gerritsen EJ, Stam ED, Hermans J, van den Berg H, Haraldsson A, van Tol MJ, et al. Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children. Bone Marrow Transplant. 1996;18(2):377–82.PubMedGoogle Scholar
  36. 36.
    Zutter MM, Martin PJ, Sale GE, Shulman HM, Fisher L, Thomas ED, et al. Epstein-Barr virus lymphoproliferation after bone marrow transplant. Blood. 1988;72(2):520–9.PubMedGoogle Scholar
  37. 37.
    Shapiro R, Nalesnik M, McCauley J, Fedorek S, Jordan ML, Scantlebury VP, et al. Posttransplant lymphoproliferative disorders in adult and pediatric renal transplant patients receiving tacrolimus-based immunosuppression. Transplantation. 1999;68(12):1851–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Nee R, Hurst FP, Dharnidharka VR, Jindal RM, Agodoa LY, Abbott KC. Racial variation in the development of posttransplant lymphoproliferative disorders after renal transplantation. Transplantation. 2011;92(2):190–5.PubMedCrossRefGoogle Scholar
  39. 39.
    VanBuskirk AM, Malik V, Xia D, Pelletier RP. A gene polymorphism associated with posttransplant lymphoproliferative disorder. Transplant Proc. 2001;33(1–2):1834.PubMedCrossRefGoogle Scholar
  40. 40.
    Lee TC, Savoldo B, Barshes NR, Rooney CM, Heslop HE, Gee AP, et al. Use of cytokine polymorphisms and Epstein-Barr virus viral load to predict development of post-transplant lymphoproliferative disorder in paediatric liver transplant recipients. Clin Transplant. 2006;20(3):389–93.PubMedCrossRefGoogle Scholar
  41. 41.
    Babel N, Vergopoulos A, Trappe RU, Oertel S, Hammer MH, Karaivanov S, et al. Evidence for genetic susceptibility towards development of posttransplant lymphoproliferative disorder in solid organ recipients. Transplantation. 2007;84(3):387–91.PubMedCrossRefGoogle Scholar
  42. 42.
    Reshef R, Luskin MR, Kamoun M, Vardhanabhuti S, Tomaszewski JE, Stadtmauer EA, et al. Association of HLA polymorphisms with post-transplant lymphoproliferative disorder in solid-organ transplant recipients. Am J Transplant. 2011;11(4):817–25.PubMedCrossRefGoogle Scholar
  43. 43.
    Subklewe M, Marquis R, Choquet S, Leblond V, Garnier JL, Hetzer R, et al. Association of human leukocyte antigen haplotypes with posttransplant lymphoproliferative disease after solid organ transplantation. Transplantation. 2006;82(8):1093–100.PubMedCrossRefGoogle Scholar
  44. 44.
    Pourfarziani V, Einollahi B, Taheri S, Nemati E, Nafar M, Kalantar E. Associations of Human Leukocyte Antigen (HLA) haplotypes with risk of developing lymphoproliferative disorders after renal transplantation. Ann Transplant. 2007;12(4):16–22.PubMedGoogle Scholar
  45. 45.
    Bakker NA, van Imhoff GW, Verschuuren EA, van Son WJ, van der Heide JJ, Lems SP, et al. HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical. Transplantation. 2005;80(5):595–9.PubMedCrossRefGoogle Scholar
  46. 46.
    McAulay KA, Haque T, Crawford DH. Tumour necrosis factor gene polymorphism: a predictive factor for the development of post-transplant lymphoproliferative disease. Br J Canc. 2009;101(6):1019–27.CrossRefGoogle Scholar
  47. 47.
    Swerdlow SH. T cell and NK cell posttransplantation lymphoproliferative disorders. Am J Clin Pathol. 2007;127(6):887–95.PubMedCrossRefGoogle Scholar
  48. 48.
    Swerdlow SH, International Agency for Research on Cancer, World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.Google Scholar
  49. 49.
    Nalesnik MA. The diverse pathology of post-transplant lymphoproliferative disorders: the importance of a standardized approach. Transpl Infect Dis. 2001;3(2):88–96.PubMedCrossRefGoogle Scholar
  50. 50.
    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(2):552–65.PubMedGoogle Scholar
  51. 51.
    Nelson BP, Wolniak KL, Evens A, Chenn A, Maddalozzo J, Proytcheva M. Early posttransplant lymphoproliferative disease: clinicopathologic features and correlation with mTOR signaling pathway activation. Am J Clin Pathol. 2012;138(4):568–78.PubMedCrossRefGoogle Scholar
  52. 52.
    Chadburn A, Cesarman E, Knowles DM. Molecular pathology of posttransplantation lymphoproliferative disorders. Semin Diagn Pathol. 1997;14(1):15–26.PubMedGoogle Scholar
  53. 53.
    •Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS Guidelines. Br J Haematol. 2010;149(5):675–92. Excellent review of the literature on diagnosis and management of PTLD from a British joint working group.PubMedCrossRefGoogle Scholar
  54. 54.
    Djokic M, Le Beau MM, Swinnen LJ, Smith SM, Rubin CM, Anastasi J, et al. Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities. Gene Chromosome Canc. 2006;45(3):313–8.CrossRefGoogle Scholar
  55. 55.
    Vegso G, Hajdu M, Sebestyen A. Lymphoproliferative disorders after solid organ transplantation-classification, incidence, risk factors, early detection and treatment options. Pathol Oncol Res. 2011;17(3):443–54.PubMedCrossRefGoogle Scholar
  56. 56.
    Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol. 1998;16(6):2052–9.PubMedGoogle Scholar
  57. 57.
    Nelson BP, Nalesnik MA, Bahler DW, Locker J, Fung JJ, Swerdlow SH. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol. 2000;24(3):375–85.PubMedCrossRefGoogle Scholar
  58. 58.
    Elstrom RL, Andreadis C, Aqui NA, Ahya VN, Bloom RD, Brozena SC, et al. Treatment of PTLD with rituximab or chemotherapy. Am J Transplant. 2006;6(3):569–76.PubMedCrossRefGoogle Scholar
  59. 59.
    Maecker B, Jack T, Zimmermann M, Abdul-Khaliq H, Burdelski M, Fuchs A, et al. CNS or bone marrow involvement as risk factors for poor survival in post-transplantation lymphoproliferative disorders in children after solid organ transplantation. J Clin Oncol. 2007;25(31):4902–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Knight J, Tsodikov A, Cibrik D, Ross C, Kaminski M, Blayney D. Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol. 2009;27:1–12.CrossRefGoogle Scholar
  61. 61.
    Buell JF, Gross TG, Hanaway MJ, Trofe J, Roy-Chaudhury P, First MR, et al. Posttransplant lymphoproliferative disorder: significance of central nervous system involvement. Transplant Proc. 2005;37(2):954–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Penn I, Porat G. Central nervous system lymphomas in organ allograft recipients. Transplantation. 1995;59(2):240–4.PubMedGoogle Scholar
  63. 63.
    Cavaliere R, Petroni G, Lopes MB, Schiff D, International Primary Central Nervous System Lymphoma Collaborative G. Primary central nervous system post-transplantation lymphoproliferative disorder: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Cancer. 2010;116(4):863–70.PubMedCrossRefGoogle Scholar
  64. 64.
    Boubenider S, Hiesse C, Goupy C, Kriaa F, Marchand S, Charpentier B. Incidence and consequences of post-transplantation lymphoproliferative disorders. J Nephrol. 1997;10(3):136–45.PubMedGoogle Scholar
  65. 65.
    Dror Y, Greenberg M, Taylor G, Superina R, Hebert D, West L, et al. Lymphoproliferative disorders after organ transplantation in children. Transplantation. 1999;67(7):990–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Robson R, Cecka JM, Opelz G, Budde M, Sacks S. Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am J Transplant. 2005;5(12):2954–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc. 1969;1(1):106–12.PubMedGoogle Scholar
  68. 68.
    • Reshef R, Vardhanabhuti S, Luskin MR, Heitjan DF, Hadjiliadis D, Goral S, et al. Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder( bigstar). Am J Transplant. 2011;11(2):336–47. This was an important analysis of a large cohort of PTLD patients treated with reduced immunosuppression alone. They authors identified risk factors predictive of response to this treatment strategy. PubMedCrossRefGoogle Scholar
  69. 69.
    Trofe J, Buell JF, Beebe TM, Hanaway MJ, First MR, Alloway RR, et al. Analysis of factors that influence survival with post-transplant lymphoproliferative disorder in renal transplant recipients: the Israel Penn International Transplant Tumor Registry experience. Am J Transplant. 2005;5(4 Pt 1):775–80.PubMedCrossRefGoogle Scholar
  70. 70.
    Faull RJ, Hollett P, McDonald SP. Lymphoproliferative disease after renal transplantation in Australia and New Zealand. Transplantation. 2005;80(2):193–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Choquet S, Leblond V, Herbrecht R, Socie G, Stoppa AM, Vandenberghe P, 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(8):3053–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Milpied N, Vasseur B, Parquet N, Garnier JL, Antoine C, Quartier P, 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 1:113–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Jain AB, Marcos A, Pokharna R, Shapiro R, Fontes PA, Marsh W, et al. Rituximab (chimeric anti-CD20 antibody) for posttransplant lymphoproliferative disorder after solid organ transplantation in adults: long-term experience from a single center. Transplantation. 2005;80(12):1692–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Gonzalez-Barca E, Domingo-Domenech E, Capote FJ, Gomez-Codina J, Salar A, Bailen A, et al. Prospective phase II trial of extended treatment with rituximab in patients with B cell post-transplant lymphoproliferative disease. Haematologica. 2007;92(11):1489–94.PubMedCrossRefGoogle Scholar
  75. 75.
    Mamzer-Bruneel MF, Lome C, Morelon E, Levy V, Bourquelot P, Jacobs F, 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(21):3622–32.PubMedGoogle Scholar
  76. 76.
    Fohrer C, Caillard S, Koumarianou A, Ellero B, Woehl-Jaegle ML, Meyer C, et al. Long-term survival in post-transplant lymphoproliferative disorders with a dose-adjusted ACVBP regimen. Br J Haematol. 2006;134(6):602–12.PubMedCrossRefGoogle Scholar
  77. 77.
    Giraldi E, Provenzi M, Fiocchi R, Colledan M, Cornelli P, Torre G, et al. Fludarabine, cyclophosphamide, doxorubicin (FCD), and rituximab: a remission induction therapy for aggressive pediatric post-transplant lymphoproliferative disease (PTLD). Pediatr Blood Canc. 2011;57(2):324–8.CrossRefGoogle Scholar
  78. 78.
    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(2):273–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Oltoff KM, Somer BG, 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(8):1076–88.PubMedCrossRefGoogle Scholar
  80. 80.
    Nalesnik MA, Rao AS, Furukawa H, Pham S, Zeevi A, Fung JJ, 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(9):1200–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, et al. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet. 1995;345(8941):9–13.PubMedCrossRefGoogle Scholar
  82. 82.
    Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi MH, 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(17):1185–91.PubMedCrossRefGoogle Scholar
  83. 83.
    Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, Wingate P, et al. Allogeneic cytotoxic T cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood. 2007;110(4):1123–31.PubMedCrossRefGoogle Scholar
  84. 84.
    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(5):1549–55.PubMedGoogle Scholar
  85. 85.
    Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, 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(3):807–14.PubMedGoogle Scholar
  86. 86.
    Perrine SP, Hermine O, Small T, Suarez F, O'Reilly R, Boulad F, et al. A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood. 2007;109(6):2571–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Haddad E, Paczesny S, Leblond V, Seigneurin JM, Stern M, Achkar A, 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(6):1590–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Davis CL, Wood BL, Sabath DE, Joseph JS, Stehman-Breen C, Broudy VC. Interferon-alpha treatment of posttransplant lymphoproliferative disorder in recipients of solid organ transplants. Transplantation. 1998;66(12):1770–9.PubMedCrossRefGoogle Scholar
  89. 89.
    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(3):211–5.PubMedCrossRefGoogle Scholar
  90. 90.
    Williams KM, Higman MA, Chen AR, Schwartz CL, Wharam M, Colombani P, et al. Successful treatment of a child with late-onset T cell post-transplant lymphoproliferative disorder/lymphoma. Pediatr Blood Canc. 2008;50(3):667–70.CrossRefGoogle Scholar
  91. 91.
    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(12):2421–3.PubMedCrossRefGoogle Scholar
  92. 92.
    Mahe B, Moreau P, Le Tortorec S, Hourmant M, Harousseau JL, Milpied N. Autologous bone marrow transplantation for cyclosporin-related lymphoma in a renal transplant patient. Bone Marrow Transplant. 1994;14(4):645–6.PubMedGoogle Scholar
  93. 93.
    Haque T, Chaggar T, Schafers J, Atkinson C, McAulay KA, Crawford DH. Soluble CD30: a serum marker for Epstein-Barr virus-associated lymphoproliferative diseases. J Med Virol. 2011;83(2):311–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Majewski M, Korecka M, Kossev P, Li S, Goldman J, Moore J, et al. The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: a potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. PNAS. 2000;97(8):4285–90.PubMedCrossRefGoogle Scholar
  95. 95.
    Kirk AD, Cherikh WS, Ring M, Burke G, Kaufman D, Knechtle SJ, et al. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant. 2007;7(11):2619–25.PubMedCrossRefGoogle Scholar
  96. 96.
    Rovedo M, Longnecker R. Epstein-Barr virus latent membrane protein 2A preferentially signals through the Src family kinase Lyn. J Virol. 2008;82(17):8520–8.PubMedCrossRefGoogle Scholar
  97. 97.
    •• Bieging KT, Fish K, Bondada S, Longnecker R. A shared gene expression signature in mouse models of EBV-associated and non-EBV-associated Burkitt lymphoma. Blood. 2011;118(26):6849–59. Important analysis examining the pathogenesis of EBV-related lymphomas. The integral involvement of LMP2A in this process was elucidated.PubMedCrossRefGoogle Scholar
  98. 98.
    Fukuda M, Longnecker R. Epstein-Barr virus latent membrane protein 2A mediates transformation through constitutive activation of the Ras/PI3-K/Akt Pathway. J Virol. 2007;81(17):9299–306.PubMedCrossRefGoogle Scholar
  99. 99.
    • Evens AM Choquet S, Kroll-Desrosiers AR, et al. Primary CNS Post-Transplant Lymphoproliferative Disease (PTLD): An International Report of 84 Cases in the Modern Era. Am J Transplant, 2013. This is the largest report of primary CNS PTLD; it was an international collaboration of 84 such patients. Outcomes were overall modest, although long-term survival was achieved in 35–40 % of patients. Treatment paradigms similar to immunocompetent CNS lymphomas appeared important. Google Scholar
  100. 100.
    Taj MM, Messahel B, Mycroft J, Pritchard-Jones K, Baker A, Height S, et al. Efficacy and tolerability of high-dose methotrexate in central nervous system positive or relapsed lymphoproliferative disease following liver transplant in children. Br J Haematol. 2008;140(2):191–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Zeina Al-Mansour
    • 1
  • Beverly P. Nelson
    • 2
  • Andrew M. Evens
    • 1
    Email author
  1. 1.Division of Hematology/OncologyThe University of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of PathologyNorthwestern University Feinberg School of MedicineChicagoUSA

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