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Current Oncology Reports

, Volume 12, Issue 6, pp 383–394 | Cite as

Post-Transplantation Lymphoproliferative Disorders: Diagnosis, Prognosis, and Current Approaches to Therapy

  • Andrew M. Evens
  • Rupali Roy
  • Danielle Sterrenberg
  • Michelle Z. Moll
  • Amy Chadburn
  • Leo I. Gordon
Article

Abstract

Post-transplantation lymphoproliferative disorders (PTLD) are a heterogenous group of abnormal lymphoid proliferations that occur after solid organ transplant (SOT) or hematopoietic transplantation. PTLDs consist of a disease spectrum ranging from hyperplasia to aggressive lymphomas with 60–70% being Epstein–Barr virus positive. The majority of cases are B-cell, although 10–15% are of T-cell origin or rarely Hodgkin lymphoma. Recent SOT series suggest PTLD occurs at a median of 36–40 months after transplant. Clinically, extra-nodal disease is common (up to 75–85%) including CNS involvement, which is seen in 10–15% of all cases. Since the first report over 40 years ago, PTLD has remained one of the most morbid complications associated with SOT. However, recent data suggests improved survival in the modern era, especially with the integration of early rituximab-based therapy. These studies utilized first line rituximab (+/− chemotherapy) together with reduced immune suppression (RI) for monomorphic and polymorphic PTLD. It will be critical in future studies to determine which PTLDs are most amenable to initial therapy with RI alone, versus RI/rituximab, versus RI/rituximab/chemotherapy. Additionally, novel therapeutics, such as adoptive immunotherapy, should continue to be explored.

Keywords

Lymphoma Solid organ transplant Post-transplantation complications Rituximab Prognosis Treatment 

Notes

Disclosure

Dr. Evens has been a consultant for and received honoraria from Millennium, Seattle Genetics, Celgene, Pharmacyclics, and Ziopharm.

References

Paper of particular interest, published recently, have been highlighted as: • Of Importance, •• Of Major Importance

  1. 1.
    Penn I, Hammond W, Brettschneider L, Starzl TE: Malignant lymphomas in transplantation patients. Transplant Proc 1969, 1:106–112.PubMedGoogle Scholar
  2. 2.
    • Ghobrial IM, Habermann TM, Maurer MJ, et al.: Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol 2005, 23:7574–7582. This is one of the largest PTLD series reported to date; the authors studied 107 patients over a 33-year period.Google Scholar
  3. 3.
    Leblond V, Dhedin N, Mamzer Bruneel MF, et al.: Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol 2001, 19:772–778.PubMedGoogle Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    • Evens AM, David KA, Helenowski I, 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, 28:1038–1046. This is a multicenter analysis of 80 PTLD patients treated over a recent 10-year period. There appeared to be significantly improved OS from early rituximab-based therapy.Google Scholar
  6. 6.
    •• Trappe R CS, Oertel S: Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD: Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial. Blood 2009, 100a. This is a recent presentation of a large prospective multicenter PTLD analysis that utilized early rituximab-based therapy. One-year PFS was 93% using risk-stratified therapy using R-CHOP for patients who did not achieve CR to 4 weeks of rituximab.Google Scholar
  7. 7.
    Loren AW, Porter DL, Stadtmauer EA, Tsai DE. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 2003, 31:145–155.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedGoogle Scholar
  9. 9.
    Leblond V, Davi F, Charlotte F, et al.: Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 1998, 16:2052–2059.PubMedGoogle Scholar
  10. 10.
    Dotti G, Fiocchi R, Motta T, et al.: Lymphomas occurring late after solid-organ transplantation: influence of treatment on the clinical outcome. Transplantation 2002, 74:1095–1102.PubMedCrossRefGoogle Scholar
  11. 11.
    Elstrom RL, Andreadis C, Aqui NA, et al.: Treatment of PTLD with rituximab or chemotherapy. Am J Transplant 2006, 6:569–576.PubMedCrossRefGoogle Scholar
  12. 12.
    • Knight J, Tsodikov A, Cibrik D, et al.: Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center. J Clin Oncol 2009, 27:1–12. The authors examined 7040 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.Google Scholar
  13. 13.
    • Maecker B, Jack T, Zimmermann M, 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, 25:4902–4908. A total of 55 pediatric PTLD patients were studied. The 5-year EFS and OS were 59% and 68%, respectively.Google Scholar
  14. 14.
    McDonald RA, Smith JM, Ho M, et al.: Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant 2008, 8:984–989.PubMedCrossRefGoogle Scholar
  15. 15.
    Opelz G, Dohler B: Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004, 4:222–230.PubMedCrossRefGoogle Scholar
  16. 16.
    Dharnidharka VR, Sullivan EK, Stablein DM, et al.: 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, 71:1065–1068.PubMedCrossRefGoogle Scholar
  17. 17.
    Cockfield SM: Identifying the patient at risk for post-transplant lymphoproliferative disorder. Transpl Infect Dis 2001, 3:70–78.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Caillard S, Dharnidharka V, Agodoa L, et al.: Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation 2005, 80:1233–1243.PubMedCrossRefGoogle Scholar
  20. 20.
    Oton AB, Wang H, Leleu X, et al.: Clinical and pathological prognostic markers for survival in adult patients with post-transplant lymphoproliferative disorders in solid transplant. Leuk Lymphoma 2008, 49:1738–1744.PubMedCrossRefGoogle Scholar
  21. 21.
    • Gonzalez-Barca E, Domingo-Domenech E, Capote FJ, et al. Prospective phase II trial of extended treatment with rituximab in patients with B-cell post-transplant lymphoproliferative disease. Haematologica 2007, 92:1489–1494. This is a prospective phase 2 trial of single-agent rituximab after failure of RI. The initial ORR was 79% with 34% CR; 3-year OS was approximately 58%.Google Scholar
  22. 22.
    Penn I, Porat G: Central nervous system lymphomas in organ allograft recipients. Transplantation 1995, 59:240–244.PubMedGoogle Scholar
  23. 23.
    • Swerdlow SH CE, Harris NL: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, edn 4. Lyon, France: International Agency for Research on Cancer; 2008. This is an updated comprehensive WHO classification of pathology of PTLD.Google Scholar
  24. 24.
    •• 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.PubMedGoogle Scholar
  25. 25.
    Chadburn A, Cesarman E, Knowles DM: Molecular pathology of posttransplantation lymphoproliferative disorders. Semin Diagn Pathol 1997, 14:15–26.PubMedGoogle Scholar
  26. 26.
    Novoa-Takara L, Perkins SL, Qi D, 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, 123:104–112.Google Scholar
  27. 27.
    Djokic M, Le Beau MM, Swinnen LJ, et al.: Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities. Genes Chromosomes Cancer 2006, 45:313–318.PubMedCrossRefGoogle Scholar
  28. 28.
    Rinaldi A, Capello D, Scandurra M, et al.: Single nucleotide polymorphism-arrays provide new insights in the pathogenesis of post-transplant diffuse large B-cell lymphoma. Br J Haematol. 2010, 149:569–577.PubMedCrossRefGoogle Scholar
  29. 29.
    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, 30:1604–1612.PubMedCrossRefGoogle Scholar
  30. 30.
    Craig FE, Johnson LR, Harvey SA, et al.: Gene expression profiling of Epstein-Barr viruspositive and -negative monomorphic B-cell posttransplant lymphoproliferative disorders. Diagn Mol Pathol 2007, 16:158–168.PubMedCrossRefGoogle Scholar
  31. 31.
    Heslop HE: How I treat EBV lymphoproliferation. Blood 2009, 114:4002–4008.PubMedCrossRefGoogle Scholar
  32. 32.
    Starzl TE, Nalesnik MA, Porter KA, et al.: Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1984, 1:583–587.PubMedCrossRefGoogle Scholar
  33. 33.
    Swinnen LJ, Mullen GM, Carr TJ, et al.: Aggressive treatment for postcardiac transplant lymphoproliferation. Blood 1995, 86:3333–3340.PubMedGoogle Scholar
  34. 34.
    Choquet S, Leblond V, Herbrecht R, et al.: Efficacy and safety of rituximab in B-cell posttransplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood 2006, 107:3053–3057.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedGoogle Scholar
  36. 36.
    Davis CL, Wood BL, Sabath DE, et al.: Interferon-alpha treatment of posttransplant lymphoproliferative disorder in recipients of solid organ transplants. Transplantation 1998, 66:1770–1779.PubMedCrossRefGoogle Scholar
  37. 37.
    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.PubMedCrossRefGoogle Scholar
  38. 38.
    Choquet S, Trappe R, Leblond V, et al.: CHOP-21 for the treatment of post-transplant lymphoproliferative disorders (PTLD) following solid organ transplantation. Haematologica 2007, 92:273–274.PubMedCrossRefGoogle Scholar
  39. 39.
    Fohrer C, Caillard S, Koumarianou A, et al.: Long-term survival in post-transplant lymphoproliferative disorders with a dose-adjusted ACVBP regimen. Br J Haematol 2006, 134:602–612.PubMedCrossRefGoogle Scholar
  40. 40.
    Pirsch JD, Stratta RJ, Sollinger HW, et al.: Treatment of severe Epstein-Barr virusinduced lymphoproliferative syndrome with ganciclovir: two cases after solid organ transplantation. Am J Med 1989, 86:241–244.PubMedCrossRefGoogle Scholar
  41. 41.
    Schmidt W, Anagnostopoulos I, Scherubl H: Virostatic therapy for advanced lymphoproliferation associated with the Epstein-Barr virus in an HIV-infected patient. N Engl J Med 2000, 342:440–441.PubMedCrossRefGoogle Scholar
  42. 42.
    Oertel SH, Ruhnke MS, Anagnostopoulos I, et al.: Treatment of Epstein-Barr virusinduced posttransplantation lymphoproliferative disorder with foscarnet alone in an adult after simultaneous heart and renal transplantation. Transplantation 1999, 67:765–767.PubMedCrossRefGoogle Scholar
  43. 43.
    Funch DP, Walker AM, Schneider G, et al.: Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients. Am J Transplant 2005, 5:2894–2900.PubMedCrossRefGoogle Scholar
  44. 44.
    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.PubMedCrossRefGoogle Scholar
  45. 45.
    Buell JF, Gross TG, Hanaway MJ, et al.: Posttransplant lymphoproliferative disorder: significance of central nervous system involvement. Transplant Proc 2005, 37:954–955.PubMedCrossRefGoogle Scholar
  46. 46.
    Caillard S, Lelong C, Pessione F, Moulin B: Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French Registry. Am J Transplant 2006, 6:2735–2742.PubMedCrossRefGoogle Scholar
  47. 47.
    • Cavaliere R, Petroni G, Lopes MB, Schiff D: Primary central nervous system posttransplantation lymphoproliferative disorder: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Cancer 2010, 116:863–870. This is an analysis of 34 primary CNS PTLD patients treated over a 25-year period. Median OS was 47 months. Treatment with aggressive therapy, similar to immunocompetent primary CNS, is recommended (eg, high-dose methotrexate-based therapy).Google Scholar
  48. 48.
    Choquet S OS, Anagnostopoulos I, et al.: Results of the largest study on post-transplantlymphoproliferations (PTLDs) of the central nervous system (CNS) in the rituximab era: a surprising overrepresentation of kidney transplantations, key importance of methotrexate, cytarabine and radiotherapy for long term survival and low impact of rituximab. Blood (ASH Annual Meeting Abstracts) 2008, 3614.Google Scholar
  49. 49.
    Evens AM, Smith SM: Reply to D. Dierickx et al. J Clin Oncol 2010, In press.Google Scholar
  50. 50.
    Moise L MC, Pilorge S, et al.: High-dose methotrexate and cytarabine chemotherapy may be effective and safe in solid organ transplant recipients with primary CNS lymphomas (PCNSL). Blood (ASH Annual Meeting Abstracts) 2008, 3611.Google Scholar
  51. 51.
    Taj MM, Messahel B, Mycroft J, 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, 140:191–196.PubMedCrossRefGoogle Scholar
  52. 52.
    Nalesnik MA, Rao AS, Furukawa H, 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
  53. 53.
    Fujita Y, Rooney CM, Heslop HE: Adoptive cellular immunotherapy for viral diseases. Bone Marrow Transplant 2008, 41:193–198.PubMedCrossRefGoogle Scholar
  54. 54.
    Moosmann A, Bigalke I, Tischer J, et al.: Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells. Blood 2010, 115:2960–2970.PubMedCrossRefGoogle Scholar
  55. 55.
    •• Haque T, Wilkie GM, Jones MM, et al.: Allogeneic cytotoxic T-cell therapy for EBVpositive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood 2007, 110:1123–1131. This multicenter study used EBV-specific partial allogeneic-matched cytotoxic T cells generated from EBV-positive donors for the treatment of EBV-positive PTLD. ORR at 6 months was 52%, including 42% CR rate. Therapy was overall well-tolerated.Google Scholar
  56. 56.
    Brewin J, Mancao C, Straathof K, et al.: Generation of EBV-specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease. Blood 2009, 114:4792–4803.PubMedCrossRefGoogle Scholar
  57. 57.
    De Angelis B, Dotti G, Quintarelli C, et al.: Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus (FK506). Blood 2009, 114:4784–4791.PubMedCrossRefGoogle Scholar
  58. 58.
    Mentzer SJ, Perrine SP, Faller DV: Epstein-Barr virus post-transplant lymphoproliferative disease and virus-specific therapy: pharmacological re-activation of viral target genes with arginine butyrate. Transpl Infect Dis 2001, 3:177–185.PubMedCrossRefGoogle Scholar
  59. 59.
    • Perrine SP, Hermine O, Small T, et al.: A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood 2007, 109:2571–2578. This is a prospective clinical trial using concurrent ganciclovir and arginine butyrate therapy; the latter was utilized in order to upregulate thymidine kinase. An ongoing related clinical trial is referenced below.Google Scholar
  60. 60.
  61. 61.
    Majewski M, Korecka M, Kossev P, 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. Proc Natl Acad Sci U S A 2000, 97:4285–4290.PubMedCrossRefGoogle Scholar
  62. 62.
    Smith SM, van Besien K, Karrison T et al.: Temsirolimus Has Activity in Non-Mantle Cell Non-Hodgkin's Lymphoma Subtypes: The University of Chicago Phase II Consortium. J Clin Oncol. 2010 Sep 13. [Epub ahead of print].Google Scholar
  63. 63.
    Kirk AD, Cherikh WS, Ring M, et al.: Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant 2007, 7:2619–2625.PubMedCrossRefGoogle Scholar
  64. 64.
    Ghobrial IM, Habermann TM, Ristow KM, et al.: Prognostic factors in patients with posttransplant lymphoproliferative disorders (PTLD) in the rituximab era. Leuk Lymphoma 2005, 46:191–196.PubMedCrossRefGoogle Scholar
  65. 65.
    Jain AB, Marcos A, Pokharna R, 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, 80:1692–1698.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Andrew M. Evens
    • 1
    • 2
  • Rupali Roy
    • 1
    • 2
  • Danielle Sterrenberg
    • 1
  • Michelle Z. Moll
    • 1
    • 2
  • Amy Chadburn
    • 1
    • 3
  • Leo I. Gordon
    • 1
  1. 1.Northwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Division of Hematology/OncologyChicagoUSA
  3. 3.Department of PathologyChicagoUSA

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