Post-transplant lymphoproliferative disorders (PTLDs) are a relatively common and significant complication following solid organ transplantation, occurring in up to 10% of adult patients. They constitute a heterogeneous collection of diagnoses ranging from early lesions, with reactive plasmacytic hyperplasia, to polymorphic PTLD, with polyclonal or monoclonal expansion of atypical lymphoid cells, to monomorphic PTLD, with a frank lymphoma histopathology and phenotype (Table 1, Figure 1). Monomorphic PTLD is most commonly diffuse large B-cell lymphoma, but can also be Burkitt/Burkitt-like lymphoma, myeloma, and less commonly T-cell lymphoma; classical Hodgkin lymphoma-type PTLD is very rare. They differ from non–transplant-related adult lymphomas in that they tend to be extranodal, high grade, and have an aggressive clinical course, with a mortality often exceeding 50% (Figure 2).[1,2] A number of risk factors for the development of PTLD following solid organ transplant have been identified; these have not, however, generally translated into effective prophylactic strategies. With the advent of new lymphoma treatments and with advances in our understanding of adoptive immunity, prognosis following a diagnosis of PTLD is improving. This review will outline PTLD risk factors and strategies for prevention, and PTLD prognosis and strategies to improve treatment outcomes.
Pathogenesis, Epidemiology, and Risk Factors
PTLD following hematopoietic stem cell transplantation is usually a malignancy of donor lymphoid cells, whereas PTLD following solid organ transplantation is traditionally thought to be of recipient origin in the majority of cases, though donor-derived cases have been reported and typically involve the grafted organ.[3,4] In PTLD following both hematopoietic and solid organ transplantation, more than 80% of PTLDs are of B-cell origin. PTLD following solid organ transplantation can occur early, within the first year after transplant, or late, at 1 year or longer following transplantation; the former is much more common, with an incidence of 224 per 100,000 that falls to 54 per 100,000 by the second year. More than 90% of early-onset B-cell PTLD are Epstein-Barr virus (EBV)-positive, whereas over 50% of late-onset B-cell PTLD cases are EBV-negative. Following initial EBV infection, lifelong viral persistence is established within B lymphocytes, which express a combination of 10 viral genes, thereby establishing a latency program. Each latency program is defined by expression of a specific set of viral genes, which vary both in their immunogenicity and their oncogenic transforming potential. LMP-1, for example, is a viral oncogene that induces expression of BCL2 and A20, thus inhibiting apoptosis. In healthy EBV carriers, EBV-specific cytotoxic T lymphocytes (CTLs) kill infected B lymphocytes expressing a more active latency program, thus selecting for infected B lymphocytes in which the viral genome is nearly silenced (Figure 1). Immunosuppression following solid organ transplantation, however, results in loss of this selective pressure, allowing for growth and acquisition of additional transforming mutations such as alterations in c-MYC, BCL-6, p53, and DNA hypermethylation (see Figure 3).[9,10]
EBV serologic status before transplant, as well as the degree and type of immunosuppression following transplant, are therefore important regarding the risk of developing PTLD. Patients who are EBV-naive pre-transplant are more likely to develop PTLD post-transplant as a result of primary EBV infection in an immunosuppressed state, often acquired from the donor organ, with rates reported as high as 24 times those seen in EBV-seropositive patients.[11-13] Similarly, younger age at the time of transplantation has also been correlated with higher rates of PTLD, with pediatric patients having a four- to eight-fold increased risk of PTLD compared with their adult counterparts.[1,12] The higher proportion of EBV-naive patients in the younger cohort has been proposed as an explanation for this observed difference.
Likewise, the degree to which EBV immunity is suppressed or lost in chronic carriers is also a risk factor for developing PTLD. There was an initial observed increase in PTLD following the introduction of cyclosporine into post-transplant immunosuppression regimens, but later studies reported no difference in PTLD rates in patients treated with cyclosporine, compared with azathioprine.[1,14,15] The use of tacrolimus, however, has been associated with a two- to five-fold increase in the rate of PTLD in both adult and pediatric populations, compared with cyclosporine.[1,16,17] The use of muromonab-CD3 (Orthoclone OKT3) and anti-thymocyte globulin (ATG) for antirejection prophylaxis at the time of transplantation or for steroid-refractory acute rejection has also been associated with increased rates of PTLD, with rates three- to four-fold greater than those observed in patients not treated with either of these two drugs. Whether these observed increases in rates of PTLD are due to the specific immunosuppressant rather than a cumulative dose effect is controversial, as patients receiving multiple drugs at higher doses appear to be at the highest risk.[1,18]
The proposed effect of cumulative dosing of immunosuppression on rates of PTLD is a potential explanation for the increased risk of PTLD seen during the first year following transplant, when immunosuppression is greatest, and in non–kidney transplant patients who require a higher degree of immune suppression to prevent graft rejection.[1,5,9] Indeed, the incidence of PTLD varies with the type of organ being transplanted; in adult patients this ranges from 1%–3% of kidney and liver transplants, to 1%–6% of heart transplants, 2%–6% of heart-lung transplants, 4%–10% of lung transplants, and up to 20% of small bowel transplants. This is likely to be the result of a combination of the degree of immune suppression and the number of EBV-positive lymphocytes transferred with the transplanted organ, however (Table 2).
Other viral infections have been proposed as potential risk factors in the development of PTLD, including hepatitis C virus (HCV) and cytomegalovirus (CMV).[19-21] Similar to EBV status, CMV-negative patients who receive a CMV-positive organ are 4–6 times more likely to develop PTLD than CMV-positive recipients.
Prevention: Prophylaxis and Early Detection
The identification of certain groups at high risk of developing PTLD following solid organ transplant has resulted in the development and investigation of prophylactic and early detection strategies. Antiviral agents have been studied in both the treatment and prophylaxis settings. In the former, no study has demonstrated a clear benefit, although they may have some efficacy in early or polymorphic disease. Regarding the latter, the use of prophylactic IV ganciclovir for the first 100 days post liver transplant in high-risk EBV-seronegative pediatric patients resulted in no cases of PTLD, compared with a PTLD rate of 10% in low-risk transplant recipients who were given oral acyclovir alone. Additionally, one retrospective study compared PTLD rates between two cohorts: one who received no antiviral prophylaxis and one treated prophylactically with antiviral agents. The investigators noted a reduction in the incidence of PTLD with the use of antiviral prophylaxis, from 4.2% to 0.8%, and none of the 15 high-risk EBV-seronegative patients treated with antiviral therapy developed PTLD. Antiviral therapy did not, however, prevent EBV infection, as 72% of patients treated seroconverted. Antiviral prophylaxis, then, may work by treating EBV in its lytic phase, thus decreasing viral load and subsequent infection of memory B cells and germinal center cells, which are the most prone to undergo oncogenic transformation.
EBV vaccination has also been studied in EBV-seronegative recipients. In a phase I study, 16 pediatric patients who were EBV-naive awaiting kidney transplantation received three injections of the EBV Gp350 vaccine; the vaccine was immunogenic but only 33% of patients developed neutralizing antibodies, and these antibodies were short-lived. Future studies with a prolonged vaccine schedule or improved adjuvants are proposed.
An alternative strategy to limit the morbidity and mortality of PTLD following solid organ transplantation has been to identify patients, following transplant, who are at risk for PTLD, and to detect patients with early-stage PTLD. EBV viral load has been shown to be significantly increased in patients who develop PTLD.[26,27] The use of a rising or increased viral load to alter clinical practice has been investigated following hematopoietic stem cell transplant, with a reduction in immunosuppression and/or preemptive therapy with rituximab or EBV cytotoxic T cells.[28-30] There are reported cases of documented PTLD regression. However, EBV viral load is variably predictive of the development of PTLD in solid organ transplant recipients, and perhaps a better screening strategy is to monitor the relative EBV viral load with respect to EBV-specific T-cell count, which has been shown to predict PTLD in 100% of a small cohort of patients.[31,32] This has not yet translated into studies investigating preemptive changes in clinical management in the solid organ transplant setting.
1. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transpl. 2003;4:222-230.
2. Swerdlow SH, Webber SA, Chadburn A, Ferry JA. Post-transplant lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours and Haematopoietic and Lymphoid Tissue. Lyon: IARC Press, 2008:343-349.
3. Weissman DJ, Ferry JA, Harris NL, et al. Posttransplantation lymphoproliferative disorders in solid organ recipients are predominantly aggressive tumors of host origin. Am J Clin Path. 1995;103:748-752.
4. Petit B, Le Meur Y, Jaccard A, et al. Influence of host-recipient origin on clinical aspects of posttransplantation lymphoproliferative disorders in kidney transplantation. Transplantation. 2002;265-271.
5. Morrison VA, Dunn DL, Manivel JC, et al. Clinical characteristics of post-transplant lymphoproliferative disorders. Am J Med. 1994;97:14-24.
6. Preikasaitis JK, Cockfield SM. Epstein-Barr virus infection and lymphoproliferative disease after hematopoietic stem cell or solid organ transplantation. In: Bowden RA, Ljungman P, Paya CV, et al, eds. Transplant Infections. 2nd Edition. Lippincott Williams & Wilkins, 2003:326-49.
7. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343:481-492.
8. Kuppers R. B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol. 2003;3:801-812.
9. Taylor AL, Marcus R, Bradley JA. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol/Hematol. 2005;56:155-167.
10. Capello D, Rossi D, Gaidano G. Post-transplant lymphoproliferative disorders: molecular basis of disease histogenesis and pathogenesis. Hematol Oncol. 2005;23:61-67.
11. Walker RC, Marshall WF, Strickler JG, et al. Pretransplantation assessment of the risk of lymphoproliferative disorders. Blood. 2003;102:2775-3785.
12. Dror Y, Greenberg M, Taylor G, et al. Lymphoproliferative disorders after organ transplantation in children. Transplantation. 1999;67:990-998.
13. Shapiro R, Nalesnik M, McCauley J, et al. Pottransplant lymphoproliferative disorders in adult and pediatric renal transplant patients receiving tacrolimus-based immunosuppression. Transplantation. 1999;68:1851-1854.
14. Penn I. Cancers following cyclosporine therapy. Transpl Proc. 1987;19:2211-2213.
15. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med. 1990;323:1723-1728.
16. Cao S, Cox KL, Berquist W, et al. Long-term outcomes in pediatric liver recipients: comparison between cyclosporine A and tacrolimus. Pediatr Transplant. 1999;3:22-26.
17. Caillard S, Dharnidharka V, Agodoa L, et al. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in the era of modern immunosuppression. Transplantation. 2005;80:1233-1243.
18. Melosky B, Karim M, Chui A, et al. Lymphoproliferative disorders after renal transplantation in patients receiving triple or quadruple immunosuppression. J Am Soc Nephrol. 1992;2:S290-S294.
19. Hezode C, Duvoux C, Germanidis G, et al. Role of hepatitis C virus in lymphproliferative disorders after liver transplantation. Hepatology. 1999;30:775-778.
20. Manez R, Breinig MC, Linden P, et al. Post-transplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. J Infect Dis. 1997;176:1462-1467.
21. Walker RC, Marshall WF, Strickler JG, et al. Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis. 1995;20:1346-1353.
22. Starzl TE, Porter KA, Iwatsuki S, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporine-steroid therapy. The Lancet. 1984;1:583-587.
23. McDiarmid SV, Jordan S, Kim GS, et al. Prevention and preemptive therapy of posttransplant lymphoproliferative disease in pediatric liver recipients. Transplantation. 1998;66:1604-1611.
24. Malouf MA, Chhajed PN, Hopkins P, et al. Antiviral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients. J Heart Lung Transplant. 2002;21:547-554.
25. Rees L, Tizard EJ, Morgan AJ, et al. A phase I trial of Epstein-Barr Virus Gp350 vaccine for children with chronic kidney disease awaiting transplantation. Transplantation. 2009;88:1025-1029.
26. 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.
27. 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.
28. 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.
29. 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.
30. Styczynski J, Einsele H, Gil L, et al. Outcome of treatment of Epstein-Barr virus-related posttransplant lymphoproliferative disorder in hematopoietic stem cell recipients: a compreshensive review of reported cases. Transpl Infect Dis. 2009;11:383-392.
31. Hopwood PA, Brooks L, Parratt R, et al. Persistent Epstein-Barr virus infection: unrestricted latent and lytic viral gene expression in healthy immunosuppressed transplant recipients. Transplantation. 2002;74:194-202.
32. Smets F, Latinne D, Bazin H, et al. Ratio between Epstein-Barr viral load and anti-Epstein-Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation. 2002;73:1603-1610.
33. Leblond V, Dhedin N, Bruneel M-FM, et al. Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol. 2001;19:772-778.
34. Ghobrial IM, Habermann TM, Maurer MJ, et al. Prognostic analysis for survival in adult solid organ transplant recipients with post-transplant lymphoproliferative disorders. J Clin Oncol. 2005;23:7574-7582.
35. Ghobrial IM, Habermann TM, Ristow KM, et al. Prognostic factors in patients with post-transplant lymphoproliferative disorders (PTLD) in the rituximab era. Leuk Lymph. 2005;46:191-196.
36. 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 Lymph. 2008;49:1738-1744
37. Choquet S, Oertel S, LeBlond V, et al. Rituximab in the management of post-tranpslantation lymphoproliferative disorder after solid organ transplantation: proceed with caution. Ann Hematol. 2007;86:599-607.
38. Parker A, Bowles K, Bradley JA, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines. Br J Haematol. 2010;149:693-705.
39. 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.
40. Swinnen LJ, LeBlanc M, Grogan TM, et al. Prospective study of sequential reduction in immunosuppression, interferon alpha-2B, and chemotherapy for posttransplant lymphoproliferative disorder. Transplantation. 2008;86:215-222.
41. Muti G, Cantoni S, Oreste P, et al. Post-transplant lymphoproliferative disorders: improved outcome after clinico-pathologically tailored treatment. Haematologica. 2002;87:67-77.
42. Paya CV, Fung JJ, Nalesnik MA, et al. Epstein-Barr virus-induced post-transplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International consensus Development Meeting. Transplantation. 1999;68:1517-1525.
43. Mentzer SJ, Perrine SP, Faller DV. Epstein-Barr virus post-transplant lymphoproliferative disease and virus-specific therapy: pharmacological re-activation of viral target genese with arginine butyrate. Transpl Infect Dis. 2001;3:177-185.
44. Perrine SP, Hermine O, Small T, et al. A phase I/II trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood. 2007;109:2571-2578.
45. Oertel SHK, Verschuuren E, Reinke P, et al. Effect of Anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transpl. 2005;5:2901-2906.
46. Gonzalez-Barca E, Domngo-Domenech E, Capote JE, et al. Prospective phase II trial of extended treatement with rituximab in patients with B-cell post-transplant lymphoproliferative disease. Haematoligica. 2007;92:1489-1494.
47. Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective, multicenter phase 2 study. Blood. 2006:3053-3057.
48. 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;28:1038-46.
49. Trappe R, Choquet S, Oertel SHK, et al. 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. ASH abstract 2009:100.
50. 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.
51. Swinnen LJ. Durable remission after aggressive chemotherapy for post-cardiac transplant lymphoproliferation. Leuk Lymphoma. 1997;28:89-101.
52. Buell JF, Gross TG, Hanaway MJ, et al. Chemotherpay for posttransplant lymphoproliferative disorder: the Israel Penn International Transplant Tumor Registry experience. Transplant Proc. 2005;37:956-957.
53. Komrokji RS, Oliva JL, Zand M, et al. Mini-BEAM and autologous hematopoietic stem-cell transplant for treatment of post-transplant lymphoprolierative disorders. Am J Hematol. 2005;79:211-215.
54. Koffman BH, Kennedy AS, Heyman M, et al. Use of radiation in posttransplant lymphoproliferative disorder (PTLD) after liver transplantation. Int J Cancer. 2000;90:104-109.
55. Kang SK, Kirkpatrick JP, Halperin EC. Low-dose radiation for posttransplant lymphoproliferative disorder. Am J Clin Oncol. 2003;26:210-214.
56. Penn I, Porat G. Central nervous system lymphoma in organ allograft recipients. Transplantation. 1995;59:240-244.
57. Liu Z, Savoldo B, Huls H, et al. Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the prevention and treatment of EBV-associated post-transplant lymphomas. Recent Results Cancer Res. 2002;159:123-133.
58. Feng S, Buell JF, Chari RS, et al. Tumors and transplantation: the 2003 third annual ASTS state-of-the-art winter symposium. Am J Transplant. 2003;3:1481-1487.
59. Comoli P, Maccario R, Locatelli F, 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.
60. Savoldo B, Goss JA, Hammer MM, et al. Treatment of solide organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood. 2006;108:2942-2949.
61. Haque T, Wilkie GM, Taylor C, et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360:436-42.
62. Haque T, Wilkie GM, Jones MM, et al. Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood. 2007;110:1123-1131.
63. Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative diosreders. Annu Rev Med. 2004.
64. Tosato G, Jones K, Breinig MK, et al. Interleukin-6 production in posttransplant lymphoproliferative disease. J Clin Invest. 1993;91:2806-2814.
65. Haddad E, Paczensny 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.
66. 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.
67. Nepomuceno RR, Balatoni CE, Natkunam Y, et al. Rapamycin inhibits the interleukin 10 signal transduction pathway and growth of Epstein Barr virus B-cell lymphomas. Cancer Res. 2003;63:4472-4480.
68. Garcia VD, Bonamigo Filho JL, Neumann J, et al. Rituximab in association with rapamycin for post-transplant lymphoproliferative disease treatment. Transpl Int. 2003;16:202-206.
69. Hymes LC, Warshaw BL. Sirolimus in pediatric patients: results in the first 6 months post-renal transplant. Pediatr Transplant. 2005;9:520-522.
70. Kirk AD, Cherikh WS, Ring M. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant. 2007;7:2619-2625.