Lymphoma: Risk and Response After Solid Organ Transplant
Lymphoma: Risk and Response After Solid Organ Transplant
Post-transplant lymphoproliferative disorder (PTLD) is a common and serious complication of solid organ transplantation. It is a heterogeneous collection of diagnoses with varied clinical courses and outcomes. The majority of PTLD is Epstein-Barr virus (EBV)-driven as a result of loss of immune control of EBV-positive B lymphocytes. Risk factors for the development of PTLD thus reflect loss or absence of EBV immunity; they include younger age and pre-transplant EBV naivety, as well as the degree and type of immune suppression, type of organ transplantation, and time from transplantation. Identifying patients at risk for PTLD and developing strategies to prevent PTLD is the subject of much research, and the use of antiviral medications and EBV vaccines has yielded intriguing, albeit preliminary, results. As we learn more about the prognostic factors affecting outcome and the pathogenesis of individual diseases, we are better able to tailor therapy to the individual. Further clinical investigation, including randomized controlled trials, will be important in reaching this goal.
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.