© 2000 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 28, 38-43,
2000
© 2000 Oxford University Press
Post-transplant Lymphoproliferative Disorders: Implications for Acquired Immunodeficiency Syndrome-Associated Malignancies
Presented at the Third National AIDS Malignancy Conference.
Correspondence to: Lode J. Swinnen, M.D., Division of Hematology/Oncology, Loyola University Chicago, Cardinal Bernardin Cancer Center, Rm. 245, 2160 S. First Ave., Maywood, IL 60153 (e-mail: lswinne{at}luc.edu).
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ABSTRACT |
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Post-transplant lymphoproliferative disorders (PTLDs) comprise a histologic spectrum, ranging from hyperplastic-appearing lesions to frank non-Hodgkin's lymphoma or multiple myeloma histology. Multiple clones may coexist, each representing a discrete lymphomagenic event, a situation that is unique to immunodeficiency states. The incidence varies from 1% in renal recipients to 5% in heart recipients, but can be markedly increased by the use of anti-T-cell therapies or by T-cell depletion in bone marrow transplantation. PTLD continues to arise, even many years after transplantation, and late T-cell lymphomas have recently been recognized. Pretransplant Epstein-Barr virus (EBV) seronegativity increases risk to as high as 30%–50%. PTLD has a highly variable clinical picture; certain patterns are, however, seen. Reversibility of PTLD with reduction in immunosuppressives has long been recognized. Predicting reversibility has been difficult. The presence or absence of bcl-6 mutations has recently been identified as being of predictive value. Surgical resection can be curative. Cytotoxics, although problematic, can also be curative. Long-term remission has been achieved with anti CD21 and CD24 antibodies; efficacy has been reported for interferon alfa and for rituximab. In vitro expanded EBV-specific T cells have been effective as treatment and as prophylaxis in the setting of bone marrow transplantation. EBV viral load measured in blood appears to associate with the emergence of PTLD and may facilitate prophylactic studies. PTLD is a model of immunodeficiency-related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic insights gained from the study of PTLD are likely to be applicable to the acquired immunodeficiency syndrome setting.
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INTRODUCTION |
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Malignancy following iatrogenic immunosuppression has been recognized since the beginning of organ transplantation (1). More than 20 000 organ transplants are performed per year in the United States. Longer patient survival, the increasing use of organ transplantation in the pediatric age group, and the use of potent and highly T-cell-specific immunosuppressive agents all contribute to an increasing incidence of post-transplant malignancy (2–6).
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IMMUNOSUPPRESSIVE REGIMENS |
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Immunosuppressive regimens vary from one institution to another, and a number of new agents has recently been introduced. Regimens are commonly based on an agent that inhibits T-cell function, such as cyclosporine or FK506, in combination with azathioprine and prednisone. Immunosuppression is most intense immediately after transplantation, with gradual reduction in dosage over the ensuing years. The incidence of post-transplant lymphoproliferative disorder (PTLD) is higher in nonrenal than in renal recipients. The most reliable estimates of incidence currently available are based on data obtained by the European and North American Collaborative Transplant Study. Those data are population based and multicenter and take length of follow-up into account. PTLD incidence among 45 141 renal recipients and 7634 cardiac recipients was determined. As had been noted in other series, incidence was highest in the first year after transplant. During that first year, 0.2% of renal and 1.2% of cardiac recipients developed PTLD, rates that were calculated to be 20 and 120 times higher than those seen in the general population. The incidence of PTLD in subsequent years was about 0.04% per year in renal and 0.3% per year in cardiac recipients (2). In a subsequent report, analyzing 14 284 heart recipients and 72 360 kidney recipients, a cumulative incidence of almost 5000 per 100 000 by 7 years of follow-up was noted in heart recipients and slightly more than 1000 per 100 000 by 10 years of follow-up in renal recipients, a cumulative incidence of about 5% for heart recipients and 1% for kidney recipients (3). A striking feature of this analysis is the fact that PTLD continues to arise even many years after transplantation, despite the fact that therapeutic immunosuppression is reduced over time. Prolonged survival in the face of immunodeficiency is, therefore, associated with a continued risk of lymphoid malignancy in the setting of organ transplantation. The effect of highly active antiretroviral therapy on the incidence of lymphoid malignancy in the setting of acquired immunodeficiency syndrome (AIDS) is as yet unclear. Despite improvement in CD4 counts and relatively good immune function on such therapy, the transplant experience raises some concern that the problem of lymphoma may not be obviated.
The risk of PTLD appears to be influenced by quantitative and qualitative differences in the degree of immunodeficiency. Statistically significantly higher doses of cyclosporin and azathioprine were found in heart than in kidney recipients on analysis of Collaborative Transplant Study data. A related observation was the significantly higher risk for PTLD among North American recipients than for patients transplanted at European centers, amounting to a relative risk of 2.12, which was associated with, and attributed to, higher immunosuppressive dosage among North American recipients (2). Highly potent anti-T-cell therapy has furthermore been shown to markedly influence the incidence in both organ and allogeneic bone marrow recipients. A ninefold higher incidence of PTLD was noted among patients who had received induction therapy with the immunosuppressive antibody OKT3 (11.4% versus 1.3%) in a series of cardiac transplant recipients (6). A strong dose response was observed, in that 6.2% of the patients who had received one course of the drug and 35.7% of the patients who had received two courses developed the disease. A murine monoclonal antibody directed against the human CD3 receptor-T-cell complex, OKT3 profoundly depletes circulating CD3+ T lymphocytes. Similar effects have been noted in other series (2,7,8) and with T-cell depletion of donor marrow to reduce graft-versus-host disease in allogeneic bone marrow transplantation. PTLD is relatively uncommon (<1%) in the absence of such manipulations (9), whereas incidences of 12%–24% have been reported after T-cell depletion (10,11). It is not clear whether a risk threshold can be defined in organ recipients by qualitative or quantitative measures of immune function, but such information would be of relevance to the long-term management of AIDS, now that at least partial immune reconstitution is feasible. In the AIDS setting, the risk of Epstein-Barr virus (EBV)-associated immunoblastic lymphoma, and particularly primary central nervous system (CNS) lymphoma, has been associated with severe reduction in CD4 counts (12), but it is likely that more subtle gradations of risk exist.
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EBV ASSOCIATION |
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The malignancies most clearly over-represented in organ transplant recipients are squamous skin and cervical carcinomas, B-cell lymphomas, and Kaposi's sarcoma (13), all known to be virally related tumors. The majority of PTLDs have been EBV associated, with approximately 5% of tumors being clearly EBV negative. This situation is significantly different from that seen in the AIDS setting in which EBV-negative tumors make up a third or more of the total (14), a discrepancy with other immunodeficiency states that is as yet unexplained. The tumor-associated EBV is clonal in PTLD, supporting an etiologic role for the virus rather than for subsequent infection of neoplastic B cells. The pattern of viral clones furthermore corresponds to B-cell clonality as determined by immunoglobulin gene rearrangement analysis. Lesions consisting of polyclonal or multiclonal B-cell proliferations contain multiple EBV clones, whereas monoclonal proliferations show evidence of a single infectious event (15,16).
The incidence of PTLD is much higher in patients who are EBV seronegative prior to transplant (4,5). The risk of PTLD in EBV-seronegative recipients in one series was determined to be 76 times that in seropositive recipients (17). Most adults (90% or more) are EBV seropositive. The majority of seronegatives are children, with a higher likelihood of seronegativity the younger the child (4,18). A series from the University of Pittsburgh (PA) identified a four times higher risk of PTLD for pediatric than for adult transplant recipients (4). PTLD is, therefore, a particular problem among pediatric transplant recipients, and the risk has been considered to be sufficiently high as to preclude transplantation in some instances (17).
Analysis of archived liver biopsy specimens in liver transplant recipients has shown the presence of EBV, as determined by polymerase chain reaction (PCR) or by in situ immunohistochemical staining for EBER-expressing cells, in 70% of patients who subsequently developed PTLD. Only 10% of the patients who did not go on to develop the disease had such findings (19). Identification of a preclinical phase for PTLD would be highly desirable, in that early intervention might obviate the emergence of more aggressive proliferations. Viral load, as determined in peripheral blood mononuclear cells, has been found to increase around the time of clinically detected disease (20,21). It is not clear whether such rises in EBV load indicate EBV-driven neoplasia or are simply reflective of severe immunodeficiency at the time. One extensive study (22) of EBV load in peripheral blood mononuclear cells addressing this question showed that rises in viral load occurred at some point in the post-transplant course of 73% of the patients studied. Although the mean rise in patients with PTLD was more than threefold higher, levels in patients who did not develop PTLD frequently equalled or exceeded the viral load seen in those who did. Viral load as determined in circulating mononuclear cells may, therefore, lack the specificity needed for a screening test. Attempts at defining quantitative standards with predictive value are under way, and a number of transplant centers have started monitoring patients with EBV viral load assays (23). Of interest, EBV DNA can be measured in serum from patients with PTLD with the use of very sensitive PCR techniques. In preliminary work, very high sensitivity and specificity for PTLD has been identified. It is not clear whether the presence of EBV DNA in serum might reflect tumor metabolism (24). Unlike oral hairy leukoplakia in immunodeficiency, PTLD has not been associated with a fully productive viral lytic cycle (25–27). Nevertheless, the viral Bzlf-1 protein, representing the initial entry into the lytic pathway, is generally expressed in PTLD, and there have been indications that at least partial virion production may occur (25–27).
The ability to monitor patients at risk for EBV-associated lymphoproliferations, and to intervene at a subclinical point in the disease process, is clearly attractive. PTLD represents a good model system for developing and testing such approaches. It may then be possible to apply a similar strategy to human immunodeficiency virus (HIV) disease, a setting in which HIV viral load monitoring has proven to be clinically feasible and highly useful in guiding therapy.
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PATHOLOGY AND GENETIC ALTERATIONS |
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The term PTLD encompasses a range of lymphoproliferations, extending from reactive or hyperplastic-looking morphologies to a picture indistinguishable from immunoblastic non-Hodgkin's lymphoma (28–30). Several pathologic classification systems have been proposed (28,29,31). Correlative molecular genetic analysis has recently been included to allow grouping into three relatively distinct entities. 1) Plasmacytic hyperplasia is usually polyclonal, arising from the tonsils or cervical lymph nodes, containing multiple EBV infection events, and lacking oncogene or tumor suppressor gene alterations. It is not clear to what extent this entity differs from infectious mononucleosis in the setting of immunodeficiency. 2) Polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma are usually monoclonal, containing a single form of EBV, and lacking oncogene and tumor suppressor gene alterations. 3) Immunoblastic lymphoma or multiple myeloma is monoclonal, containing a single form of EBV, and containing one or more structurally altered genes (N-RAS, C-MYC, p53, or others) (30). A recent Society of Hematopathology workshop on the subject recognized a number of other not clearly categorizable morphologies encountered among PTLDs (32).
Relatively few PTLD cases have been studied for cytogenetic abnormalities. These abnormalities have typically been seen in tumors with monomorphic histology, but no distinct abnormality has been identified as being characteristic for PTLD. In a recent series of 28 patients, no clonal cytogenetic abnormalities were identified among 10 polymorphic tumors, all of which were polyclonal or oligoclonal. Analysis of 12 monomorphic cases revealed a variety of abnormalities in 10 cases: chromosome 8 translocations involving the MYC gene, trisomy 9, trisomy 11, and 11q27 (33).
The existence of more than one clone within the same lesion as well as both differing clones and differing histopathology in lesions at separate anatomic sites in the same patient is a characteristic feature of PTLD (34,35). Such multifocal clonal evolution contrasts sharply with the homogeneity seen in classic non-Hodgkin's lymphoma and likely represents a different mechanism for lymphoid neoplasia in immunodeficiency. Under suitable conditions, EBV-driven lymphoproliferation may appear simultaneously at multiple sites in the body. Similar findings have been described in AIDS-associated adenopathy and EBV-related tumors. EBV-negative tumors and small noncleaved histology are, however, infrequent in the PTLD setting. That difference is currently unexplained. It might relate to differences in the nature of immunodeficiency, to the state of immune activation that characterizes HIV disease, which has no counterpart in the organ transplant setting other than perhaps the presence of the allograft, or to other as yet unknown factors.
The vast majority of PTLDs studied have been of B-cell origin. EBV-negative aggressive T-cell lymphomas have been identified as a rare, very late occurrence, presenting at a median of 15 years after transplantation (36). Both EBV-associated and EBV-negative T-cell PTLD have been identified in other studies (32,37). The emergence of new entities, presumably immunodeficiency associated, at late time points after transplantation should be of some interest with regard to HIV disease, in which prolonged survival in the face of continuing immunodeficiency is now a realistic prospect.
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CLINICAL ISSUES |
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The clinical presentation and behavior of PTLD are very heterogeneous. Extranodal disease and rapid tumor growth are frequently seen, as has been the case with the AIDS-related lymphomas. Despite the variability of PTLD, some clinical patterns have been identified. An infectious mononucleosis-like presentation, with prominent constitutional symptoms and rapid enlargement of the tonsils and cervical lymph nodes, is often the picture in the early post-transplant period—less than about 6 months to 1 year from the time of transplant (38,39). Highly immunosuppressed patients may present with widespread disease as well as diffusely infiltrative multiorgan involvement and pursue a fulminant clinical course (1,40). Lesions are usually polyclonal or oligoclonal in composition, and tumor histology is polymorphic rather than monomorphic. An analogous situation has not clearly been seen in the AIDS setting.
PTLD presenting later than about 1 year after transplantation tends to be more monomorphic, manifests fewer constitutional symptoms, and runs a more gradual clinical course. Clinically, this picture most closely resembles the AIDS-related immunoblastic or large-cell lymphomas. Gastrointestinal involvement is a frequent finding in PTLD (1). The transplanted organ itself appears to be a preferred site of involvement, being affected in up to 20% of cases. Central nervous system (CNS) involvement at presentation is mainly seen as part of very extensive disease. A clinical picture resembling myeloma can occur, with lytic bone lesions or the production of a monoclonal paraprotein (40,41).
A number of different approaches to treatment has met with a degree of success. PTLD is nonetheless a rapidly progressive, frequently lethal disease. Overall long-term survival after a PTLD diagnosis was about 30% in the Collaborative Transplant Study registry analysis mentioned previously (2,3).
Reduction in Immunosuppression
Reduction in immunosuppression will result in complete and durable resolution of PTLD in some cases and is typically the first treatment maneuver attempted. The same phenomenon has been described for Kaposi's sarcoma after organ transplantation. In the case of AIDS-related Kaposi's sarcoma, regression of lesions on institution of highly active antiretroviral therapy has been described anecdotally, and the incidence of this AIDS complication has clearly declined. Restoration of immune function has not had as clear an effect on the AIDS-related lymphomas. PTLD may offer some clues to possible reasons. The likelihood of response to reduced immunosuppression in an individual patient is difficult to predict. Reports have consisted of small retrospective series of patients who were not treated uniformly. In a study from the University of Pittsburgh, more than 80% of patients presenting at less than 1 year after transplantation responded to a reduction in immunosuppression, whereas none presenting at more than 1 year did so (42). More variable results with reduced immunosuppression have been reported in other series: lower response rates and greater variability in terms of the interval since transplantation (40,43). EBV is assumed to be the target of this immune response. No clear difference in the pattern of EBV antigenic expression has so far been identified in PTLD presenting early as opposed to late. Immunodominant antigens are expressed in all of the tumors, although some degree of restriction has been seen, possibly reflecting varying degrees of immune control (26,44). Tumor characteristics, specifically the presence of structural alterations conferring growth autonomy or resistance to immune-mediated destruction, may, therefore, account for the failure of immune reconstitution to eradicate the disease. In keeping with that hypothesis, the presence of mutations in the bcl-6 proto-oncogene, by use of single-strand conformation polymorphism and sequence analysis, has been shown to associate with histopathologic category and with response to reduction in immunosuppression (45). No bcl-6 mutations were identified in cases classified as plasmacytic hyperplasia. Mutations were found in 43% of polymorphic lesions and in 90% of PTLDs classified as immunoblastic lymphoma or multiple myeloma. Bcl-6 mutations were predictive for lack of response to reduced immunosuppression. Although the association was statistically significant, the correlations were retrospective and treatment was variable. Nonetheless, this finding represents the clearest predictor for response to reduced immunosuppressives to date. It would, therefore, appear that only certain PTLDs are reversible, even when immunosuppressives are reduced to the point of rejection (40).
Local Therapies
Surgical resection of PTLD can be curative. Limited-field irradiation for anatomically limited but unresectable disease has also resulted in long-term remission. Resection has furthermore been effective when a limited number of residual lesions persisted after a partial response to reduced immunosuppression (40,42). Such observations underscore the fact that PTLD differs significantly from the non-Hodgkin's lymphomas seen in the general population.
Antivirals
Regression of lymphoproliferations has been described following the use of high-dose acyclovir in a small number of cases (41,46). High-dose acyclovir has proved to be ineffective as prophylaxis for PTLD in individual bone marrow transplant recipients (47). It is not known whether other drugs, such as ganciclovir or foscarnet, are of any greater efficacy. It is also unclear whether inhibition of EBV replication could be expected to affect an established EBV-associated tumor. Uncontrolled studies (48) have suggested possible prophylactic benefit, but firm conclusions cannot be drawn in the absence of a randomized, prospective study with a no-prophylaxis control arm.
Interferon
Durable remissions have been achieved with interferon alfa 2b, given with concomitant immunosuppressives. Neither the response rate nor the mechanism of action is defined at this point. The drug might exert an antiviral and/or an antitumor effect; both early polyclonal proliferations and late-presenting monoclonal lesions have been reported to respond (47,49). In a series of 18 patients treated with interferon alfa-2b and simultaneous reduction in immunosuppression, an overall response rate of 83% (77% complete response and 6% partial response) was reported. It is unclear to what extent the responses were due to reduced immunosuppression or to interferon. Rejection and life-threatening infection occurred in half these patients, and median survival was 6 months (50).
Monoclonal Anti-B-Cell Antibodies
Anti-B-cell monoclonal antibodies have demonstrated efficacy in the treatment of PTLD. A mixture of anti-CD21 and anti-CD24 monoclonal antibodies was used in a European multicenter trial, involving both organ and bone marrow transplant recipients with PTLD (43,51). An update on this series of patients was reported (52). Fifty-eight patients with PTLD (27 following bone marrow and 31 following organ transplantation) were treated. The overall complete response rate was 61%. The relapse rate was low at 8%. The long-term overall survival was 46% (bone marrow transplant 35%, organ transplant 55%) at a median follow-up of 61 months. Complete remission was achieved in 46% of monoclonal and in 80% of oligoclonal cases (P = .05). Multivisceral disease, CNS involvement, and late onset PTLD (>1 year after transplant) were identified as predictive for poorer response on multivariate analysis. Only 29% of patients with CNS involvement and 22% of patients presenting later than 1 year after transplant achieved complete remission. The implications of these observations for AIDS-related lymphomas are unclear. Toxicity was mild, consisting of transient fever, hypotension, and neutropenia. The antibodies used are not currently clinically available. The commercially available anti-CD20 antibody rituximab has shown efficacy in PTLD, based on anecdotal reports (53), and on a retrospective study of 32 patients with PTLD related to organ transplant (26 patients) or to bone marrow transplant (six patients) (54). Immunosuppressives were modified in 27 patients; it is not clear whether that occurred simultaneously with antibody treatment. Among the 26 evaluable patients, 54% complete remission and 15% partial remission were reported. Median duration of follow-up was 5 months. Two relapses were seen at approximately 9 months, which is about the time when the effect of this antibody is known to wane. In summary, monoclonal anti-B-cell antibodies appear to have significant activity in PTLD. Whether antibodies have useful activity against disease refractory to reduced immunosuppression and particularly in tumors containing structural genetic alterations remains to be clearly defined. The latter cases would be of greatest interest in attempting to extrapolate to the setting of established AIDS-related lymphomas.
Chemotherapy
Cytotoxic chemotherapy has resulted in significantly greater toxic effects in organ transplant recipients than in the general population, mainly due to infectious complications. This is analogous to what has been seen with AIDS-related lymphomas. Cytotoxics have been considered as a treatment of last resort in PTLD, as other treatment options exist. A mortality of 70% has been reported for patients presenting at more than 1 year after transplant (41,42). Septic and other complications of chemotherapy have been the major problem in some centers, whereas others have found refractory disease to be common (1,41,43). Those poor results have been obtained with a variety of full-dose or attenuated regimens, frequently combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone. More encouraging results have been achieved in a small series of cardiac recipients treated with aggressive chemotherapy, predominantly ProMACE-CytaBOM (40). Mortality during chemotherapy was 25% (sepsis, refractory disease), growth factor support was not used; the surviving patients all achieved complete remission. No patient has relapsed, at a median follow-up of 64 months. This regimen allowed the discontinuation of all other immunosuppressives for the duration of chemotherapy and minimized exposure to doxorubicin in cardiac recipients. This approach is currently being tested in an intergroup study being conducted by the Southwest Oncology Group and the Eastern Cooperative Oncology Group. The advent of better supportive care measures, granulocyte colony-stimulating factor, and preventive antibiotics may further reduce the toxicity of chemotherapy in this patient population. The concept that immunodeficiency-related lymphomas require aggressive rather than dose-attenuated chemotherapy is currently being studied in a number of clinical trials, including a phase II study of ProMACE-CytaBOM for AIDS-related lymphomas by the Southwest Oncology Group, and an EPOCH regimen at the National Cancer Institute (55).
T-Cell Therapy
EBV-specific immunocompetence has been rapidly restored in T-cell-depleted allogeneic bone marrow recipients by the infusion of a limited number of peripheral blood leukocytes from the donor (56). More recently, highly selective adoptive transfer of T-cell immunity has been achieved with the use of in vitro-expanded EBV-specific cytotoxic T cells as treatment and prophylaxis for PTLD in T-cell-depleted bone marrow transplant recipients (57,58). Polyclonal T-cell lines containing both CD4 and CD8 cells were generated, since it is not presently clear which antigens expressed by EBV-infected cells are important in generating an effector response. Adoptive transfer of EBV-specific T-cell immunity would clearly also lend itself to prophylaxis against PTLD. Whether exogenously expanded T cells would be effective in tumors refractory to reduced immunosuppression is unknown. Using such approaches in the organ transplant or AIDS setting will require significant adaptations, in view of the major histocompatibility complex-restricted nature of the T-cell response. The vast majority of organ transplant-related PTLDs is of recipient origin (59–61), not of donor origin as is the case following bone marrow transplantation. T cells must, therefore, be generated from the patient.
In summary, significant differences and similarities exist between PTLD and AIDS-related lymphoma, in terms of viral association, histopathology and molecular pathology, clinical behavior, and response to treatment. PTLD can be a valuable model system for EBV-related lymphoid neoplasia in immunodeficiency, allowing the development and testing of screening, prophylactic, and therapeutic measures that may be directly applicable to the setting of AIDS-related lymphoma.
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