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Originally published as JCO Early Release 10.1200/JCO.2005.01.0934 on September 26 2005 © 2005 American Society of Clinical Oncology. Prognostic Analysis for Survival in Adult Solid Organ Transplant Recipients With Post-Transplantation Lymphoproliferative DisordersFrom the Division of Hematology, Department of Internal Medicine, Department of Biostatistics, Department of Pathology, Division of Infectious Diseases, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Division of Nephrology, Division of Transplantation Surgery, and Department of Surgery, Mayo Clinic, Rochester, MN Address reprint requests to Thomas M. Habermann, MD, Division of Hematology, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, 200 First St, SW, Rochester, MN 55905; e-mail: habermann.thomas{at}mayo.edu
PURPOSE: The objective of this study was to determine prognostic factors for overall survival in patients with post-transplantation lymphoproliferative disorders (PTLDs). PATIENTS AND METHODS: This study focused on the 107 adult solid organ transplantation patients who were diagnosed with PTLDs at Mayo Clinic (Rochester, MN) between December 1970 and May 2003. RESULTS: The median age at the time of diagnosis was 48 years (range, 15 to 75 years). Extranodal disease including grafted organ involvement was present in 85 patients (80%). The graft organ was involved in 30 patients (28%). At the time of these analyses, 62 patients (58%) had died. The median survival for the entire cohort was 31.5 months (95% CI, 10.7 to 72.5 months). The median follow-up of living patients was 51.8 months (range, 5.6 to 202.6 months). In univariate analyses for overall survival from the time of PTLD diagnosis, the following poor prognostic factors were identified: poor performance status with Eastern Cooperative Oncology Group levels 3 and 4 (P < .0001), grafted organ involvement (P = .0005), the presence of one or more extranodal sites (P = .005), both nodal and extranodal disease (P = .002), high International Prognostic Index (P = .006), advanced stage (P = .001), and elevated lactate dehydrogenase (P = .03). A final multivariable model for survival was constructed using three factors: poor performance status (3 to 4), monomorphic disease, and graft organ involvement. CONCLUSION: A prognostic model has been developed for PTLD patients using one center's 30 years of experience. We propose additional confirmation and validation of these prognostic factors in larger prospective studies.
Post-transplantation lymphoproliferative disorders (PTLDs) represent one of the most commonly observed fatal consequences of immunosuppression in patients undergoing organ transplantation. PTLDs constitute the most common malignancy complicating organ transplantation after nonmelanomatous skin cancer and in situ cervical cancer.[1] The overall incidence of PTLD is approximately 1% to 3% in the transplantation population.[2,3] PTLDs differ in their pathogenesis and clinical characteristics from lymphoproliferative disorders that occur in immunocompetent individuals. PTLDs are a heterogeneous group of lymphoproliferative disorders that range from benign polyclonal lymphoid hyperplasia through polymorphous to monomorphous lymphomas. The most common pathologies include diffuse large B-cell lymphoma and immunoblastic lymphoma, whereas T-cell lymphomas, Hodgkin's disease, and plasma cell neoplasms are less common.[4-6] The major risk factors historically associated with this disease that have been identified to date include the Epstein-Barr virus (EBV) serostatus of the recipient, the cytomegalovirus seroconversion of the recipient, and the degree and type of immunosuppressive regimens used.[2,7] In addition, other risk factors have also been implicated in the development of PTLDs.[8] The EBV virus plays a critical role in the development of PTLDs. The EBV latent membrane protein 1 leads to the transformation of B lymphocytes through its activation of transcription factors such as nuclear factor kappa B.[9] However, not all occurrences of PTLDs are associated with EBV infection. EBV-negative occurrences have been reported to occur in 20% to 30% of patients.6,9 PTLDs may occur early after transplantation (within 1 year) or late (> 1 year).[6,10-12] Early PTLDs characteristically are EBV positive, whereas late PTLDs may be EBV negative.[6,9,13,14] Adult solid organ transplantation patients who develop PTLDs have been managed with a variety of approaches including immunosuppression reduction, antiviral therapy, interferon therapy, chemotherapy, radiation therapy, and rituximab monoclonal antibody therapy, as reported previously in the guidelines of therapy of PTLDs.[2,15-18] Cellular therapy with EBV-specific cytotoxic T lymphocytes is currently under investigation in patients with PTLDs after solid organ transplantation.[19] To date, the overall and disease-specific survival in patients who develop PTLDs has been based on reports from small patient series. The suggested rates of overall survival in the published literature have ranged between 25% and 60%.[20] Frequently reported prognostic factors include multivisceral disease (five or more sites involved), severe organ dysfunction, presence of "B" symptoms, stage, advanced age, elevated lactate dehydrogenase (LDH), monoclonality, EBV negative status, late onset of PTLDs, CNS-PTLDs, and bone-marrow transplantation for hematologic malignancies.[16,20-23] PTLDs present with different characteristics than non-Hodgkin's lymphomas arising in immunocompetent individuals. In this study, we propose a prognostic model for patients with adult PTLDs arising after solid organ transplantation. The objective of this study was to determine prognostic factors for overall survival in patients with PTLDs from the time of their PTLD diagnosis that can allow future comparison of data among transplantation centers, interpretation of the literature, adequate management of patients, and the design of clinical trials.
This study focused on 107 adult solid organ transplantation patients who were diagnosed with PTLDs and treated at Mayo Clinic (Rochester, MN) between December 1970 and May 2003. Patients underwent clinical staging with computed tomography of the chest, abdomen, and pelvis; and bilateral bone marrow biopsy, and aspiration. Computed tomography was available at Mayo Clinic in 1970. Retrospective chart review of all patients was performed to ensure uniform staging for all patients diagnosed before the application of the Ann Arbor staging. Histologic diagnosis was performed by two hematopathologists specializing in the diagnosis of lymphoma and included a retrospective review of all pathology specimens that were available for review. Tissue biopsies were retrospectively classified according to The Society for Hematopathology PTLD Workshop.[24] EBV RNA in situ hybridization (EBER) was performed on routinely processed sections. Patients were treated according to a clinicopathologic model that was followed prospectively by the PTLD specialist (T.M.H.). Most all patients were evaluated or treated by this specialist, who followed the following algorithm of therapy for these patients. Surgery was performed as initial therapy in patients who had clinical indications such as bowel perforation or localized disease. All patients had reduction of immunosuppression unless clinically contraindicated. Reduction of immunosuppression was performed according to the previously described recommended guidelines using 50% reduction of immunosuppression: cyclosporine, tacrolimus, and prednisone were decreased to a maintenance level; and azathioprine and mycophenolate were discontinued.[2] If the patient did not respond during a period of 2 weeks, then systemic therapy was initiated. For patients treated before the PTLD treatment guidelines in 1999, 50% reduction in immunosuppression was performed in a more variable fashion and was continued for 2 weeks before the addition of systemic therapy if no response was observed. Starting in 1997, when rituximab was approved by the US Food and Drug Administration, patients with CD20-positive and EBER in situ hybridization status–positive tumors who did not respond to immunosuppressive reduction were treated with single-agent rituximab at 375 mg/m2 weekly for 4 to 8 weeks. If patients were CD20 negative or EBV genome negative, then they were treated with other modalities of treatment such as systemic CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone), or radiation therapy as in CNS lymphoma. Factors evaluated in these patients included the following: time from transplantation to diagnosis of PTLD, type of transplant, sex, age at the time of diagnosis of PTLD, EBER status at histopathologic diagnosis, histology, CD20 status, International Prognostic Index (IPI), stage, performance score, elevated LDH, involvement of the grafted organ, nodal involvement, extranodal involvement (including involvement of the grafted organ), monomorphic/polymorphic disease, interventions, and response to therapy. Interventions were evaluated as reduction of immunosuppression, use of chemotherapy, use of rituximab, and others. This retrospective study was approved by the Mayo Foundation Institutional Review Board and was conducted in accordance with the ethical guidelines mandated by the Declaration of Helsinki.
Statistical Analysis A classification and regression tree analysis (CART) was performed on the candidates to further validate and define the final prognostic model. Comparisons were made of Cox proportional hazards models consisting of the prognostic model against models that included these variables as well as other candidate variables. A scoring function was generated from the final model, in which the presence of each of the variables was scored 1 point and the sum of the variables constituted the final score. A Kaplan-Meier survival curve was plotted for each of the different scores, and scores were categorized if appropriate (eg, high v low score). The hazard ratio for the scoring function from the prognostic model was compared with the hazard ratio for scoring functions from other candidate models. Data on different prognostic factors were missing from the patients' files. No data on survival outcome were missing. Missing data were dealt with by carrying out so-called complete case analyses, in which patients were excluded from particular analyses if studies on the required variables were not performed. In addition, validity of the resulting final prognostic models was checked by completing the model-building exercise with a data set for which missing data were imputed.
Patient Characteristics From December 1970 and May 2003, 107 adult solid organ transplantation patients were diagnosed with PTLDs and managed at Mayo Clinic. The median age at the time of diagnosis of PTLD was 48 years (range, 15 to 75 years), and 23 patients (22%) were older than 60 years ([Table 1]). The majority of patients (62%) were male. The types of organ transplantation included renal (34%), liver (33%), cardiac (14%), renal/pancreas (7%), pancreas (5%), lung (4%), and multiorgan (5%).
As expected, the majority (80%) of patients presented with extranodal disease. Thirty (28%) patients had involvement of the grafted organ. Seventy (78%) of 90 patients were EBV positive by in situ hybridization, and 71 (86%) of 83 patients were histologically CD20 positive ([Table 2]). Sixty-one percent were stage 3 to 4, 29% had an Eastern Cooperative Oncology Group performance score (PS) of 3 to 4, and 63% (36 of 57) had an elevated LDH. Of those patients with an available LDH value, high-intermediate IPI of 3 to 5 was manifest in 36 (63%) of 57 patients.
Initial therapy consisted of reduction of immunosuppression with no other interventions in 40 patients (37%), surgery with or without reduction of immunosuppression in 26 patients (24%), chemotherapy with or without rituximab in nine patients (8%), rituximab in eight patients (7%), radiation therapy in eight patients (7%), and no therapy in 16 patients (15%; [Table 3]). Forty-nine (46%) patients received a second intervention, which included chemotherapy in 43%, rituximab in 27%, and chemotherapy with rituximab in 6%. One patient was treated with autologous stem-cell transplantation as a fourth-line therapy and died 19 days after transplantation. Reduction of immunosuppression was performed in 75% of the patients; only 20% of the patients achieved remission with this modality of therapy with no subsequent relapses and no additional therapy required. Rituximab was used for therapy as a single agent or in combination with chemotherapy in 29 patients (27%) from January 1999 to May 2003. Thirteen (12%) patients treated with single-agent rituximab achieved a complete response and required no additional therapy. Single-agent rituximab was used as a first-line therapy or after previous therapies (second- or third-line therapy). The median time to follow-up of these patients from the time of diagnosis to the last time of follow-up at the time this article was written was 1.8 years (range, 0.8 to 3.9 years). Twelve of these patients were still alive at the time of last follow-up.
Univariate Results The median survival for all patients was 31.5 months (95% CI, 10.7 to 72.5 months) and the median follow-up on 45 living patients was 51.8 months (range, 5.6 to 202.6 months). The overall response rate (complete response [CR] and partial response [PR]) to therapies instituted was 58%; the response rate to initial therapy was 44%. At the time of these analyses, 62 patients (58%) had died. In univariate analyses for overall survival from diagnosis of PTLDs, the following poor prognostic factors were identified: advanced stage (P = .003), age at diagnosis of PTLD (P = .04), poor PS (P < .0001), grafted organ involvement (P = .0005), elevated LDH (0.03), the presence of one or more extranodal sites (P = .005), and the presence of both nodal and extranodal disease (P = .002). High-intermediate to high IPI was a significant model for poor prognosis (P < .001). Response to therapy (P < .0001) and reduction of immunosuppression (P = .002) were related to improved overall survival. The EBV (EBER) tumor status was not statistically significant in this patient cohort (P = .51). Age at transplantation (P = .06) and CD20 status were borderline significant (P = .08) for survival. The use of rituximab therapy did not lead to a significant improvement in the overall survival of this cohort of patients (P = .33).
Multivariable Analysis
To further validate the utility of this model, the prognostic model generated here was compared to the existing IPI model (albeit descriptively; [Figs 3] and [4]). However, such a comparison requires that patients have an LDH value because it is used to calculate the IPI; an LDH level was missing on nearly half of the patients in this analysis. Our generated prognostic model was thus compared with the IPI model in various ways. One approach used was to impute whether the patient had an elevated LDH value using a logistic regression model from other factors for those patients missing LDH data. Although LDH data yielded information and explained some variability in a multivariate model, the final prognostic model did not include LDH level. Models with monomorphic disease and graft organ involvement had better prognostic ability, as measured by the hazard ratio, than models including LDH data. Models containing EBV status, CD20 status, age, and time to PTLD diagnosis were also examined; these models were inferior in their prognostic ability (as assessed by hazard ratios and examination of Kaplan-Meier survival curves) than the final model presented above.
Our prognostic model was also compared with IPI using the 57 patients for whom LDH data were available. The prognostic model remained highly significant for survival in the subset of patients with LDH data available (hazard ratio, 7.83; P < .0001). This was superior to the IPI (hazard ratio, 3.30; P = .006). An examination of Kaplan-Meier survival curves ([Fig 5]) is displayed graphically.
Advances in the diagnosis, classification, and molecular histopathology of PTLDs have been made in recent years.[13,25-27] However, the overall outcome of these diseases in adult patients remains poor.[20,21] The lack of curative therapies and the absence of a prognostic model that predicts survival at diagnosis specific for patients with PTLDs has hindered the development of treatment models based on the prognostic risk of individual patients. Comparison of data among different transplantation centers has been difficult. We sought to analyze all adult solid organ transplant recipients who developed PTLDs and were managed and followed up at the Mayo Clinic. The objective of this study was to develop a prognostic model for predicting survival in patients diagnosed with PTLDs. This prognostic model was designed to predict the outcome of patients diagnosed with PTLDs based on risk factors identified at diagnosis using baseline clinical and pathologic characteristics. Our purpose with this model was to develop an approach that would individualize therapy based on risk factors assessment. Between December 1970 and May 2003, 107 adult solid organ transplantation patients diagnosed with PTLDs were diagnosed and managed at Mayo Clinic. Patients diagnosed with PTLDs after allogeneic bone marrow transplantation and children younger than the age of 15 were excluded from this analysis because these patients differ in their prognosis and potential management strategies. Patients diagnosed with CNS PTLDs were included in the analysis, but did not affect the survival outcome when excluded in this subset of patients. Data in this series were collected during 33 years. Changes that occurred in the management and staging of these patients, such as the addition of rituximab therapy in 1999. To overcome some of these variables, we retrospectively reviewed all of the patient cases and restaged them according to the Ann Arbor staging system. In addition, all of the pathology slides were retrospectively reviewed by expert pathologist and classified according to The Society for Hematopathology PTLD Workshop.[24] Finally, most of the patients were evaluated and treated by an expert lymphoma specialist (T.M.H.), and followed the same treatment algorithm that was implemented prospectively for these patients. The response rate and survival of patients diagnosed with PTLDs remains poor despite the advances in management strategies and the addition of monoclonal antibody therapy with rituximab.[21] In this series, the median survival was 31.5 months (95% CI, 10.7 to 72.5); 62 patients (58%) have died at the time of this analysis. The median follow-up of patients who were alive was 51.8 months (range, 5.6 to 202.6 months). The median survival reported by Leblond et al[20] for 61 patients diagnosed with PTLDs from 1980 to 1999 in two institutions was 24 months, and the median follow-up time among the survivors was 22 months (range, 2 to 105 months). Muti et al[17] reported on 40 solid organ transplantation adult patients diagnosed with PTLDs and showed a cumulative probability of survival at 1 year of 57% (95% CI, 37.6 to 73.4), with a median survival reported that was not reached at 54 months. These data indicate that larger series and data sets need to be explored. Additional interventions for prevention, early detection, and treatment of these disorders are required to improve the response and survival of patients diagnosed with PTLDs. Our patients were treated according to the clinicopathologic model described. Reduction of immunosuppression occurred in 75% of the patients, with only 20% of the patients achieving long-term remission with this modality of therapy. These results are consistent with previous reports suggesting a 25% remission rate after reduction of immunosuppression.[16] Reduction of immunosuppression was a predictor of overall survival in this series. This suggests that there is a significant role of cytotoxic T cells and immune reconstitution in controlling PTLDs. Additional studies are being pursued using new immunosuppressive agents, such as rapamycin, which may control PTLD growth without significantly compromising graft rejection strategies.[28,29] The overall response to therapy was a strong prognostic marker for overall survival in these analyses. The overall response rate (CR and PR) in this series was 58%, which confirms the response rate reported by Leblond et al,[20] in which 38 patients (62%) achieved CR or PR. The data on prognosis of patients with PTLDs is derived predominantly from small case series from multiple transplantation centers. These include data on children and bone marrow transplant recipients, contributing to a significant heterogeneity in the groups of reported patients. This leads to difficulty when interpreting the data in relation to adult solid organ transplant recipients. The largest study published to date included a retrospective analysis of 61 patients from two transplantation centers and reported that performance score of 2 or more, the number of sites (one v > one), primary CNS localization, T-cell origin, monoclonality, nondetection of EBV, and treatment with chemotherapy were poor prognostic factors for overall survival on univariate analysis.[20] In this series, univariate analyses for overall survival from diagnosis of PTLDs in 107 patients identified the following poor prognostic factors: age, advanced stage, poor PS, high LDH, grafted organ involvement, extranodal disease with or without additional nodal involvement, and intermediate to high IPI ([Tables 1] and [2]). Graft organ involvement occurs more commonly within the first year of transplantation (early PTLDs). In some cases, it is secondary to donor-origin PTLDs that characteristically involve the grafted organ. In this series, organ involvement occurred in 28% of the patients. The involvement of the graft organ by PTLDs has not been previously reported to correlate with survival. In this series, the graft organ involvement was a strong predictor of overall survival and was a component of our prognostic model. The presence of extranodal disease in many patients with PTLDs, and consequently the high incidence of stage 4 disease, has been reported previously to correlate with poor prognosis.[20] Nalesnik et al[23] and Benkerrou et al[22] have shown previously that the tumor burden is a poor prognostic factor in patients with PTLDs. Similar to our study, Leblond et al[20] have reported that the involvement of one or more extranodal sites was predictive of poor survival. The high incidence of extranodal involvement of lymphoma in patients with PTLDs compared with patients who develop lymphoma in the immunocompetent state is not well understood. Extranodal disease with or without the presence of nodal disease was a strong predictor of poor prognosis (P < .01); however, graft organ involvement was a more meaningful prognostic indicator when adjusted for poor performance score and monomorphic disease. Thus, extranodal disease was not used in the final prognostic model. Elevated LDH level was a predictor of poor survival in our series, which is consistent with other reports such as by Horwitz et al[30] in 27 patients, but conflicting with the results of Leblond et al[20] The IPI (developed in 1993 by Shipp et al[31]) was developed for patients with newly diagnosed aggressive non-Hodgkin's lymphoma. The model used clinical data that reflect the growth of the tumor (tumor stage, serum LDH level, and number of extranodal disease sites), the patient's response to the tumor (performance status), and the patient's ability to tolerate intensive therapy (age and performance status). This model has been validated for most types of lymphomas including indolent lymphomas and T-cell lymphomas. Using the IPI, we were able to detect the prognosis of our patients with PTLDs accurately. However, because PTLDs comprise many different pathologic entities, including B- and T-cell lymphomas with different grades of aggressiveness, and because previous reports by Leblond et al[20] and Horwitz et al[30] reported that the IPI was not predictive of survival, we sought to develop a model that would predict survival in PTLD patients. In addition, we compared our proposed PTLD model with the IPI model in this group of patients. Examination of Kaplan-Meier survival curves and a comparison of hazard ratios suggest the proposed prognostic model performed better than IPI in separating the survival outcomes of patients. These data suggest that the proposed model should be verified in patients with PTLDs by comparing it with the IPI to predict overall survival accurately. In conclusion, ongoing and future studies using molecular analysis techniques will aid in the identification of differences in these patients that may be more precise in predicting prognosis and survival of patients with PTLDs. However, the proposed PTLD prognostic model comprises three simple factors that can be applied to patients diagnosed with PTLDs in any transplantation center. Given the limited available sample size and retrospective nature of this study, we propose additional confirmation and validation of this model in larger prospective series. We propose analysis of a unified prognostic model across multiple transplantation centers. Given the relatively uncommon incidence of PTLDs, and limited available samples at individual transplantation centers, this approach will provide a larger cohort of patients and will potentially overcome inherent differences in the management of these patients. The use of a unified prognostic model by transplantation centers will aid in the follow-up, management, comparison of data, and the design of future multicenter clinical studies.
The authors indicated no potential conflicts of interest.
Supported in part by Grant No. CA P50 CA97274, the Lymphoma Research Foundation, an ASCO Young Investigator Award, and an ASH Scholar award (I.G.). I.G. is a Lymphoma Research Scholar. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Penn I: Cancers complicating organ transplantation. N Engl J Med 323:1767-1769, 1990[Medline] 2. Paya CV, Fung JJ, Nalesnik MA, 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 68:1517-1525, 1999[Medline] 3. Dharnidharka VR, Tejani AH, Ho PL, et al: Post-transplant lymphoproliferative disorder in the United States: Young Caucasian males are at highest risk. Am J Transplant 2:993-998, 2002[CrossRef][Medline] 4. Weissmann DJ, Ferry JA, Harris NL, et al: Posttransplantation lymphoproliferative disorders in solid organ recipients are predominantly aggressive tumors of host origin. Am J Clin Pathol 103:748-755, 1995[Medline] 5. 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 73:265-271, 2002[CrossRef][Medline] 6. Leblond V, Davi F, Charlotte F, et al: Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: A distinct entity? J Clin Oncol 16:2052-2059, 1998[Abstract] 7. Walker RC, Marshall WF, Strickler JG, et al: Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis 20:1346-1353, 1995[Medline] 8. Kapelushnik J, Ariad S, Benharroch D, et al: Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi's sarcoma. Br J Haematol 113:425-428, 2001[CrossRef][Medline] 9. Nelson BP, Nalesnik MA, Bahler DW, et al: Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: A distinct entity? Am J Surg Pathol 24:375-385, 2000[CrossRef][Medline] 10. Armitage JM, Kormos RL, Stuart RS, et al: Posttransplant lymphoproliferative disease in thoracic organ transplant patients: Ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 10:877-887, 1991[Medline] 11. Aris RM, Maia DM, Neuringer IP, et al: Post-transplantation lymphoproliferative disorder in the Epstein-Barr virus-naive lung transplant recipient. Am J Respir Crit Care Med 154:1712-1717, 1996[Abstract] 12. Nalesnik MA: Clinicopathologic characteristics of post-transplant lymphoproliferative disorders. Recent Results Cancer Res 159:9-18, 2002[Medline] 13. Nalesnik MA: Clinicopathologic features of posttransplant lymphoproliferative disorders. Ann Transplant 2:33-40, 1997 14. Ghobrial IM, Habermann T, Macon W, et al: Differences between early and late post transplant lymphoproliferative disorders (PTLD) in solid organ transplant patients: Are they two different diseases? Transplantation 79:244-247, 2005[CrossRef][Medline] 15. O'Brien S, Bernert RA, Logan JL, et al: Remission of posttransplant lymphoproliferative disorder after interferon alfa therapy. J Am Soc Nephrol 8:1483-1489, 1997[Abstract] 16. 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 71:1076-1088, 2001[CrossRef][Medline]
17. Muti G, Cantoni S, Oreste P, et al: Post-transplant lymphoproliferative disorders: Improved outcome after clinico-pathologically tailored treatment. Haematologica 87:67-77, 2002 18. Choquet S, Leblond V, Herbrecht R, et al: Efficacy and safety of rituximab in B-cell post transplantation lymphoproliferative disorders (B-PTLD): Final results of a multicenter, open label, phase II trial (M 39037 TRIAL). Blood 102:277a, 2003 (abstr 986)
19. Comoli P, Labirio M, Basso S, et al: Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood 99:2592-2598, 2002
20. Leblond V, Dhedin N, Mamzer Bruneel MF, et al: Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol 19:772-778, 2001 21. Choquet S, Mamzer BM, Hermine O, et al: Identification of prognostic factors in post-transplant lymphoproliferative disorders. Recent Results Cancer Res 159:67-80, 2002
22. Benkerrou MJJ, 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 92:3137-3147, 1998 23. Nalesnik MA, Jaffe R, Starzl TE, et al: The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol 133:173-192, 1988[Abstract] 24. Harris NL, Ferry JA, Swerdlow SH: Posttransplant lymphoproliferative disorders: Summary of Society for Hematopathology Workshop. Semin Diagn Pathol 14:8-14, 1997[Medline]
25. Capello D, Cerri M, Muti G, et al: Molecular histogenesis of posttransplant lymphoproliferative disorders. Blood 102:3775-3785, 2003 26. Nalesnik MA, Zeevi A, Randhawa PS, et al: Cytokine mRNA profiles in Epstein-Barr virus-associated post-transplant lymphoproliferative disorders. Clin Transplant 13:39-44, 1999[CrossRef][Medline]
27. Murray PG, Swinnen LJ, Constandinou CM, et al: BCL-2 but not its Epstein-Barr virus-encoded homologue, BHRF1, is commonly expressed in posttransplantation lymphoproliferative disorders. Blood 87:706-711, 1996
28. Nepomuceno RR, Balatoni C, Natkunam Y, et al: Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 63:4472-4480, 2003
29. 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 97:4285-4290, 2000 30. Horwitz SM, Ranheim EA, Morgan DS, et al: A unified approach to posttransplant lymphoproliferative disorder (PTLD): Improved outcome and analysis of prognostic factors. Blood 94:513a, 1999 (suppl 1; abstr 2295) 31. The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987-994, 1993 Submitted January 3, 2005; accepted July 20, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
