Occurrence Of Posttransplant Lymphoproliferative Disorder Research Articles

The Changing Face of Adult Posttransplant Lymphoproliferative Disorder: Dramatic Changes in Histology between 1999-2013

INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different, resulting in two distinct malignancies with different prognoses and responsiveness to therapy. We attempted to confirm reports suggesting that the relative frequency of these two histologies is shifting over time.METHODS: 3,040 adult PTLD cases in the United Network for Organ Sharing database from 1999 to 2013 were included. We analyzed changes in PTLD histology over time and used a multivariate logistic regression model to determine factors associated with monomorphic versus polymorphic histology.RESULTS: We found that the relative proportion of polymorphic vs. monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; p<0.001) (see figure). The change in proportion is driven by a gradual increase in the number of monomorphic PTLD cases (1999-2003, 460 cases; 2004-2008, 597 cases; 2009-2013, 821 cases), with a steady number of polymorphic PTLD cases (1999-2003, 378 cases; 2004-2008, 427 cases; 2009-2013, 357 cases), and was most prominent in recipients who were EBV serostatus positive at the time of transplant. Significant changes in the care and outcomes of solid organ transplant patients occurred during this time period, including changes from cyclosporine based immunosuppressive regimens to tacrolimus based regimens and increased survival of allografts and patients. Multivariate logistic regression revealed that tacrolimus use (p=0.034) and increased survival among transplant patients leading to later occurrence of PTLD (p<0.001) were associated with monomorphic PTLD during the time frame analyzed.CONCLUSION: As the practice of organ transplantation has evolved over time, PTLD has coevolved, shifting from predominately polymorphic to monomorphic histology. These changes in histology have important implications regarding the origin and clinical management of PTLD. [Display omitted] DisclosuresHuntington:Celgene: Consultancy, Other: Travel; Janssen: Consultancy; Pharmacyclics: Honoraria. Schuster:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Nordic Nanovector: Consultancy; Merck: Research Funding.

Identification of Epstein-Barr Virus Related Risk Factors for the Occurrence of Post-Transplant Lymphoproliferative Disorder in Lung Transplant Recipients

<h3>Purpose</h3> Post-transplant lymphoproliferative disorder (PTLD) is the second most common malignancy in solid organ transplantation. Based on recent registry data, ≈ 1.1% of lung transplants (LTx) develop PTLD within the first year. PTLD confers significant morbidity and mortality and has been associated with Epstein-Barr virus (EBV) infection. The threshold for EBV viremia predictive of PTLD is unknown. In the current study we examined risk factors for PTLD development and the relationship between EBV viremia and PTLD in LTx was assessed. <h3>Methods</h3> A single-center, retrospective review of all LTx recipients from 1/1/2009 - 7/31/2019 with EBV viremia was conducted. All patients (pts) with at least one positive EBV PCR test were reviewed for EBV viremia progression and PTLD occurrence. PTLD was confirmed by review of oncology notes, biopsy results, computed tomography and positron emission tomography scans. <h3>Results</h3> One hundred and forty-seven pts were included. Thirty-four (24.8%) underwent work-up for PTLD, of whom ten were diagnosed with PTLD. Median time from transplant to EBV viremia was 368 days (IQR 111-1201) with PTLD diagnosis occurring at a median of 521 days (IQR 150-741) after LTx. The PTLD(+) group had a higher baseline median EBV PCR of 2613 copies/mL (IQR 680-6099) vs 528 copies/mL (IQR 369-930) in PTLD(-) pts and an increased number of positive PCRs; 3.5 (IQR 2-10) vs 1 (IQR 1-2). In patients with EBV IgG data available, (<i>n</i>=66), Donor(+)/Recipient(-) pts were more likely to develop PTLD than other groups, RR = 18.3 (95% CI 3.93, 85.32); p<0.001. A cut-point analysis of EBV viral load determined that pts with a baseline EBV viral load >1930 copies/mL had a significantly higher risk of PTLD development, RR = 31.03 (95 %CI 9.44, 102.02); p<0.001. <h3>Conclusion</h3> EBV mismatch, higher viral loads, and persistence of viremia may be indicative of PTLD development. Patients with an EBV viral load >1930 copies/ml may benefit from closer surveillance.

Low-Dose Antithymocyte Globulin Has No Disadvantages to Standard Higher Dose in Pediatric Kidney Transplant Recipients: Report From the Pediatric Nephrology Research Consortium

IntroductionRabbit antithymocyte globulin (rATG) dosing strategies for induction in pediatric kidney transplantation vary between centers. It is not known whether a lower rATG induction dose provides safe and effective immunosuppression compared with a “standard” higher dose.MethodsWe performed a retrospective multicenter study of all isolated first-time kidney transplant recipients <21 years old who received rATG induction between 1 January 2010 and 31 December 2014 at 9 pediatric centers. An a priori cutoff of a 4.5-mg/kg cumulative rATG dose was used to identify low (≤ 4.5 mg/kg) and standard (> 4.5 mg/kg) exposure groups. Outcomes examined included 12 months posttransplant graft function (estimated glomerular filtration rate [eGFR]); the occurrence of acute rejection, donor-specific antibody (DSA), neutropenia, and viral infection (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and BK virus); and 24-month outcomes of posttransplant lymphoproliferative disorder (PTLD) occurrence and patient and graft survival.ResultsTwo hundred thirty-five patients were included. Baseline features of the low and standard rATG dose groups were similar. By 12 months, the rATG dose group had no significant impact on the occurrence of neutropenia, positive DSA, or viral polymerase chain reaction (PCR). Graft function was similar. Acute rejection rates were similar at 17% (low dose) versus 19% (standard dose) (P = 0.13). By 24 months, graft survival (96.4% vs. 94.6%) and patient survival (100% vs. 99.3%) were similar between the low- and standard-dose groups (P = 0.54 and 0.46), whereas the occurrence of PTLD trended higher in the standard-dose group (0% vs. 2.6%, P = 0.07).ConclusionA low rATG induction dose ≤ 4.5 mg/kg provided safe and effective outcomes in this multicenter low immunologic risk pediatric cohort. Prospective studies are warranted to define the optimal rATG induction dose in pediatric kidney transplantation.

The changing face of adult posttransplant lymphoproliferative disorder: Changes in histology between 1999 and 2013.

Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different with different prognoses and responsiveness to therapy, resulting in 2 different malignancies. We attempted to confirm reports suggesting that the relative frequency of these 2 histologies is shifting over time. We analyzed 3040 adult PTLD cases in the UNOS OPTN database from 1999 to 2013. Changes in PTLD cases over time were analyzed for histology, time from transplant to diagnosis, and patient EBV serostatus. We found that the relative proportion of polymorphic versus monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; P = <.001). The change is driven by a gradual increase in the number of monomorphic PTLD with a steady number of polymorphic PTLD. The change is most strongly seen in transplant recipients who were EBV serostatus positive at the time of transplant. Potential causes are changes in immunosuppressive regimens with increased tacrolimus use (P = .009) and increased survival among transplant patients leading to later occurrence of PTLD (P = .001) that have occurred during the time frame analyzed. As organ transplantation has evolved over time, PTLD has coevolved. These changes in histology have important implications regarding the origin and clinical management of PTLD.

Persistent Epstein-Barr viral load in Epstein-Barr viral naïve pediatric heart transplant recipients: Risk of late-onset post-transplant lymphoproliferative disease.

AIMTo examine the risk of late-onset post-transplant lymphoproliferative disorder (PTLD) in the presence of persisting high Epstein-Barr virus (EBV) in EBV naïve pediatric heart transplant (HT) recipients.METHODSA retrospective review of the medical records of the 145 pediatric HT recipients who had serial EBV viral load monitoring at our center was performed. We defined EBV naive patients whose EBV serology either IgM or IgG in the blood were negative at the time of HT and excluded passive transmission from mother to child in subjects less than 6 mo of age.RESULTSPTLD was diagnosed in 8 out of 145 patients (5.5%); 6/91 (6.5%) in those who were EBV seropositive and 2/54 (3.7%) in the EBV naïve group at the time of HT (P = 0.71). We found 32/145 (22%) patients with persistently high EBV load during continuing follow-up; 20/91 (22%) in EBV seropositive group vs 12/54 (22%) in EBV naïve group (P = 0.97). There was no significant association between pre-HT serostatus and EBV load after transplant (P > 0.05). In the EBV seropositive group, PTLD was diagnosed in 15% (3/20) of patients with high EBV vs 4.2% (3/71) of patients with low or undetectable EBV load (P = 0.14) whereas in EBV naïve patients 8.3% (1/12) of those with high EBV load and 2.3% (1/42) with low or undetectable EBV load (P = 0.41). There was a highly significant association between occurrence of PTLD in those with high EBV load and duration of follow up (4.3 ± 3.9 years) after HT by Cochran-Armitage test for the entire cohort (P = 0.005). At least one episode of acute rejection occurred in 72% (23/32) of patients with high EBV vs 36% (41/113) patients with low or undetectable EBV after HT (P < 0.05).CONCLUSIONThere is an association between persistently high EBV load during post-HT follow up and the occurrence of late-onset PTLD in pediatric HT recipients irrespective of serostatus at the time of transplant. The occurrence of allograft rejection increased in patients with high EBV load presumably due to reduction in immunosuppression.

Comparison of different rabbit ATG preparation effects on early lymphocyte subset recovery after allogeneic HSCT and its association with EBV-mediated PTLD

Rabbit antithymocyte globulin (ATG) is commonly used before allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent graft-versus-host disease. Studies comparing the effect of different ATG preparations and dosages on immune reconstitution and risk for Epstein-Barr virus (EBV)-mediated post-transplant lymphoproliferative disorder (PTLD) are rare. In this retrospective study, we determined T and B cell subsets by flow cytometry after allo-HSCT in children, who received ATG-Genzyme (ATG-G, n = 15), ATG-Fresenius (ATG-F, n = 25) or no-ATG treatment (n = 19). Additionally, PCR-quantified EBV-genome copy counts were correlated with incidence of PTLD. We could confirm a dose-dependent impairment of CD8(+) and CD4(+) T cell regeneration by ATG-G, including naïve and memory CD4(+) T cells. No differences were seen between the currently applied dosages of 5-10 mg/kg ATG-G and 20-60 mg/kg ATG-F. Significantly delayed T cell subset reconstitution was determined only at high dosages of 20-60 mg/kg ATG-G compared to ATG-F. B cell reconstitution was comparably impaired in ATG-G- and ATG-F-treated patients. Although the incidence of EBV reactivation was similar in both ATG groups, EBV copy counts of >10(4) copies/10(5) peripheral blood mononuclear cells and the occurrence of PTLD were only found in ATG-G-treated patients. We conclude that high, but importantly not currently applied low dosages of ATG-G, impair thymic T cell regeneration and memory T cell immunity to a greater extent than ATG-F in pediatric patients. In addition, our results suggest an increased risk for EBV-PTLD when treated with ATG-G. Prospective studies are warranted to compare different ATG preparations with regard to the immune reconstitution and EBV-PTLD.

Risk of posttransplant lymphoproliferative disorder associated with use of belatacept

Published evidence on a rare but serious malignancy associated with use of the first biological agent approved for long-term maintenance immunosuppression in renal transplant recipients is reviewed. Belatacept (Nulojix, Bristol-Myers Squibb) is approved by the Food and Drug Administration for use in combination therapy to prevent renal graft rejection in patients who are Epstein-Barr virus seropositive. Belatacept appears to offer some advantages over calcineurin inhibitor-based regimens (e.g., no need for therapeutic drug monitoring), but its use poses a risk of posttransplant lymphoproliferative disorder (PTLD), a rapidly progressing and often lethal malignancy. The efficacy and safety of more-intensive and less-intensive belatacept regimens were established in two Phase III clinical trials, which found that rates of patient and graft survival were comparable to those in cyclosporine users; belatacept was shown to be superior in preserving renal function. The occurrence of PTLD, particularly PTLD involving the central nervous system, in 0-4% of belatacept-treated patients in clinical trials prompted postmarketing initiatives: (1) implementation of a risk evaluation and mitigation strategy (REMS) program to help ensure the safe and proper use of belatacept, (2) longitudinal studies to better define the risks and outcomes of belatacept therapy, and (3) a manufacturer-created patient registry to track belatacept use and encourage voluntary reporting of associated adverse events. Appropriate patient selection and adherence to REMS requirements, including patient counseling and facilitation of registry enrollment, are essential in mitigating the increased risk of PTLD associated with belatacept therapy.

Lymphoma after living donor kidney transplantation: an Iranian multicenter experience

Post-transplant lymphoproliferative disorders (PTLD) are well-recognized complications in solid organ recipients. Limited data exist about the development of PTLDs in living kidney recipients. This study deals with a multicenter nationwide experience with kidney recipients from living donors. We reviewed data of PTLD patients from a total population of 6,500 patients transplanted at three different transplant centers in Iran from 1984 to 2006. We also compared their data with 2,250 normal kidney recipients of Baqiyatallah Transplant Center. Data were analyzed to determine potential correlates with the occurrence of PTLD and patient outcome. Overall, 31 patients were diagnosed as having post-transplant lymphomas. The incidence of PTLD in our kidney transplant population comprised 0.47%. Sixteen (53%) PTLD patients were females, whereas 15 (47%) were males. The mean ages at transplantation and diagnosis were 37.1 and 41.9, respectively. Twelve (63%) patients died, and seven are alive. All deaths occurred within the 1st year after PTLD diagnosis. The mean time period from transplantation to diagnosis of PTLD was 64 (0.7-173) months. Localization of PTLD in the brain associated the worst outcome. Compared to non-PTLD patients, PTLD patients were significantly female predominated (51.6% vs. 32.2%; P = 0.03) and had lower age at transplantation (36.9 years vs. 42.9 years, respectively; P = 0.01). Patients under immunosuppressive regimens containing azathioprine were at higher risk for acquiring PTLDs compared to those with a MMF-containing regimen. PTLD is a major threat to kidney transplant recipients. Immunosuppressive agents have a significant role in developing the disease. Early detection of the disease and using more safe immunosuppresants may have beneficial effects on patient outcomes and incidence of the disease.

Epstein–Barr virus early‐antigen antibodies before allogeneic haematopoietic stem cell transplantation as a marker of risk of post‐transplant lymphoproliferative disorders

The occurrence of post-transplant lymphoproliferative disorders (PTLDs) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents a clinical problem. Pretransplant Epstein-Barr virus serological status and viral load was determined in 21 recipients and 28 control transplanted patients, with (+) and without (-) PTLD, respectively. Early-antigen immunoglobulin G (EA-IgG) was detected in 12/21 PTLD+ patients, but only 2/28 PTLD patients (P = 0.00023, Odds ratio = 17.42). High viral load was detected in peripheral blood mononuclear cells at PTLD diagnosis, independently of deleted LMP1. Detection of EA-IgG in allo-HSCT recipients pretransplantation might be considered as risk factor for PTLD development.

Occurrence of post-transplant lymphoproliferative disorders among over thousand adult recipients: any role for hepatitis C infection?

Post-transplant lymphoproliferative disorders represent an increasingly important complication of organ transplantation. Although the majority of the post-transplant lymphoproliferative disorder are etiologically related to Epstein-Barr virus infection other factors may play a role. Hepatitis C virus may induce clonal expansion of B-lymphocytes and has been associated with extrahepatic lymphoproliferative disorders. In this study, we have evaluated: (i) the prevalence of post-transplant lymphoproliferative disorder; (ii) presence of Epstein-Barr virus in post-transplant lymphoproliferative disorder tissue; and (iii) the potential association between post-transplant lymphoproliferative disorder development and hepatitis C virus infection in a large cohort of adult solid organ transplant recipients. The study involved 1011 liver, heart and kidney-transplanted patients. Different immunosuppression therapy was recorded from all patients, all were screened for hepatitis C virus infection. When post-transplant lymphoproliferative disorder developed, Epstein-Barr virus encoded RNA by in-situ hybridization and EBNA-1 and gp220 by polymerase chain reaction was assessed in tissue samples. The overall prevalence of post-transplant lymphoproliferative disorder was 1.4% (2.5% in heart, 0.9% in liver and 0.8% in kidney-transplanted patients) and significantly higher in hepatitis C virus positive than in hepatitis C virus negative patients (3.6 % vs 1.2 %; P=0.04). Epstein-Barr virus was present in 10 (77%) out of 13 tumors tested. Two out of three Epstein-Barr virus-negative post-transplant lymphoproliferative disorder developed in hepatitis C virus-positive patients. Thirteen out of 15 (86%) post-transplant lymphoproliferative disorder patients had undergone antithymocyte globulin/OKT3 induction therapy. Epstein-Barr virus, induction immunosuppression, rejection therapy and also hepatitis C virus infection may play a role in the multifactorial pathogenesis of post-transplant lymphoproliferative disorder.

Rituximab (Chimeric Anti-CD20 Antibody) for Posttransplant Lymphoproliferative Disorder after Solid Organ Transplantation in Adults: Long-Term Experience from a Single Center

Occurrence of posttransplant lymphoproliferative disorder (PTLD) after transplantation is known. Drastic reduction or withdrawal of immunosuppression with anti-viral therapy for Ebstein-Barr virus (EBV) is the primary treatment for all PTLD. Many PTLD are B cell in origin have CD20 antigen on the cell surface. Rituximab is a chimeric anti CD20 antibody, which has been used to treat PTLD with variable success. This study aims to report long-term experience with rituximab for PTLD from a single center. Seventeen patients (13 male, 4 female, mean age 51.2 years) received rituximab to treat PTLD. Five patients received rituximab with drastic reduction in immunosuppression (primary). Nine patients received rituximab after failure of primary therapy (rescue) and three patients received it after resolution of PTLD (prophylactic). Mean follow-up period was 60 months. Overall 1-, 3-, and 5-year patient survivals were 64.7%, 47.1% and 35.3%, respectively. In the primary group, three patients had complete and one had partial response; however, only two (40%) patients are currently alive. In the rescue group, none of the patients had a complete response, four patients had partial response, and only two (22%) patients are currently alive. In the prophylactic group, two patients died at 28 and 41 months due to recurrence and graft failure, respectively. Sixty percent (3 of 5) of patients who received rituximab as primary therapy had complete resolution, and 44% (4 of 9) of patients who received it as rescue therapy had partial response. Overall 5-year patient survival was a disappointing 35%.

Risk factors for post‐transplant lymphoproliferative disorder in pediatric patients: A case‐control study

Post-transplant Lymphoproliferative Disorder (PTLD) because of the Epstein-Barr Virus (EBV) is a major concern after pediatric transplantation. The group at greatest risk is EBV-seronegative recipients who receive EBV-seropositive organs. Additional risk factors remain to be determined, including those among EBV-seropositive recipients. In this case-control study, PTLD cases were biopsy-proven over a period of 4 yr (1997-2000, inclusive). Each case was matched with 2 controls, based on the type of organ transplanted and the period of transplantation (+/-1 yr). Variables compared between cases and controls included those relating to the clinical and virologic profiles and immunosuppressive therapy. Twenty-two cases of PTLD were diagnosed during the study period. PTLD cases occurred at a median of 22.8 months post-transplantation (range 1-131). The median age of cases was 26.2 months (range 6.1-194) compared with 47.4 months (range 0.8-202.2) for controls (p = 0.93). Cases had a higher mean baseline EBV load compared with controls (3.1 log(10) (s.d. +/- 1.0) vs. 1.6 log(10)/10(6) PBMCs (s.d. +/- 1.4), with every 1 log increase in viral load resulting in a three times increase in the likelihood of PTLD (p < 0.007). Close to one in four cases of PTLD were EBV-seropositive pretransplantation. These seropositive recipients tended to be older patients with a trend to a worse outcome compared with their seronegative counterparts. The occurrence of PTLD was not associated with the use of any specific immunosuppressants. A significant proportion of PTLD cases occurred among EBV-seropositive transplant recipients, with a tendency towards an unfavorable outcome. Besides EBV-seronegative recipients who receive seropositive organs, some EBV-seropositive pediatric patients are at risk of PTLD. Additional studies are warranted to further define the factors associated with PTLD in EBV-seropositive transplant recipients.

Recipient Epstein Barr Virus (EBV) Seropositivity with IgG Antibodies Against Early Antigens (EA) Could Be a Predictive Marker for the Early Onset of Post Transplant Lymphoproliferative Disorders (PTLDs) after Allogeneic Non T Depleted Stem Cell Transplantation.

After allogeneic bone marrow (BM) or peripheral blood stem (PBSC)cells transplantation, the occurrence of PTLDs most frequently associated with EBV represent a serious clinical management problem. Identification of risk factors to allow preventive strategies could be useful. In this single center retrospective study from1999 to 2003, we analyzed the EBV virus load in the graft and the EBV serological pretransplant status from 21 recipients with a PTLD and 28 control allografted patients without PTLDs. All patients received a non T cells depleted stem cells transplantation from geno and matched unrelated identical donors for various hematological disorders. The median time from graft to he onset of PTLD was two months (range 1–8 months). All the PTLDs patients received ATG in the conditioning regimen and had an EBV real time-PCR (RT-PCR) highly positive at time of diagnostic.First, we assessed the EBV viral load in the infused cells by RT-PCR. In the PTLDs group, only 2 cases( one BM and one PBSC) contained infected EBV cells: 1,3x10e7 and 4,33x10e8 per 10e6 cells respectively. In the control group, we did not detect copies (the difference was not significant). The recipient pretransplant EBV infection status (median time: 15 days before transplant) was completed with serology anti-EA (IgA,IgG) and anti -VCA(IgA). Results are in the table 1. We found only a significant difference (p=0,00023) between the recipients with PTLDs and the control group for the early antigens positivity. Anti-EA are associated with a reactivation of EBV.In conclusion, the EBV viral load in the infused cells is not associated with the onset of PTLD. However, our findings suggest that the detection of IgG antibodies to EA antigens in the recipient pretransplant serology could be a predictive marker of the early onset of a PTLD.EBV recipient pre transplant statusanti-VCA IgGanti-VCA IgAanti-EBNA IgGanti-EA IgGanti-EA IgAPTLDs pts n=2121/21 (100%)0/21 (0%)21/21 (100%)12/21 (57%)#0/21 (0%)Control pts n=2828/28 (100%)0/28 (0%)28/28 (100%)2/28 (7%)#0/28 (0%)# p=0,00023

High incidence of PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a consequence of intensive immunosuppressive treatment.

The occurrence of post-transplant lymphoproliferative disorder (PTLD) in relation to immunosuppressive treatment was determined in 257 patients treated with non-T-cell-depleted allogeneic stem cell transplantation from an HLA-matched sibling (173 patients) or unrelated donor (84 patients). The conditioning consisted of total body irradiation and cyclophosphamide (myeloablative conditioning, 250 patients), or fludarabine combined with cyclophosphamide or a single 2 Gy dose of TBI (nonmyeloablative conditioning, seven patients). In transplantations from an unrelated donor, the patients also received antithymocyte globulin (ATG). The prophylaxis against graft-versus-host disease (GVHD) consisted of cyclosporine A, methotrexate, and methylprednisolone. The autopsy reports of deceased patients were systematically reviewed, and the autopsy materials of cases suggestive of PTLD were re-examined histologically for Epstein-Barr virus (EBV). Nineteen patients with EBV-positive PTLD were identified, of whom six had been transplanted from a sibling donor and 13 from an unrelated donor. All the patients who developed PTLD had been given ATG either for the treatment of steroid-resistant acute GVHD (all PTLD patients with a sibling donor and one with an unrelated donor), or as part of the conditioning (all patients with an unrelated donor). In conclusion, in transplantations from an HLA-identical donor with a non-T-cell-depleted graft, the risk of PTLD correlated strongly with the intensity of the immunosuppressive treatment.

Post-Transplant Lymphoproliferative Disorder in the United States: Young Caucasian Males are at Highest Risk

We have previously documented Caucasian race and cadaver donor source as risk factors for post-transplant lymphoproliferative disorder (PTLD) development in recipients registered in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). We analyzed data from the Scientific Registry of the United Network of Organ Sharing (UNOS) (from January 1988 to December 1999) to determine risk factors for the development of PTLD in all organ systems and its frequency, and we compared these factors to the risk factors in the most recent NAPRTCS database (1987-2000). In the UNOS database, PTLD was reported in 2365 of 205114 organ-transplant recipients (1.2%). PTLD was reported in 3% or more of all intestinal and thoracic organ recipients, but in less than 1% of other abdominal organ recipients. Recipient age < 18 years, Caucasian race and male gender were independent risk factors [Odds Ratios (OR) 2.81, 2.22 and 1.40, respectively, p = 0.0001], but not cadaver donor source. The combination of all three risk factors increased the OR to 8.78. The occurrence of PTLD showed a significant rise per year for heart-lung, kidney, kidney-pancreas and liver transplants, but decreased significantly for heart transplants (p < 0.001). Similar frequencies of PTLD were found in smaller organ-specific registries of heart, intestine, pediatric liver and pediatric kidney transplants. The PTLD incidence per year and incidence density have increased in recent years. Young Caucasian males are at highest risk for PTLD development among solid-organ-transplant recipients. The incidence of PTLD is increasing.

Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).

Posttransplant lymphoproliferative disorder (PTLD) is an important complication of transplantation. The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database has documented 56 cases of PTLD, the largest such series to date. We analyzed the available longitudinal and multicenter data in the NAPRTCS database to evaluate the demographic and therapeutic risk factors and the temporal trends for PTLD in children after renal transplantation. The overall incidence of PTLD was 1.2% of all patients or 298/100,000 posttransplantation years of follow-up. However, this incidence increased from 254/100,000 years between 1987 and 1991 to 395/100,000 years from 1992 onwards. In the same periods, the time to PTLD decreased from a median of 356 days (range 843048) to a median of 190 days (range 42-944). PTLD occurred with greater frequency in white children (P=0.003) and in cadaver donor transplants (P=0.019), but there was no significant predilection for gender, younger children (0-5 years), or primary diagnosis. No significant difference was found in the use of anti-T-cell antibodies or in doses of CsA, azathioprine, or prednisone at 1 month, 6 months, and 1 year. Between 1996 and 1997, 69 patients were initiated with tacrolimus. Eight cases of PTLD were identified in these recipients to date (prevalence rate 11.5%), compared with 46/4084 (1.1%) where cyclosporine was used (P<0.0001). There is a trend towards increasing incidence and earlier occurrence of PTLD in the pediatric renal transplant population. White race and cadaver donor sources are risk factors not reported before. Continued monitoring of tacrolimus immunosuppression is important.

Role of hepatitis C virus in lymphoproliferative disorders after liver transplantation

It has been suggested that hepatitis C virus (HCV) infection could be associated with B-cell clonal expansion. The aim of this study was to analyze the relationship between lymphoproliferative disorders and HCV infection in liver transplant recipients. We studied 157 patients receiving a liver transplant between January 1989 and May 1997 with a follow-up longer than 3 months. The incidence of posttransplant lymphoproliferative disorders (PTLDs) was analyzed with reference to the indication for liver transplantation, the induction and maintenance immunosuppression, the incidence of acute rejection episodes, and Epstein-Barr virus (EBV) infection. Six PTLDs occurred after a median posttransplant follow-up of 7 months (3.8%). Four of the 6 PTLDs occurred among the 38 patients transplanted for HCV-related cirrhosis, and 2 PTLDs occurred in the 119 patients receiving a liver transplant for non-HCV liver diseases (10.5% vs. 1.7%, respectively; P =.03). The 4-year probability of PTLD was significantly higher in patients receiving a liver transplant for HCV-related cirrhosis than non-HCV liver diseases (12.3% vs. 2.2%, respectively; P =.015). Patients receiving a liver transplant for HCV-related cirrhosis were more likely to receive antithymocyte globulins (ATG). However, in patients treated with ATG, the 4-year probability of PTLD was higher among those patients receiving a liver transplant for HCV-related cirrhosis than for non-HCV liver diseases (27.1% vs. 6.4%, respectively; P =.08). EBV gene products were detected in tumor tissues in 3 of 4 patients with HCV-associated PTLD. Our data suggest that, in addition to EBV infection, 2 mutually nonexclusive factors, i.e., the use of ATG and HCV infection, could play a role in the occurrence of PTLD after a liver transplant for HCV-related cirrhosis.