Post‐transplant lymphoproliferative disorder in adult liver transplant recipients: a South American multicenter experience

Post‐transplant lymphoproliferative disorder (PTLD) is a major and potentially life‐threatening complication after solid‐organ transplantation. The aim of this study was to describe the disease characteristics, clinical practices, and survival related to PTLD in adult orthotopic liver transplant (OLT) recipients in South America. We conducted a survey at four different transplant groups from Argentina, Brazil, and Chile. Among 1621 OLT recipients, 27 developed PTLD (1.7%); the mean age at diagnosis was 53.7 (±14) yr with a mean time of 39.7 (±35.2) months from OLT to PTLD diagnosis. Initial therapy included reduction in immunosuppression alone in 23.1% of the patients. Either rituximab or chemotherapy was employed as initial or second‐line therapy in 76.9% of the patients. PTLD location was frequently extranodal (80.7%) and mostly involving the transplanted liver (59.3%). The overall survival at one and five yr post‐PTLD diagnosis was 53.8% and 46.2%, respectively. Significant univariate risk factors for post‐PTLD mortality included lactate dehydrogenase ≥250 U/L (HR 9.66, p = 0.02), stage III/IV PTLD (HR 5.34, p = 0.004), and HCV infection (HR 7.68, p = 0.01). In conclusion, PTLD in OLT adult recipients is predominantly extranodal, and although mortality is high, long‐term survival is possible.     

Epstein–Barr Virus‐Related Post‐Transplant Lymphoproliferative Disorders: Pathogenetic Insights for Targeted Therapy

Post‐transplant lymphoproliferative disorder (PTLD) is a spectrum of major, life‐threatening lymphoproliferative diseases occurring in the post‐transplant setting. The majority of PTLD is of B‐cell origin and is associated with several risk factors, the most significant being Epstein‐Barr virus (EBV) infection. EBV's in vitro transforming abilities, distinctive latency, clonality within the malignant cells and response to targeted therapies implicate a critical role in the biology of PTLD. This minireview focuses on EBV‐related PTLD pathogenesis, in particular the interplay between aspects of the EBV life cycle and latency with nonviral factors resulting in the wide spectrum of histology and clinical presentations encountered in PTLD. With the increased prevalence of transplantation a rise in the incidence of PTLD may be expected. Therefore the importance of laboratory and animal models in the understanding of PTLD and the development of novel therapeutic approaches is discussed.     

Characteristics,risks, and outcomes of post‐transplant lymphoproliferative disease >3 years after pediatric heart transplant: A multicenter analysis

Post‐transplant lymphoproliferative disorder (PTLD) is a significant complication after pediatric heart transplantation (HT), occurring in 5%‐15% of patients within 3 years. Data >3 years from HT are limited. We sought to describe the prevalence, risk factors, and outcomes of PTLD occurring late (>3 years) after pediatric HT in the Pediatric Heart Transplant Study from 1993 to 2010. Among 3844 primary HT patients, 110 (3%) developed late, nonrecurrent PTLD. The hazard rate for late PTLD was constant at 0.01 events/year out to 20 years after HT. Risk factors for late PTLD were younger age at HT (HR 1.06, P = 0.003) and Epstein‐Barr virus (EBV) naivety (HR 1.65, P = 0.02). Survival after late PTLD was 86% and 68% at 1 and 5 years, with nonwhite race (HR 2.27, P = 0.03) and earlier year of HT (HR 1.03, P = 0.04) independently associated with mortality. Acute rejection and infection were both common after late PTLD, occurring in 26% and 34% of patients. The constant late hazard and contribution of EBV to late PTLD suggest that vigilance for development of PTLD, including for EBV conversion, should persist indefinitely after pediatric HT. The reasons for elevated risk of death for nonwhites after late PTLD are unclear and warrant further investigation.     

Effect of Anti-CD 20 Antibody Rituximab in Patients with Post-Transplant Lymphoproliferative Disorder (PTLD)

Post-transplant lymphoproliferative disorders (PTLD) are a life-threatening complication following solid organ transplantation. Treatment with rituximab, a humanized anti-CD20 monoclonal antibody, has proved to be a promising approach and shown a low toxicity profile. Between February 1999 and April 2002, we conducted a multicentre phase II trial investigating rituximab as single agent in 17 patients with PTLD. Transplanted organs were heart (n = 5), kidney (n = 4), lung (n = 4) and liver (n = 4). Patients were treated with four weekly doses of 375 mg/m² of rituximab. The mean follow-up time is 24.2 months. Histology was distributed in 10 diffuse large cell-, 2 marginal zone-, 1 Burkitt-like lymphoma, 1 Hodgkin-like PTLD and 3 polymorphic lymphoproliferations. Therapy was well tolerated and no severe adverse events were observed. The mean overall survival period is 37.0 months with 11 patients still living. In total, 9 patients (52.9%) achieved a complete remission, with a mean duration of 17.8 months. Partial remission was observed in 1 patient, minor remission in 2 patients, no change in 3 patients and 1 patient experienced progressive disease. Two patients relapsed, at intervals 3 and 5 months after obtaining complete remission. Rituximab proved to be well tolerated and effective in the treatment of PTLD.     

Post‐transplant lymphoproliferative disorders with naso‐ and oropharyngeal manifestation

The nasopharyngeal/oropharyngeal lymphatic tissues represent the anatomical site of Epstein–Barr virus (EBV) entry. Post‐transplant lymphoproliferative disorders (PTLD) are often associated with EBV, but little is known about the characteristics of nasopharyngeal/oropharyngeal mass‐forming PTLD. Retrospective evaluation of our own PTLD database (n = 79) and the PubMed^® database (n = 61) has been performed. Sinonasal/oro‐/nasopharyngeal lymphatic masses were early lesions (n = 54/140, 38.5%), polymorphic PTLD (n = 32/140, 23%), monomorphic B‐PTLD (n = 47/140, 33.5%) and T‐PTLD (n = 7/140, 5%). One‐fourth of lesions manifested as masses in the Waldeyer's ring, and in two‐thirds of cases, swelling of tonsils was related to manifestation of benign early lesions. Tonsil infiltration by polymorphic PTLD and monomorphic PTLD was present in one‐third of cases. Extratonsillar masses were mainly monomorphic PTLD. Meta‐analysis of our data in combination with previously published data revealed that lung transplantation and young patients are at a higher risk for earlier manifestation of monomorphic PTLD. Therapy is similar to PTLD therapy strategies, in general reduced immunosuppression and chemotherapy for polymorphic and monomorphic PTLD, and diagnostic and therapeutic surgical gross tumour resection of tonsillar/adenoid lesions. In summary, it is relevant for the clinical differential diagnosis that oro‐/nasopharyngeal aggressive PTLD manifested in ~30% as tonsillar masses and >90% at extratonsillar sites.     

Analysis of Factors that Influence Survival with Post-Transplant Lymphoproliferative Disorder in Renal Transplant Recipients: The Israel Penn International Transplant Tumor Registry Experience

Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1–310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.     

Post‐transplant lymphoproliferative disorder after pancreas transplantation: a United Network for Organ Sharing database analysis

There are not a great deal of data on post‐transplant lymphoproliferative disorder (PTLD) following pancreas transplantation. We analyzed the United Network for Organ Sharing national database of pancreas transplants to identify predictors of PTLD development. A univariate Cox model was generated for each potential predictor, and those at least marginally associated (p < 0.15) with PTLD were entered into a multivariable Cox model. PTLD developed in 43 patients (1.0%) of 4205 pancreas transplants. Mean follow‐up time was 4.9 ± 2.2 yr. In the multivariable Cox model, recipient EBV seronegativity (HR 5.52, 95% CI: 2.99–10.19, p < 0.001), not having tacrolimus in the immunosuppressive regimen (HR 6.02, 95% CI: 2.74–13.19, p < 0.001), recipient age (HR 0.96, 95% CI: 0.92–0.99, p = 0.02), non‐white ethnicity (HR 0.11, 95% CI: 0.02–0.84, p = 0.03), and HLA mismatching (HR 0.80, 95% CI: 0.67–0.97, p = 0.02) were significantly associated with the development of PTLD. Patient survival was significantly decreased in patients with PTLD, with a one‐, three‐, and five‐yr survival of 91%, 76%, and 70%, compared with 97%, 93%, and 88% in patients without PTLD (p < 0.001). PTLD is an uncommon but potentially lethal complication following pancreas transplantation. Patients with the risk factors identified should be monitored closely for the development of PTLD.     

Systematic review and meta‐analysis of post‐transplant lymphoproliferative disorder in lung transplant recipients

A systematic review of papers in English on post‐transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random‐effects model, and heterogeneity among studies was quantitated using I² values. Fourteen studies published from 2005 to 2015 were included in the meta‐analysis. One hundred and sixty‐four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67‐fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98‐29.70; P = .003). pOR of death for early onset PTLD (<1 year post‐LT) vs late onset (> 1 year post‐LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20‐1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI ?0.48‐0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08‐2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31‐3.52, P = .94). This meta‐analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.     

Association of HLA Polymorphisms with Post‐transplant Lymphoproliferative Disorder in Solid‐Organ Transplant Recipients

The association between HLA polymorphisms and PTLD was investigated in a case–control study, comparing 110 predominantly adult solid‐organ transplant recipients who developed PTLD to 5601 who did not. Donor and recipient HLA were analyzed. We detected a significant association between recipient HLA‐A26 and the development of PTLD (OR 2.74; p = 0.0007). In Caucasian recipients, both recipient and donor HLA‐A26 were independently associated with development of PTLD (recipient A26 OR 2.99; p = 0.0004, donor A26 OR 2.81; p = 0.002). Analysis of HLA‐A and ‐B haplotypes revealed that recipient HLA‐A26, B38 haplotype was strongly correlated with a higher incidence of EBV‐positive PTLD (OR 3.99; p = 0.001). The common ancestral haplotype HLA‐A1, B8, DR3, when carried by the donor, was protective against PTLD (OR 0.41; p = 0.05). Several other HLA specificities demonstrated associations with clinical and pathological characteristics as well as survival. These findings demonstrate the importance of HLA polymorphisms in modulating the risk for PTLD, and may be useful in risk stratification and development of monitoring and prophylaxis strategies.     

How Useful is PET/CT Imaging in the Management of Post‐Transplant Lymphoproliferative Disease After Liver Transplantation?

Post-transplant lymphoproliferative disease (PTLD) is a serious and potentially life-threatening complication after solid organ transplantation. Here, we report our first experience with the use of PET/CT (positron emission tomography combined with computed tomogram) for the management of patients with PTLD after liver transplantation. Four patients with histologically proven PTLD were analyzed. Conventional work-up included physical examination and head-to-pelvis CT. PET/CT was used in one patient for initial staging and in all patients for follow-up. PET/CT positive findings underwent biopsy. Information provided by PET/CT resulted in a change of medical management in three of the four patients. Conventional work-up missed residual disease after surgery in one and failed to detect a tumor relapse in another patient. However, one patient disclosed a false positive PET/CT finding in the lungs. In conclusion, PET/CT may be a useful tool for staging and therapy monitoring of PTLD after liver transplantation.     

Post‐transplant lymphoproliferative disorders,Epstein‐Barr virus infection,and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, management, and prevention of post‐transplant lymphoproliferative disorders (PTLD) and other Epstein‐Barr virus (EBV) syndromes after solid organ transplantation. PTLD are a heterogeneous spectrum of predominantly B‐cell disorders, often extra‐nodal, with complex distinct pathogeneses and variable clinical presentations determined by pathologic subtype. Recent epidemiologic studies report a decrease in early EBV‐positive (+) PTLD and an increase in late EBV‐negative (?) PTLD. Pre‐transplant EBV‐seronegativity and primary EBV infection, often from donor‐transmitted infection, are an important risk factors for EBV syndromes and early EBV + PTLD. Low‐quality evidence supports preemptive prevention strategies for early EBV + PTLD in EBV‐seronegative recipients that involve EBV DNA measurement in peripheral blood using assays requiring further result harmonization, combined with interventions to lower viral load. Reduction in immunosuppression (RIS) is the best validated intervention. WHO pathology classification of a tissue biopsy remains the gold standard for PTLD diagnosis; optimal staging procedures are uncertain. Treatment of CD20⁺ PTLD with the response‐dependent sequential use of RIS, rituximab, and cytotoxic chemotherapy is recommended. Evidence gaps requiring future research and alternate treatment strategies including immunotherapy are highlighted.     

Post‐transplant lymphoproliferative disorder following kidney transplantation: a population‐based cohort study

Post‐transplant lymphoproliferative disorder (PTLD) incidence is difficult to determine, mainly because both early and other lesions may go unrecognized and unregistered. Few studies have included systematic pathology review to maximize case identification and decide more accurately PTLD frequency after long‐term post‐transplantation follow‐up. A retrospective population‐based cohort study including all kidney transplant recipients at two Danish centres (1990–2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies to identify possible PTLDs. Candidate PTLDs underwent histopathological review and classification. Seventy PTLD cases were identified in 2175 transplantations (3.2%). The incidence rate (IR) after first transplantation was 5.4 cases per 1000 patient‐years (95% CI: 4.0–7.3). Most PTLDs were monomorphic (58.5%), or early lesions (21.5%). Excluding early lesions and patients <18 years, IR was 3.7 (95% CI: 2.9–5.5). Ten patients with PTLD were retransplanted, 2 developing further PTLDs. Post‐transplant patient survival was inferior in patients with PTLD, while death‐censored graft survival was not. Using registry data together with extensive pathological review and long follow‐up, a rather high incidence of PTLD was found.     

Use of EBV PCR for the Diagnosis and Monitoring of Post-Transplant Lymphoproliferative Disorder in Adult Solid Organ Transplant Patients

Epstein-Barr virus (EBV) is known to be involved in the majority of patients who develop post-transplant lymphoproliferative disorder after solid organ transplant. We conducted a retrospective study to determine the utility of qualitative and quantitative Epstein-Barr virus polymerase chain reaction (PCR) for the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients. Peripheral blood leukocytes obtained from 35 adult solid organ transplant patients consecutively referred for evaluation of possible post-transplant lymphoproliferative disorder, were tested by EBV PCR at the time of initial evaluation and at time points thereafter. Eighteen of 35 (51%) patients were ultimately diagnosed with post-transplant lymphoproliferative disorder by tissue biopsy. Fifteen of 18 (83%) patients were found to have EBER-1 positive tumors by in situ hybridization. EBV PCR was positive in 7 of 15 patients, suggesting a sensitivity of 39%. Seventeen patients without post-transplant lymphoproliferative disorder and three with EBER-1 negative post-transplant lymphoproliferative disorder all had negative EBV PCR tests, suggesting a specificity of 100%. We observed that declines in EBV DNA load were associated with response to therapeutic interventions, such as reduction in immunosuppression, rituximab therapy and chemotherapy. We conclude that peripheral blood EBV PCR may have a role in the diagnosis and monitoring of post-transplant lymphoproliferative disorder in adult solid organ transplant patients.     

Monitoring Infection with Epstein–Barr Virus among Seromismatch Adult Renal Transplant Recipients

Patients who undergo Epstein–Barr virus (EBV) seromismatch (D+/R − ) transplants have a higher risk for the development of post‐transplant lymphoproliferative disorder (PTLD). Adult renal transplant recipients at a single institution were prospectively monitored for EBV during the first year post‐transplant. Over a 2‐year period, 34 patients (7.78%) were identified as being EBV D+/R − recipients. Patients who developed symptoms or had persistent viremia were pre‐emptively administered rituximab. Six recipients were discharged without monitoring on the protocol. Of those six, three (50%) developed PTLD and all three lost their grafts. Twenty (60.6%) of the 34 recipients developed viremia during the first year post‐transplant. Of the recipients who became viremic, six (30%) received rituximab. None of the six who received rituximab‐developed PTLD. We found that recipients who were not monitored on the protocol were more likely to have PTLD and graft loss compared to those who were (p = 0.008). Post‐transplant monitoring of adults who undergo EBV D+/R − kidney transplants for viremia and symptoms associated with EBV infection may prompt intervention which reduces the incidence of PTLD within the first year. Use of rituximab in preventing PTLD among patients with primary EBV infection requires further prospective study to determine its overall safety and efficacy.     

Risk factors for post‐transplant lymphoproliferative disorder after Thymoglobulin‐conditioned hematopoietic cell transplantation

Epstein‐Barr virus (EBV)‐induced post‐transplant lymphoproliferative disorder (PTLD) occurs frequently when rabbit antithymocyte globulin (ATG) is used in hematopoietic cell transplant (HCT) conditioning. We retrospectively studied 554 patients undergoing ATG‐conditioned myeloablative HCT. Strategies used to minimize mortality due to PTLD were either therapy of biopsy‐diagnosed PTLD in the absence of EBV DNAemia monitoring (n = 266) or prompt therapy of presumed PTLD (based on clinical/radiologic signs and high EBV DNAemia, in the setting of weekly EBV DNAemia monitoring) (n = 199). Both strategies resulted in similar mortality due to PTLD (0.7% vs 1% at 2 years, P = .43) and similar overall survival (63% vs 67% at 2 years, P = .23) even though there was a trend toward higher PTLD incidence with the prompt therapy. Donor positive with recipient negative EBV (D+R?) serostatus was a risk factor for developing PTLD. Older patient age, HLA‐mismatched donor, and graft‐versus‐host disease were not associated with increased risk of PTLD. In summary, in ATG‐conditioned HCT, D+R? serostatus, but not older age, mismatched donor or GVHD is a risk factor for developing PTLD. EBV DNAemia monitoring may be a weak risk factor for developing/diagnosing PTLD; the monitoring coupled with prompt therapy does not improve survival.     

Syk‐Induced Phosphatidylinositol‐3‐Kinase Activation in Epstein–Barr Virus Posttransplant Lymphoproliferative Disorder

Posttransplant lymphoproliferative disorder (PTLD)‐associated Epstein–Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV‐associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol‐3′‐kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV‐infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib‐treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV‐associated malignancies.