Diagnosis Of Post-transplant Lymphoproliferative Disorder Research Articles

A Pathology Experience of Posttransplant Lymphoproliferative Disorder From One Tertiary Hospital: Pathology Concepts and Diagnostic Approach.

Solid organ transplantation and bone marrow/hematologic stem cell transplantation recipients face a heightened risk of developing malignancies or cancer as a result of immunosuppression. Posttransplant lymphoproliferative disorders (PTLD) are a range of disorders from benign lymphoid growth to lymphoma found post-transplant. Risk factors for PTLD include high immunosuppressive use and oncogenic effects of Epstein-Barr virus (EBV). There is a lack of comprehensive clinical and pathological documentation of PTLD cases among Saudi patients, and the available data are limited to a few case reports. As a result, a deeper understanding of this disease requires more clinicopathological information. In this review, we share our insights on cases diagnosed with PTLD at King Faisal Specialist Hospital and Research Center, a prominent tertiary center in the western region of Saudi Arabia, from 2005-2023. We have diagnosed a total of 14 cases of PTLD in our department, with an age range spanning from 3 to 62 years. These diagnoses were made based on biopsies or tumor resection procedures. The survival rate of patients is believed to be influenced by multiple factors, including histology, tumorigenesis, disease biology, and clinical stage. Additionally, Kaplan-Meier curve analysis indicates that female patients tend to have a higher estimated survival rate compared to males. PTLD diagnosis and therapy have greatly improved in the past 20 years. PTLD is treated with reduced immunosuppression, rituximab, chemotherapy, adoptive therapy, surgery, antiviral therapy, and radiotherapy. In this study, we present our experience from a large tertiary center in the western region of Saudi Arabia. Moreover, we will go through etiology, clinical features, and pathologic morphology along with the corresponding genetics, prevention, and valid treatment options.

The role of 18F-FDG PET/CT metabolic parameters in the differential diagnosis of post-transplant lymphoproliferative disorder after pediatric liver transplantation.

Post-transplant lymphoproliferative disorder (PTLD) is a significant complication after liver transplantation. Research on the diagnostic value of the Fluorine-18 fluorodeoxyglucose positron emission tomography/computerized tomography (18F-FDG PET/CT) metabolic parameters of PTLD in pediatric liver transplantation (pLT) recipients is limited. This study sought to evaluate the diagnostic efficacy of 18F-FDG PET/CT in differentiating between PTLD and non-PTLD lymphadenopathy in pLT recipients. This retrospective study collected the 18F-FDG PET/CT scans with clinical and pathological information of all consecutive children who were clinically suspected of PTLD from November 2016 to September 2022 at the Beijing Friendship Hospital. The 18F-FDG PET/CT metabolic parameters of the two groups were analyzed. We then established a diagnostic model composed of the clinical characteristics and metabolic parameters. In total, 57 eligible patients were enrolled in this study, of whom 40 had PTLD and 17 had non-PTLD lymphadenopathy. Of the metabolic parameters examined in this study, total lesion glycolysis (TLG) had the highest area under the curve (AUC) value [0.757, 95% confidence interval (CI): 0.632-0.883, P=0.002]. The AUCs of the other metabolic parameters were all less than the AUC of TLG, including the maximum standardized uptake value (SUVmax) (AUC: 0.725, 95% CI: 0.597-0.853, P=0.008), mean standardized uptake value (SUVmean) (AUC: 0.701, 95% CI: 0.568-0.834, P=0.017), metabolic tumor volume total (MTVtotal) (AUC: 0.688, 95% CI: 0.549-0.827, P=0.040), TLG total (AUC: 0.674, 95% CI: 0.536-0.812, P=0.026). The diagnostic model, which was composed of clinical characteristics (digestive symptoms), the SUVmax, TLG, and the MTVtotal, showed excellent performance in the differential diagnosis (sensitivity: 0.675, 95% CI: 0.508-0.809; specificity: 0.941, 95% CI: 0.692-0.997; positive predictive value: 0.964, 95% CI: 0.798-0.998; and negative predictive value: 0.552, 95% CI: 0.360-0.730). The 18F-FDG PET/CT metabolic parameters can be used to distinguishing between PTLD and non-PTLD lymphadenopathy in pLT recipients.

Infectious Complications and Mortality in Post-Transplant Lymphoproliferative Disorder Following Solid Organ Transplantation: Experiences of 10 Years in a Single Center

Introduction: An estimated 2 to 20% of patients with solid organ transplants (SOT) are later diagnosed with post-transplant lymphoproliferative disorder (PTLD). These patients receive immunosuppression therapy for SOT, however, there is a paucity of research examining the infection complications and morbidity in those diagnosed with PTLD. Our single center study examined infections following a PTLD diagnosis and the potential risk of morbidity. Methods: We reviewed the Cleveland Clinic electronic medical record (EMR) of SOT patients who were diagnosed with PTLD between 2010 and 2020. 98 patients met the inclusion criteria. These were further stratified by transplant type: 26 liver, 24 renal, 22 lung, 19 heart, and 2 combined heart and lung transplant patients. All data were analyzed using R software. Results: The mean onset of biopsy confirmed PTLD following transplant was 7.13 ± 7.28 years,. Abdominal pain was the most common presenting symptom prompting further work up, seen in 29% of patients. Patients were also diagnosed based on other chief complaints, including fatigue (n = 20), weight loss (n = 16), and fever (n = 14). Additionally, a smaller subset of patients were diagnosed incidentally on imaging. The most frequent primary site of PTLD was the lymphoid tissue / enlarged lymph nodes (34% of patients) and followed by gastrointestinal tract (29%). Elevated lactate dehydrogenase was present in 42% of patients, diagnostic criteria for acute kidney injury in 23%, and hyperuricemia was noted in 16%. Diffuse large B-lymphoma was the most common subtype diagnosed in 72 of 98 patients followed by EBV related. After diagnosis, 60% of PTLD patients presented to the hospital due to infections, with a mean of 49.9 ± 55.3 days following PTLD diagnosis. Of those patients, bacterial infections were the most common (49.3%), followed by viral infections (34.5%), fungal infections (14.9%), and parasitic infections (1.15%). The bacterial infections were predominantly encapsulated organisms including Pseudomonas aeruginosa (33%), Escherichia coli (19%), and Streptococcus pneumoniae (14%). Rituximab was used in 40% of patients following diagnosis while rituximab, cyclophosphamide, doxorubicin, and vincristine (R-CHOP) was used in 41% of patients. There was no significant difference in infection risk in the first 100-days, following initiation of rituximab infections were seen in 33%, while the infection risk with R-CHOP was 35% (p = 0.31). Moreover, the most common cause of death was infection seen in 39% of patients, while PTLD itself with progressive disease was the second most common cause of death in 27%. The 6-month mortality following PTLD was 16% with 56% of those deaths being attributed to infection. The one-year mortality rate following PTLD was 25% with 48% of those being attributed to infection. Conclusions: In patients with PTLD diagnosis, the most common cause of death was infection (39%), followed by complications related to PTLD such as progressive disease with multi-organ failure. High serious infection risk may be due to aberrant monoclonal B-cell proliferation which paradoxically leads to decreased cellular immunity. The increased risk of B-cell PTLD in patients with SOT is likely due to the chronic immunosuppression, where patients gain acquired somatic driver mutations leading to a malignant state yet with an increased infection risk. Additionally, there was no difference in infection at 100 days between rituximab chemotherapy compared to R-CHOP. This necessitates the question of initiating viral, bacterial and fungal infection prophylaxis, similar to that following splenectomy or post BMT, should be implemented in patients diagnosed with PTLD. Further larger prospective studies are needed to further analyze the potential need and benefit of prophylactic vaccinations at the time of diagnosis in the PTLD patient population.

Post-Transplant Lymphoproliferative Disorders (PTLD) in Real Life: Data from the French K-Virogref Registry on 525 Adult Patients

Introduction Post-transplant lymphoproliferative disorders (PTLD) are rare and severe complications of organ or allogeneic stem cell transplants (AST), often linked to EBV. The recommended first-line management of systemic PTLD, in addition to lowering immunosuppression, currently consists of response-tailored treatment (RTT): monotherapy with rituximab (R) and, in case of CR, a continuation of rituximab as monotherapy (RM), otherwise 4 courses of R-CHOP. The data in the literature are limited to a few very rare prospective studies and limited series, generally monocentric. Patients and methods The French national K-virogref database, supported by the French Institute against Cancer (INCa), started in September 2013, gathers data from PTLDs confirmed by biopsy and re-reading in the Lymphopath network. Data from 10 years of this registry have been analyzed. Results A total of 525 adult patients are analyzed, the median age of transplant is 44 years, that of diagnosis of PTLD 58 years, 63% are men. Transplants are 61% kidneys, 17% livers, 6% lungs, 6% hearts, 8% stem cells. The median time from transplant to diagnosis of PTLD is 97 months, with 16% of diagnosis within the first year. The histology is of early lesion type in 4.6%, polymorphic in 12% and of lymphoma type in 83.3%, 46.7% are linked to EBV. Of the total 435 are systemic and 90 (17%) are localized to the central nervous system (CNS); predictors of CNS PTLD are later age at transplant (52 years vs 43 years), male gender ( p=1.10-3), a kidney transplant (69% vs 60%), CNS PTLDs are more often late after the transplant, more often of the lymphoma type and almost always linked to EBV (97.8%). The EBV status of the recipient at the time of transplantation was known in 242 cases, of which 50 were EBV negative; the negative EBV status is linked to an earlier age at diagnosis (43 years vs 58 years), a shorter time between transplant and diagnosis (11.5 months vs 66.5), more often early forms, more frequent localization in the graft (24% vs 9%), better survival. The median overall survival (OS) of all patients is 2700 days, tumor EBV status has no influence on OS, progression-free survival (PFS) is 1500 days. Median survivals are 2600 days for AST, 4600 for hearts, 5400 for lungs and not reached (NR) for livers and kidneys. Among the classic prognostic criteria, the IPI is not discriminating between 0 and 2, whereas the personal status is clearly discriminating (cf figure). Of the patients CD20+ without CNS localization nor Burkitt, treatment data were known for 274 patients: 27% received only immuno-chemotherapy (IC), 38% had RM and 35% R then R-CHOP. Survival is identical between IC and R then R-CHOP, with less chemotherapy in the sequential treatment, and is significantly higher (p=0.011) for RM, the RTT has a trend to a better OS than IC (p=0.062). In the event of chemotherapy, the use of an anthracycline has a better OS (median NR vs 750 days). Conclusion To our knowledge, this is the largest series of PTLD presented to date. The results of OS are similar to those presented in the prospective studies with selected patients and our data confirm the interest of RTT, with in case of chemotherapy, the need to use an anthracycline. The most discriminating and simplest prognostic criterion is PS. However, this very large series only concerns adult patients and cannot describe real-life pediatric PTLD.

The Effect of Preemptive Rituximab Treatment in Patients with EBV Viremia after Solid Organ Transplantation on the Development of Post-Transplant Lymphoproliferative Disorder

The association between Epstein-Barr Virus (EBV) reactivation after solid organ transplantation (SOT) and Post-Transplant Lymphoproliferative Disorder (PTLD) is well described. There are currently no guidelines regarding the use of rituximab preemptively in patients with EBV viremia after SOT to reduce the risk of PTLD. We sought to determine whether rituximab in SOT patients with EBV viremia has benefit in preventing PTLD. This retrospective analysis of electronic medical record data identified SOT recipients who experienced EBV viremia post-transplant between January 2010 and February 2023 at Columbia University Irving Medical Center (CUIMC). Data queries were clinically reviewed. Logistic regression analysis was performed to investigate the relationship between predictor variables including rituximab administration, log-transformed EBV peak titer, duration of EBV viremia, and time from SOT to EBV reactivation, with the binary primary outcome of PTLD diagnosis status. The analysis encompassed both univariate and multivariate logistic regression. There were 2,168 patients who met the inclusion criteria of having EBV reactivation after SOT, out of 6,395 total SOT performed at CUIMC during this timeframe. Patient characteristics are described in table 1. The median peak EBV titer was 154 (range: not quantifiable - 5,335,816), the median duration of EBV viremia was 78 days (range: 1 - 6,980), and the median time from SOT to EBV reactivation was 688 days (range: 0-11103). Of the 2,168 patients, 185/2168 (8.5%) received rituximab for indications other than PTLD including EBV viremia, treatment of rejection, antibody desensitization therapy/immunosuppression peri-transplant, and other non-transplant related indications (e.g. lupus nephritis). Of the patients who received rituximab, 182/185 (98.4%) did not develop PTLD. The 3/185 (1.6%) patients who did develop PTLD were all ≤ 20 years-old at time of diagnosis, and had EBER(+), monomorphic PTLD, diffuse large B-cell lymphoma type, with a non-germinal center phenotype, involving the gastrointestinal tract. Two were CD20 positive, all 3 had partial weak CD30 positivity, and all 3 had clonal immunoglobulin heavy chain rearrangements. Among the patients who did not receive preemptive rituximab post-SOT, 195/1983 (9.8%) developed PTLD, whereas 1788/1983 (90.2%) did not. Prior rituximab therapy for any indication in patients with EBV viremia post-SOT was associated with lower risk of subsequent PTLD by univariate analysis (0.14% vs 8.39%, OR 0.15, p = 0.0013, 95% CI 0.048-0.48). Receipt of rituximab (OR 0.12, p=0.0002), log-transformed peak EBV titer (OR 1.10, p<0.0001), and duration of EBV viremia in months (OR 1.01, p<0.0001) were all independently associated with risk for PTLD by multivariate analysis (figure 1). The relationship between time from SOT to EBV viremia was not significantly associated with development of PTLD. This retrospective analysis suggests that administering preemptive rituximab in SOT patients with EBV viremia may lower the risk of developing PTLD. The fact that peak EBV titer and duration of EBV viremia remain associated with PTLD in multivariate analyses suggests that the benefit of rituximab may be independent of the degree or duration of EBV viremia. A prospective analysis of factors such as area under the curve of EBV exposure, HLA status, T cell clonotype diversity, organ type, and immunosuppression type, is needed to better understand individual risks for improved selection of those who would benefit from preemptive rituximab.

Diagnostic Challenge in Renal Transplantation: Splenosis vs. Post-Transplant Lymphoproliferative Disorder—A Case Report

Splenosis is a benign, acquired condition characterized by the auto-implantation of focal deposits of splenic tissue throughout the peritoneal cavity, most commonly occurring after splenic injury and/or splenectomy. Post-Transplant Lymphoproliferative Disorder (PTLD) is a well-known complication of solid organ transplantation that results from unregulated B-cell proliferation due to chronic immunosuppression. Given their clinical and radiologic similarities, these two entities may pose a diagnostic dilemma in select solid-organ transplant recipients. We present the case of a 54-year-old kidney-transplant recipient presenting with abdominal pain and found to have a retroperitoneal soft-tissue mass concerning for PTLD. He underwent a CT-guided biopsy of the mass, and histopathological studies revealed lymphoid tissue consistent with splenic tissue, thus ruling out PTLD. The patient subsequently underwent symptomatic management, with the eventual resolution of his symptoms. The early diagnosis of PTLD is paramount, as prompt intervention has a substantial impact on the high rate of morbidity and mortality associated with this condition. Additionally, the diagnosis of splenosis in the setting of a retroperitoneal mass is critical in order to avoid invasive diagnostic and therapeutic procedures that may result in significant complications. A detailed surgical history, including prior splenic trauma and/or splenectomy, should raise clinical suspicion for splenosis and guide further diagnostic and therapeutic decision making.

A pediatric case series of catastrophic gastrointestinal complications of posttransplant lymphoproliferative disease with increasing incidence, high association with coronavirus disease 2019, higher mortality, and a plea for early endoscopy to prevent late fatal outcome

BackgroundPosttransplant lymphoproliferative disorder is one of the most severe complications after transplantation, caused by uncontrolled proliferation of Epstein–Barr virus-positive B-cells in the setting of chronic immunosuppression. As one of the biggest transplant centers worldwide, we observed a potential increase in the number of patients with posttransplant lymphoproliferative disorder presenting with gastrointestinal symptoms in 1 year, during the coronavirus disease 2019 pandemic. There is limited information about dysregulation of the immune system following coronavirus disease 2019 infection, which may lead to Epstein–Barr virus reactivation in Epstein–Barr virus-positive B-cells and development of posttransplant lymphoproliferative disorder. Furthermore, there is no consensus in literature on a modality that can help in early diagnosis of posttransplant lymphoproliferative disorder with nonspecific gastrointestinal presentations before late and fatal complications occur.Case presentationOur case series includes five Iranian (Persian) patients, three female (2, 2.5, and 5 years old) and two male (2 and 2.5 years old), who developed gastrointestinal posttransplant lymphoproliferative disorder after liver transplantation. All of our patients were on a similar immunosuppressant regimen and had similar Epstein–Barr virus serologic status (seronegative at time of transplantation but seropositive at time of posttransplant lymphoproliferative disorder diagnosis). Four patients had either a positive coronavirus disease 2019 polymerase chain reaction test or exposure within the family. Although all of our patients presented with nonspecific gastrointestinal symptoms, four patients developed late posttransplant lymphoproliferative disorder complications such as bowel perforation and obstruction. All five patients with gastrointestinal posttransplant lymphoproliferative disorder received chemotherapy, but only two survived and currently are continuing the therapy. In one of the surviving patients, prompt endoscopic investigation resulted in early diagnosis of posttransplant lymphoproliferative disorder and a better outcome.ConclusionSince 80% of our patients had exposure to coronavirus, a potential relationship might be suggested between the two. Furthermore, as we witnessed in one case, urgent endoscopic investigation in immunocompromised patients presenting with gastrointestinal symptoms can improve the clinical outcomes and therefore should be considered for early diagnosis of posttransplant lymphoproliferative disorder.

Incidence and Features of Lymphoid Proliferation and Lymphomas after Solid Organ or Hematopoietic Stem Cell Transplantation in a National Database Cohort.

Post-transplantation lymphoproliferative disorders (PTLDs) after hematopoietic stem transplantation (HCT) or solid organ transplantation (SOT) result in poorer outcomes, including death. There are limited large cohort data on the incidence and natural course of PTLD in Asians. We investigated PTLD using Korean national health insurance claims data of 47,518 patients who underwent HCT or SOT in 2008-2020. Patient demographics, time and type of PTLD diagnosis, type of PTLD treatment, and death data were collected. We used Fine and Gray subdistribution hazard models to calculate the cumulative incidence and risk factors for PTLD. During median follow-up of 5.32 years, PTLD occurred in 294 of 36,945 SOT patients (0.79%) and 235 of 10,573 HCT patients (2.22%). Cumulative incidence of PTLD were 0.49% at 1 year, 1.02% at 5 years, and 1.50% at 10 years post-transplantation. Age < 20 years (subdistribution hazard ratio [SHR] of 1.67 in age 10-19, SHR 1.51 in age 0-9), HCT (SHR 3.02), heart transplantation (SHR 2.27), and liver transplantation (SHR 1.47) were significant risk factors for PTLD. The presence of PTLD was associated with an increased risk of death (hazard ratio of 2.84). Overall, 5-year survival of PTLD patients was 68.9% (95% confidence interval, 64.9 to 73.2). We observed a steady increase in PTLD over 10 years after HCT or SOT in this large cohort study. Pediatric age group, HCT, liver transplantation, and heart transplantation were suggested to be risk factors for PTLD, and PTLD was associated with a higher risk of death.

Diagnostic and management roles of FDG PET/CT imaging in post-transplant lympho-proliferation in pediatric heart transplantation.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of pediatric heart transplant (PHTx). 18F-FDG PET/CT has been used to differentiate early lympho-proliferation from more advanced PTLD. We report our experience with PET/CT in the management of PTLD following PHTx. This was a retrospective study of 100 consecutive PHTx recipients at our institution between 2004 and 2018. Patients who underwent PET/CT or conventional CT scans to evaluate for PTLD or high Epstein-Barr viral load were included. Males, eight females. Median age at transplant was 3.5 months (IQR=1.5-27.5). Median age at PTLD diagnosis was 13.3 years (IQR=9.2-16.1). Median time between transplant and PTLD diagnosis was 9.5 (IQR=4.5-15) years. Induction agents were used in 12 patients (50%): Thymoglobulin (N=9), anti-IL2 (N=2), and Rituximab (N=1). Eighteen patients (75%) had PET/CT, of whom 14 had 18FDG-avid PTLD. Six had conventional CT. Nineteen patients (79.2%) had diagnostic biopsy confirmation of PTLD, and 5 (20.8%) had excisional biopsies. Two patients had Hodgkin's lymphoma; nine had monomorphic PTLD; eight had polymorphic PTLD; five were classified as other. Nine patients had monomorphic PTLD, including seven with diffuse large cell lymphoma (DLBC) and one with T cell lymphoma. The majority (16/24) had multi-site involvement at PTLD diagnosis, and PET/CT showed that 31.3% (5/16) had easily accessible subcutaneous nodes. Seventeen patients (overall survival 71%) underwent successful treatment without recurrence of PTLD. Of seven deaths (7/24, 29%), five had DLBC lymphoma, one had polymorphic PTLD and one had T-cell lymphoma. PET-CT allowed simultaneous anatomical and functional assessment of PTLD lesions, while guiding biopsy. In patients with multiple lesions, PET/CT revealed the most prominent and active lesions, improving diagnostic accuracy.

Outcomes of subsequent neoplasms after umbilical cord blood transplantation in Europe.

Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantation. We performed a retrospective analysis of SNs in 10 358 recipients ofumbilical cord blood transplantation (UCBT) from 1988 to 2018. SNs developed in 233patients and 84 were of pediatric age. Indications for UCBT were malignant hematological diseases in 199 patients (85%). Three groups of SNs were observed. Posttransplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a median of 4 months after UCBT. Of these, 9 patients died from relapse, 83 from PTLD, and 24 from transplant-related causes. At last follow-up, 29 were alive; 5-year overall survival (OS) after PTLD diagnosis was 21%. Acute leukemia/myelodysplasia (AL/MDS) was diagnosed in 23 patients in a median of 28 months after UCBT and included 3 donor-cell AL. Four of 23 patients died from relapse of primary disease, 8 from progression of SNs, and 4 from TRM. Seven patients remain alive; the 5-year OS after AL/MDS diagnosis was 36%. Solid tumors (ST) were reported in 65 patients in a median of 54 months after UCBT. Most common tumor sites were lung, thyroid, bone, and soft tissue. A total of 33 patients died (26 owing to ST, 6 to relapse of primary disease, and 1 cause missing). At last follow-up, 32 of 65 patients were alive; the 5-year OS after the diagnosis of ST was 51%. In conclusion, despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of risk factors and early detection may help to improve OS.

Real-world evidence of the safety and survival with CD19 CAR-T cell therapy for relapsed/refractory solid organ transplant-related PTLD.

The use of CD19 chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory solid organ transplantation (SOT)-related post-transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT-associated PTLD. Among 22 relapsed/refractory SOT-PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre-CAR-T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR-T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell-associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR-T. The two-year progression-free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post-CAR-T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR-T therapy in relapsed/refractory SOT-related PTLD appeared similar to pivotal CAR-T data, including approximately one-third of patients achieving sustained remission.

Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients.

Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. A total of 558 children and infants underwent cardiac transplantation at our institution between 1985 and 2019 and were followed until March 2021. Forty-nine of 558 patients developed PTLD (8.8%). As compared to older children (>one year of age), infant recipients (<three months of age) were less likely to develop PTLD. Monomorphic PTLDs (M-PTLD, 61%) was the most common subtype at initial diagnosis, followed by non-destructive (21%), polymorphic (14%), and classic Hodgkin lymphoma (cHL, 4%). Patients who underwent transplantation at a young age (<three months) had significantly lower rates of M-PTLD or cHL and a longer time from transplant to PTLD diagnosis as compared to children older than one year at transplant (p = 0.04). Although not reaching statistical significance, patients with a shorter time to PTLD diagnosis showed a trend toward higher rates of M-PTLD or cHL. As expected, the overall survival (OS) of patients with M-PTLD or cHL was significantly lower than patients with non-destructive or polymorphic PTLD.

Tonsillectomy Outcomes in Children After Solid-Organ Transplantation: A 15-Year Single-Center Experience.

Solid-organ transplantation (SOT) has become the standard of care for children with terminal organ failure. Long-term immunosuppression has improved survival substantially but is associated with secondary malignancies and impaired wound healing. Our goal was to review the incidence, outcomes, complications, and rate of posttransplant lymphoproliferative disorder on pathologic examination following tonsillectomy/adenotonsillectomy (T/AT) in children after SOT. A retrospective cohort study. Tertiary care children's hospital. Data were extracted from charts of children with a history of kidney, heart, or liver transplantation, who underwent T/AT between 2006 and 2021. A total of 110 patients met the inclusion criteria, including 46 hearts, 41 kidneys, 19 livers, and 4 liver-and-kidney transplants. The mean age at transplantation was 4.2 years, and the mean transplantation-to-T/AT time interval was 28.8 months. The posttransplantlymphoproliferative disorder was diagnosed in 52 (47.3%) patients, and 25% of these had no tonsillar hypertrophy. There was no difference in age at transplantation, organ received, transplantation-to-T/AT time interval, immunosuppressive medications, tonsil size, or tonsillar asymmetry between patients diagnosed with the posttransplant lymphoproliferative disorder and patients with benign tonsillar/adenotonsillar hypertrophy. Posttonsillectomy complications were similar between the groups. The incidence of posttransplant lymphoproliferative disorder undergoing tonsillectomy for any indication was 47.3%. There was no association between preoperative signs and symptoms and the histopathological diagnosis of posttransplant lymphoproliferative disorder. Stratification by organ received and immunosuppressive medications did not identify differences among the groups relative to the incidence of posttransplant lymphoproliferative disorder and other postoperative complications.

209. Epstein-Barr Virus Surveillance in Lung Transplantation: Post-transplant Lymphoproliferative Disorder and Impact on Survival

Abstract Background Epstein-Barr virus (EBV) donor seropositive/recipient seronegative (D+/R-) status is a risk factor for post-transplant lymphoproliferative disorder (PTLD) which is associated with increased mortality post-lung transplant. The optimal surveillance strategy for PTLD post-lung transplant stratified by EBV serostatus for early diagnosis is unknown. We assessed serial EBV viral loads (VL) for early diagnosis of PTLD and compared outcomes in EBV D+/R- and R+ lung transplant recipients at our center. Methods A single-center retrospective study of lung transplants between January 2017 and September 2021 was performed, with a 6-month minimum follow-up. Recipient characteristics, outcomes, and serial EBV VL (biweekly months 1-3, monthly 4-12; using the cobas quantitative PCR assay on serum) were assessed. Results Of the 242 lung transplant recipients, 14 (6%) were EBV D+/R- and 228 (94%) were EBV R+ [Figure 1]. Median age and lung allocation score were similar between the two cohorts [Table 1]. 7 (50%) EBV D+/R- recipients had 2 consecutive, detectable EBV VL in the first-year post-transplant compared to 30 (13%) R+ recipients (p=0.002). 5 (71%) EBV D+/R- recipients with 2 consecutive, detectable EBV VL developed PTLD compared with 2 (7%) R+ recipients (p=0.001). Median weeks post-transplant for two consecutive, detectable EBV VL were 14 (IQR 7, 15) and 10 (IQR 6, 24); and median weeks post-transplant for diagnosis of PTLD were 22 (IQR 17, 31) and 17 (IQR 16, 17) for EBV D+/R- and R+, respectively. Only recipients with at least 2 consecutive, detectable VL in the first-year post-transplant developed PTLD. EBV VL level was not associated with development of PTLD. 6-month outcomes were similar between EBV D+/R- and R+. Though there were no differences in mortality at 1 and 2-years stratified by EBV serostatus, all 5 EBV D+/R- recipients with PTLD were alive 2 years post-transplant, whereas both EBV R+ PTLD recipients died &amp;lt; 2 years post-transplant (p=0.048). Figure 1:Study cohort characteristics and PTLD outcomes based on serial EBV viral loads within the first-year post-lung transplant*7 recipients were excluded per study criteria due to having died less than 1-month post-transplant and therefore not having sufficient EBV VL testing post-transplant for this analysis.Table 1:Baseline characteristics, index hospitalization, and clinical outcomes of lung transplant recipients stratified by EBV serostatus*P-values are based on Fisher’s two-sided exact test (for categorial variables) or the Wilcoxon rank-sum test (for continuous variables).**Time to ≥2 consecutive, detectable EBV VL was calculated based on the date of the second consecutive, detectable result. Conclusion Two consecutive, detectable EBV VL within the first-year post-lung transplant should prompt additional work-up for the early diagnosis of PTLD in all recipients regardless of the EBV VL level or serostatus. Though the attack rate of PTLD was greater in EBV D+/R- recipients, survival outcomes were similar irrespective of serostatus. Disclosures Nicolas C. Issa, MD, AiCuris: Grant/Research Support|Merck: Grant/Research Support.

2096. Associations with Pneumocystis Pneumonia in Solid Organ Transplant Recipients: Impact of Posttransplant Lymphoproliferative Disorder

Abstract Background Pneumocystis jirovecii pneumonia (PCP) is a potentially deadly infection afflicting the immunocompromised population, including solid organ transplant recipients. Several risk factors have been described, including acute rejection, lymphopenia, and cytomegalovirus (CMV) infection. However, little is known regarding the risk imparted by posttransplant lymphoproliferative disorder (PTLD). Methods We performed a nested case-control study of solid organ transplant recipients diagnosed with PCP from 2000-2020. PCP was defined as positive smear or polymerase chain reaction testing with compatible clinical symptoms and radiographic findings. Two control were matched to each case by year of first transplant, first transplanted organ, and sex. Each control had at least as much follow-up from their transplant date to their matched case’s PCP diagnosis date. Multivariable conditional logistic regression was performed to analyze theorized risk factors. Results Sixty-seven cases met inclusion criteria and were matched to 134 controls (Table 1). Median age was 60.9 years, and the most common transplant type was kidney (52.2%). Fourteen patients had a history of PTLD, 12 of which developed PCP. All cases of PTLD were monomorphic, 6 were EBV-positive, 9 were receiving chemotherapy at the index date, and only 1 control patient was receiving PCP prophylaxis. The cases with PTLD developed PCP a median of 85 days after PTLD diagnosis, while the two controls were diagnosed more than 1 year earlier. After adjusting for age, acute rejection requiring treatment within the last 6 months, CMV infection within 6 months, current PCP prophylaxis, and lymphopenia (lymphocyte count &amp;lt; 0.5 x109/L) within 6 months, PTLD had a significant association with PCP (OR 14.0, 95% CI 1.7-114.5; p = .014). Lymphopenia was also associated with PCP (OR 8.2, 95% CI 3.2-20.7; p &amp;lt; .001), while the other factors were not. Table 1:Characteristics of 67 Solid Organ Transplant Recipients with Pneumocystis Pneumonia and 134 Matched Controls Conclusion Diagnosis of PTLD is independently associated with subsequent PCP after adjustment for recognized risk factors. This association is likely influenced by PTLD-directed chemotherapy, particularly regimens containing rituximab. PCP prophylaxis should be initiated in solid organ transplant recipients with PTLD, particularly those undergoing active therapy, and those with severe lymphopenia. Disclosures All Authors: No reported disclosures.

Characteristics and Outcome of Post-Transplant Lymphoproliferative Disorders After Solid Organ Transplantation: A Single Center Experience of 196 Patients Over 30 Years.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening complication after transplantation. In this retrospective, monocentric study we aimed to collect real life data regarding PTLD and determine the role of Epstein Barr Virus (EBV) status and year of diagnosis on prognosis. We identified 196 biopsy-proven PTLD after solid organ transplantation (SOT) diagnosed at the University Hospitals Leuven (Belgium) from 1989 to 2019. EBV status was positive in 61% of PTLD. The median overall survival (OS) was 5.7years (95% CI: 2.99-11.1). Although EBV positivity was not significantly correlated with OS in multivariate analyses (HR: 1.44 (95% CI: 0.93-2.24); p = 0.10), subgroup analysis showed a significantly better median OS for EBV negative post-transplant diffuse large B-cell lymphoma (DLBCL) compared to EBV positive post-transplant DLBCL (8.8 versus 2.5 years respectively; p = 0.0365). There was a significant relation between year of PTLD diagnosis and OS: the more recent the PTLD diagnosis, the lower the risk for death (adjusted HR: 0.962 (95% CI: 0.931-0.933); p = 0.017). In conclusion, the prognosis of PTLD after SOT has improved in the past decades. Our analysis shows a significant relation between EBV status and OS in post-transplant DLBCL.

Impact of Extranodal Disease Involvement on Outcomes in Post-Transplant Lymphoproliferative Disorder

Background: Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ or hematopoietic transplantation and is composed of a heterogeneous group of lymphoid disorders ranging from plasmacytic hyperplasia to aggressive lymphomas. Several factors such as age, performance status, lactate dehydrogenase, presence of B-symptoms, and disease stage have been identified as poor prognostic factors in PTLD. Extranodal disease (END) is present in the majority (50-80%) of patient (pts) at the time of diagnosis and has been shown to a be predictor of overall survival in this patient population; in particular, the presence of disease involvement in the central nervous system (CNS) or bone marrow (BM) has been shown to be poor prognostic factor. In this single center, retrospective analysis we examine the impact of END on outcomes in pts with PTLD. Methods: Pts with a diagnosis of PTLD were identified by Electronic Medical Records database query. Inclusion criteria were age ≥ 18 years at the time of diagnosis, confirmation of PTLD by internal pathology review, primary diagnosis from 2008-2018, and receipt of therapy and surveillance care at Northwestern University in Chicago, Illinois, USA. Exploratory univariate analyses were performed using Kaplan-Meier estimates with 95% confidence intervals and log-rank p-values for time-to-event outcomes; significance was set at p < 0.05. Response to treatment and disease progression were classified per provider-specific interpretations of clinical data as assessed by patient chart review. Results: A total of 182 pts with a diagnosis of PTLD were identified by database query and 111 pts met inclusion criteria. Of the 111 pts included in this analysis, 82 pts (73.9%) were male with a median age at diagnosis of 56 years (range 19-85) (table 1). The median time from transplant to diagnosis was 79 months (range 2-324). For all pts, the five-year overall-survival (OS) and progression-free survival (PFS) were 70.7% and 49.7%, respectively. Eighty-two pts (73.9%) had END at the time of diagnosis. There was no difference in 5yr OS between pts with END and those without END (69.5% vs 73.3%, p=0.56). A trend towards improved PFS was noted in patients without END compared to those patients with END; however, this difference was not statistically significant (70.6% vs 42.4%, p=0.09). Out of the 82 pts with END, 12 pts (14.6%) had multiple-site disease involvement, 41 pts (50%) had only gastrointestinal (GI) involvement, 13 pts (15.9%) CNS, 5 pts (6.1%), 4 pts (4.9%) pulmonary involvement, and 7 pts (8.5%) had other organ site involvement (renal, musculoskeletal, or oropharyngeal). There was no difference in 5yr OS and PFS between patients with single organ involvement of END vs multiple-site END at time of diagnosis. There was no difference in OS in patient with PTLD when stratified out by specific site involvement; however, patients with END disease involvement of GI tract had significantly inferior PFS than those patients without GI (27.3% vs 60.6%, p=0.05) (Figure 1). There was no difference in PFS across the other sites of END involvement. Conclusions: This study represents one of the largest retrospective cohorts of PTLD reported in the literature. We show that overall, the presence of END does not correlate to worse PFS or OS in patients with PTLD. The presence of GI involvement at the time of diagnosis may correlate to worse PFS. No additional specific site of organ involvement, including presence of BM or CNS disease, correlated to worse overall prognosis in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Posttransplant Lymphoproliferative Disorder (PTLD) Following Transplantation at Northwestern University: Choice of Immunosuppressive Agents Does Not Impact Outcomes in PTLD

Background: Posttransplant lymphoproliferative disorder (PTLD) is a spectrum of lymphoid diseases associated with the use of potent immunosuppressive drugs following solid organ or hematopoietic stem cell transplantation. The most widely accepted mechanism of PTLD pathogenesis is diminished cytotoxic T-lymphocyte and natural killer cell function, resulting from post-transplant immunosuppressive therapy, allowing for unregulated proliferation of lymphocytes infected with Epstein-Barr virus (EBV). However, approximately 1/3 of the cases of PTLD occur in EBV-negative individuals, suggesting additional immunopathologic mechanisms of disease pathogenesis. Immunosuppressive therapy with the calcineurin inhibitor tacrolimus and antimetabolite azathioprine have both demonstrated higher risk for developing PTLD than other immunosuppressive regimens. However, limited information exists regarding the relationship between immunosuppressive agents and outcomes in PTLD. Here we report the results of a single-center, retrospective analysis with the primary objective to examine whether post-transplant immunosuppressive agents impact outcomes in PTLD. Methods: Patients (pts) with a diagnosis of PTLD were identified by Electronic Medical Records database query. Inclusion criteria were age ≥ 18 years at the time of diagnosis, confirmation of PTLD by internal pathology review, primary diagnosis from 2008-2018, and receipt of therapy and surveillance care at Northwestern University in Chicago, Illinois, USA. Exploratory univariate analyses were performed using Kaplan-Meier estimates with 95% confidence intervals and log-rank p-values for time-to-event outcomes; significance was set at p < 0.05. Response to treatment and disease progression were classified per provider-specific interpretations of clinical data as assessed by patient chart review. Results: A total of 182 pts with a diagnosis of PTLD were identified by database query and 111 pts met inclusion criteria. Of the 111 pts included in this analysis; 82 pts (73.9%) were male with a median age at diagnosis of 56yrs (range 19-85) [Table 1]. The median time from transplant to diagnosis of PTLD was 78.9 months (range 2-324). Eighty-four pts (75.7%) received immunosuppression with a multi-drug regimen, with the most common combination of medications being mycophenolate mofetil and tacrolimus (n=54, 48.6%). Overall, 85 pts (76.6%) were treated with a tacrolimus containing regimen, 68 pts with mycophenolate, 26 pts with prednisone, 11 pts with azathioprine, 8 pts with cyclosporine, 5 pts with sirolimus, and 3 pts with a disease-modifying antirheumatic drug (DMARD) [Table 2]. Immunosuppression was decreased in 100 out of the 111 pts prior to starting treatment for PTLD and 11 pts were treated with immunosuppression reduction alone [Table 1]. Eighteen pts (16.2%) experienced graft rejection, of which 27.8% required re-transplantation. For all pts, the five-year OS and PFS were 70.7% and 49.7%, respectively. When stratified by exposure to different immunosuppressive agents, there was no difference in outcomes across all groups [Table 2]. Conclusions: Here we report one of the largest retrospective cohorts of pts with PTLD reported in the literature. Our analysis suggests that choice of immunosuppressive agent in the post-transplant setting does not impact outcomes in PTLD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A case of delayed primary-CNS post-transplant lymphoproliferative disorder in a patient with concurrent metastatic colorectal malignancy

Introduction: Post-transplant lymphoproliferative disorders (PTLD) are a complication of immunosuppression following organ transplantation. Due to their heterogeneous presentation, diagnosis of PTLD can be challenging. Case Report: In this case report, we present a patient with metastatic colon cancer, with remote history of multivisceral organ transplant 20-years prior, who presented with altered mental status and was diagnosed with primary central nervous system PTLD. Conclusion: This case illustrates the importance of continued suspicion of PTLD long after transplantation in solid-organ transplant recipients, even in the setting of multiple comorbidities.

Abstract 12595: De Novo Lymphoproliferative Disorders in Heart Transplant Recipients: Predictors and Clinical Outcomes

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is an important cause of morbidity and mortality in heart transplant (HTx) recipients. However, clinical characteristics and predictors of PTLD in the real world have not been well studied. Methods We retrospectively analyzed clinical characteristics, predictors, and outcomes of PTLD, in 28,136 recipients of heart alone transplants between January 2000 and June 2015 from the International Society for Heart and Lung Transplantation Thoracic Organ Transplant Registry. Results Ten-year incidence of PTLD after successful discharge from HTx during 2000-2007 was 3.8%. The adjusted overall risk of mortality was significantly higher in patients diagnosed with PTLD within 3 years after HTx compared to those without PTLD (HR 2.22, 95% CI 1.86-2.65, p&lt;0.001). Bimodal age peak of the PTLD incidence within the 3 years of HTx and mortality after the diagnosis of PTLD was noted. Both adjusted risk of PTLD incidence and mortality were lower in recent HTx; lower incidence and mortality in era of 2008-2015, compared to 2000-2007 (Incidence: HR 0.75, 95% CI 0.57-0.98, p=0.038) (Mortality: HR 0.86, 95% CI 0.81-0.91, p&lt;0.001). Age at transplant, male recipient, high risk Epstein-Barr virus (EBV) mismatch (donor positive and recipient negative for EBV) were independent risk factors, while primary maintenance therapy with cyclosporine (vs. tacrolimus) at initial discharge was a protective factor for PTLD within 3 years. Conclusions The incidence as well as mortality of PTLD has decreased in recent years of HTx, possibly with advances in changed pattern of immunosuppression according to patient profile. Clinical characteristics such as age, male gender, EBV status and rejection history are key factors for assessing the risk of PTLD, which can be detrimental in the course of post HTx care.