Cases Of Post-transplant Lymphoproliferative Disorder Research Articles

Epstein-Barr virus positive post-transplant lymphoproliferative disorder with significantly decreased T-cell chimerism early after transplantation: A case report

BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation (allo-HCT) or solid organ transplantation (SOT). Unlike SOT, PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism. CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma (DLBCL) with significantly decreased T-cell chimerism early after allo-HCT. A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission. Nearly 3 mo after transplantation, the patient developed cervical lymph node enlargement and gastric lesions, both of which were pathologically suggestive of DLBCL. Meanwhile, the patient experienced a significant and persistent decrease in T-cell chimerism. A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy. CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.

A Case of Post-transplant Lymphoproliferative Disorder Developed 45 Years after Kidney Transplantation

A Case of Post-transplant Lymphoproliferative Disorder Developed 45 Years after Kidney Transplantation

An Atypical Case of Post-transplant Lymphoproliferative Disorder of the Bladder in a Kidney Transplant Recipient

An Atypical Case of Post-transplant Lymphoproliferative Disorder of the Bladder in a Kidney Transplant Recipient

Long-term Safety in Epstein-Barr Virus-Seropositive Kidney-only Transplant Recipients Treated With Belatacept in Clinical Practice: Final Study Results From the ENLiST Registry.

Belatacept, a selective T-cell costimulation blocker, was associated with improved survival and renal function but also with a risk of posttransplant lymphoproliferative disorder (PTLD) in adult kidney transplant recipients in phase 3 trials. This registry examined long-term safety in Epstein-Barr virus (EBV)-seropositive kidney transplant recipients treated with belatacept. This US-based, prospective, voluntary, multicenter registry (Evaluating Nulojix Long-Term Safety in Transplant [ENLiST]) included adult EBV-seropositive kidney-only transplant recipients treated de novo (within 14 d of transplantation) with belatacept. Primary objectives were to estimate incidence rates of confirmed PTLD, central nervous system (CNS) PTLD, and progressive multifocal encephalopathy (PML). The minimum follow-up was 2 y. Of 985 enrolled transplant recipients, 933 EBV-seropositive patients received belatacept, with 523 (56.1%) receiving concomitant tacrolimus at transplant (for up to 12 mo). By study end, 3 cases of non-CNS PTLD (incidence rate, 0.08/100 person-years), 1 case of CNS PTLD (0.03/100 person-years), and no cases of PML had been reported. Two patients with non-CNS PTLD received concomitant belatacept and tacrolimus and 1 received belatacept and lymphocyte-depleting therapy. Incidence rates were comparable between patients who received concomitant belatacept and tacrolimus and those who did not receive tacrolimus (0.09/100 person-years and 0.07/100 person-years, respectively; P = 0.96). Two of 4 patients with PTLD died, and 2 were alive at the end of the study. Cumulatively, 131 graft losses or deaths were reported by study end. Our results from the ENLiST registry, a large, prospective real-world study, showed that the incidence rates of PTLD and CNS PTLD in belatacept-treated EBV-seropositive transplant recipients were consistent with findings from previous phase 3 trials.

Epidemiology of Epstein-Barr Virus Chronic High Viral Load in Kidney Transplant Recipients

Background. Epstein-Barr virus (EBV) chronic high viral load (CHVL) may be defined by >16 000 copies/mL whole blood or >200 copies/105 peripheral blood mononuclear cells in >50% samples exceeding 6 mo. EBV CHVL has only been characterized in a few small pediatric studies, with heterogeneous results and unclear clinical significance. Methods. This single-center observational study evaluated adult and pediatric kidney transplant recipients transplanted between 2010 and 2021 on tacrolimus/mycophenolate-based/prednisone immunosuppression. The primary outcome was EBV CHVL prevalence. Secondary outcomes included recipient characteristics, DNAemia kinetics, and posttransplant lymphoproliferative disorder (PTLD) in recipients with EBV CHVL versus low-grade DNAemia or no DNAemia. Results. Five hundred forty-one recipients had a mean follow-up of 4.6 y. Fourteen recipients (2.6%) developed EBV CHVL, 70 (12.9%) had low-grade EBV DNAemia, and 457 (84.5%) had no EBV DNAemia. EBV CHVL was more common in recipients who were Caucasian (P = 0.04), younger (P = 0.04), received induction immunosuppression (P = 0.02), and had high-risk donor–recipient EBV serologic mismatch (P < 0.0001). CHVL patients had a higher first viral load (P = 0.03), longer time to maximum viral load (P = 0.02), and did not achieve sustained DNAemia clearance versus low-grade DNAemia. Three EBV-positive PTLD cases occurred in recipients with a history of EBV DNAemia. PTLD was present in 7.1% (1/14) CHVL versus 2.9% (2/70) low-grade DNAemia patients (P = 0.002). EBV DNAemia developed in 32 EBV seronegative recipients (32/59; 54%); clearance was achieved in 70% (14/20) with low-grade DNAemia but no CHVL (0/12; P = 0.0001). Conclusions. CHVL was uncommon and appeared to occur after primary EBV infection. Future studies should explore other potentially modifiable risk factors for PTLD, including optimal management of EBV DNAemia.

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.

Post-transplant lymphoproliferative disorder risk and outcomes in renal transplant patients treated with belatacept immunosuppression.

Post-transplant lymphoproliferative disorder (PTLD) is a rare but life-threatening malignancy that arises in the setting of immunosuppression (IS) after solid organ transplant. IS regimens containing belatacept have been associated with an increased risk of PTLD in Epstein-Barr virus (EBV)-seronegative renal transplant recipients, and the use of belatacept is contraindicated in this population. However, the impact of belatacept-based regimens on PTLD risk and outcomes in EBV-seropositive renal transplant recipients is less well characterized. A case-control study was conducted to investigate how combinatorial IS regimens impact the risk of PTLD and survival outcomes in renal transplant recipients at a large transplant center between 2010 and 2019. In total, 17 cases of PTLD were identified and matched 1:2 to controls without PTLD by age, sex, and transplanted organ(s). We compared baseline clinical characteristics, examined changes in IS regimen, viral loads, and renal function over time, and evaluated time-to-event analyses, including graft rejection and survival. Cases of PTLD largely resembled matched controls in terms of baseline characteristics, although expected differences in EBV serostatus trended toward significance (42.9% of PTLD cases were donor-positive/recipient-negative vs. 8.3% controls, p = 0.063). PTLD cases were not more likely to have received belatacept than controls. Belatacept was not associated with graft rejection or failure, re-transplant, hospitalization, or decreased survival. Belatacept was not associated with an increased risk of PTLD, and was not associated with decreased survival in either PTLD cases or in the entire cohort. Our case-control study supports the concept that belatacept remains a safe and effective option for IS in EBV-seropositive renal transplant patients.

Programmed cell death ligand 1 expression associated with subtypes of post-transplant lymphoproliferative disorder among pediatric kidney transplant recipients.

Programmed cell death ligand 1 (PD-L1) expression on tumor cells engages the PD-1 receptor on T cells, inhibiting anti-tumor responses. PD-L1 has been detected in cases of post-transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD-L1 expression and evaluate for clinical correlations. Twenty-one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin-embedded tissue biopsies, we examined 21 primary tumors for expression using PD-L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD-L1 on lesional B-cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. Applying revised 2017 WHO PTLD classification showed five non-destructive, nine polymorphic, and seven monomorphic cases. Average PD-L1 expression based upon PTLD subtype was: non-destructive 11%, polymorphic 43%, and monomorphic 73% (p=.01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B-cells expressed PD-L1. In this case series, significant differences in PD-L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD-L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis.

PD-L1 and PD-1 expression in pediatric post-transplant Burkitt lymphoma and other monomorphic post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS). Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed. We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS. Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.

A case of post renal transplant PTLD of lung.

Post Transplant Lymphoproliferative Disorder (PTLD) is a heterogeneous group of Lymphoid proliferative disorders that occur in patients post Hematogenous or Solid organ transplants. They are closely associated with Ebstein-Barr Virus and can range from polyclonal lesions to frank lymphomas. PTLD is usually a rare post-transplant complication, with the incidence being higher post Lung or Heart Transplantation and less commonly seen post-renal transplantation. The incidence post renal transplantation is less than 1%, with most of the cases being limited to the Gastro-Intestinal Tract and Lymph nodes, and incidence in the lungs being extremely rare. Here we present a case report of PTLD of the lung in a post-renal transplant recipient.

Primary CNS EBV-positive post-transplant lymphoproliferative disorder with polymorphic and classic Hodgkin lymphoma features: A case report and literature review.

Post-transplant lymphoproliferative disorders (PTLD) are typically Epstein-Barr virus (EBV)-associated lymphoid or plasmacytic proliferations that occur when immunosuppressed after transplantation. Only 2 cases of primary central nervous system (PCNS) classic Hodgkin lymphoma PTLD and 1 case of PCNS Hodgkin lymphoma-like PTLD have been previously reported. A 59-year-old male presented with malaise, headaches, and dizziness; neuroimaging revealed a 1.7-cm right cerebellar mass and a 0.6-cm right frontal mass. Microscopic examination demonstrated a perivascular and parenchymal polymorphous infiltrate composed of lymphocytes (CD3-positive T cells and CD20-positive B cells), plasma cells, and macrophages. Focally, macrophages had a spindled morphology with a fascicular arrangement amounting to poorly formed granulomata. Mitoses were seen. Scattered large atypical cells were visualized with irregular hyperchromatic nuclei, reminiscent of lacunar cells, mononuclear Hodgkin and binucleate Reed-Sternberg (RS) cells. EBV in situ highlighted a significant number of small lymphoid cells as well as many large atypical forms. Large atypical cells were seen to co-express CD15 and CD30. To our knowledge, this is the first such case with hybrid polymorphic PTLD and classic Hodgkin lymphoma features and the first such case to arise following liver transplantation. This case highlights the histological and immunophenotypic spectrum of these lymphoid proliferations and the resulting challenges in diagnosis and definitive subtyping.

Characterization and outcome of post-transplant lymphoproliferative disorders within a collaborative study.

Post-transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that can arise after solid organ transplantation (SOT) and allogeneic hematopoietic transplantation (allo-HSCT). In this multi-center retrospective study, we compare patient characteristics, therapies, and outcomes of PTLD after allo-HSCT and SOT. Twenty-five patients (15 after allo-HSCT and 10 after SOT) were identified who developed PTLD between 2008 and 2022. Median age (57 years; range, 29-74 years) and baseline characteristics were comparable between the two groups (allo-HSCT vs SOT), but median onset of PTLD was markedly shorter after allo-HSCT (2 months vs. 99 months, P<0.001). Treatment regimens were heterogeneous, with reduction of immunosuppression in combination with rituximab being the most common first-line treatment strategy in both cohorts (allo-HSCT: 66%; SOT: 80%). The overall response rate was lower in the allo-HSCT (67%) as compared to the SOT group (100%). Consequently, the overall survival (OS) trended towards a worse outcome for the allo-HSCT group (1-year OS: 54% vs. 78%; P=0.58). We identified PTLD onset ≤150 days in the allo-HSCT (P=0.046) and ECOG >2 in the SOT group (P=0.03) as prognostic factors for lower OS. PTLD cases present heterogeneously and pose unique challenges after both types of allogeneic transplantation.

Post-transplant Lymphoproliferative Disorder (PTLD) in the US Population: Demographics, Treatment Characteristics, and Survival Analysis.

Post-transplant lymphoproliferative disorder (PTLD) is a lymphoplasmacytic proliferative disorder in the setting of hematopoietic stem cells and solid organ transplants. PTLD is divided into nondestructive, polymorphic, monomorphic, and classical Hodgkin lymphoma subtypes. Most cases of PTLDs are Epstein-Barr virus (EBV) related (two third of the cases), and most are of B cell (80-85%) origin. The polymorphic PTLD subtype can be locally destructive and show malignant features. Treatment for PTLD includes a reduction in immunosuppression, surgery, cytotoxic chemotherapy and/or immunotherapy, anti-viral agents, and/or radiation. The aim of this study was to examine the demographic factors and treatment modalities that influence survival in patients with polymorphic PTLD. About 332 cases of polymorphic PTLD were identified from 2000 to 2018 using the Surveillance, Epidemiology, and End Results (SEER) database. The median age of the patients was found to be 44 years. The most common age groups were between the ages of 1-19 years (n=100. 30.1%) and 60-69 years (n=70. 21.1%). The majority of cases in this cohort underwent systemic (cytotoxic chemo and/or immuno) therapy only (n=137, 41.3%), while 129 (38.9%) cases did not undergo any treatment. The overall five-year observed survival was 54.6% (95% confidence interval (CI), 51.1 - 58.1). One-year and five-year survival with systemic therapywas 63.8% (95% CI, 59.6 - 68.0) and 52.5% (95% CI, 47.7 - 57.3), respectively. The one-year and five-year survival with surgerywas 87.3% (95% CI, 81.2-93.4) and 60.8% (95% CI., 42.2 - 79.4), respectively. The one-year and five-year without therapy were 67.6% (95% CI, 63.2-72.0) and 49.6% (95% CI, 43.5-55.7), respectively. Univariate analysis revealed thatsurgery alone (hazard ratio (HR) 0.386 (0.170-0.879), p = 0.023) was a positive predictor of survival. Race and sex were not predictors of survival, although age >55 years was a negative predictor for survival (HR 1.128 (1.139-1.346), p <0.001). Polymorphic PTLD is a destructive complication of organ transplantation that is usually associated with EBV positivity. We found that it most often presents in the pediatric age group, and its occurrence in those older than 55 years was associated with a worse prognosis. Treatment with surgery alone is associated with improved outcomes and should be considered in addition to a reduction in immunosuppression in cases of polymorphic PTLD.

Primary lymphoma of the kidney

To document the clinicopathological features of primary renal lymphoma (PRL) at 2 tertiary hospitals in the western region of the Kingdom of Saudi Arabia. Data were retrieved from all PRLs that were diagnosed at King Abdulaziz University Hospital and King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia, between January 2002 and April 2022. Histopathological and immunohistochemical slides were reviewed, and additional immunohistochemistry stains were carried out in selected cases. Follow-up data were also collected. There were 17 identified cases of PRL. The age of the patients ranged from 4-76 years (median: 50.5 years and mean: 46.8 years), 11 (64.7%) were males, and 6 (35.3%) were females. There were 12 cases of diffuse large B-cell lymphoma, 3 cases of Burkitt's lymphoma, and 2 cases of post-transplant lymphoproliferative disorder. The median follow-up duration was 22 months. The one-year overall survival rate was 71% and the 2-year overall survival rate was 43% during follow-up. Primary renal lymphomas in Saudi patients are more common in males and seen in a relatively younger age group compared to the available worldwide data. The diagnosis of PRL is important to avoid tumor dissemination and unnecessary nephrectomy. Diffuse large B-cell lymphoma is the most common pathological type and non-germinal center B-cell is the most common subtype.

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.

Short-term decreased post transplant lymphoproliferative disorder risk after kidney transplantation using two novel regimens

BackgroundBelatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone. MethodsThe records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B0, n = 235) or low-doses of mycophenolate, tacrolimus and belatacept (B1, n = 119). All recipients underwent induction with antithymocyte globulin and a rapid glucocorticosteroid taper. Relevant donor and recipient information were analyzed and endpoints of PTLD were assessed. ResultsThere were no cases of PTLD in either cohort within the study period. Recipients in the belatacept cohort experienced lower estimated glomerular filtration rates at 12 months (B0: 67.48 vs. B1: 59.10, p = 0.0014). Graft failure at 12 (B0: 1.28% vs. B1: 0.84%, p = 1.0) and 24 months (B0:2.55% vs. B1: 0.84%, p = 0.431) were similar. There was no difference in rejection rates at 12 (B0: 1.27% vs. B1: 2.52%, p = 0.408) or 24 months (B0: 2.12% vs. B1: 2.52%, p = 1.000). Both groups had similar rates of malignancy, mortality and CMV/BK viremia. ConclusionNon-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

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

Genomic Landscaping of Post-Transplant Lymphoproliferative Disorders Using Circulating Tumor DNA

Introduction: Identification of post-transplant lymphoproliferative disorder (PTLD) is a diagnostic challenge. The current diagnostic framework usually require analysis on tissue and imaging through PET/CT scans. Yet, these methods have diagnostic limitations. For instance due to missing information on tumor heterogeneity and relatively low sensitivity of PET/CT scans. Measuring cell free DNA (cfDNA) represents a novel, minimally-invasive method for tumor detection and genotyping. In this study we explored the feasibility of plasma cfDNA tumor genotyping with targeted deep sequencing to detect copy number variation (CNV), single nucleotide variants (SNVs) and Epstein Bar Virus (EBV) sequences, using a new in-house variant calling pipeline. Methods: In this multi-center observational cohort study of 18 patients diagnosed with monomorphic PTLD, we performed deep targeted NGS for SNV detection and low-coverage whole genome sequencing (lcWGS) for CNV detection. NGS was targeted on a panel of genes (n = 39) known to be recurrently mutated in B-cell lymphomas (244 kbp). All patients gave written informed consent. The R package CNAclinic was used to identify genome wide CNAs and fraction of the genome altered (FGA). The ichorCNA package was used to determine the ctDNA fraction in cfDNA samples. SNVs were called using a pipeline, combining 4 (cfDNA) SNV calling tools: Mutect2, LoFreq, VarDict & SiNVICT. Variants were filtered on presumed functional effect (Synonymous-, UTR-, Intron-, 2 kb upstream-, 2 kb downstream variants were removed). A "panel of normals” (variant blacklist) was generated from variants found in cfDNA from healthy controls, which was used to produce a variant blacklist to filter out technical artifacts and SNPs. Finally, variants with a variant allele frequency (VAF) < 1% and variants with an allele frequency (AF) of > 1% in 1000Genomes and/or gnomAD were filtered out. Results: The cohort included 18 PTLD patients. The majority of patients had stage IV disease (n=13, 76%). All of the PTLD cases were histologically proven, of diffuse large B cell lymphoma type and 10/18 patients (55%) were considered to have an EBV-negative tumor. EBV copy number in plasma was performed by qPCR in 12 patients and was considered to be elevated in four patients (>5000 copies/mL). The fraction of reads mapping to the EBV genome was compared between controls (n=8), EBV-negative PTLD (n=10) and EBV-positive PTLD (n=8). The median fraction of EBV reads for controls and EBV-negative PTLD were similar with a fraction of 1.5x10-4 (Q1-Q3: 1.3x10-4-1.6x10-4) and 1.8x10-4 (Q1-Q3: 1.4x10-4-3.9x10-4), respectively (p>0.05, Kruskal-Wallis). In EBV-positive tumors, the median fraction of EBV reads was 3-log higher, 5.3x10-1 (Q1-Q3: 7.3 x10-2-2) (p≤0.05, Kruskal-Wallis) CNVs were detected in cfDNA of 11/18 (61%) patients. Two of the patients in whom no CNVs were detected had initiated therapy at the time of plasma sampling. Median fraction of genome altered was higher in EBV-negative tumors (0.03, Q1-Q3: 2.5x10-4-0.12) than in EBV-positive tumors (5x10-4, Q1-Q3: 0-0.03), but this difference was not significant (p>0.05, Mann-Whitney U) (Figure 1). In the top 15 recurrently mutated genes (described below), across all 18 samples, 180 SNVs were found in total. The median amount of SNVs found in each sample was 11 (range 6-25). The most frequently mutated gene was CREPPB (12/18, 67%), in which the most prevalent mutation was p.K1497T (8/18, 44%). ARID1A was mutated in 10/18 cases (56%), followed by KMT2D (9/18, 50%). TET2, TP53, MEF2B & TNFAIP3 were all mutated in 7/18 cases (39%). SPEN & IRF2BP2 were mutated in 6/18 cases (33%). PIM1, NOTCH1, ATM, CARD11, DDX3X, IGLL5 were all mutated in 5/18 cases (28%) (Figure 2). Few of the mutations that are called in the top 15 recurrently mutated genes (8/180, 0.04%) lay close to 50% VAF, which might imply that these are SNPs not filtered out by the pipeline. Our SNV findings are comparable with previous literature, in which KMT2D, TET2 & TP53 are also amongst top-mutated genes (Menter et al., 2017), highlighting disruption of epigenetic regulation, NFkB pathway, and DNA damage response as drivers of PTLD. Conclusion: lcWGS in combination deep targeted sequencing allows for detection of CNV an SNV in diagnostic samples of patients with monomorphic PTLD. These data can potentially be used at screening, diagnosis and response monitoring, which is part of the ongoing prospective study NTR 7402. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pre-Hematopoietic Stem Cell Transplantation Rituximab for Epstein-Barr Virus and Post-Lymphoproliferative Disorder Prophylaxis in Alemtuzumab Recipients

Epstein-Barr virus (EBV) reactivation and EBV-related post-transplantation lymphoproliferative disorder (PTLD) are often fatal complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The risk of EBV reactivation may be mitigated by depletion of B cells with rituximab. Starting in January 2020, allo-HSCT recipients undergoing T-cell depletion with alemtuzumab received 1 dose of rituximab before transplantation. The objective of this study was to evaluate the cumulative incidence of EBV reactivation and EBV-PTLD in recipients of allo-HSCT and in vivo T-cell depletion with alemtuzumab who received pre-HSCT rituximab compared to patients who did not. This was a single-center retrospective analysis of adult patients who consecutively received an HLA-identical allo-HSCT between January 2019 and May 2021 and in vivo T-cell depletion with alemtuzumab. Patients were included in the rituximab cohort if they received rituximab within 6 months before their transplantation. The primary endpoint was incidence of EBV reactivation at day 180 among those receiving pre-HSCT rituximab versus those not receiving rituximab. Secondary endpoints included cumulative incidence of EBV-PTLD at 1 year, time to engraftment, immune reconstitution, and incidence of infections and acute graft-versus-host disease (aGVHD) at day 180. Eighty-six consecutive patients who received an allo-HSCT with alemtuzumab T-cell depletion were reviewed; 43 patients who received pre-HSCT rituximab after our protocol modification were compared to 43 patients who did not receive pre-HSCT rituximab before this change. Median age was 57 (interquartile range [IQR] 40-69) years, and the majority of patients had acute myeloid leukemia or myelodysplastic syndrome. Baseline characteristics were similar between the cohorts. EBV reactivation at day 180 occurred in 23 (53%) patients without prior rituximab exposure versus 0 patients with pre-HSCT rituximab exposure (P < .0001). Similarly, 6 patients without prior rituximab exposure developed PTLD at 1 year compared to no cases of PTLD among patients receiving pre-HSCT rituximab. There was no difference in neutrophil engraftment, incidence of infections, or aGVHD at day 180 between the 2 cohorts. There was a delay in time to platelet engraftment in the rituximab cohort (median 16 [IQR 15-20] days versus 15 [IQR 14-17] days; P=.04). Administration of pre-HSCT rituximab before allo-HSCT in patients receiving T-cell depletion with alemtuzumab was associated with a significant decrease in the risk for EBV reactivation and EBV-PTLD, without increasing aGVHD or infection rates.

S2763 Post-Transplant Lymphoproliferative Disorder Presenting as an Isolated Pre-Pouch Ileal Ulcer in a Liver Transplant Patient With Crohn’s Disease

Introduction: Post-transplant lymphoproliferative disorder (PTLD) can occur in solid organ and hematopoietic cell transplant recipients in the setting of chronic immunosuppression. It often results from Epstein-Barr virus (EBV) affected B-cell propagation. We present a case of PTLD in a liver transplant (LT) patient with Crohn’s disease (CD) on biologic therapy. Case Description/Methods: A 67-year-old male with primary sclerosing cholangitis (PSC) cirrhosis status post living donor LT in 2001 on tacrolimus, multiple skin cancers, recurrent PSC after transplant and pan-ulcerative colitis on sulfasalazine underwent total proctocolectomy with ileo-anal anastomosis in 2013 to 2014 for colonic dysplasia. In 2019, he was diagnosed with moderate-to-severe CD of the J-pouch and pre-pouch ileum, up to 50cm from the entry site. Vedolizumab (VDZ), an α4β7 integrin monoclonal antibody, was initiated with steroid-free clinical response on every four week dosing. Repeat pouchoscopy on VDZ showed pre-pouch ileitis up to 30cm and a large, isolated ulcer in the pre-pouch ileum, 10cm proximal to the ileitis (Figure). Biopsies revealed B-cell lymphoma, consistent with PTLD. Negative EBV-encoded RNA (EBER) in-situ hybridization suggested that this diagnosis was unrelated to EBV exposure. Positron emission tomography (PET) scan did not identify distant disease activity, and bone marrow biopsy was unremarkable. VDZ was stopped due to loss of response, budesonide resumed and R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) was subsequently initiated. Follow-up pouchoscopy showed lymphoma regression but persistent CD activity. Discussion: PTLD typically presents as extra-nodal masses involving the central nervous system, lungs, gastrointestinal tract, liver, skin or allograft within one year of transplant. Immunosuppression reduction is the cornerstone of management; however, more aggressive cases, as in our patient, require systemic therapy. This case highlights a unique presentation of PTLD as an isolated ileal ulcer in a CD patient 19 years post-LT. Interestingly, the ulcer did not appear endoscopically distinct from CD-related ulceration. Furthermore, while malignancy is a potential risk of certain treatments for inflammatory bowel disease (IBD), our patient had never received thiopurines or anti-tumor necrosis factor (TNF) agents, and VDZ has not been associated with an increased risk of B-cell lymphoma. He is currently stable on low dose tacrolimus and budesonide.Figure 1.: Isolated pre-pouch ileal ulcer.