Monomorphic Post-transplant Lymphoproliferative Disease Research Articles

Age and Epstein-Barr viral load at diagnosis of post-transplant lymphoproliferative disease are associated with patient survival in kidney transplant recipients.

This study investigated variables associated with mortality in kidney transplant recipients (KTRs) diagnosed with post-transplant lymphoproliferative disease (PTLD) and a simultaneous Epstein-Barr virus (EBV) viremia. This was a retrospective cohort study enrolling KTRs diagnosed with PTLD between 2018 and 2020. Outcome: death within two years after diagnosis. Among 1,625 KTRs who collected EBV viremia (by PCR, 2018-2020) for any reason, 238 (14.6%) had a positive viral load and 41 (17.2%) simultaneous PTLD. These 41 patients were 40.1 years old at diagnosis and 8.6 years after transplantation; 26.8% were induced with rATG and 92.7% were maintained on tacrolimus and azathioprine (TAC/AZA) as immunosuppressive regimen. Lymph nodes (75.6%) was the most common site of PTLD, followed by the gastrointestinal tract (48.8%), with 61.0% at Lugano stage IV and 80.5% monomorphic PTLD. The mean EBV viral load was 12,198 IU/mL. One- and two-year patient survival post-diagnosis was 60.4% and 46.8%, respectively. In the Cox regression analysis, age at PTLD diagnosis (HR for each year = 1.039; p < 0.001) and EBV viral load (HR for each log = 1.695; p = 0.026) were associated with risk of death. This study suggests that in patients predominantly on TAC/AZA, PTLD with simultaneous EBV positive viral load is a late event, and worse survival is associated with older age and EBV viral load at diagnosis.

MO993: Incidence of Ptld and Its Relationship with Cmv-Serostatus Positivity Among Childhood and Adulthood Population: A Registry Data Study

Abstract BACKGROUND AND AIMS It is unknown how the epidemiology of post-transplant lymphoproliferative disease (PTLD) and its relationship with CMV infection differ between adult and pediatric kidney transplant recipients. In addition, with current advancements in immunosuppressive therapy, the incidence of PTLD has changed dramatically. The aim of our study is to elucidate the relationship between PTLD and CMV infection. Moerover, to assess the incidence of PTLD among Adult and pediatric renal transplant patients in the current era. METHOD All renal transplant patients registered in the Organ Procurement and Transplantation Network between 2005 and 2019 were retrospectively reviewed. Patient were followed up till December 2020. Patients who had multiple organ transplant or those with previous renal transplants were excluded from the study. Data about recipient factors (age, sex ethnicity, diabetes, CMV serostatus, and EBV serostatus), donor factors (living or deceased), transplant factors (PRA, Cold ischemia time, HLA mismatches, induction and immunosuppressive therapy) were reviewed. Incidence rate of PTLD at one year and five years post-transplant were calculated among the Adult and Pediatric population. Univariate and Multivariate cox-hazard regression models were performed to assess the relationship between CMV serostatus and occurrence of PTLD. RESULTS About 10 947 pediatric renal transplant patients were included. About 315 pediatric patients developed PTLD during the follow-up time (2.88%). About 50.55% of PTLD occurred within the first-year post-transplant. 60% occurred within two-year post-transplant, while 80.63% of them occurred within five years post-transplant. CMV recipient infection was not associated with PTLD occurrence in the pediatric population (HR = 0.88, Pvalue = 0.81, 95% confidence interval ranged between 0.66 and 1.18). Proportional hazard assumption was not violated with P = 0.55. Among the adult population, 1990/277 955 developed PTLD (0.77%). About 25.77% of PTLD among the adult population occurred within the first-year post-transplant. About 39.39% of PTLD in the adult occurred within two-year post-transplant. About 66.55% of PTLD in the adult occurred within five-years post-transplant. CMV recipient positive serostatus was associated with a protective effect against occurrence of PTLD (HR = 0.82, Pvalue &amp;lt;0.01, 95% confidence interval ranged between 0.73 and 0.94). The most common type of PTLD among the pediatric and adult population was monomorphic PTLD ( 40% and 34%, respectively). CONCLUSION PTLD is a rare complication of renal transplantation in the current era. The risk of development of PTLD is highest during the first-year post-transplant. CMV recipient positive serostatus has a protective effect against development of PTLD.

Plasmacytoma/multiple myeloma type posttransplant lymphoproliferative disorder.

A 38-year-old male with a history of lupus nephritis and kidney transplantation 3 years ago, presented with fever, night sweats, and lymphadenopathy while being treated with tacrolimus, mycophenolate mofetil, and prednisone. Evaluation with PET and CT scan showed generalized lymphadenopathy and splenomegaly. (Left-sided figure). Biopsy of an inguinal lymph node showed a monotypic plasma cell proliferation (CD138+, kappa+, CD20-), as part of a monomorphic variant of post-transplant lymphoproliferative disease (PTLD) (Right-sided figure). The specific type was determined as plasmacytoma/multiple myeloma type PTLD. However, a diagnosis of PTLD type plasma cell-rich marginal zone lymphoma was also possible, although no separate malignant lymphocytic B-cell component could be demonstrated. No Epstein–Barr virus (EBV) positivity was found. Bone-marrow showed a similar monomorphic PTLD with an increased amount of plasma cells. Laboratory testing showed only mild anemia and no kidney function decline or hypercalcemia. M-protein was identified as IgA-kappa, 24 g/L. There were no bone lesions. Cytogenetics of the bone marrow showed no abnormalities. A diagnosis of plasmacytoma/multiple myeloma type PTLD was made, and treatment was commenced with thalidomide, bortezomib, and dexamethasone. Multiple myeloma/plasmacytoma-like PTLD is a rare complication of solid organ transplant. It is characterized by plasmacytic histology with the presence of CD138 and lack of CD20. Only 3.5% of PTLD are of this subtype [1]. In a retrospective cohort and case series, the median time from organ transplant to disease was 3–10 years [1-4]. Bone lesions were only present in a minority of patients [2] and many patients presented with extranodal disease [1, 3, 4] Similar to our patient, no significant hypercalcemia or renal insufficiency was found, and only mild anemia [3, 4] Patients had both positive and negative EBV immunohistochemical staining [2-4]. Patients underwent a reduction in immunosuppression and treatment with proteasome inhibitor-based regimens with 20% also receiving autologous stem cell transplants. The median overall survival was 2.4 years and survival was decreased compared to regular multiple myeloma patients [1]. In conclusion, plasmacytoma/multiple myeloma type PTLD often presents without bone lesions, hypercalcemia, or renal insufficiency. Differentiation between this entity and other PTLD's with a prominent component of plasma cells (including marginal zone lymphoma) can be difficult, as both can produce monoclonal paraproteins. Treatment for plasmacytoma/multiple myeloma type PTLD is currently similar to conventional myeloma, however outcomes are inferior.

Incidence and Outcomes of Post-Transplant Lymphoproliferative Disease after 5365 Solid Organ Transplants over a 20 Year Period at 2 UK Transplant Centres

Background:Post-transplant lymphoproliferative disease (PTLD) confers a high morbidity and mortality in a vulnerable population. We present the epidemiology and outcomes of PTLD in a large UK cohort of solid organ transplant (SOT) recipients who were transplanted over a 20-year period.Methods:This is a retrospective study of 5365 SOT recipients who had their first transplant between 2000 and 2021 at two UK transplant centres (Addenbrooke's Hospital and Papworth Hospital). We reviewed the records of all patients and found 142 who subsequently developed PTLD. For each type of transplant, we calculated the incidence rate of PTLD and cumulative incidence using a competing risk of death model.Survival was compared with the age-adjusted life expectancy of the UK population using the National life tables and a landmark analysis was performed to compare overall survival (OS) of PTLD patients from the date of diagnosis with the background survival of the transplant population. To compare treatment outcomes, a subset of 90 cases of monomorphic PTLD, DLBCL subtype were identified. 66 were treated with first-line Rituximab monotherapy and 24 received first-line R-Chemotherapy. Demographics, treatment response, and survival data were analysed with univariate and multivariate analysis to identify covariates associated with death in the first year post diagnosis of PTLD.Results:With a median follow-up time of 5.3 years, 142 of 5365 solid organ transplant recipients have developed PTLD (56/1965 kidney, 22/1428 liver, 12/327 simultaneous kidney-pancreas (SPK), 21/113 multivisceral (MVT), 10/778 heart, 15/503 bilateral lung, 3/148 single lung and 3/85 heart and lung). The incidence rate of PTLD was highest in the first year post-transplant in lung and MVT recipients. Cumulative incidence (shown in Figure 1) was 18% at 5 years post-MVT and 1-3% at 5 years following the other SOT types. Cumulative incidence was lowest for liver and heart transplants and was 10% at 20 years post-kidney transplantation.Median OS following SOT was 16 years which is significantly reduced compared with the age-adjusted UK population. There is a relatively high early mortality rate following diagnosis of PTLD and only patients surviving two years post diagnosis regained a similar longer-term survival to the non-PTLD SOT cohort.Treatment with rituximab monotherapy (RM) is now a standard of care for monomorphic PTLD 1. Outcomes for monomorphic patients were compared between those treated with RM (n=66, median follow-up 2.2 y) and R-Chemotherapy (n=24, median follow-up 5.2 y). The two groups were well matched for age and IPI. Of the 66 RM patients, 22 (33%) achieved complete remission with RM and required no further treatment. A further 18 (27%) patients achieved remission following further treatment with chemotherapy/surgery/CTL. 6/66 (9%) patients died of progressive disease (PD), 9/66 (14%) died pre-remission of non-PTLD causes and 11/66 (17%) died in remission of unrelated causes. In the R-Chemotherapy group, 22 patients received R-CHOP and 2 received R-CVP (n=24). 8 (33%) patients are alive and in remission after first line treatment and a further 3 patients (13%) after second line treatment. 2/24 (8%) patients died of PD, 4/24 (17%) died pre-remission of non-PTLD causes and 7/24 (30%) died post-remission of unrelated causes. There is no significant difference in OS between the two groups. Only a minority of deaths were due to PD and death from non-lymphoma causes pre and post remission remain considerably higher than non-PTLD SOT patients up to 2 years post treatment (Figure 1). Multivariate analysis of all 90 monomorphic PTLD patients identified IPI3+ as the strongest pre-treatment variable associating with inferior 1 year OS. Interestingly IPI3+ did not retain this significance when R-chemo patients were analysed alone.Conclusion:With this large SOT dataset we have mapped the cumulative incidence of PTLD over a 20 year period and highlight transplanted organ-specific differences in PTLD incidence over time. Treating monomorphic DLBL patients first-line with RM rather than R-chemotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes pre- and post-treatment remains high with both treatment approaches, with poor OS compared with age-matched non-PTLD SOT recipients.1Trappe et al. Lancet Oncol; 2012 13(2):196-206 [Display omitted] DisclosuresSantarsieri: Janssen: Honoraria. Uttenthal: Roche: Other; Takeda: Other; Jazz: Other. Follows: Janssen, Abvie, Roche, AZ: Other.

Outcome of Post Solid Organ Transplant Burkitt Lymphoma (PSOT-BL): A Report from the Pediatric PTLD Collaborative (PPC)

BackgroundPost solid organ transplant Burkitt lymphoma (PSOT-BL) is a rare form of monomorphic post-transplant lymphoproliferative disease (M-PTLD). Outcome data in pediatric patients are limited and guidelines on optimal treatment in PSOT-BL are lacking.MethodsRetrospective study and analysis of clinical characteristics, treatment, and outcome data from patients diagnosed with PSOT-BL at age ≤ 21 years (y) in 11 US pediatric transplant centers.ResultsWe identified 28 patients transplanted between 1993-2016 who developed PSOT-BL. Median age at organ transplantation and at diagnosis of PSOT-BL was 2.9y (range, 0.1-14) and 7.5y (range, 7-17), respectively, with median interval from transplant to PSOT-BL diagnosis of 3.8y (range 2-7). Heart and liver were the most frequently transplanted organs (n=14, 11), while bowel, kidney, and lung were each transplanted in one patient. Immunosuppressive therapy at the time of PSOT-BL diagnosis was tacrolimus alone (n=9), or in combination with mycophenolate (n=7), azathioprine (n=6), cyclosporin (n=3), or prednisone (n=3). None were receiving an mTOR inhibitor at time of PSOT-BL diagnosis.Six, twelve, and ten patients corresponded to Murphy stages II, III, and IV, respectively. Lactate dehydrogenase was elevated in 23 patients (82%) and was > 2x upper limit of normal in 14 (50%). All tumors were pathologically consistent with BL; MYC FISH testing was positive in 10/10 tumors tested, while 21/23 tumors (90%) had detectable Epstein Barr Virus.Rituximab-containing regimens were given to 25/28 patients (93%). These treatment regimens were as follows: rituximab alone (n=2), low dose cyclophosphamide, prednisone, and rituximab (CPR) (n=10), Burkitt lymphoma specific therapy: (FAB/LMB chemotherapy (n=3) or FAB/LMB therapy with rituximab (n=8)), reduced dose FAB/LMB (n=2), diffuse large B-cell lymphoma (DLBCL) regimens including EPOCH-R (n=2) and R-CHOP (n=1).Treatment modifications/reductions were infrequent. Methotrexate dose modification and/or omission were required in four patients due to renal dysfunction (n=3) and ascites (n=1). Doxorubicin was electively eliminated in one cardiac transplant recipient due to concern for cardiotoxicity and dose-reduced in another due to prolonged myelosuppression. There was no treatment related mortality.There were two episodes of rejection, one was a liver rejection that was successfully treated without graft loss, the other occurred after achieving partial response (PR) to 3 cycles of CPR, required intensive immune suppression, and was followed by PTLD/DLBCL and death from PTLD progression. There were two additional cases of a second PTLD/DLBCL. One died of PTLD progression nine months after developing a second PTLD and the other is alive in complete remission (CR) 17 months after diagnosis of a second PTLD.Of the two patients treated with rituximab alone, one had no response and the other relapsed. Both were subsequently treated with BL chemotherapy and are alive in CR 15- and 7-years following BL diagnosis, respectively.For all study patients over a median of 6.8y follow-up (range, 0.5-17), 3-year event-free survival (EFS) was 73.5% and 3-year overall survival (OS) was 92.6%, see figure. Three patients died of Burkitt lymphoma (all had been treated with CPR, experienced treatment failure and required treatment escalation to intensive BL chemoimmunotherapy but died of progressive disease). Of the 11 patients who received Burkitt lymphoma intensive therapy, all are alive in CR. One had progressed on treatment but achieved CR with further treatment intensification. Another developed a second PTLD/DLBCL, with subsequent CR.ConclusionThis collaborative study represents the largest pediatric series of PSOT-BL reported to date. In this study patients with PSOT-BL treated with intensive BL directed therapy appear to have comparable outcome to immunocompetent pediatric patients with BL. [Display omitted] DisclosuresOrjuela: ATARA Pharmaceuticals: Other: Scientific Advisory Board.

Clinical Outcomes of Post-Transplant Lymphoproliferative Disease (PTLD): Role of Radiation Therapy in Improvement of Disease Response

Post-transplant lymphoproliferative disease (PTLD) is a rare disease complicating solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Management of PTLD includes immunosuppression reduction, systemic therapy, surgery and radiation therapy (RT). Data regarding the efficacy and outcomes of radiation therapy in treatment of PTLD is limited. Here, we report our institution's experience with the treatment of PTLD including RT outcomes.We retrospectively reviewed patients with biopsy proven PTLD who were treated at our institution. After obtaining Institutional Review Board approval, patient demographics, disease characteristics, treatment modalities and follow-up data were recorded. Disease response before and after RT use was assessed per response evaluation criteria in solid tumors (RECIST) 1.1 including complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Cox Proportional Hazards models were utilized to determine variables associated with OS.We identified and reviewed medical records of 48 patients with PTLD. Median follow up was 38 months. The median age was 58 (range:10-81). The majority were white (79%) and male (56%). 50% of the cohort were SOT recipients, 44% were HCT recipients and 6% underwent combined transplants. The most common site of PTLD was CNS (29%). Monomorphic PTLD was the most common histological type with EBV positivity in 75% of patients. Median time from SOT-to-PTLD was 77 months (range:5-322) and HCT-to-PTLD was 5 months (range: 2-46). Systemic therapy was the most commonly used modality in 92% of patients. The most commonly used regimen was Rituximab monotherapy. Surgery was employed in 10% of patients. RT was utilized after induction therapy in 37.5%. The most common treated site was the brain (61%). Overall response of the entire cohort was 87% (58% CR and 29% PR), 6% achieved SD and 7% had PD. Among the RT cohort, 55% achieved CR, 33% achieved PR and 12% had SD. Local control rate was 100%. Of 21 patients who did not respond completely to induction therapy, 6 patients with initial PR achieved CR, 1 patient with initial SD achieved CR, 1 patient with initial PD achieved CR, and 2 patients with initial PD achieved PR and SD, respectively, after RT receipt. The median RT dose was 3,600 cGy (range: 2400-4600). 3- and 5-year PFS were 90% and 85%, respectively, while 3- and 5-year OS were 70% and 55%, respectively. Cox hazards modeling confirmed that HCT receipt was associated with better OS on multivariate analysis (HR 0.26, 95% CI 0.008- 0.671, P = 0.007).RT provides excellent local control and improves overall disease response of PTLD. Further optimization and standardization of combined modality paradigms are needed to improve clinical outcomes of this rare entity.

Neuropathological Variability within a Spectrum of NMDAR-Encephalitis.

To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+ /CD8- T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. ANN NEUROL 2021;90:725-737.

Post-Transplant Lymphoproliferative Disorder after Liver Transplant in the Pediatric Population: A Systematic Review

Background: Post-transplant lymphoproliferative disease (PTLD), a group of lymphoid disorders ranging from indolent polyclonal proliferation to aggressive lymphomas is a known complication following solid organ transplantation. The aim is to study the characteristics, predictive factors, management, and outcomes of PTLD among pediatric groups after liver transplantation in particular. Methods: Following the PRISMA guideline, we performed a comprehensive literature search on PubMed, Cochrane Library, Embase, and clinicaltrials.gov from the past ten years on May 04, 2020. We used the MeSH terms of organ transplantation and lymphoproliferative disorders. Initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found five retrospectives observational, one observational cohort study, and one multicenter cohort in the pediatric population. We extracted the data for baseline characteristics, the reason for transplantation, recipient &amp; donor EBV status, immunosuppression used, type &amp; stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, response to therapy, adverse effects of therapy and mortality. Results: We included seven retrospective observational studies with a total (n) number of 3116 post-liver transplant pediatric patients, out of which 135 (4.33%) patients who developed PTLD as a complication of transplantation were studied. The male to female ratio was 41: 55 with the gender of 6 patients unknown. In five studies, with 118 PTLD patients, 34 recipients and 24 donors were positive for EBV at the time of liver transplantation. In addition to EBV, CMV status of patients in 5 studies showed 11/25 (44%) PTLD patients positive for CMV at the time of transplant. Post-transplant immunosuppression was achieved among these seven cohorts with cyclosporine, tacrolimus, OKT3, mycophenolate mofetil, prednisone, and basiliximab. The diagnosis was made via biopsy, showing all histopathological types including early lesions 14/46 (30.4%), polymorphic 13/46 (28.3%), monomorphic 18/46 (39.1%), and classic Hodgkin's lymphoma PTLD 1/46 (2.1%). Diffuse large B-cell lymphoma was the most common subtype in 6/18 (33.3%) of samples with monomorphic PTLD. Hsu, et al. in their study showed a five-year survival rate of 33.3% for St. Jude's classification stage IV lymphoma compared to 88.9% for stage I-III. The median age for 36 patients from three studies at the diagnosis of PTLD was 39.6 months (range 24-48 months). The median duration from transplantation to the diagnosis of PTLD was 13.48 months (range 8-24 months) in 54 patients from four studies. PTLD treatment was achieved with a combination of reduction or withdrawal of the immunosuppressive drugs with antiviral prophylaxis, chemotherapy, irradiation &amp; the use of monoclonal antibodies in a total of 57 PTLD patients for which post-transplant immunosuppression data was available. Study by Hsu, et al. reported that 5/16 (31.3%) patients had acute graft rejection and 2 had a chronic rejection in a group of 16 PTLD patients undergoing treatment for PTLD with a reduction in immunosuppressive therapy. The overall mortality in patients who developed PTLD was 15/54 (27.8%) in four of the studies. Conclusions: Pre-transplant EBV-naive status in patients was associated with a higher incidence of PTLD. Advanced stage (Stage IV) lymphoma was associated with poor survival outcomes. Monomorphic histopathology may be most commonly associated with PTLD post-liver transplant. The main approach for the treatment of PTLD is the reduction or complete withdrawal of immunosuppressive drugs, administration of antiviral drugs (ganciclovir/valganciclovir),and lymphoma treatment with chemotherapy or irradiation, and monoclonal antibody therapy such as rituximab. Management of PTLD with reduction or withdrawal of post-transplant immunosuppressive drugs in one cohort was associated with an increased risk of graft rejection. Thus immunosuppressive therapy maintaining a fine balance between the risk of graft rejection and risk of developing PTLD may be associated with better patient outcomes post-liver transplant. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Relationship between rabbit anti-thymocyte globulin and development of PTLD and its aggressive form in renal transplant population

ABSTRACT: Introduction The aim of our study is to explore the relationship of rabbit anti-thymocyte globulin (R-ATG) on development of post-transplant lymphoproliferative disease (PTLD) and its aggressive forms (monomorphic PTLD and Hodgkin lymphoma) in renal transplant recipients. Methodology All patients diagnosed with PTLD post-renal transplant in the United States’ Organ Procurement and Transplantation Network from 2003 till 2013 and followed up till 2017 were retrospectively reviewed. Multi-variable logistic regression analysis assessed association of R-ATG to development of PTLD and its aggressive form. Results Risk of developing PTLD post renal transplant is 1.35%. In comparison to interleukin-2 blocker induction therapy, R-ATG is associated with increased risk of development of PTLD (Odds Ratio = 1.48, confidence interval ranges from 1.04 to 2.11, p = .02) and is associated with higher risk of development of aggressive PTLD (Odds Ratio = 1.83, confidence interval ranges from 1.001 to 3.34, p = .04). Conclusion We conclude that R-ATG induction is associated with a higher risk of PTLD and its aggressive form (monomorphic PTLD and Hodgkin lymphoma). Careful monitoring for development of PTLD in renal transplant recipients receiving R-ATG induction therapy is advised.

Post-transplant lymphoproliferative disease of the larynx

Laryngeal post-transplant lymphoproliferative disease (PTLD) is rare. Here, we describe two pediatric cases. The first, a 15-month-old who underwent liver transplantation at 5 weeks, presented with airway distress. Airway evaluation identified epiglottic and arytenoid infiltrate, and biopsy was consistent with polymorphic PTLD. The second, a 23-month-old who underwent liver transplantation at 13 months, presented with progressive stridor. Airway evaluation revealed sub-mucosal infiltrate of the epiglottis, arytenoids, post-cricoid region, and uvula. Biopsy was consistent with monomorphic PTLD. Airway findings and symptoms resolved for both after immunosuppression reduction. PTLD diagnosis requires a high index of suspicion in post-transplant patients with airway obstruction.

Risk factors and clinical outcomes of pediatric liver transplant recipients with post-transplant lymphoproliferative disease in a multi-ethnic Asian cohort.

We aimed to evaluate clinical characteristics, risk factors, and disease outcomes for liver transplant recipients (LTR) with post-transplant lymphoproliferative disease (PTLD) at our center. Retrospective review of data of all pediatric LTR (1991-2015) was conducted. The overall incidence of PTLD was 16.4% (18/110), the majority (13/18) were early lesions, while 3/18 were polymorphic/monomorphic PTLD. The risk factors significant on univariate analysis were as follows: mean age (years) at transplant (1.66 vs 4.76, P=.006); age <2years at transplant (odds ratio [OR] 3.53 [95% confidence interval [CI]: 1.16-10.73], P=.026); cytomegalovirus (CMV) primary infection (OR 11.39 [95% CI: 3.44-37.7], P<.001); recipient CMV seronegativity (OR 7.50 [95% CI: 2.02-27.78], P=.003); presence of CMV end-organ disease (OR 4.00 [95% CI: 1.22-13.16], P=.022); Chinese ethnicity; and higher mean duration of intravenous ganciclovir prophylaxis. In multivariate analysis, CMV primary infection (OR 5.22 [95% CI: 1.25-21.87], P=.024), CMV seronegativity (OR 5.91 [95% CI: 1.13-30.90, P=.035]), and having acute cellular rejections (ACR) prior to PTLD (OR 5.53 [95% CI: 1.43-21.48, P=.013]) were significant risk factors for PTLD, with the latter two factors having a synergistic effect in increasing PTLD risk in a stratified analysis. The final multivariate model in predicting the risk of PTLD, utilizing CMV primary infection, recipient CMV seronegativity, and ACR before PTLD as predictive variables, was statistically significant (likelihood ratio chi square statistic=25.18, P<.0001 with df=3). We report a unique clinicopathologic and risk factor profile in our cohort-early lesion PTLD accounts for the majority and the incidence of monomorphic PTLD remains low. In addition, we show a synergism between CMV naivety and ACR on PTLD risk, a higher prevalence of gastrointestinal manifestations, and a lack of significant association with Epstein-Barr virus seronegativity.

Lymphocyte/Monocyte Ratio (LMR) at Diagnosis Is Predictive of Survival with Post Transplant Lymphoproliferative Disease (PTLD) after Renal Transplant: An Analysis of 96 Patients of a Brazilian Cohort

Introduction: Post-Transplant Lymphoproliferative Disease (PTLD) is a well-recognized group of lymphoid and or plasmacytic proliferations that occur following both solid organ (SOT) and allogenic hematopoietic stem cell transplantation (HSCT) as a result of immunossupression. A continuum of disease has been described, including early lesions, polymorphic PTLD and monomorphic PTLD. Epstein-bar virus (EBV) is considered the most important causative factor, with EBV positivity observed within up 90% of tumor lymphocytes. There is paucity of prognostic factors in PTLD, but studies have shown that IPI, Performance status and number of disease sites are related to mortality. LMR has shown to be prognostic in different lymphomas, including Hodgkin's Lymphoma (HL), Diffuse Large B-cell lymphomas among others.Objectives: To assess the role of lymphocyte/monocyte ratio at diagnosis in predicting outcome and survival in PTLD patients.Patient and Methods: This is a retrospective study conducted by the Universidade Federal de São Paulo, São Paulo, Brazil. Only confirmed cases of PTLD, diagnosed from 2001 to 2015, with clinical, epidemiological and laboratorial parameters available were included in this study. Event was defined as treatment related mortality, progression (defined as time for initiation of salvage therapy) or relapse. Patients with conflicted data or loss of follow up were excluded from the analysis.Results: A total of 98 patients were diagnosed with PTLD in the study period. Two patients were excluded from the analysis due to conflict clinical data. Median age at diagnosis was 41.4 years (range from 4-74), with a 0,6:1 Female:Male ratio. Median time of transplant to PTLD was 56 months (range 0-967). Twenty-six patients (27%) received anti-thymocyte globulin (ATG), and the most common immunossupressive regimens consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (68,7%). Monomorphic PTLD was observed in 78% of patients, and two patients presented with HL. With a median follow up of 33.3 months, 35% of patients died. In a univariate analysis, the number of extranodal sites and LMR were associated with worst survival (p=0.026 and p=0.004).Conclusions: PTLD is a known complication of immunossupresion, usually related to EBV. In our cohort of 96 kidney recipients with PTLD, LMR and number of extranodal sites was associated with inferior outcome. DisclosuresNo relevant conflicts of interest to declare.

Clinical Outcome of 96 Post-Transplant Lymphoproliferative Disease Patients in a Renal Transplant Cohort

Introduction: Post-Transplant Lymphoproliferative Disease (PTLD) is a rarewell-recognized group of lymphoid and or plasmacytic proliferations that occur following both solid organ (SOT) and allogenic hematopoietic stem cell transplantation (HSCT) as a result of immunossupression. A continuum of disease has been described, including early lesions, polymorphic PTLD and monomorphic PTLD. Epstein-bar virus (EBV) is considered the most important causative factor, with EBV positivity observed within up 90% of tumor lymphocytes. Optimal risk stratifications specific to kidney transplantation are still lacking.Patient and Methods: In our series, we retrospectively analyzed 98 consecutively cases of PTLD diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of São Paulo, São Paulo, Brazil. HRim is considered the leading renal transplant hospital in the world for the past 15 years. For this study, only PTLD patients with tumors whose histology could be confirmed by hemopathologist review, EBV-association established and whose clinical, epidemiological and laboratorial parameters could be retrieved were included in this study. Response was defined as complete (CR) or less than CR (partial response or refractory disease). Event was defined as treatment related mortality, progression (defined as time for initiation of second-line therapy) or relapse. Patients with conflicted data or loss of follow up were excluded.Results: A total of 98 patients were diagnosed with PTLD from 7665 renal transplants performed in this period, with a incidence of 1,3%. Two patients were excluded from the analysis due to conflicting clinical data. Median age at diagnosis was 41.4 years (range from 4-74), with a 0,6:1 Female:Male ratio. Median time of transplant to PTLD diagnosis was 56 months (range 1-967). Thirty-six patients (37.5%) received anti-thymocyte globulin (ATG), and the most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (66, 69%). Monomorphic PTLD was observed in 75 (78%) patients, and two patients presented with HL. EBV positivity was seen in 67 patients (70.5%), being more frequent within PTLD cases diagnosed during the first 3 years of transplantation (90%). All patients had their IR reduced after PTLD diagnosis. The incidence of loss of engraftment following IR reduction was 19% (20 patients). Overall responses were: CR in 67% (n=64) and Partial response/Refractory disease in 33% (n=32); 30 patients died due to treatment-related toxicity and/or disease progression. Overall Survival (OS) for the entire group was 63% in 5 years (CI95% 73-83%), with a progression free survival (PFS) of 58% (CI95% 91-97%). EBV positivity was seen in 67 patients (70.5%). Median number of extra nodal sites involved was 1,2. The median overall survival time was 97 months. Patient survival following diagnosis was 77% at 1 year, 63% at 5 years and 38% at 10 years. The most common extra-nodal sites involved were: Gastro-intestinal Tract (43, 45%) followed by Central Nervous System (23, 24%). Extra nodal involvement was correlated with poorer outcome (p 0.014) as was the loss of engraftment (p<0.0001).Conclusions: PTLD is a rare complication of immunossupression, usually related to EBV, specially for PTLD diagnosed within the first 3 years of transplantation. Basically, the initial treatment consists of reduction or withdrawal of the immunossupressive regimen followed by specific imuno-chemotherapy as needed. In our cohort, the incidence of loss of engraftment was low, although it was correlated with inferior outcome, together with extranodal involvement. To date this is the largest cohort of post-renal transplant lymphoproliferative disease ever reported. DisclosuresNo relevant conflicts of interest to declare.

Post-Transplant Lymphoproliferative Disease (PTLD): Risk Factors, Diagnosis, and Current Treatment Strategies

Post-transplant lymphoproliferative diseases (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that complicate solid organ or hematopoietic transplantation. Risk factors for PTLD include viral infections, degree of immunosuppression, recipient age and race, allograft type, and host genetic variations. Clinically, extra-nodal disease is common including 10-15 % presenting with central nervous system (CNS) disease. Most PTLD cases are B cell (5-10 % T/NK cell or Hodgkin lymphoma), while over one-third are EBV-negative. World Health Organization (WHO) diagnostic categories are: early lesions, polymorphic, and monomorphic PTLD; although in practice, a clear separation is not always possible. Therapeutically, reduction in immunosuppression remains a mainstay, and recent data has documented the importance of rituximab +/- combination chemotherapy. Therapy for primary CNS PTLD should be managed according to immunocompetent CNS paradigms. Finally, novel treatment strategies for PTLD have emerged, including adoptive immunotherapy and rational targeted therapeutics (e.g., anti-CD30 based therapy and downstream signaling pathways of latent membrane protein-2A).

Transplantations-assoziierte Lymphoproliferationen

Transplantation of solid organs and haematopoietic stem cells requires immunosuppressive drug therapy in order to prevent rejection or graft-versus-host disease. Depending on dosage and type of drug, the risk of developing an Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is increased. The lesion spectrum ranges from hyperplastic lesions to manifest lymphomas, the latter being classified as monomorphic PTLD. Hyperplastic changes, which are not distinguishable from viral reactions, comprise early or mononucleosis-like lesions. Those with effaced lymph node architecture or extranodal manifestation without a lymphoma-like phenotype are designated polymorphic PTLD. Monomorphic PTLD are either high grade B cell lymphomas, plasma cell neoplasms or Hodgkin lymphomas and only very rarely T cell lymphomas. Low grade B cell lymphomas do not occur. In a subfraction of cases, including even monomorphic PTLD, reduction of immunosuppression alone is sufficient to induce remission of the pathological process.

Clinical Usefulness of FDG-PET/CT Scan Imaging in the Management of Posttransplant Lymphoproliferative Disease

Posttransplant lymphoproliferative disease (PTLD) is, aside skin cancer, the most common malignancy occurring after solid organ transplant in adults. Fluorodeoxyglucose (FDG) positron emission tomography (PET) has proved useful in the management of lymphomas. We report our experience with the use of FDG-PET inline with computed tomography (CT) scanning in the management of four transplant recipients with histologically confirmed PTLD, including three monomorphic PTLDs and one polymorphic PTLD. FDG-PET/CT scan at diagnosis showed increased FDG uptake in all examined PTLD lesions, and the disease was upstaged on the basis of FDG-PET/CT scan results over conventional CT scanning in one patient. At the end of treatment, PET/CT scans no longer demonstrated FDG uptake in the original PTLD lesions in all patients. Complete remission of disease persisted for at least 1 year after diagnosis in all. Our results strongly support that FDG-PET scanning is highly specific for diagnosis and follow-up of PTLD. The clinical relevance of including FDG-PET/CT scanning in the management of PTLD should be evaluated in a larger prospective cohort study.

A Comparative Study of Diffuse Large B-Cell Lymphoma (DLBCL) between African Americans and Caucasians: Single-Center Experience at the University of Alabama at Birmingham (UAB).

Background: SEER data indicate that African Americans (AA) have a lower incidence of DLBCL but a higher mortality rate than Caucasians (C). To investigate this, we conducted a single-center analysis of AA and C patients with DLBCL at UAB. UAB is a primary care facility and the main tertiary referral center in Alabama. It is located in Jefferson County where the average African American population of 39% is nearly triple the national average.Methods: After IRB approval, patients diagnosed with DLBCL from 1995 to 2007 were identified from pathology, referral, and UAB tumor registry databases. Baseline demographic data including race, age at diagnosis, stage, treatment administered, response to treatment, and survival were extracted. Serum LDH levels and performance status were not consistently available in medical records and therefore not included in the final analysis. Patients with monomorphic post-transplant lymphoproliferative disease and primary CNS lymphoma were excluded. Associations between race and stage, treatment (first-line rituximab, anthracycline, or combination therapy), response, and outcome were analyzed using Chi-squared or Cochran Mantel-Haenszel statistical analysis.Results: A total of n=309 (n=32 AA and n=277 C) patients were identified. AA patients were diagnosed at a significantly younger age than C patients [median age 49 (range: 22–90) vs. 61 (range: 16–91), respectively; p=0.0131]. AA patients also presented with advanced stage disease (Ann Arbor stage III–IV) more frequently (69% vs. 52%, p=0.046). No difference in extranodal disease presentation or in complete response rate to first-line therapy was noted. As expected, those with early stage disease, age <60, and those given first-line rituximab +/− anthracycline therapy had superior survival regardless of race. No difference in overall survival was seen between AA and C patients (p=0.1306). However, AA patients had an inferior survival to C patients when the analysis was restricted to patients who received either first-line treatment with rituximab (p=0.0658), anthracycline (p=0.0188), or combination (p=0.0196). [Display omitted] Conclusions: Compared to C patients, AA patients were diagnosed with DLBCL at a significantly younger age, more advanced stage, and had worse survival despite first-line rituximab +/− anthracycline therapy. This single-center experience confirms SEER data and suggests a possible difference in tumor biology or treatment effect, although potential socioeconomic factors can not be excluded.

Successful Renal Retransplantation after Post-Transplant Lymphoproliferative Disease

Post-transplant lymphoproliferative disease (PTLD) is a rare but severe complication of renal transplantation. Reduction of immunosuppression is essential for controlling PTLD but may induce graft loss. Retransplantation after PTLD is considered dangerous, because immunosuppressive treatment resumption may trigger hematological relapse. We retrospectively report six patients (five adults, one child) who underwent a second renal transplantation after successfully treated PTLD. Epstein-Barr virus (EBV) serology was positive before the first transplantation in all patients except the child. Post-transplant lymphoproliferative disease was detected 6.6 months (range 4.5-9.4) after transplantation. Lymphoproliferation was always monomorphic, B-cell, and EBV-related. Post-transplant lymphoproliferative disease was confined to the renal allograft (n = 4), multilocular (n = 1) or cerebral (n = 1). Immunosuppression tapering (6/6) and transplantectomy (5/6) led to hematological remission in all patients. Retransplantation was performed 77 months (range 50-128) after PTLD diagnosis. Immunosuppression included steroids (n = 6), ATG (n = 2), anti-CD25 (n = 2), cyclosporine (n = 4), tacrolimus (n = 2), mycophenolate mofetil (n = 4) and azathioprine (n = 1). After a median follow up of 30 months (range 24-47) patient survival was 100%, with no recurrence of PTLD. In conclusion, renal retransplantation can be considered in patients with monomorphic PTLD history, without major risk of hematological recurrence.

Successful treatment of relapsed PTLD with YT-90/anti-CD20 radioimmunotherapy

Background: Posttransplant lymphoproliferative disease (PTLD), is a major cause of morbidity and mortality following lung transplantation, responsible for 4% of mortality after 30 days post-transplant in pediatric recipients. Chemotherapy related mortality in thoracic organ recipients is reported from 30–70%. Therefore, initial treatment is usually reduced immunosuppression and anti-CD20 monoclonal antibody (rituximab). Rituximab is well tolerated and achieves a 60–70% response rate. However, rituximab refractory relapse may occur, requiring the use of chemotherapy. The Zevalin therapeutic protocol (ZTP), including radioimmunotherapy with a Yttrium-90 tagged anti-CD20 antibody (ibritumomab tiuxetan; Zevalin), is a minimally toxic, effective therapy for relapsed or refractory low grade, follicular, or transformed B-cell nonHodgkin’s lymphoma (NHL). We found no published reports of radioimmunotherapy for PTLD. We report the successful use of ZTP in a 16-yr-old bilateral cadaveric lung transplant recipient. Abdominal PTLD was diagnosed 8 months post-transplant. Remission was achieved with reduced immunosuppression and rituximab. Relapse occurred 28 months posttransplant. Procedures: Relapsed CD20 positive, monomorphic B-cell PTLD was diagnosed by biopsy of sinus and esophagus. The patient received 1 dose of rituximab and reduced immunosuppression, with some improvement in symptoms. Once available, she received ZTP, including 0.3 mCi/kg Yt-90 ibritumomab tiuxetan. Efficacy was monitored with PET, CT and endoscopic biopsies (GI and lung). The anticipated hypogammaglobulinemia has been treated with IVIG. Results: Treatment with ZTP resulted in a complete remission without evidence of graft dysfunction. At 8 months post-treatment, there was no evidence of recurrent PTLD. There has been no significant infection. Conclusions: In our patient, ZTP was effective treatment of relapsed PTLD. Although further study is needed to confirm this observation, minimal toxicity makes ZTP an attractive alternative to chemotherapy for relapsed or rituximab refractory PTLD.

Epstein-Barr virus infections in children after transplantation of the small intestine.

Epstein-Barr virus (EBV) infection in association with immunosuppressive drugs used for solid organ transplantation can produce a spectrum of illnesses. Forty-one children who ranged in age from 6 months to 18.5 years received small intestinal transplants alone or in combination with other organs while undergoing primary tacrolimus (FK506) immunosuppression between July 1990 and June 1995. We reviewed hematoxylin and eosin-stained sections from all biopsy, surgical, and autopsy material from these children to determine the incidence and morphology of EBV-associated disease. Nuclear staining with in situ hybridization for EBV early RNA transcript (EBER) using the EBER-1 probe confirmed the presence of EBV. The EBV lymphoproliferations were graded as 1 to 4 according to histopathology and EBV quantitation determined in the area of greatest positivity. Twenty-one patients (51%) had EBV documented histologically on one or more occasions; only 8 (38%) are alive; 5 of these had the highest grade of 2. Posttransplant lymphoproliferative disease (PTLD) developed in 13 patients. Three of 10 patients (30%) with grade 3 lesions (polymorphous PTLD) are alive with intermittent evidence of EBV infection; 6 died with PTLD. Monomorphic PTLD (grade 4) was the cause of death in the three additional patients. Thirteen of 20 patients (65%) with no histologic evidence of EBV are alive. The incidence of EBV infection in pediatric small intestinal transplant recipients is higher than reported for any other solid organ cohort. With the aid of frequent EBER staining we were able to diagnose EBV infections in 51% of 41 patients; PTLD (grade 3 or 4) developed in 32% of these children. Low-grade EBV infections often preceded the development of PTLD and were identified in gastrointestinal biopsy samples from patients with concurrent PTLD; however, results of gastrointestinal biopsy samples may be negative for EBV in some patients with PTLD and, thus, underestimate systemic EBV-associated lymphoproliferations. Rejection and EBV infection can occur simultaneously, therefore, attention to low-grade infection may be useful to patient management.