Treatment Of Post-transplant Lymphoproliferative Disease Research Articles

EPSTEIN-BARR VIRUS POSITIVE (EBV+) ORAL ULCER IN PATIENT WITH POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER

A 55-year-old male patient, after hematopoietic stem cell transplantation (HSCT) due to myelodysplastic syndrome, presented plaques not resistant to scraping in the lingual ventral surface region 65 days after HSCT that were suggestive of oral candidiasis, for which he was prescribed topical antifungal and therapeutic dose of fluconazole. After 5 days, the patient developed cervical lymph node enlargement, increased oral plaques, and multiple oral ulcers. Both lymph nodes and oral lesions were Epstein-Barr virus (EBV)-positive, which contributed to the diagnosis of posttransplant lymphoproliferative disease (PTLD). The first-choice treatment was rituximab, which was started immediately. Symptomatic control and photodynamic therapy for oral ulcers were performed. After 2 months of follow-up, the lesions in the oral cavity improved, but the clinical condition worsened, and the patient died. Mucocutaneous ulcer EBV-positive is a clinical entity recently described in immunosuppressed patients that can assist in the diagnosis and institution of appropriate treatment for PTLD.

P1339: CLINICAL OUTCOMES OF PATIENTS WITH EBV+ PTLD FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION WHO FAIL RITUXIMAB: A MULTINATIONAL, RETROSPECTIVE CHART REVIEW STUDY

Background: Post-transplant lymphoproliferative disease (PTLD) occurs following allogeneic hematopoietic stem cell transplantation (HCT) as a consequence of immunosuppression. In most cases following HCT, PTLD is associated with Epstein-Barr Virus (EBV) infection of B cells, either due to reactivation, or from primary EBV infection (Styczynski J, Haematol. 2016; Allen UD, Am J Transplant, 2019; Nijand M, Transplant Direct, 2016). Clinical practice treatment guidelines recommend rituximab as preemptive therapy for EBV reactivation (based on EBV virus load) and for treatment of EBV-driven (EBV+) PTLD following HCT. However, EBV+ PTLD patients (pts) who fail rituximab have very poor outcomes with limited treatment options. Published evidence on the clinical outcomes of these pts who fail rituximab is also limited. Aims: To describe the outcomes for pts diagnosed with EBV+ PTLD following HCT who fail rituximab in a multinational real-world setting. Methods: We conducted a large multinational, multicenter retrospective chart review study of EBV+ PTLD pts following HCT or solid organ transplantation who received rituximab or rituximab plus chemotherapy (CT) between January 2000-December 2018 and were refractory (failed to achieve complete response [CR] or partial response [PR]) or relapsed at any point after such therapy. Data was collected from 29 centers across North America (United States and Canada) and the European Union. This analysis includes pts with EBV+ PTLD following HCT who were refractory or relapsed after rituximab ± CT as first line of therapy. The Kaplan-Meier (KM) method was used to estimate the overall survival (OS). Rituximab failure date was defined as the earliest date when pts became refractory or relapsed following rituximab ± CT. Results:: A total of 81 pts with EBV+ PTLD following HCT who failed rituximab ± CT were included in the analysis. Median age at PTLD diagnosis was 49 years (interquartile range [IQR]: 33‒57) and median time to PTLD onset from transplant was 3 months (IQR: 1.9‒4.2). Median follow-up time was 1.7 months (IQR: 0.6‒3.4) from the date of PTLD diagnosis. Of all the PTLDs, 52 (64.2%) were monomorphic, 18 (22.2%) polymorphic, 2 (2.5%) early lesions, and 9 (11.1%) were unknown. The most common PTLD subtype was diffuse large B-cell lymphoma (DLBCL) (46, 56.8%). Sixty-eight (84%) pts received rituximab monotherapy and 13 (16%) pts received rituximab plus CT as first line of therapy. Seven out of 13 pts who received rituximab plus CT had received preemptive rituximab treatment for EBV viremia prior to PTLD treatment. Median OS was 0.7 months (95% CI: 0.3‒1; IQR: 0.1‒2.7) for 81 pts from rituximab failure date (Figure 1). Median OS from PTLD diagnosis was 1.7 months (95% CI: 1.1‒2.3; IQR: 0.6‒3.4). Seventy-four (91.4%) out of the 81 pts ultimately died. Causes of death comprised 50 (67.6%) related to PTLD and therapy, 10 (13.5%) graft-versus-host disease (GvHD), 5 (6.8%) from sepsis/infection, 3 (4.1%) due to primary disease leading to HCT, 2 (2.7%) organ failure, 1 (1.4%) graft failure, 1 (1.4%) from hepatic failure, and 2 (2.7%) unknown. Image:Summary/Conclusion: The prognosis of EBV+ PTLD pts following HCT who fail rituximab ± CT remains very poor with an estimated median OS of less than 1 month, highlighting the significant unmet need in this population.

Clinical Outcomes of Patients with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease Following Hematopoietic Stem Cell Transplantation Who Fail Rituximab: A Multinational, Retrospective Chart Review Study

Background: Post-transplant lymphoproliferative disease (PTLD) occurs following allogeneic hematopoietic stem cell transplantation (HCT) as a consequence of immunosuppression. In most cases following HCT, PTLD is associated with Epstein-Barr Virus (EBV) infection of B cells, either due to reactivation, or from primary EBV infection (Styczynski J, Haematol. 2016; Allen UD, Am J Transplant, 2019; Nijand M, Transplant Direct, 2016). Clinical practice treatment guidelines recommend rituximab as preemptive therapy for EBV reactivation (based on EBV virus load) and for treatment of EBV-driven (EBV +) PTLD following HCT. However, EBV + PTLD patients (pts) who fail rituximab have very poor outcomes with limited treatment options. There are ongoing clinical studies investigating innovative therapies to address unmet needs in these pts. Published evidence on the clinical outcomes of these pts who fail rituximab is also limited. We aimed to describe the outcomes for pts diagnosed with EBV + PTLD following HCT who fail rituximab in a multinational real-world setting.Methods: We conducted a large multinational, multicenter retrospective chart review study of EBV + PTLD pts following HCT or solid organ transplantation who received rituximab or rituximab plus chemotherapy (CT) between January 2000-December 2018 and were refractory (failed to achieve complete response [CR] or partial response [PR]) or relapsed at any point after such therapy. Treatment response was assessed by either clinical diagnosis, radiographic/imaging, biopsy/cytology, or a combination of such assessments. Data was collected from 29 centers across North America (United States and Canada) and the European Union. The study population was aligned with the ongoing investigational trial (Clinicaltrials.gov Identifier: NCT03394365). This analysis includes pts with EBV + PTLD following HCT who were refractory or relapsed after rituximab ± CT as first line of therapy. The Kaplan-Meier (KM) method was used to estimate the overall survival (OS). Rituximab failure date was defined as the earliest date when pts became refractory or relapsed following rituximab ± CT.Results: A total of 81 pts with EBV + PTLD following HCT who failed rituximab ± CT were included in the analysis. Median age at PTLD diagnosis was 49 years (interquartile range [IQR]: 33‒57) and median time to PTLD onset from transplant was 3 months (IQR: 1.9‒4.2). Median follow-up time was 1.7 months (IQR: 0.6‒3.4) from the date of PTLD diagnosis. Of all the PTLDs, 52 (64.2%) were monomorphic, 18 (22.2%) polymorphic, 2 (2.5%) early lesions, and 9 (11.1%) were unknown. The most common PTLD subtype was diffuse large B-cell lymphoma (DLBCL) (46, 56.8%).Sixty-eight (84%) pts received rituximab monotherapy and 13 (16%) pts received rituximab plus CT as first line of therapy. Seven out of 13 pts who received rituximab plus CT had received preemptive rituximab treatment for EBV viremia prior to PTLD treatment. Median OS was 0.7 months (95% CI: 0.3‒1; IQR: 0.1‒2.7) for 81 pts who failed first line rituximab ± CT (Figure 1). Median OS from PTLD diagnosis was 1.7 months (95% CI: 1.1‒2.3; IQR: 0.6‒3.4).Seventy-four (91.4%) out of the 81 pts ultimately died. Causes of death comprised 50 (67.6%) related to PTLD and therapy, 10 (13.5%) graft-versus-host disease (GvHD), 5 (6.8%) from sepsis/infection, 3 (4.1%) due to primary disease leading to HCT, 2 (2.7%) organ failure, 1 (1.4%) graft failure, 1 (1.4%) from hepatic failure, and 2 (2.7%) unknown.Conclusions: The prognosis of EBV + PTLD pts following HCT who fail rituximab ± CT remains very poor with an estimated median OS of less than 1 month, highlighting the significant unmet need in this population. [Display omitted] DisclosuresStorek: Atara Biotherapeutics: Other: Site PI, Research Funding. Socié: Alexion: Research Funding. Thirumalai: Atara Biotherapeutics: Current Employment. Guzman-Becerra: Atara Biotherapeutics: Current Employment. Xun: Atara Biotherapeutics: Current Employment. Kumar: Roche: Research Funding; GSK: Research Funding; Amplyx: Research Funding; Merck: Research Funding; Takeda & Atara: Research Funding. Sadetsky: Atara Biotherapeutics: Current Employment. Dierickx: Sandoz: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Roche: Consultancy, Research Funding; Takeda, Incyte, Atara: Consultancy. Reitan: Atara, Kite, Janssen: Research Funding. Barlev: Atara Biotherapeutics: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

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.

Current Practices on Diagnosis, Prevention and Treatment of Post-Transplant Lymphoproliferative Disorder in Pediatric Patients after Solid Organ Transplantation: Results of ERN TransplantChild Healthcare Working Group Survey.

(1) Background: Post-transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation (SOT). However, there is lack of consensus in PTLD management. Our aim was to establish a present benchmark for comparison between international centers and between various organ transplant systems and modalities; (2) Methods: A cross-sectional questionnaire of relevant PTLD practices in pediatric transplantation was sent to multidisciplinary teams from 17 European center members of ERN TransplantChild to evaluate the centers’ approach strategies for diagnosis and treatment and how current practices impact a cross-sectional series of PTLD cases; (3) Results: A total of 34 SOT programs from 13 European centers participated. The decision to start preemptive treatment and its guidance was based on both EBV viremia monitoring plus additional laboratory methods and clinical assessment (61%). Among treatment modalities the most common initial practice at diagnosis was to reduce the immunosuppression (61%). A total of 126 PTLD cases were reported during the period 2012–2016. According to their histopathological classification, monomorphic lesions were the most frequent (46%). Graft rejection after PTLD remission was 33%. Of the total cases diagnosed with PTLD, 88% survived; (4) Conclusions: There is still no consensus on prevention and treatment of PTLD, which implies the need to generate evidence. This might successively allow the development of clinical guidelines.

Course of renal allograft function after diagnosis and treatment of post-transplant lymphoproliferative disorders in pediatric kidney transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication in renal transplant recipients. Immunomodulatory and chemotherapeutic treatment potentially affect allograft function. The aim of this study was to evaluate graft function of pediatric kidney transplant recipients following diagnosis and standardized treatment of PTLD. Patients were identified from the German Ped-PTLD registry, and data on renal function were retrospectively retrieved from patient charts. For PTLD treatment, immunosuppressive therapy was reduced and all children received rituximab (375mg/m2 ) for up to six doses. Two patients required additional low-dose chemotherapy. Renal allograft function was monitored by consecutive measurements of estimated glomerular filtration rate (eGFR) at defined time points. Follow-up was up to 60months after PTLD. Twenty patients were included in this cohort analysis. Median time from transplantation to PTLD was 2.4years. Histopathology showed monomorphic lesions in 16 and polymorphic in 4 patients. Two patients experienced PTLD relapse after 2 and 14months. Range-based analysis of variance showed stable allograft function in 17 of 20 patients (85%). Mean eGFR increased during early treatment phase. One patient experienced graft rejection 5.3years after diagnosis of PTLD. Another patient developed recurrence of primary renal disease (focal-segmental glomerulosclerosis) and lost his renal allograft 3.8years post-transplant (2.0years after PTLD diagnosis). Treatment of PTLD with rituximab with or without low-dose chemotherapy in combination with reduced immunosuppression, mostly comprising of an mTOR inhibitor-based, calcineurin inhibitor-free regimen, is associated with stable graft function and favorable graft survival in pediatric renal transplant patients.

Exploring the burden of short-term CHOP chemotherapy adverse events in post-transplant lymphoproliferative disease: a comprehensive literature review in lymphoma patients

Purpose Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) is a treatment for post-transplant lymphoproliferative disease (PTLD) following solid organ transplant (SOT) after failing rituximab, an aggressive and potentially fatal lymphoma. This study explores the humanistic and economic burden of CHOP-associated adverse events (AEs) in PTLD patients. Since PTLD is rare, searches included lymphoproliferative disease with lymphoma patients. Design This comprehensive literature review used the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocol, pre-specifying the search strategy and criteria. CHOP-associated short-term AEs with an incidence of >4% were sourced from published literature and cancer websites to inform the search strategy. PubMed and EMBASE searches were used to identify humanistic and economic burden studies. Results PubMed and EMBASE searches identified 3946 citations with 27 lymphoma studies included. Studies were methodologically heterogeneous. Febrile neutropenia (FN) was the AE most encountered, followed by chemotherapy-induced (CI) anemia (A), infection, CI-nausea and vomiting, thrombocytopenia, and CI-peripheral neuropathy (PN). FN and infections were associated with significant disutility, increased hospitalization, and extended length of stay (LOS). Infections and CIPN significantly impacted the utility of patients and CIA-related fatigue showed reductions in quality of life (QoL). Many patients continue to have QoL deficits continued even after AEs were treated. Management costs varied greatly, ranging from nominal (CIPN) to over $100,000 in the USA for infections, EUR 10,290 in Europe for infections, or CAN$1012 in Canada for FN. Cost of outpatient care varied but had a lower economic impact compared to hospitalizations. Conclusions Short-term AEs from CHOP in the lymphoma population were associated with substantial humanistic and economic burden.

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

Background: Post-transplant lymphoproliferative disease (PTLD), is one of the major complications after organ transplantation. The aim of this study is to study the incidence, risk factors especially EBV status, histopathological types, management, and outcomes of PTLD in the pediatric groups. 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. The initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found twenty-eight studies. We extracted the data for baseline characteristics, recipient & donor EBV status, immunosuppression used, type & stage of PTLD, organ system involved, duration between transplant and PTLD diagnosis, treatment, and mortality. Results: We included 32 studies with a total (n) of 15597 pediatric patients after a solid organ transplant. 1210 (7.75%) patients developed PTLD, out of which 609 (50.33%) were male participants, 453 (37.4%) female, and 148 (12.23%) the gender was unknown. (Table 1) Data from 19 studies showed that among PTLD patients, 115 recipients & 76 donors tested positive for Epstein-Barr Virus (EBV), 187 recipients were seronegative and the rest were unknown at the time of transplant. Immunosuppressive drugs used after organ transplantation included; cyclosporine, tacrolimus, sirolimus, azathioprine, mycophenolate, prednisone, mTOR inhibitors, induction therapy with OKT3, IL-2 inhibitors (basiliximab, daclizumab) and anti-thymocyte/anti-lymphocyte globulin. In two studies, antiviral prophylaxis with ganciclovir/valganciclovir was achieved. Data from nine studies showed the median age at PTLD diagnosis was 6.8 years. L'Huillier et al. stated that the median duration for EBV positive recipients to develop PTLD was 1.92 years (0.35-3.09 years), compared to EBV negative recipients, which was 0.95 years (2.48-2.92 years). Overall, the median duration from organ transplant to the diagnosis of PTLD among 15 studies was 29.1 months, ranging from 0.9 months to 186 months. The histopathology of PTLD was confirmed via biopsy specimen showing predominance in monomorphic type, i.e; 265/1210 (21.9%), followed by polymorphic type with 140/1210 (11.5%), an early lesion with 46/1210 (3.80%), Non-Hodgkin lymphoma 28/1210 (2.3%), Hodgkin lymphoma 33/1210 (2.72%) and mixed type (polymorphic & monomorphic) 4/1210 (0.33%). Histopathological data for 694 patients were not available. Treatment of PTLD was achieved with reduction or complete cessation of immunosuppressive therapy, anti-CD20 antibody (rituximab), antiviral treatment with ganciclovir/valganciclovir, lymphoma treatment with chemotherapeutic agents, radiotherapy, and surgical resection. Gajarski et al. concluded that patients who received induction therapy [OKT3, IL-2 antagonists (basiliximab, daclizumab) and anti-thymocyte globulin] had significantly less PTLD development as compared to those who did not receive induction therapy, i.e., (2.9% vs. 4.9%) among 2374 total patients. According to Hayes Jr. et al., recipient EBV seronegativity continued to be associated with lower mortality hazard (HR 0.715; 95 % CI 0.547, 0.935; p = 0.014). Data from 19 studies showed the mortality rate among 494 PTLD diagnosed patients was 22.7% (112) with an overall survival of 84.2% respectively from three studies. Data from five studies showed that direct PTLD related mortality accounted for 63% (17/27) of deaths in PTLD diagnosed patients. Conclusion: Our analysis shows that post-transplant EBV positive recipients who undergo multiorgan transplants are more likely to develop PTLD compared to EBV positive recipients with single organ transplantation. The median duration from organ transplants to the diagnosis of PTLD ranged from months to years, however, this duration was reported to be less in EBV negative recipients compared to EBV positive recipients with organ transplants. The most common histological type of PTLD among pediatric groups was monomorphic and the least common was Classic Hodgkin lymphoma. Rituximab use in the treatment of PTLD was associated with a decreased use of alkylating agents and as a result, the side effects associated with these agents were reduced. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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 & donor EBV status, immunosuppression used, type & 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 & 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.

Post-Transplant Lymphoproliferative Disorder after Liver Transplant: 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 incidence, characteristics, predictive factors, management, and outcomes of PTLD 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. The initial search revealed 1741 articles. We excluded all case reports, case series, pre-clinical trials, review articles, and meta-analysis. We found fifteen studies including retrospective observational and cohort studies. We extracted the data for baseline characteristics, the reason for transplantation, recipient & donor EBV status, immunosuppression used, type & 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 15 studies with a total (n) of 10706 post-liver transplant patients. 294 (2.74%) patients developed PTLD as a complication, out of which 104 (35.3%) were males, 106 (36%) females, and 84 unknowns. Table 1. The incidence of PTLD in the pediatric group was 135/3116 (4.3%) whereas in the adult population it was 115/7545 (1.5%). Data from eleven studies show that out of 202 participants, 67 recipients were positive, 39 negative, and 18 donors positive for EBV infection at the time of transplant. Data on the EBV serostatus for the remaining 106 recipients was not known at the time of transplant. Data from two studies showed that 25/29 patients who later developed PTLD were seronegative for EBV prior to the transplant and 26/29 were reported to undergo seroconversion partly due to transplantation with EBV positive donors (7/13). Post-transplant immunosuppression was achieved with cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus, prednisone, OKT3 for acute cellular rejection and induction with monoclonal antibodies. Data from four studies conclude the median age at the time of PTLD diagnosis is 47.6 months in the pediatric population while 54 years in adults, overall ranging from 1 year to 73 years. Ten studies show the overall median duration from organ transplant to the diagnosis of PTLD is 23.5 months. The median duration for the pediatric population was 11.6 months from the data collected from 55 patients whereas five studies with 166 adult liver transplant recipients showed a median duration of 35.5 months. Histopathological types were diagnosed via biopsy samples, with monomorphic in 76 (25.8%), early lesions in 22 (7.4%), polymorphic in 19 (6.4%), and classic Hodgkin lymphoma like PTLD in 8 (2.7%) of the samples. Among the monomorphic type, Diffuse Large B-Cell Lymphoma (DLBCL) was the most commonly reported i.e. 10/50 (20%) of patients with monomorphic type in two studies. Treatment of PTLD consisted of reduction or cessation of the post-transplant immunosuppressive drugs, anti-CD20 antibody (rituximab), antiviral treatment with ganciclovir, and lymphoma treated with chemotherapy, radiotherapy, and surgical resection. Data from eight studies show a mortality rate of 61/214 (28.5%) with Huang, et al. reporting ¾(75%) of total deaths due to PTLD progression. Two studies report an overall survival rate of 26/32 (81.3%) and five-year survival of 15/41 (36.6%). Conclusions: Our analysis shows the incidence of PTLD after liver transplant is low with no significant gender predominance but a difference in the incidence was observed with significantly higher rates in the pediatric group as compared to the adult population. The most common biopsy proved histopathological type was monomorphic, with the least common type being Hodgkin lymphoma like PTLD. Among the monomorphic, DLBCL was the most common subtype. After liver transplantation, the development of PTLD is observed earlier in pediatric patients in comparison to adult recipients. EBV naive patients prior to liver transplantation are at higher risk for seroconversion post-transplant if transplanted with EBV positive donors and hence at increased risk of PTLD development. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Graft outcomes following diagnosis of post-transplant lymphoproliferative disease in pediatric kidney recipients: a retrospective study.

Data related to graft outcomes following post-transplant lymphoproliferative disease (PTLD) in pediatric kidney transplantation are scarce. Data were analyzed retrospectively from 12 children (eight boys) for 3years after diagnosis of PTLD, with a loss of follow-up after 2years in two of 12. In all cases, intensity of immunosuppressive therapy was reduced, which switched from calcineurin inhibitor to a mammalian target of rapamycin (mTOR) inhibitor in ten cases. Nine children were treated with six doses of rituximab according to the PED-PTLD-2005 protocol, with additional treatment in one child as per protocol. One patient received EuroNet-PHL C1. In four patients, donor-specific antibodies were detected after PTLD diagnosis at 3, 4, 5 and 7years, respectively. One patient developed chronic antibody-mediated rejection (cAMR) 12years after diagnosis, losing the graft 1year later. Three patients with recurrence of the original disease also lost their grafts, one at the time of diagnosis of PTLD, and two after 4years. Range-based analysis of variance showed that there was no decrease in estimated GFR at 1, 2, or 3years after diagnosis of PTLD (P=0.978). In conclusion, treatment of PTLD with reduced immunosuppression is safe and efficient. This may be due to B-cell-depleting therapy of PTLD with rituximab.

Management of post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disease (PTLD) is a major complication of hematopoietic stem cell and solid organ transplantation. The incidence of transplantation in childhood has been steadily rising, making PTLD the most common form of lymphoproliferation in childhood. The purpose of this review is to summarize the role of the Epstein-Barr virus (EBV) in the pathophysiology and discuss the management of PTLD. More than 90% of pediatric PTLD is EBV-positive. In immunocompetent hosts, the virus is controlled by cytotoxic T-cells, the cells targeted by immunosuppression to avoid graft-versus-host disease and/or organ rejection in transplant patients. The majority of pediatric transplant candidates are EBV-negative prior to transplant increasing the risk of EBV-induced lymphoproliferation upon seroconversion after transplant. Treatment options include reduction of immunosuppression, anti-CD20 monoclonal antibodies, and/or chemotherapy. Advanced understanding of the importance of cellular immunity in controlling lymphoproliferation has led to the development of cellular therapies targeting virus-specific antigens. PTLD is the most common form of lymphoproliferation in childhood due to the rising incidence of transplantation. EBV plays a pivotal role in the pathophysiology. Cellular therapies targeting viral antigens may replace chemotherapy in the treatment of PTLD in the near future.

Risk factors, diagnosis, and management of posttransplant lymphoproliferative disorder: improving patient outcomes with a multidisciplinary treatment approach

Risk factors, diagnosis, and management of posttransplant lymphoproliferative disorder: improving patient outcomes with a multidisciplinary treatment approach Kinga Ligeti, Lutz P Müller, Carsten Müller-Tidow, Thomas Weber Department of Hematology and Oncology, University Hospital Halle (Saale) and Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany Abstract: Posttransplant lymphoproliferative disease (PTLD) is a major complication after solid organ transplantation and allogeneic hematopoietic stem cell transplantation. The spectrum of PTLD ranges from benign hyperplasia to malignant lymphoma, representing one of the most relevant malignancies in these patients. Most PTLDs are driven by latent Epstein–Barr virus infections. The backbone of treatment is reduction of immunosuppression. Further treatment depends on the type of PTLD and the type of transplantation. A multidisciplinary approach involving transplant team, hematologists, and other disciplines is crucial for the diagnosis and treatment of PTLD and for concurrent preservation of the transplant function. In this study, known pathomechanisms, risk factors, preemptive management, and especially emerging treatment algorithms in PTLD were reviewed. Keywords: lymphoproliferative disease, Epstein-Barr virus, management, rituximab, ­preemptive therapy

Post-transplant lymphoproliferative disorder in paediatric patients: the Irish perspective-a single centre experience.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of both solid organ and haematopoietic stem cell transplantation in children. Its incidence has increased over the last decade as a result of more potent immunosuppressive regimens. Many treatments have been explored however optimal therapy remains controversial. We report on the diagnosis, treatment and outcome of ten patients who were diagnosed with PTLD in Our Lady's Hospital for Sick Children in Dublin between 2004 and 2015 inclusive. Data were collected by retrospective review of patient medical records. 9 out of ten of our patients are alive and disease free following treatment for PTLD with rituximab alone or in combination with chemotherapy. The outcome of paediatric patients treated for PTLD at our institution is at least comparable to published international series and supports the use of rituximab±low dose chemotherapy in the treatment of this malignancy.

Risk-adapted Treatment for Severe B-Lineage Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation in Children.

Optimal management of posttransplant lymphoproliferative disease (PTLD) remains to be defined due to heterogeneity of this condition and lack of predictors of the outcome. Here we report our experience with pediatric PTLD nonresponsive to immunosuppression (IS) withdrawal, managed after stratification into high and low risk according to the presenting features. This is a single-center retrospective review of prospectively enrolled patients. From 2001 to 2011, 17 children were diagnosed with severe B-lineage, CD20+, PTLD after a median of 37 months (range, 5-93) from liver (12), heart (4), or multiorgan (1) transplantation. Treatment was tailored on 2 risk groups: (1) standard-risk (SR) patients received IS reduction and rituximab; (2) high-risk (HR) patients received IS discontinuation, rituximab and polychemotherapy. The cumulative incidence of rejection at 1 and 5 years after the diagnosis of PTLD was 35% (95% confidence interval [95% CI], 18-69%) and 53% (33-85%), respectively, whereas the disease-free survival at 1 and 5 years was 94% (95% CI, 65-99%) and 75% (45-90%), respectively. Three children died, PTLD-free, from different transplant-related complications: primary nonfunction after retransplantation (liver), cytomegalovirus disease 21 months after PTLD treatment (liver), graft dysfunction 25 months after PTLD (heart). Severe B-lineage PTLD after solid organ transplantation may be classified as SR or HR and treated accordingly with a tailored protocol obtaining a satisfactory long-term outcome. This approach accomplishes the control of lymphoproliferation in severe forms as well as the minimization of toxicity in milder PTLDs.

Outcomes of kidney retransplantation in recipients with prior post-transplant lymphoproliferative disorder.

Post-transplant lymphoproliferative disease (PTLD) is an uncommon but serious complication of solid organ transplantation. Reduction in immunosuppression is the mainstay of PTLD treatment, but it may precipitate graft loss. Retransplantation remains controversial, as immunosuppression resumption may trigger PTLD relapse. Herein, we describe the experience of eight patients who underwent kidney retransplantation after successful PTLD treatment. Epstein-Barr virus (EBV) serology was not known before the first transplantation. PTLD was diagnosed 62.5 months (range 5-323 months) after transplantation and was confined to the renal allograft (n = 1), lymph nodes (n = 2), gastrointestinal tract (n = 4), or central nervous system (n = 1). Immunosuppression tapering (8/8), chemotherapy (6/8), oral cavity lymphoma excision (1/8), and allograft nephrectomy (1/8) led to hematological remission in all patients. Retransplantation was performed at a median of 55.5 months (range 29-95 months) after PTLD diagnosis. After a median follow-up of 62.5 months (range 2-125 months) allograft survival was 87.5% (seven functioning grafts, one failed graft from chronic rejection), with no recurrence of PTLD. In all, five patients remain alive; the other three died from causes other than PTLD. In conclusion, kidney retransplantation appears to be safe in patients with prior PTLD and without major risk of hematological recurrence provided that PTLD has remitted.

Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management.

Posttransplant lymphoproliferative disease (PTLD) is a potentially fatal complication after (solid organ) transplantation, which is highly associated with Epstein-Barr virus (EBV). The EBV-specific cytotoxic T cell response that is essential in controlling the virus in healthy individuals is suppressed in transplant recipients using immunosuppressive drugs. A primary EBV infection in EBV-seronegative patients receiving an EBV-seropositive donor organ or a reactivation in those who are already latently infected pretransplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD. Effective preventive strategies, such as vaccines and antiviral agents, are lacking. Because not every transplant recipient with increasing EBV viral load develops PTLD, it is hard to decide how intensively these patients should be monitored and how and when a preemptive intervention should take place. There is a need for other tools to help predict the development of PTLD in patients at risk to make timing and strategy of preemptive intervention easier and more reliable.The cornerstone of the treatment of patients with PTLD is restoring the host's immunity by reduction of immunosuppressive drug therapy. American and British guidelines recommend to add rituximab monotherapy or rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone, depending on histology and clinical characteristics. Although response to these therapies is good, toxicity is a problem, and PTLD still has a relatively high mortality rate. An evolving therapy, especially in PTLD occurring in allogeneic stem cell transplantation, is restoring the host's immune response with infusion of EBV-specific cytotoxic T cells. This may also play a role in the future in both prevention and treatment of PTLD in SOT.

Treatment of post-transplant lymphoproliferative disease with rituximab

Post-transplant lymphoproliferative disorder (PTLD) is one of the main complications after stem cell transplantation and is often induced by EBV. The optimal treatment of PTLD includes reduction of immunosuppressant dose, transplant organ resection, radiotherapy and chemotherapy, and so on. Recently, a new therapeutic approach was developed in PTLD: the anti-CD20 monoclonal antibody or rituximab. In this review, the application of rituximab in treatment of PTLD is summarized, including risk factors and mechanism of PTLD, therapeutic strategy, application of rituximab in PTLD and so on.

Establishment of a bank of blood donor derived epstein barr virus specific cytotoxic T cell lines for treatment of post-transplant lymphoproliferative disease

Epstein-Barr virus (EBV) driven lymphomas associated with immunosuppression are a significant problem, particularly after transplantation. Conventional treatment (withdrawal of immunosuppression, administration of rituximab/chemotherapy) is often effective but risks organ rejection and causes significant side effects. EBV specific cytotoxic T cells (CTL) generated in vitro from autologous lymphocytes can be effective with few side effects, but take months to prepare so are difficult to use in clinical practice. We have established a bank of EBV CTLs derived from platelet / plasma donors for issuing ‘off the shelf product’ to partially human leucocyte antigen (HLA) matched patients on a named patient basis. Donors from the New Zealand platelet / plasma panel were sourced to reduce the risk of Creutzfeldt-Jakob disease (CJD). The current panel of donors selected was EBV positive, Blood Group O, and met all current requirements for mandatory virology markers. The panel was also chosen to maximize the probability of HLA class I and II matches and minimize the number of mismatches. We estimated that this initial panel of 25 donors should provide a partial match for at least three (HLA-A, -B, -DRB1) loci for ∼80% of Caucasian patients. So far, lymphoblastoid cell lines have been made from 25 donors ready for use in stimulating CTLs and 18 CTLs have been manufactured and cryopreserved for clinical use. Since the bank was granted a ‘Specials’ license by the MHRA for this Advanced Therapy Medicinal Product in January 2012, there have been enquiries about 14 patients: 4 improved on conventional therapy without requiring CTLs, 3 died before any cells could be issued and 6 cell lines have been released. The indications for issue have been: 3 cases of post-transplant lymphoproliferative disorder (1 CD20- rituximab resistant 1 with concomitant graft versus host disease precluding reduction of immunosuppression 1 unfit for chemotherapy) 2 cases with congenital immunosuppression as a bridge to allogeneic haematopoietic stem cell transplant and 1 case of EBV-associated leiomyosarcoma post-cardiac transplant (related donor). Clinical improvement has been seen in 4 out of 6 assessable patients. A 3rd party donor-derived anti-EBV CTL cell bank can be operated under current legislation and is a valuable addition to existing therapies for selected patients.

Combination of immunoglobulins and natural killer cells in the context of CMV and EBV infection

Cytomegalovirus (CMV)-specific hyperimmunoglobulin (CMV-HIG) is used to treat and prevent CMV infection in immunocompromised patients, and anti-CD20 monoclonal antibody is successfully used in the treatment for post-transplant lymphoproliferative disease caused by Epstein-Barr virus (EBV). Two immunological approaches have been suggested to further improve the control of viral reproduction in patients with active disease: first, the use of monoclonal antibodies with specificity against viral epitopes and second, coadministration of cells with the capacity to promote antibody-dependent cell-mediated cytotoxicity. Here, we have evaluated the effectiveness of these strategies in vitro (alone and in combination) with neutralization and cytotoxicity assays. Our results indicate that monoclonal antibodies (in particular SM5-1) can be as effective as CMV-HIG in neutralizing-cell-free CMV. Moreover, our data indicate that antibody-mediated elimination (either by moAb or by HIG) of EBV-infected cells can be significantly enhanced by NK cells. Using human NK cells that have been purified, cultured and expanded under GMP conditions, we were able to demonstrate that the combination of NK cells and antibodies could represent a feasible and highly effective clinical approach to achieve control of EBV infections. Especially in leukopenic patients with low numbers of ADCC-promoting cells, the combination of adoptively transferred NK cells and antiviral antibodies offers a promising strategy that should be tested in clinical trials.