Management Of Post-transplant Lymphoproliferative Disorder Research Articles

Incidence and Management of Posttransplantation Lymphoproliferative Disorder After Pediatric Solid Organ Transplantation: The Norwegian Experience.

Posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation (SOT) due to immunosuppression. In 2023, a pediatric PTLD register was established in Norway because of a perceived increase in the incidence of pediatric PTLD. This study aimed to analyze population-based data on the incidence and management of pediatric PTLD after SOT using the pediatric PTLD registry in Norway. This retrospective quality assurance study collected the data of pediatric patients with PTLD after SOT in Norway from January 1, 1995, to December 31, 2023. For comparison and calculation of incidence rates, SOT patients without PTLD required a minimum of 1 year posttransplant follow-up to be included. A total of 457 patients underwent SOT (57% males) and 22 (4.8%) developed PTLD (73% males). The median age at transplant in the SOT and PTLD groups were 9.5 (interquartile range, 2.4-14.5) and 4.3 (1.1-12.5) years, respectively. Twenty patients with PTLD (91%) were Epstein-Barr virus naive at the time of transplantation. Eighteen (82%) and four (18%) patients developed early and late PTLD, respectively. Ten patients had monomorphic PTLD (45%). All patients received a reduction in immunosuppression, 15 received rituximab, and six required chemotherapy. Six patients (27%) died after PTLD, five of whom had active PTLD disease at the time of death. None of the patients experienced graft loss. Our findings regarding the incidence, EBV status, sex, and age at transplantation align with those of previous studies.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Screening and Management of PTLD.

Posttransplant lymphoproliferative disorder (PTLD) represents a heterogeneous group of lymphoproliferative diseases occurring in the setting of immunosuppression following hematopoietic stem cells transplant and solid organ transplantation. Despite its overall low incidence, PTLD is a serious complication following transplantation, with a mortality rate as high as 50% in transplant recipients. Therefore, it is important to establish for each transplant recipient a personalized risk evaluation for the development of PTLD based on the determination of Epstein-Barr virus serostatus and viral load following the initiation of immunosuppression. Due to the dynamic progression of PTLD, reflected in the diverse pathological features, different therapeutic approaches have been used to treat this disorder. Moreover, new therapeutic strategies based on the administration of virus-specific cytotoxic T cells have been developed. In this review, we summarize the available data on screening and treatment to suggest a strategy to identify transplant recipients at a higher risk for PTLD development and to review the current therapeutic options for PTLD.

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

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

Important Considerations in the Diagnosis and Management of Post-transplant Lymphoproliferative Disorder.

A relative lack of molecular and clinical studies compared to other lymphoid cancers has historically made it difficult to determine optimal management approaches in post-transplant lymphoproliferative disorder (PTLD). We sought to better define the "state of the science" in PTLD by examining recent advances in risk assessment, genomic profiling, and trials of PTLD-directed therapy. Several major clinical trials highlight risk-stratified sequential therapy incorporating rituximab with or without chemotherapy as a rational treatment strategy in patients with CD20+ PTLD who do not respond to reduction of immunosuppression alone. Epstein Barr virus (EBV)-targeted cytotoxic lymphocytes are a promising approach in patients with relapsed/refractory EBV+ PTLD, but dedicated clinical trials should determine how autologous chimeric antigen receptor T cell therapy (CAR-T) may be safely administered to PTLD patients. Sequencing studies underscore the important effect of EBV infection on PTLD pathogenesis, but comprehensive genomic and tumor microenvironment profiling are needed to identify biomarkers that predict response to treatment in this clinically heterogeneous disease.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: I-Methodology for the development of consensus practice guidelines.

The International Pediatric Transplant Association (IPTA) Consensus Conference on Practice Guidelines for the Diagnosis, Prevention, and Management of Post-Transplant Lymphoproliferative Disorders after Solid Organ Transplantation in Children took place on March 12-13, 2019, and the work of conference members continued until the end of December 2021. The goal was to produce evidence-based consensus guidelines on the definitions, diagnosis, prevention, and management of PTLD and related disorders based on the critical review of the literature and consensus of experts. This report describes the goals, organization, and methodology of the consensus conference and follow-up activities. The results of each working group (Definitions, Prevention, Management, and Epstein-Barr viral [EBV] load/Biomarker Monitoring) are presented in separate manuscripts within this volume of Pediatric Transplantation.

Gastrointestinal manifestations, risk factors, and management in patients with post-transplant lymphoproliferative disorder: A systematic review.

BACKGROUNDPatients with a history of solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT) are at an increased risk of developing post-transplant lymphoproliferative disorder (PTLD). The gastrointestinal (GI) tract is commonly affected as it has an abundance of B and T cells.AIMTo determine typical GI-manifestations, risk factors for developing PTLD, and management.METHODSMajor databases were searched until November 2021.RESULTSNon-case report studies that described GI manifestations of PTLD, risk factors for developing PTLD, and management of PTLD were included. Nine articles written within the last 20 years were included in the review. All articles found that patients with a history of SOT, regardless of transplanted organ, have a propensity to develop GI-PTLD.CONCLUSIONGI tract manifestations may be nonspecific; therefore, consideration of risk factors is crucial for identifying GI-PTLD. Like other lymphoma variants, PTLD is very aggressive making early diagnosis key to prognosis. Initial treatment is reduction of immunosuppression which is effective in more than 50% of cases; however, additional therapy including rituximab, chemotherapy, and surgery may also be required.

The Changing Face of Adult Posttransplant Lymphoproliferative Disorder: Dramatic Changes in Histology between 1999-2013

INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different, resulting in two distinct malignancies with different prognoses and responsiveness to therapy. We attempted to confirm reports suggesting that the relative frequency of these two histologies is shifting over time.METHODS: 3,040 adult PTLD cases in the United Network for Organ Sharing database from 1999 to 2013 were included. We analyzed changes in PTLD histology over time and used a multivariate logistic regression model to determine factors associated with monomorphic versus polymorphic histology.RESULTS: We found that the relative proportion of polymorphic vs. monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; p<0.001) (see figure). The change in proportion is driven by a gradual increase in the number of monomorphic PTLD cases (1999-2003, 460 cases; 2004-2008, 597 cases; 2009-2013, 821 cases), with a steady number of polymorphic PTLD cases (1999-2003, 378 cases; 2004-2008, 427 cases; 2009-2013, 357 cases), and was most prominent in recipients who were EBV serostatus positive at the time of transplant. Significant changes in the care and outcomes of solid organ transplant patients occurred during this time period, including changes from cyclosporine based immunosuppressive regimens to tacrolimus based regimens and increased survival of allografts and patients. Multivariate logistic regression revealed that tacrolimus use (p=0.034) and increased survival among transplant patients leading to later occurrence of PTLD (p<0.001) were associated with monomorphic PTLD during the time frame analyzed.CONCLUSION: As the practice of organ transplantation has evolved over time, PTLD has coevolved, shifting from predominately polymorphic to monomorphic histology. These changes in histology have important implications regarding the origin and clinical management of PTLD. [Display omitted] DisclosuresHuntington:Celgene: Consultancy, Other: Travel; Janssen: Consultancy; Pharmacyclics: Honoraria. Schuster:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Nordic Nanovector: Consultancy; Merck: Research Funding.

A systematic review of post-transplant lymphoproliferative disorder after lung transplant.

e19046 Background: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ transplantation. This study aims to explore the association of PTLD diagnosed after lung transplant with infectious agents and immunosuppression regimen, explore types of PTLD, and their outcome. Methods: Following the PRISMA guideline, we searched the literature on PubMed, Cochrane, Embase, and clinicaltrials.gov. 1741 articles were screened and included five studies. Results: We analyzed data from five studies, n=13,643 transplant recipients with n=287 (2.10%) developed PTLD. Four studies showed that 32/63 (51%) PTLD patients were male and 31 (49%) were female. Three studies reported 53/55 (96.4%) patients were EBV positive at PTLD diagnosis. Courtwright. et al, reported that 217/224 (97%) PTLD was associated with either EBV positive donor or recipient. Four studies showed that the monomorphic B cell type 48/63 (76%) was the most common histological type of PTLD diagnosed with DLBCL the most common subtype 31/48 (64.6%). Data from 3 studies showed that the onset of PTLD following lung transplant varies with a median duration of 18.3 months (45 days to 20.2 years). Three studies showed that 26/55 (47.3%) patients had early-onset (≤ 1 yr of Tx) and 29/55 (52.7%) patients had late-onset PTLD (&gt; 1 yr of Tx). Management of PTLD included a reduction in immunosuppression including corticosteroids, CNI, purine synthesis inhibitors, Rituximab, and chemotherapeutic agents. Three studies showed a mortality rate of 30/45 (66.7%) and 13/30 (43.3%) deaths were PTLD related. Conclusions: Our review concludes that PTLD is a serious complication, only 2% of lung transplant recipients developed PTLD. EBV seropositivity is the most factor associated with PTLD diagnosis. Monomorphic PTLD was reported as the most common type in the adult population and no association between gender and PTLD was found. The analysis shows that there is a slightly lower incidence of early (≤ 1 yr of Tx) than late-onset (&gt; 1 yr of Tx) PTLD. Table 1 PTLD after a Lung transplant in adults - a review. [Table: see text]

Management of PTLD After Hematopoietic Stem Cell Transplantation: Immunological Perspectives.

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications of iatrogenic immune impairment after allogeneic hematopoietic stem cell transplantation (HSCT). In the pediatric setting, the majority of PTLDs are related to the Epstein–Barr virus (EBV) infection, and present as B-cell lymphoproliferations. Although considered rare events, PTLDs have been increasingly observed with the widening application of HSCT from alternative sources, including cord blood and HLA-haploidentical stem cell grafts, and the use of novel agents for the prevention and treatment of rejection and graft-vs.-host disease. The higher frequency initially paralleled a poor outcome, due to limited therapeutic options, and scarcity of controlled trials in a rare disease context. In the last 2 decades, insight into the relationship between EBV and the immune system, and advances in early diagnosis, monitoring and treatment have changed the approach to the management of PTLDs after HSCT, and significantly ameliorated the prognosis. In this review, we summarize literature on the impact of combined viro-immunologic assessment on PTLD management, describe the various strategies for PTLD prevention and preemptive/curative treatment, and discuss the potential of novel immune-based therapies in the containment of this malignant complication.

Posttransplant Lymphoproliferative Disorder in Children: A 360-degree Perspective.

An earlier incorrect version of this article appeared online. This article was corrected on December 17, 2019.

Management of post-transplant lymphoproliferative disorders.

Management of post-transplant lymphoproliferative disorders.

Post-transplantation lymphoproliferative disease in pediatric liver recipients in Taiwan

Post-transplantation lymphoproliferative disorder (PTLD) is a heterogeneous, potentially life-threatening complication after liver transplantation in children. In this study, the disease characteristics, outcomes, and prognostic factors of PTLD were investigated. A retrospective, observational study was conducted on 16 pediatric liver transplant (LT) recipients who developed PTLD between February 2001 and December 2013at a tertiary referral center in Taiwan. The disease characteristics and treatment outcomes of the patients were analyzed. The median time from liver transplantation to the development of PTLD was 8 months. Early onset (<1 year post-transplantation) PTLD constituted 62.5% of the cases. PTLD location was frequently extranodal (81.3%) and mostly involved the gastrointestinal tract (68.8%). Histopathologic findings showed polymorphic PTLD in six cases (37.5%), diffuse large B-cell lymphoma in five cases (31.3%), and Burkitt's PTLD in two cases (12.5%). Early lesions in PTLD, T-cell lymphoma, and Hodgkin's lymphoma were observed in one case each (6.3%). Overall survival at 1- and 5-years post-PTLD diagnosis was 87.5% and 79.5%, respectively. St Jude's classification stage IV disease was associated with poor survival (hazard ratio [HR]=13.37, P=0.037). Two patients (12.5%) had chronic rejection after the treatment for PTLD and one patient (6.3%) developed graft failure. PTLD is a major complication in pediatric LT recipients, but long-term survival is possible in most cases with an adequate treatment strategy. Stage IV disease is a major risk factor for poor survival in pediatric PTLD patients. During the management of PTLD, the possibility of chronic rejection and even graft failure should be considered.

Treatment Patterns for Patients with Post-Transplant Lymphoproliferative Disorder Who Fail Rituximab after Allogeneic Hematopoietic Stem Cell Transplantation: Findings from a Systematic Literature Review

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized disease after allogeneic hematopoietic stem cell transplantation (HCT) and is one of the most common post-transplant malignancies. In most cases, PTLD is associated with Epstein-Barr Virus (EBV) infection. The management of PTLD remains a challenge, with no approved treatments for patients. Clinical practice treatment guidelines recommend rituximab as first-line therapy for PTLD post-allogeneic HCT; however, treatment options for PTLD patients who fail rituximab are not clearly defined. We conducted a systematic literature review of the published literature to better understand treatment patterns for patients with PTLD who fail rituximab post-allogeneic HCT in a real-world setting.Methods: The systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined in terms of Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. Using extensive search terms for the indication and study designs, studies were identified using key biomedical literature databases: EMBASE, MEDLINE, and Cochrane. The literature search was conducted on July 19, 2018 and included studies published between database inception in January 1, 1959 and July 19, 2018. Relevant congress abstracts published between January 2015 and June 2018 were also identified. The PICOS-based inclusion and exclusion criteria were used to review identified citations. No treatment limitations were imposed to ensure inclusion of all relevant evidence; the study designs were limited to prospective and retrospective observational studies. Case reports were included regardless of sample size. Two independent reviewers screened all citations and full-text articles; any discrepancies were resolved by a third independent reviewer. Data from included studies were extracted into a pre-defined template, and results were summarized using the PRISMA flow diagram.Results: A total of 69 studies were identified that described patients with PTLD post-allogeneic HCT. The majority (61 studies) were retrospective chart reviews, of which 54 studies were single-center studies. Forty-eight studies reported data on treatment of patients with PTLD. Among these, 5 studies included data prior to 2000, 33 studies included data from 2000-2010, and 26 studies included data from 2010-2016. The sample size for PTLD patients was between 1 and 144 patients, with only one study of > 100 patients. First-line therapy in PTLD included rituximab (41 studies), various chemotherapy regimens (15 studies), and lymphocyte infusion (10 studies). Nine studies reported treatment for patients who failed first-line rituximab (13-67% of PTLD patients); the number of patients with second-line treatments ranged from 2-10 across studies. Second-line treatments varied greatly across studies and included cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP, n=1); rituximab plus CHOP (R-CHOP, n=1-2); cyclophosphamide, etoposide/cytarabine (VP16/ARA-C, n=1); rituximab plus cyclophosphamide (n=1); rituximab plus high-dose cytarabine (n=1); chemotherapy unspecified (n=2-4), and lymphocyte infusion (n=3-5). Only 2 studies reported treatment outcomes in rituximab-refractory patients. One study (N=62, second-line n=10, median age 49 years) reported no complete or partial remission in the chemotherapy group; 60% had complete remission in the lymphocyte infusion group. The second study (N=12, second-line n=3, mean age 5 years) reported complete remission in 1 patient with lymphocyte infusion as second-line treatment.Conclusions: This systematic literature review demonstrates that data on treatment patterns for PTLD patients who failed rituximab post-allogeneic HCT are limited (9 studies with a sample size ≤ 10). Published data suggest that the percentage of patients who fail rituximab vary greatly (13-67%), there is no consistent standard of care for PTLD patients who fail rituximab, and outcomes are poor. There continues to be a significant unmet need among PTLD patients who fail rituximab, and further studies are needed to better understand rituximab response rates in the real-world setting. DisclosuresXu:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Forsythe:Novartis: Consultancy. Barlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

Post-transplant lymphoproliferative disorder presenting with multifocal aggressive osseous lesions.

Post-transplantation lymphoproliferative disorder (PTLD) encompasses a broad category of lymphoid and plasmacytic proliferations that occur following solid organ and/or allogeneic stem cell transplantation. PTLD manifests in the setting of chronic immunosuppression and is thought to be associated with the Epstein Barr Virus, although Epstein Barr Virus infection or reactivation is not required for the process to occur. Pathologic correlation is necessary for diagnosis with B-cell lymphocytes the most commonly isolated cellular etiology. There is a broad range of clinical and imaging presentations of PTLD with intestinal and nodal involvement being the most common. Imaging plays an integral part in the diagnosis and management of PTLD, as it is utilized in the initial diagnosis and staging, guiding biopsy of lesions, and gauging treatment response. Presenting symptoms of PTLD are often vague and nonspecific and depend on the organ systems affected. Musculoskeletal involvement is especially rare, with only a few cases described in the literature. We present a case with multifocal osseous manifestations of PTLD occurring years after a renal living donor transplant.

Management of Non-Diffuse Large B Cell Lymphoma Post-Transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorder (PTLD) is one of the most common neoplasms seen after solid organ and hematopoietic stem cell transplantation, and is associated with significant morbidity and mortality. The pathogenesis is related to post-transplant immunosuppression and EBV infection. Prevention of PTLD depends upon judicious use of immunosuppression and serial EBV monitoring. Preemptive therapy consists of reduction of immunosuppression, antiviral medications, and single-agent rituximab. There are no randomized phase III trials on PTLD treatment, so current management guidelines are largely based on recent phase II trials, single-institution retrospective studies, and expert opinion. Management of PTLD is dependent upon its subtypes. Early-type and polymorphic PTLD generally respond to reduction of immunosuppression and rituximab monotherapy, whereas monomorphic PTLD often requires additional concurrent or sequential use of chemotherapy. For rare subtypes of PTLD, standard-of-care guidelines for de novo lymphomas are recommended. Surgical resection or radiotherapy may be used as adjunctive therapy depending on the extent of disease. Non-chemotherapy options such as adoptive T cell therapy have shown promising efficacy and must be explored further. Despite progress in the last decade, overall survival rates continue to be low in published series. This review highlights the need for prospective randomized trials incorporating novel agents to improve outcomes in PTLD.

The changing face of adult posttransplant lymphoproliferative disorder: Changes in histology between 1999 and 2013.

Posttransplant lymphoproliferative disorder (PTLD) typically presents with either polymorphic or monomorphic histology. While both are the end result of immunosuppressive therapies, their origins are felt to be different with different prognoses and responsiveness to therapy, resulting in 2 different malignancies. We attempted to confirm reports suggesting that the relative frequency of these 2 histologies is shifting over time. We analyzed 3040 adult PTLD cases in the UNOS OPTN database from 1999 to 2013. Changes in PTLD cases over time were analyzed for histology, time from transplant to diagnosis, and patient EBV serostatus. We found that the relative proportion of polymorphic versus monomorphic histology has changed with an increase in the proportion of monomorphic cases with time (1999-2003, 54.9% vs. 45.1%; 2004-2008, 58.3% vs. 41.7%; 2009-2013, 69.7% vs. 30.3%; P = <.001). The change is driven by a gradual increase in the number of monomorphic PTLD with a steady number of polymorphic PTLD. The change is most strongly seen in transplant recipients who were EBV serostatus positive at the time of transplant. Potential causes are changes in immunosuppressive regimens with increased tacrolimus use (P = .009) and increased survival among transplant patients leading to later occurrence of PTLD (P = .001) that have occurred during the time frame analyzed. As organ transplantation has evolved over time, PTLD has coevolved. These changes in histology have important implications regarding the origin and clinical management of PTLD.

Epstein-barr virus DNAemia monitoring for the management of post-transplant lymphoproliferative disorder

BackgroundPost-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD. MethodsWe retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin-conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation. ResultsReactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000–500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4–20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD occurred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable. DiscussionIn conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000–500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse.

The impact of targeting repetitive BamHI-W sequences on the sensitivity and precision of EBV DNA quantification.

BackgroundViral load monitoring and early Epstein-Barr virus (EBV) DNA detection are essential in routine laboratory testing, especially in preemptive management of Post-transplant Lymphoproliferative Disorder. Targeting the repetitive BamHI-W sequence was shown to increase the sensitivity of EBV DNA quantification, but the variability of BamHI-W reiterations was suggested to be a source of quantification bias. We aimed to assess the extent of variability associated with BamHI-W PCR and its impact on the sensitivity of EBV DNA quantification using the 1st WHO international standard, EBV strains and clinical samples.MethodsRepetitive BamHI-W- and LMP2 single- sequences were amplified by in-house qPCRs and BXLF-1 sequence by a commercial assay (EBV R-gene™, BioMerieux). Linearity and limits of detection of in-house methods were assessed. The impact of repeated versus single target sequences on EBV DNA quantification precision was tested on B95.8 and Raji cell lines, possessing 11 and 7 copies of the BamHI-W sequence, respectively, and on clinical samples.ResultsBamHI-W qPCR demonstrated a lower limit of detection compared to LMP2 qPCR (2.33 log10 versus 3.08 log10 IU/mL; P = 0.0002). BamHI-W qPCR underestimated the EBV DNA load on Raji strain which contained fewer BamHI-W copies than the WHO standard derived from the B95.8 EBV strain (mean bias: - 0.21 log10; 95% CI, -0.54 to 0.12). Comparison of BamHI-W qPCR versus LMP2 and BXLF-1 qPCR showed an acceptable variability between EBV DNA levels in clinical samples with the mean bias being within 0.5 log10 IU/mL EBV DNA, whereas a better quantitative concordance was observed between LMP2 and BXLF-1 assays.ConclusionsTargeting BamHI-W resulted to a higher sensitivity compared to LMP2 but the variable reiterations of BamHI-W segment are associated with higher quantification variability. BamHI-W can be considered for clinical and therapeutic monitoring to detect an early EBV DNA and a dynamic change in viral load.

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.