Summary
It is currently unclear whether post‐transplant diffuse large B‐cell lymphomas (PT‐DLBCL) display a similar genomic landscape as DLBCL in immunocompetent patients (IC‐DLBCL). We investigated ...50 post‐transplant lymphoproliferative disorders (PTLDs) including 37 PT‐DLBCL samples for somatic mutations frequently observed in IC‐DLBCL. Targeted Next Generation Sequencing (NGS) using the Ion Torrent platform and a customized panel of 68 genes was performed on genomic DNA. Non‐tumoural tissue was sequenced to exclude germline variants in cases where available. A control cohort of 76 IC‐DLBCL was available for comparative analyses. In comparison to IC‐DLBCLs, PT‐DLBCL showed more frequent mutations of TP53 (P = 0·004), and absence of ATM and B2M mutations (P = 0·004 and P = 0·016, respectively). In comparison to IC‐DLBCLs, Epstein–Barr virus (EBV)+ PT‐DLBCL had fewer mutated genes (P = 0·007) and particularly fewer mutations in nuclear factor‐κB pathway‐related genes (P = 0·044). TP53 mutations were more frequent in EBV‐ PT‐DLBCL as compared to IC‐DLBCL (P = 0·001). Germinal centre B cell (GCB) subtype of PT‐DLBCL had fewer mutations and mutated genes than GCB‐IC‐DLBCLs (P = 0·048 and 0·04 respectively). Polymorphic PTLD displayed fewer mutations as compared to PT‐DLBCL (P = 0·001). PT‐DLBCL differs from IC‐DLBCL with respect to mutations in genes related to DNA damage control and immune‐surveillance, and EBV association is likely to have a bearing on the mutational pattern.
We examined the associations of Epstein–Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ ...transplant recipients diagnosed with PTLD between 1990 and 2013 (58 33% EBV‐negative; 118 67% EBV‐positive). The proportion of EBV‐negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (p < 0.001). EBV‐negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high‐risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV‐positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV‐negative versus EBV‐positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV‐negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV‐negative PTLD.
In a study of 176 solid organ transplant recipients with posttransplantation lymphoproliferative disorder, the authors show that the proportion of Epstein–Barr virus–negative cases has increased over time, but Epstein–Barr virus negativity is not associated with high‐risk features, worse response to initial therapy, or worse overall survival.
Background. The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)—related posttransplant lymphoproliferative disorder (PTLD) ...after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. Methods. A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. Results. One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extra-lymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0–1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. Conclusions. More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.
Epstein-Barr virus-related post-transplant lymphoproliferative disorders are recognized as a significant cause of morbidity and mortality in patients undergoing hematopoietic stem cell ...transplantation. To better define current understanding of post-transplant lymphoproliferative disorders in stem cell transplant patients, and to improve its diagnosis and management, a working group of the Sixth European Conference on Infections in Leukemia 2015 reviewed the literature, graded the available quality of evidence, and developed evidence-based recommendations for diagnosis, prevention, prophylaxis and therapy of post-transplant lymphoproliferative disorders exclusively in the stem cell transplant setting. The key elements in diagnosis include non-invasive and invasive methods. The former are based on quantitative viral load measurement and imaging with positron emission tomography; the latter with tissue biopsy for histopathology and detection of Epstein-Barr virus. The diagnosis of post-transplant lymphoproliferative disorder can be established on a proven or probable level. Therapeutic strategies include prophylaxis, preemptive therapy and targeted therapy. Rituximab, reduction of immunosuppression and Epstein-Barr virus-specific cytotoxic T-cell therapy are recommended as first-line therapy, whilst unselected donor lymphocyte infusions or chemotherapy are options as second-line therapy; other methods including antiviral drugs are discouraged.
Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic ...features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as followsextranodal involvement13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P<0.05). Overall survival did not differ significantly between the groups. On univariate analysis, the predictive factors for progression-free survival included plasma cell infiltrate for CHL, eosinophil infiltrate, age above 70 years, and extensive necrosis for Poly-LPD, while they were Epstein-Barr virus encoded RNA positivity and International Prognostic Index risk for DLBCL on multivariate analysis. In conclusion, histologic categorization and histology-specific factors could be useful for predicting MTX-LPD progression after MTX withdrawal.
Solid-organ and hematopoietic stem-cell transplants are widely used for various life-threatening medical disorders. Prophylaxis against transplant rejection and graft-versus-host disease is often ...immunosuppressive and can increase the risk of lymphoproliferative disease.
Summary
Post‐transplant lymphoproliferative disorder (PTLD) is rare and heterogeneous lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant (SOT) and ...haematopoietic stem cell transplant (HSCT) with the majority being driven by EBV. Although some histologies are similar to lymphoid neoplasms seen in immunocompetent patients, treatment of PTLD may be different due to difference in pathobiology and higher risk of treatment complications. The most common treatment approach in SOT PTLD after failing immunosuppression reduction (RIS) takes into consideration a risk‐stratified sequential algorithm with rituximab +/− chemotherapy based on phase 2 studies. In HSCT PTLD, RIS alone and chemotherapy are usually ineffective making rituximab +/− RIS as the gold standard of frontline treatment. In this review, we give an update on the treatment of PTLD beyond RIS. We highlight the most recent studies that attempted to incorporate more aggressive chemotherapy regimens and novel treatments into the traditional risk‐stratified sequential approach. We also discuss the role of EBV‐cytotoxic T lymphocytes in treatment of EBV‐driven PTLD. Other novel agents with potential role in PTLD will be discussed in addition to the challenges that could arise with chimeric antigen receptor T‐cell therapy and immune checkpoint inhibitors in this population.
Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein–Barr virus (EBV) infection. The role of ...antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow‐up duration of 23 807 person‐years (py). Fifty‐seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV− PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 95% CI 0.199–1.436, p = .264; late EBV+ PTLD: SHR 2.213, 95% CI 0.751–6.521, p = .150). However, none of the patients (0/191) who received a rituximab‐containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD‐free survival was significantly longer (0.104 years 95% CI 0.077–0.131) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.
In this nationwide cohort study of solid organ transplant recipients, rituximab given as part of the induction regimen, in contrast to antiviral prophylaxis, is associated with a lower incidence of posttransplant lymphoproliferative disorders.
Aims
The clinical implications of the programmed cell death 1 (PD1)/programmed cell death‐ligand 1 (PD‐L1) axis in patients with post‐transplant lymphoproliferative disorders are largely unknown, and ...its association with Epstein–Barr virus (EBV) status and PD‐L1 copy number alterations (CNAs) has not been thoroughly studied.
Methods and results
PD1/PD‐L1 expression was studied in 50 adult post‐transplant lymphoproliferative disorders, and the correlations with PD‐L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty‐seven (74%) cases were classified as diffuse large B‐cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty‐four cases were EBV‐positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD‐L1 expression in tumour cells and tumour‐associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD‐L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non‐germinal centre type DLBCL (P < 0.001). Cases with PD‐L1‐positive tumour cells showed a higher number of PD‐L1 CNAs than PD‐L1‐negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD‐L1 expression showed the worst overall survival (P < 0.001).
Conclusions
The PD1/PD‐L1 axis is deregulated in post‐transplant lymphoproliferative disorders, with frequent PD‐L1 expression and PD1 negativity. PD‐L1 expression is associated with EBV latency II or III and PD‐L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD‐L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.
Background Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory ...tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders. Objective This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. Methods Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. Results Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. Conclusion Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome.
PDF
