Monomorphic B-cell Post-transplant Lymphoproliferative Disorder Research Articles

Tumor Infiltrating Lymphocytes Predict Survival in Solid Organ Transplant Recipients With Monomorphic Post-transplant Lymphoproliferative Disorders.

The tumor microenvironment (TME) in post-transplant lymphoproliferative disorders (PTLDs) remains unexplored. Tumor infiltrating lymphocytes (TILs) are prognostic in other lymphomas. We assessed the prognostic impact of TILs in monomorphic B-cell PTLD. TIL density (CD3+ cells/mm2) was determined by CD3 immunohistochemistry in archived diagnostic biopsies from patients diagnosed with monomorphic B-cell PTLD. Amongst monomorphic PTLDs (N=107), low TIL-count was associated with inferior 2-year progression-free survival (PFS) (41% versus 86%, P=.003) and 2-year overall survival (OS) (52% versus 93%, P=.003) by Kaplan-Meier analysis. Low TIL-count was significant on Cox univariate regression for inferior PFS (HR 4.5, 95% CI 2.0-9.9, P < .001) and OS (HR 4.6, 95% CI 1.8-11.8, P < .001). Multivariate analysis with clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) and TIL-count showed significance for PFS (HR 3.3, 95% CI 1.3-8.3, P=.010) and a non-significant trend for OS (HR 2.6, 95% CI 0.9-7.3, P=.064). A composite score including TILs and clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) effectively stratified monomorphic PTLD patients by PFS and OS (2-year OS: low-risk 93%, intermediate-risk 61%, high-risk 23%, P < .001). The TME and TILs are prognostically relevant in monomorphic PTLD. Prognostic models including measures of the TME may improve risk stratification for patients with monomorphic PTLDs.

Real World Evidence (RWE) of Safety, Efficacy, and Outcomes of CD19 CAR-T Therapy in 20 Patients with Solid Organ Transplant (SOT)-Related Post-Transplant Lymphoproliferative Disorder (PTLD)

Real World Evidence (RWE) of Safety, Efficacy, and Outcomes of CD19 CAR-T Therapy in 20 Patients with Solid Organ Transplant (SOT)-Related Post-Transplant Lymphoproliferative Disorder (PTLD)

O01 Post-transplant lymphoproliferative disorder (PTLD) in a patient with rheumatoid arthritis

O01 Post-transplant lymphoproliferative disorder (PTLD) in a patient with rheumatoid arthritis

Epstein-Barr virus infection-related post-transplant lymphoproliferative disorders in transplanted lung: a clinicopathological analysis

Objective: To investigate the clinicpathological characteristics of post-transplant lymphoproliferative disorders (PTLD) in transplanted lung, and to improve its diagnosis and treatment. Methods: The clinicopathological characteristics of PTLD in three transplanted lungs were evaluated at Wuxi People's Hospital Affiliated to Nanjing Medical University from 2014 to 2019. HE, immunohistochemical staining and in situ hybridization were performed. The relevant literature of PTLD was reviewed. Results: All three patients had chronic obstructive pulmonary disease (COPD) before lung transplantation. After receiving both lung transplants, they were all treated with anti-rejection drugs tacrolimus or mycophenolate mofetil, and combined with antiviral and/or rituximab. The time from transplantation to diagnosis of PTLD was four years, seven months, and five months, respectively. Two patients died one month and five months after initial diagnosis, and one patient was alive with no disease after one year. Histologically, all cases were monomorphic B-cell PTLD (diffuse large B-cell lymphoma, unspecified), and the tumor cells were positive for Epstein-Barr virus by in situ hybridization; one of the late-onset patients had herpes simplex virus infection. Conclusions: PTLD in the post-transplant lung tissue shows unique morphology and clinical characteristics, and is closely related to Epstein-Barr virus infection. Patients who receive lung transplantation due to COPD are more susceptible to develop PTLD, while late-onset ones occur more commonly in the hilum of lungs, and the prognosis is relatively poor.

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children.

Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood. We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and TP53 gene mutational status were performed. 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in TP53 gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.

Successful Treatment of Pediatric Refractory Burkitt Lymphoma PTLD after Liver Transplantation using Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

In the immunocompromised setting, recipients of solid-organ or hematopoietic stem-cell transplants carry an increased risk of post-transplant lymphoproliferative disorder (PTLD). Burkitt lymphoma (BL) PTLD is a rare form of monomorphic B-cell PTLD, which lacks a standard best treatment. Here, we report the successful treatment of refractory BL-PTLD with autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. A male patient was diagnosed with BL-PTLD, with an increasing Epstein-Barr virus (EBV) viral load, at 21 months after undergoing living liver transplantation from his mother due to neonatal biliary atresia. After 10 cycles rituximab +/− intensive chemotherapy and surgical tumor resection, the tumors significantly advanced. Next-generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded tumor tissue, revealing one mutation in exon 5, TP53: p.A159 V, which may be associated with chemo-resistance. Thus, treatment was started with autologous anti-CD19 CAR T-cell therapy. We administered 9.0 × 106/kg autologous anti-CD19 CAR T-cells, after conditioning with cyclophosphamide and fludarabine. Unexpectedly, the patient experienced only mild (Grade II) cytokine release syndrome (CRS) without neurotoxicity. Finally, he went into complete remission (CR), and has achieved 16-month event-free survival to date. In addition, liver function has remained stably within the normal range without any immunosuppressive therapy. The literature includes only five previously reported BL cases treated with CAR T-cell therapy. In conclusion, the present case suggests that autologous anti-CD19 CAR T-cell therapy may represent a new therapeutic option for some cases of refractory BL-PTLD. Clinical trial number: ChiCTR2000032211.

EBV-negative monomorphic B-cell post-transplant lymphoproliferative disorders are pathologically distinct from EBV-positive cases and frequently contain TP53 mutations

AbstractMonomorphic post-transplant lymphoproliferative disorder commonly resembles diffuse large B-cell lymphoma or Burkitt lymphoma, and most are Epstein–Barr virus (EBV) positive. We retrospectively identified 32 cases of monomorphic post-transplant lymphoproliferative disorder from two institutions and evaluated EBV in situ hybridization; TP53 mutation status; p53, CD30, myc, and BCL2 expression by immunohistochemistry; proliferation index by Ki67; and germinal center vs non-germinal center immunophenotype by Hans criteria. Post-transplant lymphoproliferative disorder arose after hematopoietic stem cell transplant in five and solid organ transplant in 27 patients, a median of 4 and 96 months after transplant, respectively (overall median latency 71 months, range 2–295). The most common morphology was diffuse large B-cell lymphoma (28 cases), with three cases of Burkitt lymphoma, and one case of plasmablastic lymphoma. Ten cases (31%) were EBV negative. Of those with the morphology of diffuse large B-cell lymphoma, the EBV-negative cases were more frequently TP53-mutated (P<0.001), p53 positive by immunohistochemistry (P<0.001), CD30 negative (P<0.01), and of germinal center immunophenotype (P=0.01) compared with EBV-positive cases. No statistically significant difference in overall survival was identified based on EBV, TP53 mutation status, germinal center vs non-germinal center immunophenotype, or other immunohistochemical parameters evaluated. Patients who died of post-transplant lymphoproliferative disorder were older with a longer latency from time of transplant to diagnosis (P<0.05). Our study demonstrates that diffuse large B-cell lymphoma-related immunohistochemical prognostic markers have limited relevance in the post-transplant setting and underscores differences between EBV-positive and EBV-negative post-transplant lymphoproliferative disorder in terms of immunophenotype and TP53 mutation frequency, supporting an alternative pathogenesis for EBV-negative post-transplant lymphoproliferative disorder.

Remission of late-onset post-heart transplantation lymphoproliferative disorder following treatment with rituximab and modified mini-CHOP chemotherapy: A case report.

Post-transplant lymphoproliferative disorder (PTLD) is one of the most frequent secondary malignancies that can follow immunosuppressive therapy for solid organ transplantation, and may result in severe morbidities and even mortality. A middle-aged Han Chinese patient, prescribed with immunosuppressive cyclosporine and prednisone, developed PTLD that manifested as a painless cervical lymph node enlargement, 12 years following heart transplantation. Histology revealed monomorphic B-cell PTLD (diffuse large-cell lymphoma); as a result the immunosuppressive regimen of the patient was changed to tacrolimus and mycophenolate mofetil. In addition, the patient was changed to 6-cycle rituximab with a modified mini-CHOP (R-mini-CHOP) regimen for induction, and 8-cycle quarterly rituximab treatment and maintenance therapy. R-mini-CHOP therapy was well tolerated, and no allograft rejection occurred. The patient exhibited clinical remission as demonstrated by the results of the positron emission tomography-computed tomography at the 5-year follow-up visit following R-mini-CHOP therapy. In conclusion, R-mini-CHOP therapy following reduced immunosuppression is effective and safe for the treatment of late-onset PTLD following heart transplantation.

Early post-transplant lymphoproliferative disorder - case of fatal lymphoma after kidney transplantation

Post-transplant lymphoproliferative disorder (PTLD) is a common malignancy following organ transplantation. Risk for PTLD is associated with the use of anti-thymocyte globulin in the prevention and treatment of acute rejection following kidney transplantation. We report a case of fatal PTLD presented with sudden onset of fever. A 33-year-old male patient with primary diagnosis of left kidney agenesia underwent kidney transplantation six years following hemodialysis treatment initiation. Deceased donor was a 66-year-old female whose cause of death was cerebrovascular accident. Immunosuppressive regimen consisted of basiliximab, corticosteroids, tacrolimus, and mycophenolate mofetil. Six months upon transplantation the patient was hospitalized due to fever of unknown origin. All microbiological samples were negative, but abdominal ultrasound revealed round solid mass in the right native kidney. Right nephrectomy was performed showing tumor 35 × 35 × 20 mm in size within the 70 × 40 × 35 mm kidney. Pathohistological analysis confirmed very rare monomorphic B-cell PTLD – B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. We consider this case of PTLD following kidney transplantation particular because of the tumor mass in native kidney after basiliximab induction and rare pathohistology. In a transplanted patient with fever, PTLD must always be considered, irrespective of immunosuppressive regimen.

II. Challenges in the management of post-transplant lymphoproliferative disorder.

II. Challenges in the management of post-transplant lymphoproliferative disorder.

Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation

Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population-based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n = 41), or HLA genotyping in cases of identical sex but different HLA type (n = 52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n = 38), liver (n = 12), heart (n = 10) and lung (n = 7). The most common recipient-derived lymphomas were monomorphic B-cell PTLDs (n = 45), monomorphic T cell PTLDs (n = 9), indolent lymphomas (n = 6), and polymorphic PTLD (n = 4). Half of the recipient-derived PTLDs were Epstein-Barr virus-positive. Twelve of the recipient-derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin.

Plasmablastic Posttransplant Lymphoma

Plasmablastic posttransplant lymphoma is a rare subtype of monomorphic B-cell posttransplant lymphoproliferative disorder (PTLD). There is little published clinical data to guide treatment. The German prospective PTLD registry D2006-2012 records baseline features, treatment, and outcome of rare PTLD subtypes in adults after solid organ transplantation. Treatment is at the discretion of the local physician. Clinical data on the patients in the registry is collected before, during, and at least 4 weeks, 6 months, 12 and 24 months after treatment. Eight cases of plasmablastic posttransplant lymphoma were reported to the registry until 2011. The majority occurred as late PTLD in male heart transplant recipients. Extranodal manifestations were common in stage I and in stage IV disease. Histological Epstein-Barr virus (EBV) association was confirmed in five of eight cases. MYC/IGH rearrangement was present in two of six patients examined. Although five of eight patients died from early disease progression, we observed that long-term survival can be achieved in localized (2/3) and in disseminated disease (1/5) by immunosuppression reduction (IR) followed by immediate systemic chemotherapy. However, all patients with cytogenetic aberrations and patients with non-EBV-associated PTLD were refractory to IR and to chemotherapy. Chemotherapy parallel to IR was associated with a high rate of infectious complications. In this series, IR and local therapy were not sufficient to treat plasmablastic posttransplant lymphoma even in localized disease whereas IR and systemic chemotherapy (CHOP-21) could achieve lasting complete remissions. Cytogenetic aberrations and lack of EBV association were linked with poor outcome.

Concomitant Epstein-Barr Virus (EBV)-Positive B-Cell and EBV-Negative T-Cell Posttransplant Lymphoproliferative Disorders After Renal Allografting: Pathogenetic Implications

Concomitant Epstein-Barr Virus (EBV)-Positive B-Cell and EBV-Negative T-Cell Posttransplant Lymphoproliferative Disorders After Renal Allografting: Pathogenetic Implications

Predictors of outcome in post-transplant lymphoproliferative disorder: an evaluation of tumor infiltrating lymphocytes in the context of clinical factors

We hypothesized that the number of tumor infiltrating cytotoxic T-cells (CTCs) and regulatory T-cells (Tregs), shown to have prognostic value in other lymphoproliferative disorders, could predict survival in post-transplant lymphoproliferative disorder (PTLD). Sixty-two patients were diagnosed with PTLD between 1987 and 2007, with 44 cases representing monomorphic B-cell PTLDs with diffuse aggressive morphologic features. Of these 44 cases, 31 had sufficient tissue for further study. On univariate analysis, high tumor infiltrating CD3+ T-cell (≥550/10 hpf) and TIA-1+ CTC (≥300/10 hpf) counts were associated with favorable overall survival (OS), PTLD-specific survival (PTLD-SS), and progression-free survival (PFS) while Treg counts were not predictive of outcome. However, on multivariate analysis, clinical factors were the most powerful predictor of PTLD outcome (performance status and CHOP as first line therapy for OS; performance status and number of extranodal sites for both PTLD-SS and PFS).

Prognostic Value of Tumor-Infiltrating TIA-1+ Cytotoxic T Cells (TIA1-CTCs) and FOXP3+ Regulatory T Cells (Tregs) in Post-Transplant Lymphoproliferative Disorder (PTLD) Following Solid Organ Transplant (SOT).

Background: PTLD is a rare, often fatal, complication of SOT. Several studies have identified clinical prognostic factors in PTLD. However, no published studies to our knowledge have yet correlated outcome with the number (#) or type of tumor infiltrating T-cells, which in other types of lymphoma may have prognostic value. We hypothesized that tumor infiltrating T-cells, including TIA1-CTCs and Tregs, would predict survival in SOT PTLD.Methods: We searched the Cleveland Clinic pathology archives for SOT patients (pts), who were diagnosed with PTLD between 1987 and 2007; reviewed the medical records and extracted clinical information and outcomes; performed immunohistochemical (IHC) studies for CD3, TIA-1, and FOXP3; and analyzed the data by Cox proportional univariate and multivariate analyses.Results: We identified 62 SOT pts (heart, 22; lung, 17; kidney 15; liver, 7; pancreas, 1), who were diagnosed with PTLD at median age of 51 years (range 7–73). The median time from SOT to PTLD was 1.8 years (range 0.2–20.9). 1st therapeutic intervention (1st TI) (usually >1) included “complete” resection (4), decreased immunosuppression (51), acyclovir or gancyclovir (32), rituximab (R) (18), “CHOP” chemotherapy (11), radiation therapy (7), and interferon (4). Response to 1st TI was CR (34) or PR (10). The median follow-up among surviving pts is 3.6 years (range 0.1–11.7). 35 (including 4 CHOP and 9 R) pts have died; only 2 CHOP but all 9 R pts died from PTLD. IHC studies in 42 evaluable cases showed the following median # (and range) of cells /10 hpf: CD3 525 (8–2451), TIA1-CTCs 304 (6–1238) and FOXP3 13 (1–338). On univariate analysis, younger age, prior rejection episodes <2, PS <2, LDH normal, extranodal sites (ENS) <2, IPI <4, 1st TI >1, 1st TI with CHOP, # of CD3 cells >550/10 hpf, and # of TIA1-CTCs >300/10 hpf were associated with an improved overall survival (OS), PTLD-specific survival (PSS), and/or progression-free survival (PFS). On multivariate analyses, only PS <2, ENS <2, and 1st TI with CHOP remained independent predictors of outcome. Among the subset of 47 pts with monomorphic B-cell (MMBC) PTLD, these same clinical factors were also independently statistically significant.Conclusions: High #s of infiltrating T cells and TIA1-CTCs are associated with a favorable outcome and may reflect a relatively intact local anti-tumor response. Tregs, which may potentially antagonize such a response, are uniformly low and do not correlate with outcome in PTLD. In this analysis, a significant minority of SOT pts treated initially with single agent R still died from PTLD while pts treated initially with CHOP (with or without R) appeared to have a better outcome, arguing for its early use - at least in a subset of pts. Future studies should attempt to identify biological factors that predict which MMBC PTLD pts might benefit from the addition of CHOP to standard R as part of 1st TI.

Gene Expression Profiling of Epstein-Barr Virus-positive and -negative Monomorphic B-cell Posttransplant Lymphoproliferative Disorders

Although most posttransplant lymphoproliferative disorders (PTLD) are related to Epstein-Barr virus (EBV) infection, approximately 20% lack detectable EBV (EBV-). It is uncertain whether the latter cases are truly distinct from EBV+ PTLD or possibly relate to another infectious agent. This study used gene expression profiling to further investigate the relationship between EBV+ and EBV- monomorphic B-cell PTLD, and to search for clues to their pathogenesis. Affymetrix HU133A GeneChips were used to compare 4 EBV+ and 4 EBV- cases of monomorphic B-cell PTLD. Hierarchical clustering successfully distinguished the EBV+ and EBV- groups. Relative to EBV- PTLD, 54 transcripts were over-expressed in EBV+ PTLD. The transcripts identified included IRF7 (a known regulator of EBV LMP1 expression), EBI2 (EBV-induced gene 2), and 3 that are interferon induced (MX1, IFITM1, and IFITM3). In addition, the EBV+ group contained 232 transcripts decreased relative to the EBV- group, including changes concordant with those previously reported after EBV infection of cultured B-cell lines. In summary, in a small group of monomorphic B-cell PTLD, EBV+ cases demonstrated a subset of gene expression changes associated with EBV infection of B cells. By contrast, EBV- PTLD lacked viral-associated changes suggesting that they are biologically distinct.

Impact of Epstein-Barr Virus in Monomorphic B-cell Posttransplant Lymphoproliferative Disorders

The heterogeneity of the posttransplant lymphoproliferative disorders (PTLDs) is well recognized. However, in contrast to other immunodeficiency-associated lymphomas or diffuse large B-cell lymphomas in general, studies of the histogenetic spectrum of the large category of monomorphic B-cell cases have been more limited, produced conflicting results, and have paid little attention to the impact of Epstein-Barr virus (EBV). Therefore, 30 monomorphic B-cell PTLD from 27 patients were analyzed using EBER in situ hybridization for EBV and a panel of antibodies directed against CD20, CD3/bcl-6, CD10, MUM-1/IRF4, CD138, and bcl-2. The results were correlated with the histopathologic features and clinical outcome. All PTLD were CD20 with 23% CD10, 53% bcl-6, 67% MUM-1/IRF4, 13% CD138, 83% bcl-2 and 67% EBV. 30% of the PTLD had a germinal center (GC) profile (CD10, bcl-6, MUM-1/IRF4, CD138), 53% a "late GC/early post-GC" profile (CD10, bcl-6, MUM-1/IRF4, CD138), 13% a post-GC profile (CD10, bcl-6, MUM-1/IRF4, CD138) and 3% an indeterminate profile (all markers negative). EBV positivity was associated with MUM-1/IRF4 expression (P=0.005) and with a non-GC phenotype (P=0.01). All CD138 cases were EBV. The cases with a GC phenotype were the most likely to resemble transformed GC cells (P=0.023). No statistically significant survival differences could be documented between those with a GC versus non-GC phenotype. These results highlight the broad histogenetic spectrum of monomorphic B-cell PTLD. They demonstrate the association of EBV positivity with a non-GC phenotype and suggest that EBV PTLD are more like lymphomas that arise in immunocompetent individuals. The lack of a demonstrable correlation with survival may relate to the relatively small number of cases studied.