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Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients.

ABSTRACT: Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. A total of 558 children and infants underwent cardiac transplantation at our institution between 1985 and 2019 and were followed until March 2021. Forty-nine of 558 patients developed PTLD (8.8%). As compared to older children (>one year of age), infant recipients (p = 0.04). Although not reaching statistical significance, patients with a shorter time to PTLD diagnosis showed a trend toward higher rates of M-PTLD or cHL. As expected, the overall survival (OS) of patients with M-PTLD or cHL was significantly lower than patients with non-destructive or polymorphic PTLD.

SUBMITTER: Liu Y

PROVIDER: S-EPMC9913467 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients.

Liu Yan Y Wang Billy C BC Zuppan Craig W CW Chau Peter P Fitts James J Chinnock Richard R Wang Jun J

Cancers 20230203 3

Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. A total of 558 children and infants underwent cardiac transplantation at our institution between 1985 and 2019 and were followed until March 2021. F ...[more]

PMID: 36765933

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Project description:Post-transplant lymphoproliferative disorders (PTLD) are among the most serious complications after solid organ transplantation (SOT). Monomorphic diffuse large B-cell lymphoma (DLBCL) is the most common subtype of PTLD. Historically, outcomes of PTLD have been poor with high mortality rates and allograft loss, although this has improved in the last 10 years. Most of our understanding about PTLD DLBCL is extrapolated from studies in non-PTLD DLBCL, and while several clinical factors have been identified and validated for predicting non-PTLD DLBCL outcomes, the molecular profile of PTLD DLBCL has not yet been characterized. Compartment-specific metabolic reprograming has been described in non-PTLD DLBCL with a lactate uptake metabolic phenotype with high monocarboxylate transporter 1 (MCT1) expression associated with worse outcomes. The aim of our study was to compare the outcomes of PTLD in our transplant center to historic cohorts, as well as study a subgroup of our PTLD DLBCL tumors and compare metabolic profiles with non-PTLD DLBCL. We performed a retrospective single institution study of all adult patients who underwent a SOT between the years 1992-2018, who were later diagnosed with PTLD. All available clinical information was extracted from the patients' medical records. Tumor metabolic markers were studied in a subgroup of PTLD DLBCL and compared to a group of non-PTLD DLBCL. Thirty patients were diagnosed with PTLD following SOT in our center. Median time from SOT to PTLD diagnosis was 62.8 months (IQR 7.6; 134.4), with 37% of patients diagnosed with early PTLD, and 63% with late PTLD. The most common PTLD subtype was DLBCL. Most patients were treated with reduction of their immunosuppression (RIS) including a group who were switched from calcineurin inhibitor (CNI) to mTOR inhibitor based IS, in conjunction with standard anti-lymphoma chemoimmunotherapy. Progression free survival of the PTLD DLBCL cohort was calculated at 86% at 1 year, and 77% at 3 and 5-years, with overall survival of 86% at 1 and 3-years, and 75% at 5 years. Death censored allograft survival in the kidney cohort was 100% at 1 year, and 93% at 3, 5 and 10 years. MCT1 H scores were significantly higher in a subset of the non-PTLD DLBCL patients than in a PTLD DLBCL cohort. Our data is concordant with improved PTLD outcomes in the last 10 years. mTOR inhibitors could be an alternative to CNI as a RIS strategy. Finally, PTLD DLBCL may have a distinct metabolic profile with reduced MCT1 expression compared to non-PTLD DLBCL, but further studies are needed to corroborate our limited cohort findings and to determine if a specific metabolic profile is associated with outcomes.

Project description:Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. In our previous studies EBV infection was demonstrated to markedly alter the expression of host B cell microRNA (miR). Specifically, miR-194 expression was uniquely suppressed in EBV+ B cell lines from PTLD patients and the 3'untranslated region of IL-10 was determined to be targeted by miR-194. Although EBV has been shown to regulate host miR expression in B cell lymphoma cell lines, the expression of miRs in the circulation of patients with EBV-associated PTLD has not been studied. The objective of this study was to determine if changes in miR expression are associated with EBV+ PTLD. In this study, we have shown that miR-194 is significantly decreased in EBV+PTLD tumors and that additional miRs, including miRs-17, 19 and 106a are also reduced in EBV+PTLD as compared to EBV-PTLD. We quantitated the levels of miRs-17, 19, 106a, 155, and 194 in the plasma and extracellular vesicles (EV; 50-70 nm as determined by nanoparticle tracking analysis) from pediatric recipients of solid organ transplants with EBV+ PTLD+ that were matched 1:2 with EBV+ PTLD- pediatric transplant recipients as part of the NIH-sponsored Clinical Trials in Organ Transplantation in Children, (CTOTC-06) study. Levels of miRs-17, 19, 106a, and 194 were reduced in the plasma and extracellular vesicles (EV) of EBV+ PTLD+ group compared to matched controls, with miRs-17 (p = 0.034; plasma), miRs-19 (p = 0.029; EV) and miR-106a (p = 0.007; plasma and EV) being significantly reduced. Similar levels of miR-155 were detected in the plasma and EV of all pediatric SOT recipients. Importantly, ~90% of the cell-free miR were contained within the EV supporting that EBV+ PTLD tumor miR are detected in the circulation and suggesting that EVs, containing miRs, may have the potential to target and regulate cells of the immune system. Further development of diagnostic, mechanistic and potential therapeutic uses of the miRs in PTLD is warranted.

Dataset Information

Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients.

Publications

Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients.

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