EARLY AND RAPID IDENTIFICATION IS CRITICAL FOR OPTIMAL DISEASE MANAGEMENT OF EBV+ PTLD

EVERY TRANSPLANT PATIENT SHOULD BE EVALUATED FOR THEIR RISK OF DEVELOPING EBV+ PTLD

Solid organ transplant and EBV+ PTLD

Patient Risk Factors

Following SOT, the primary factors associated with increased risk of PTLD development include the type of organ transplanted, the degree and duration of immunosuppressive therapy, the EBV serostatus before transplantation, and the age of the patient.1

SOT recipients have a lifelong risk of developing PTLD corresponding to their lifelong immunosuppression.2,3 PTLD following SOT can develop from within a few months to more than 20 years after the transplant.4

Overall, 47% to 68% of cases following SOT are found to be EBV positive.5-10 Nearly 80% of cases develop more than one year after transplant.3 EBV is found in the majority (>90%) of B-cell PTLD occurring within the first year after solid organ transplantation.3

The risk of EBV+ PTLD in SOT recipients depends on the specific organ and is related to the amount of lymphoid tissue transplanted and the intensity of the immunosuppression required to prevent acute graft rejection.11

PTLD 5-year cumulative incidence by organ*:

Kidney12

PTLD incidence after kidney transplant

0.6%
(adult)

2.0%
(pediatric)

Liver13

PTLD incidence after liver transplant

1.0%
(adult)

4.1%
(pediatric)

Heart14

PTLD incidence after heart transplant

0.9%
(adult)

4.5%
(pediatric)

Lung15

PTLD incidence after lung transplant

1.7%
(aged 12+ years)

5.7%
(aged 0-11 years)

Pancreas16

PTLD incidence after pancreas transplant

Alone
2.5% (adults)

With kidney simultaneous
0.8% (adults)

After kidney
1.1% (adults)

Intestine17

PTLD incidence after intestine transplant

Without liver
9.1% (total)

With liver
7.7% (total)

*These 5-year cumulative incidence do not represent the lifetime risk of post-SOT PTLD as it doesn't include the risk beyond 5 years after transplant.

Hematopoietic cell transplant (HCT) and EBV+ PTLD

Patient Risk Factors

Pre-transplant risk factors include T-cell depletion (either in vivo or ex vivo), EBV serology donor/recipient mismatch, cord blood transplantation (CBT), HLA mismatch, splenectomy, and a second hematopoietic stem cell transplant (HSCT).18

Post-transplant risk factors include severe acute (especially steroid-refractory) or chronic graft-vs-host disease (GvHD) requiring intensive immunosuppressive therapy, high or rising EBV viral load, and treatment with mesenchymal stem cells.18

The incidence of PTLD following HCT is 1% to 2%, with the majority of cases occurring within a year post-transplant, corresponding to the temporary administration of immunosuppressive therapy prior to the patient's immune system reconstitution.18-21

Nearly all cases of PTLD following HCT are EBV positive.18

The incidence of EBV+ PTLD is higher in pediatric patients than adult patients due to the increased incidence of pre-transplant negative EBV serostatus among children.2

MONITORING AND CLINICAL PRESENTATION

Vigilance for signs of EBV+ PTLD is important

In addition to monitoring viral loads, patients should be monitored for symptoms, including22:

  • Swollen lymph glands
  • Weight loss
  • Fever or night sweats
  • Sore throat
  • Malaise and lethargy
  • Chronic sinus congestion and discomfort
  • Abdominal pain
  • Anorexia
  • Nausea
  • Vomiting
  • Gastrointestinal bleeding
  • Bowel perforation

SOT patients who are EBV negative at the time of transplant are at high risk of
developing EBV+ PTLD and should be monitored frequently for changes in EBV viral load.22

Frequent EBV viral load monitoring is most useful in SOT recipients who are EBV negative
pre-transplant and possibly in all intestinal transplant recipients.22

All HCT patients should be monitored for EBV+ PTLD development, with more frequent monitoring
in patients with rising EBV DNAemia.18

HCT patients should be monitored for EBV DNAemia within the first month after an allogeneic
HCT, and monitoring should continue for at least 4 months, with a frequency of at least once per week.18

EBV+ PTLD can develop across a wide range of EBV viral loads.

While a higher or rapidly increasing viral load is associated with an increased risk of EBV+ PTLD, EBV viral load can vary widely at the time of clinical presentation.4,23

EBV+ PTLD can develop across a wide range of viral loads. One study showed that 23% of patients presented with EBV+ PTLD, at EBV level ≥10,000 copies per mL.23

Signs and symptoms of PTLD

EBV+ PTLD Evaluation18,22,24*

Clinical History

  • EBV serostatus of transplant recipient and donor
  • Time from transplantation to PTLD diagnosis
  • Type of allograft

Clinical Assessment

  • Fever
  • Tonsillitis
  • Adenopathy
  • Organomegaly
  • Endoscopy in case of gastrointestinal symptoms

Laboratory Tests

Additional Diagnostic Testing

Essential:

  • Adequate immunophenotyping to establish diagnosis
    • IHC panel: CD3, CD5, CD10, BCL6, BCL2, IRF4/MUM1, CD20, CD79a, PAX5, Ki-67, kappa, lambda with or without
    • Cell surface marker analysis by flow cytometry with peripheral blood and/or biopsy specimen: CD3, CD5, CD7, CD4, CD8, CD19, CD20, CD10, kappa, lambda
  • EBV evaluation by EBV latent membrane protein 1 (EBV-LMP1) or EBV-encoded RNA in situ hybridization (EBER-ISH) (if EBV-LMP1 negative, EBER-ISH is recommended)

Workup

Essential:

  • Performance
  • Albumin
  • History of therapy for transplant
  • Lactate dehydrogenase (LDH), electrolytes, blood urea nitrogen (BUN), creatinine
  • Complete blood count (CBC) with differential
  • Hepatitis B testing
  • EBV polymerase chain reaction (PCR) for cell-free plasma EBV DNA marker
  • PET/CT scan (including neck) and/or C/A/P CT with contrast
  • Pregnancy testing in women of child-bearing age (if chemotherapy or RT planned)

For additional diagnostic testing useful under certain circumstances and workup useful in select cases, see National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®).24*

*NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Standard diagnosis for PTLD is histopathological examination of the tumor tissue, biopsy, or resection of the whole lymph node, and categorization based on World Health Organization (WHO) standards.2,11,18

WHO distinguishes six subclasses of PTLD: three types of non-destructive PTLD (plasmacytic hyperplasia, infectious mononucleosis-like PTLD, and florid follicular hyperplasia), polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma-like PTLD.4

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References

1. Crombie JL, LaCasce AS. Epstein Barr virus associated B-cell lymphomas and iatrogenic lymphoproliferative disorders. Front Oncol. 2019;9:109. 2. Nijland ML, Kersten MJ, Pals ST, Bemelman FJ, ten Berge IJM. Epstein-Barr virus-positive posttransplant lymphoproliferative disease after solid organ transplantation: pathogenesis, clinical manifestations, diagnosis, and management. Transplant Direct. 2015;2(1):e48. 3. Allen UD, Preiksaitis JK. Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant. 2013;13(suppl 4):107-120. 4. Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Eng J Med. 2018;378(6):549-562. 5. Trappe RU, Dierickx D, Zimmermann H, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol. 2017;35(5):536-543. 6. Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Eng J Med. 2018;378(6):549-562. 7. Jagadeesh D, Tsai DE, Wei W, et al. Post-transplant lymphoproliferative disorder (PTLD) after solid organ transplant (SOT): a multicenter real world analysis (RWA) of 877 patients (pts) treated in the modern era. J Clin Oncol. 2020;38(suppl 15). doi:10.1200/JCO.2020.38.15_suppl.e20026 8. Sprangers B, Riella LV, Dierickx D. Posttransplant lymphoproliferative disorder following kidney transplantation: a review. Am J Kidney Dis. 2021. doi:10.1053/j.ajkd.2021.01.015 9. Luskin MR, Heil DS, Tan KS, et al. The impact of EBV status on characteristics and outcomes of post-transplantation lymphoproliferative disorder. Am J Transplant. 2015;15(10):2665-2673. 10. Walti LN, Mugglin C, Sidler D, et al. Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLD): a nationwide cohort study. Am J Transplant. 2020. doi:10.1111/ajt.16423 11. Dharnidharka VR. Comprehensive review of post-organ transplant hematologic cancers. Am J Transplant. 2018;18(3):537-549. 12. Hart A, Lentine KL, Smith JM, et al. OPTN/SRTR 2019 annual data report: kidney. Am J Transplant. 2021;21(suppl s2):21-137. 13. Kwong AJ, Kim WR, Lake JR, et al. OPTN/SRTR 2019 annual data report: liver. Am J Transplant. 2021;21(suppl s2):208-315. 14. Colvin M, Smith JM, Ahn Y, et al. OPTN/SRTR 2019 annual data report: heart. Am J Transplant. 2021;21(suppl s2):356-440. 15. Valapour M, Lehr CJ, Skeans MA, et al. OPTN/SRTR 2019 annual data report: lung. Am J Transplant. 2021;21(suppl 2):441-520. 16. Kandaswamy R, Stock PG, Miller J, et al. OPTN/SRTR 2019 annual data report: pancreas. Am J Transplant. 2021;21(suppl 2):138-207. 17. Horslen SP, Smith JM, Ahn Y, et al. OPTN/SRTR 2019 annual data report: intestine. Am J Transplant. 2021;21(suppl s2):316-355. 18. Styczynski J, van der Velden W, Fox CP, et al. Management of Epstein-Barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica. 2016;101(7):803-811. 19. Dierickx D, Tousseyn T, Sagaert X, et al. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymphoma. 2013;54(11):2433-2440. 20. Socié G, Pigneux A, Herbaux C, et al. Clinical outcomes of EBV+ PTLD patients following HCT who fail rituximab: a retrospective chart review study from France. Presented at: 46th Annual Meeting of the European Society for Blood and Marrow Transplantation; August 2020. 21. Styczynski J, Gil L, Tridello G, et al. Response to rituximab-based therapy and risk factor analysis in Epstein Barr virus–related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis. 2013;57(6):794-802. 22. Allen UD, Preiksaitis JK. Post‐transplant lymphoproliferative disorders, Epstein‐Barr virus infection, and disease in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13652. 23. Fox CP, Burns D, Parker AN, et al. EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era. Bone Marrow Transplant. 2014;49(2):280-286. 24. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.3.2021. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed April 21, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org.