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Disease Pathogenesis

What is EBV+ PTLD?

  • Patients who receive SOT or allogeneic HCT are at risk of developing PTLD due to immunosuppression 1–4
     
  • EBV+ PTLD occurs as a result of deficient T cell surveillance and inadequate control of a primary EBV infection, or reactivation of a pre-existing, latent EBV infection, leading to unrestricted proliferation of transformed B cells1,3,5,6

EBV+ PTLD can be aggressive, life-threatening, and remains a challenging disease to manage2,4

Mechanism of Disease of EBV+ PTLD

  1. Primary infection occurs as the EBV invades host B cells, typically at a young age1

  2. Cytotoxic T cells recognize infected B cells through expression of cell-surface viral proteins, however not all infected B cells are eliminated, causing a low-level latent infection that remains1,6

  3. In immunocompromised patients (e.g., in the transplant setting), EBV cannot be controlled efficiently by EBV-specific cytotoxic T cells and may induce hyperproliferation of infected B cells, leading to EBV+ PTLD1,6
     

EBV+ PTLD as a complication arising from immunosuppression after SOT or HCT

SOT3

Immunosuppression

  • Patients receive induction and maintenance therapy to prevent allograft rejection
  • Induction therapy is given in the peri-transplantation period
  • Maintenance therapy begins at transplantation and continues during the lifetime of the allograft

EBV Infection

  • EBV-infected B cells proliferate due to impaired T-cell immunity; extended B-cell lifespan allows for genetic aberrations

A decrease in T-cell immune surveillance is a major contributing factor in the development of EBV+ PTLD

HCT2

Immunosuppression

  • Patients receive conditioning regimens and immunosuppressive agents
  • The pre-transplant conditioning regimen is given prior to donor stem cell infusion
  • Immunosuppressive agents are given after transplant

EBV Infection

  • EBV-infected B cells proliferate due to impaired T-cell immunity; extended B-cell lifespan allows for genetic aberrations

The combination of T-cell dysfunction plus cytokine-induced inflammation is a major risk factor for EBV+PTLD

Comparison of PTLD after HCT versus after SOT

 

SOT

HCT

Typical cell of origin

Recipient origin2

Donor origin2

Incidence*

1–33%2

0.8–4%2

EBV-associated PTLD

~80%1

~100%8

*After SOT, incidence rates of PTLD may vary based on the type of organ transplanted, the recipient’s pre-transplant EBV antibody status, and the age of the recipient1; after HCT, incidence rates of PTLD may vary based on patient characteristics, stem cell source, degree of HLA mismatch, and conditioning regimen2

References

1.Nijland ML, et al. Transplant Direct. 2015;2(1):e48.
2.Fujimoto A, Suzuki R. Cancers (Basel). 2020;12(2):328.
3.Dierickx D, Habermann TM. N Engl J Med. 2018;378(6):549–562.
4.Clerico M, et al. J Clin Med. 2022;11(24):7542.
5.Cohen JI. N Engl J Med. 2000;343(7):481–492.
6.Zimmermann H, Trappe RU. Ther Adv Hematol. 2011;2(6):393–407.
7.Veltmaat N, et al. J Hematol Oncol. 2023;16(1):104.
8.Socié  G, et al. Bone Marrow Transplant. 2024;59(1):52–58.

Abbreviations

  • BCL6  B-cell lymphoma 6
  • c-MYC  cellular MYC
  • EBV(+)  Epstein–Barr virus (positive)
  • GvHD   graft-versus-host disease
  • HCT  haematopoietic cell transplantation
  • HLA  human leukocyte antigen
  • IL-6  interleukin
  • KMT2D  lysine methyltransferase 2D
  • mTOR  mammalian target of rapamycin
  • p53  tumour protein 53
  • PTLD  post-transplant lymphoproliferative disorder
  • SOT  solid organ transplantation
  • SPEN  Spen Family Transcriptional Repressor
  • TET2  ten-eleven translocation 2
  • TNF-α  tumour necrosis factor-alpha