MECHANISM AND BURDEN OF DISEASE IN PATIENTS WITH EBV+ PTLD

PATHOPHYSIOLOGY OF EBV+ PTLD

EBV is one of the most common human viruses and is associated with more than a dozen malignancies in both hematological and solid tumors.1 EBV infects 90% of people before adulthood across the world.2

EBV primarily infects B cells. Primary EBV infection usually occurs prior to adulthood through exposure to saliva or other fluids of an infected individual and results in either asymptomatic infection or symptomatic mononucleosis.2 Following primary infection, EBV establishes a latent infection that persists within memory B cells at low levels, which results in a lifelong infection that the immune system can usually control but cannot clear.2 In immunocompetent individuals, EBV infection is controlled by a strong immune response of virus-specific and nonspecific T cells that eliminate the majority of EBV-infected B cells.3

A consequence of EBV infection may include B-cell immortalization.2,4

B cell

EBV

EBV integrated into host cell nucleus

EBV-infected B cell in lytic phase

T cell

T-cell receptor

B-cell receptor

EBV antigen

EBV infects B cells.2

EBV infection can remain latent. When latent, EBV activates proteins that help it evade detection by the immune system.2

T cells kill infected B cells during intermittent EBV lytic phases, keeping the infection in control.3

T-cell suppression plays a significant role in the development of EBV+ PTLD.5

PATHOPHYSIOLOGY OF EBV

Epstein-Barr virus (EBV) is one of the most common human viruses and is associated with more than a dozen malignancies in both hematological and solid tumors.1 EBV infects 90% of people before adulthood across the world.2

EBV primarily infects B cells. Primary EBV infection usually occurs prior to adulthood through exposure to saliva or other fluids of an infected individual and results in either asymptomatic infection or symptomatic mononucleosis.2 Following primary infection, EBV establishes a latent infection that persists within memory B cells at low levels, which results in a lifelong infection that the immune system can usually control but cannot clear.2 In immunocompetent individuals, EBV infection is controlled by a strong immune response of virus-specific and nonspecific T cells that eliminate the majority of EBV-infected B cells.3

A consequence of EBV infection may include B-cell immortalization.2,4

T-cell suppression plays a significant role in the development of EBV+ PTLD.5

In immunosuppressed patients, EBV infection remains unchecked, resulting in EBV-infected B cells that may proliferate uncontrollably and lead to lymphoma.4

T-cell suppression and depletion

B-cell immortalization B-cell immortalization B-cell immortalization B-cell immortalization B-cell immortalization

A consequence of unchecked EBV infection may include B-cell immortalization.4

Without the T cells to keep infected cells in check, B cells may hyperproliferate. In post-transplant patients, immunosuppression may allow for the hyperproliferation of EBV-infected cells, due to reactivation or primary infection, which can lead to EBV+ PTLD.4

  • EBV+ PTLD can impact patients who have undergone a SOT or allogeneic HCT.
  • Risk rates are affected by the intensity and duration of immunosuppressive therapy as well as the graft.6
  • Every transplant patient should be evaluated and monitored for their risk of developing EBV+ PTLD.

Learn more about the EBV+ PTLD Mechanism of Disease

EBV+ PTLD
00:47
Primary EBV Infection
00:47
Latent EBV Infection
01:03
EBV Immunosurveillance
01:18
Dr Fox
EBV+ PTLD Pathogenesis
00:54
Dr Mohty
EBV+ PTLD Pathogenesis
in HCT Patients
01:13

ETIOLOGY OF EBV+ PTLD IS DISTINCT FROM EBV NEGATIVE PTLD AND LYMPHOMA IN IMMUNOCOMPETENT PATIENTS

EBV+ PTLD is a direct consequence of suppression of T-cell activity by immunosuppressive agents following transplant.6 Unlike EBV+ PTLD, which has a low mutational burden, immunocompetent lymphomas and EBV negative PTLD are associated with a high mutational burden.6 While the agents used to treat immunocompromised patients, such as those with PTLD, are similar to those used to treat patients with immunocompetent lymphomas, the treatment approach is not the same.

UNMET MEDICAL NEED

There are no EMA- or FDA-approved treatments for EBV+ PTLD. Current treatment approaches include reduction of immunosuppression (RIS), anti-CD20 therapy, and chemotherapy.

EBV+ PTLD after failure of initial treatment can be an aggressive, often deadly disease in which survival can be low, with some patients dying within a few months.7,8

Median survival for SOT patients with EBV+ PTLD

In a retrospective chart review of a German SOT PTLD registry of patients who failed first-line anti-CD20 therapy, with or without chemotherapy, the median survival was approximately 3 months.8

Median survival for HCT patients with EBV+ PTLD

In a retrospective chart review study of patients diagnosed with EBV+ PTLD following HCT who failed anti-CD20 monotherapy, the median overall survival was 1.7 months.7

There are no FDA-approved treatments for EBV+ PTLD

IMPACT OF PTLD ON THE LIVES OF
TRANSPLANT PATIENTS

The often long and arduous journey for a transplant patient starts long before the transplant itself. SOT patients frequently undergo years of treatments, hospitalizations, and surgeries to treat organ failure, with their journey continuing once they are added to a waitlist for an organ that can take years to receive. Allogeneic HCT patients have been diagnosed with underlying conditions ranging from hematologic cancers to various genetic immunodeficiencies, and having often failed previous treatments, they’ve opted to undergo a high-risk, high-mortality procedure.9

A diagnosis of EBV+ PTLD can be an unexpected shock to transplant patients, who may have expected to reclaim their lives from illness after transplant.

PTLD burden of disease

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Dr Reshef
Impact of PTLD on Patients
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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. 2016;2(1):e48. 3. Zimmermann H, Trappe RU. Therapeutic options in post-transplant lymphoproliferative disorders. Ther Adv Hematol. 2011;2(6):393-407. 4. Mrozek-Gorska P, Buschle A, Dagmar P, et al. Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection. Proc Natl Acad Sci U S A. 2019;116(32):1604616055. 5. Al-Mansour Z, Nelson BP, Evens AM. Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. Curr Hematol Malig Rep. 2013;8(3):173-183. 6. Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Eng J Med. 2018;378(6):549-562. 7. 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. 8. Zimmermann H, Xu H, Barlev A, et al. Clinical outcomes of solid organ transplant patients with EBV+ PTLD who fail first-line rituximab or rituximab plus chemotherapy: an analysis of German PTLD registry. Poster and abstract presented at: European Hematology Association 24th Annual Congress; June 13-16, 2019; Amsterdam, Netherlands. 9. Kanate AS, Majhail NS, Savani BN, et al. Indications for hematopoietic cell transplantation and immune effector cell therapy: guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2020;26(7):1247-1256.