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PTLD

Post- transplant lymphoproliferative disorder

 

BCSH guidelines

 

Key Recommendations

 

  • Donor and recipients to be screened for prior exposure and infection with EBV using approved serological assays.
  • <1yr, irrespective of antibody results should be considered sero-negative for risk stratification and post- transplant surveillance.
  • Potential risk of PTLD should not influence choice of immunosupression.
  • Sufficient biopsy for morphology and immunohistochemistry is essential for diagnosis. Specimens may need to be sent to specialist centres.
  • In biopsy proven PTLD, CT CAP is essential for staging.
  • Patients to be managed in an appropriately experienced multidisciplinary team.
  • Immunosuppression should be reduced to the lowest tolerated levels.
  • Single agent rituximab (375mg/m2) weekly for four weeks for patients with low risk PTLD who fail to respond adequately to reduction in immunosupression.
  • R + anthracycline based regime (eg R-CHOP) for those who fail to achieve an adequate response with the above.
  • Prophylactic GCSF and anti-infectives are recommended for those receiving chemo.
  • CNS involvement should be treated with reduction of immunosupression followed by local radiotherapy +/- steroids. If fit enough, could consider high dose methotrexate.
  • Retransplantation can be considered, but a minimum of 1 year from control of PTLD to reduce risk of recurrence.

 

Epidemiology

 

  • Incidence may be as high as 10% in all solid organ transplant recipients.
    • Adults – 2nd most common after skin cancer
    • Children – most common post transplant malignancy
  • Mortality approx 50%.
  • 85% B cell origin and 80% EBV associated.
  • 15% T cell origin and 30% EBV associated.
    • Some HTLV 1 associated.
  • Risk is greatest within the first year

 

Biology

 

  • In EBV+ PTLD (esp. monomorphic cases) the virus is commonly monoclonal, indicating its incorporation at an early stage of clonal expansion.
  • EBV seronegativity before transplant and primary infection post, increase the risk.
  • A decrease in EBV cytotoxic T lymphocytes and an increase in EBV viral load are strongly associated with PTLD development.
  • In solid organs, the PTLD is derived from recipient cells, suggesting EBV reactivation.
    • Reduction of immunsupression helps to restore cytotoxic T cells
    • Autologous EBV-specific CTLs can reduce viral load.
  • EBV is a gamma herpes virus.
  • EBV interacts with CD21 to enter B cells and is transported to the nucleus.
  • The virus remains latent in most cells.
    • In <1% of infected cells, it takes part in viral replication.
  • In latent infections, a set of nine latency genes are expressed.
    • Epstein-Barr nuclear antigens (EBNA 1-6) and latent membrane proteins (LMP1, LMP2A and LMP2B).
    • These genes produce a ‘rowth program’ that results in the infected B cells escaping normal growth control mechanisms.
  • In addition, infected cells also produce 2 polymerase III RNA transcripts known as EBER1 and EBER2.
    • Their precise function is unknown, but they are a useful FISH target.
  • The ‘growth program’ is polyclonal.
  • If immunocompetent, develop a cellular immune response with EBV specific CTLs.
    • EBNA2 and LMP1 viral antigens are good targets for cell killing, and the only cells that survive are those with limited viral gene expression.
    • The latter group form a reservoir of ‘resting’ cells that resemble normal memory cells.
  • If immunosupressed, the infected B-cell proliferation exceeds the rate of clearance.
    • EBV can now enter cells not normally infected, in particular germinal centre and memory B cells.
    • LMP1 and LMP2 have anti-apoptotic properties and can rescue lymphocytes with mutations that would normally undergo apoptosis.
    • These rescued cells are implicated in PTLD.
    • Molecular analysis of the immunoglobulin genome shows that most cases are derived from germinal centre and post-germinal centre B cells.
  • PTLD can be poly, oligo or mono-clonal.
  • The proliferating B cells can acquire a variety of molecular alterations:
    • Microsatellite instability due to DNA mismatch repair defects.
    • DNA hypermethylation.

 

Pre-transplant management

 

  • Vaccine – in development.
  • Screening
    • Serology better than nucleic acid amplification
    • IgG to the viral caspid antigen +/- IgM
    • <1yr, assume seronegative as antibodies may be maternal.
  • T-cell archiving – not recommended at present.

 

Post transplant surveillance

 

  • If seronegative pretransplant, at risk of primary infectious mononucleosis.
    • Usually presents with the classical symptoms
    • Don’t require biopsy unless tumour tissue seen in sites other than tonsils, cervical LNs or spleen (all of which normal in IM)
    • LDH should be normal
    • Monitored frequently, with low threshold to biopsy.
    • Usually resolves within 1 month.
  • Insufficient evidence to recommend routine surveillance of adults for EBV DNAemia by PCR outside the allogeneic HSCT setting.
  • Difficulties in interpreting, because of a lack of standardisation in processing/ reporting results.
  • In children, routine surveillance is likely to be beneficial.
  • No consensus on the frequency of monitoring- proposed weekly or twice weekly.
  • Measurement of specific cellular immune responses to EBV does not facilitate early identification of patients at risk of PTLD.
  • EBV DNA load to monitor response to therapy is not recommended.

 

Risk factors

 

  • Degree of immunosupression
    • insufficient evidence to change choice of regime based on risk
    • Possibly higher risk with ATG/ tacrolimus and lower risk with the mTOR inhibitors eg.sirolimus
  • Age
    • <10yrs or >60yrs
  • Time from transplant
    • ?
  • Ethnicity
    • Higher in cauvasians cf. African descent
  • Type of organ
    • Highest in small bowel
    • Lowest in liver/ kidney

 

Clinical features

 

  • B symptoms + interference with the organ involved (often extranodal).
    • Isolated BM involvement can occur, so falling counts may be the only sign.
  • Predeliction for the transplanted organ esp. heart, lung, liver.
  • CNS involvement reported in up to 30% (cf. 1% NHL).
  • Higher risk if liver transplant following liver failure due to HepC.
  • B2M levels may be increased in PTLD renal patients.
  • Monoclonal protein
    • Possible association with the development of a monocalonal protein and the development of PTLD.
  • Imaging
    • Xray – eg. For hilar lymphadenopathy
    • USS – eg. For abdominal LNs, liver , renal imaging
    • CT – useful for diagnosis, identifying biopsy sites, staging and response to treatment.
    • PET – better than CT at detecting bone involvement.
    • MRI – particularly useful for detecting bone and CNS involvement.

 

Histology

 

  • Adequate sample with appropriate history details
  • Fresh tissue preferred, but formalin-fixed is adequate.
  • H&E to assess distortion or effacement of the architecture.
  • Immuno
    • Lineage
    • Light chain restriction
    • Prognostic markers
    • to include an EBV stain, EBER in-situ hybridisation is more sensitive than LMP.

 

Classification

 

  • Early lesions
    • Plasmacytic hyperplasia (polyclonal)
    • Infectious mononucleosis-like
      • Preservation of the underlying architecture
      • Normally seen within 1 year, and more common in recipients withno previous exposure.
      • Can regress spontaneously or with reduction in immunosupression.
      • They can progress to polymorphic or monomorphic.
  • Polymorphic
    • Loss of the underlying architecture
    • Clonal IGH rearrangement
    • Usually express LMP1, EBER and EBNA2
  • Monomorphic
    • B-cell
      • DLBCL
      • Burkitt lymphoma
      • Plasma cell myeloma
      • Plasmacytoma-like lesion
      • Other
        • Most common type
        • Appearance of a malignant lymphoma.
        • Less variety of cell types than in the polymorphics.
    • T-cell
      • Periipheral T cell, NOS
      • Hepatosplenic
      • Other
  • Classical Hodgkin Lymphoma-type

 

Treatment

 

  • Manipulation of immunosupression
    • Under the direction of the transplant team.
    • Consider
      • Status of  the transplant
      • Risk of rejection eg. Low in liver
      • Chances of a CR
      • Side effects of chemo
      • Alternative support eg. Renal
    • Ideally be done over several months
    • Assess response
      • Change in tumour size
      • LDH
      • Resolution of B symptoms
    • Response usually seen within 2-4 weeks.
  • Surgery
    • May be indicated in localised disease
      • Of value in diagnosis and treatment of complications such as GI perforation.
    • Would normally be combined with another therapy.
  • Radiotherapy
    • May be considered in the polymorphic subtypes
    • Or in localised disease for patients not fit for more intensive therapy.
    • Should be considered for CNS disease.
  • Rituximab
    • Monotherapy probably only sufficient for low risk disease (age <60, normal LDH, PS 0-1), otherwise best combined with chemo.
  • Chemotherapy
    • Very low rates of graft loss reported.
    • R-CHOP is recommended
      • immediately for all patients with clinically aggressive disease or for those with critical organ comprominse
      • For patients with B-cell PTLD who fail to respond adequately to reduction of immunosupression and single agent rituximab within 8 weeks.
    • Alternatives
      • Reduced cardiotoxicity, consider platinum or gemcitabine based regimes
  • CNS prophylaxis
    • As per normal NHL
  • CNS treatment
    • Prognosis poor due to poor CNS penetration of the above treatments.
    • The options include radiotherapy, steroids, HD methotrexate.
    • Single case report of CR using intrathecal rituximab through an Ommaya reservoir.
  • Other subtypes
    • Generally treated the same as in the non-transplant setting.
  • Adoptive immunotherapy
    • Autologous EBV-directed cytotoxic T-cells or a bank of partially HLA matched EBV CTLs
    • Still experimental, slow to generate, expensive and require expertise
    • Avoid the risk of graft rejection
    • Good patient tolerability
  • Anti-viral treatment
    • EBV transformed cells do not express thymidine kinase, which is essential for ganciclovir/ acyclovir to be metabolised into active drug within the cell.
    • Maibavir is a new compound targeting UL97 protein kinase which has shown in vitro activity.
    • In vitro work using arginine butyrate with ganciclovir. The arginine butyrate induces expression of cellular thymidine kinase thus rendering the cells susceptible.
    • At present, anti-viral agents not recommended.

 

Immunological agents

 

  • IVIG or interferon not recommended.

 

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