post-transplant lymphoproliferative disorder (ptld) (bsh 2021)

Intro

PTLD is the umbrella term for a spectrum of lymphoproliferative disorders occurring due to immunosuppression post solid organ transplant.

 

Epidemiology

  • Occurs in up to 10% of solid organ transplant (SOT) patients

  • LPDs make up >20% of all cancers occurring after SOT (compared to 5% in general pop.)

  • 2nd commonest malignancy after skin cancer in adult transplant

  • 85% B-cell, 15% T/NK (T-cell up to 40% in Asia due to HTLV)

  • 60-80% Associated with EBV

 

Spectrum

  • From indolent polyclonal lymphoproliferation early post-transplant to rapidly fatal aggressive lymphoma.

 

EBV

  • Gamma herpes virus

  • Causes blastic transformation and uncontrolled proliferation in B-cells

  • In healthy people, EBV controlled by CD4 and CD8 T-cells

  • In healthy people causes IM, a benign self-limiting proliferation of lymphoid cells

  • In EBV PTLD, the virus is often monoclonal indicating its involvement in the early stage of clonal expansion and therefore a driver of the disease development.

  • Most NK cell PTLD is EBV positive

 

EBV-negative PTLD

  • May represent ‘incidental’ lymphomas occurring in post-transplant patients

  • Yet may still respond to reducing immunosuppression

  • Most T-cell PTLD is EBV negative

Risk Factors

 

Difficult to calculate for any one individual

Most common post Small bowel / Heart / Lung / Heart-Lung transplants

Clinical Features

 

Non-specifc and often extra-nodal

Symptoms usually relate to interference in function of the affected organ

B symptoms may be present

Isolated BM involvement can occur

 

Organ involvement

  • Tonsils/adenoids common site of involvement, esp in children

  • <10% have lymphadenopathy

 

work-up

Excision Biopsy for morphology, immunophenotyping, EBV-encoded RNA (EBER) in situ hybridisation

Bloods - FBC, U&E, LFT, Bone profile, LDH, Virology

Fertility preservation considerations

Functional assessment of transplanted organ

PET-CT staging

+/- BM Biopsy

+/- Echo

4 histopath. categories

 

Non-Destructive (usually Early PTLD)

Histology

  • Plasma cells and immunoblasts

Immunophenotype

  • Immunobloasts CD20+, CD79a+, PAX-5+, CD30+, CD15-

Molecular

  • Oligoclonal or polyclonal EBV / IGH / TCR genomes

 

Polymorphic PTLD (>90% EBV+)

Histology

  • Mixed lymphocytes and plasma cells. Necrosis, high proliferation

Immunophenotype

  • B cells CD20+, CD79a+, PAX-5+, EBER+

  • Plasma cells CD138+

Molecular

  • Clonal EBV, clonal IGH, polyclonal TCR

 

Monomorphic PTLD (60-80% of PTLD cases)

Classified according to the lymphoma sub-type they resemble

Histology

  • DLBCL type shows immunoblastic, centroblastic, pleomorphic morphology

  • BL type shows monomorphic cells with apoptosis (‘Starry Sky’)

  • Plasmacytic sheets of mature plasma cells

  • T-Cell types

Immunophenotype

  • DLBCL - CD20+, CD79a+, PAX-5+, EBER+, May have focal Cd30+

  • BL – CD20+, CD10+, BCL2-, 100% MIB1/Ki67

  • Plasmacytic – CD138+, CD79a+ CD20-

  • T-Cell markers variable - CD3, CD5, CD2, CD7, abherent CD20

Molecular

  • B-cell - Clonal IGH and EBV. Polyclonal TCR

  • T-Cell - Clonal TCR

 

Classical Hodgkin-like PTLD (>90% EBV+)

Histology

  • Matching the conventional criteria for classis hodgkins. RS cells / Hodgkin cells

Immunophenotype

  • CD30+, CD15+, CD45-, CD20-, CD3-

Molecular - variable

 

management

MDT Approach

  • Transplant physician + haematologist + pathologist + radiologist as core team

  • Surgeons + Radiation Oncologist + Microbiologist + Palliative Care often needed

 

Staging

  • Ann Arbor system

 

Prognostic scoring

  • No one formal system - IPI is a pragmatic choice

  • Adverse risk factors include: Poor performance status, EBV-negative, graft/CNS/BM involvement, monomorphic pathology, older age, raised LDG, low albumin.

Treatment

  • No Phase III randomised trials

  • Supportive Care

    • Always use GCSF to support chemotherapy

    • Antibiotic / Antifungal / Antiviral / Anti-PJP prophylaxis should be used

  • Reduction of immunosuppression (RIS) immediately if possible, under direction of transplant team

    • Assess response after 2-4 weeks. If CR then RIS may be sufficient

  • CD20+ B-Cell PTLD (PTLD-1 Trial 2012)

    • 4x Ritux then,

    • If CR —> 4 more Ritux

    • If not CR —> 4x R-CHOP

  • Other PTLD subtypes

    • Rarity means lack of trial data. Assess fitness for treatments that would be used for the non-PTLD sub-types.

  • Radiotherapy?

    • May have a role when used as it would be for non-PTLD lymphoma sub-types

  • Ibrutinib?

    • TIDaL 2024 - Negative phase 2 trial. Ibrutinib added to Rituximab for untreated PTLD did not improve response rates.

  • Relapsed/Refractory Disease

    • Poor prognosis

    • Graft function often inhibits delivery of further intensive chemo / autograft

    • ?EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy - shows research promise

Re-transplantation post treatment of PTLD

  • Can be successful, usually wait at least one year after PTLD before re-transplantation

  • Low risk of recurrence of PTLD after re-transplantation

other notes

Pre-transplant considerations  

Screening

  • Pre-transplant EBV serology

  • Assume seronegativity in under 1 year olds (false positives from maternal IgG)

Post-transplant surveillance

  • Routine surveillance of adults by EBV DNA PCR not recommended except for HSCT

  • Children at risk of primary EBV infection should be monitored

  • EBV PCR for monitoring of response to PTLD treatment is not recommended