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