PTLD

Post-transplant lymphoproliferative disorder

NDT

PTLD - Definition

A monoclonal or polyclonal lymphoid proliferation that occurs following solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT).

Incidence – in transplant recipients

• 10% in solid organ transplant recipient• 1-2 % in RTR patients• 20 times more than general population• Second only to skin cancer in adults• Commonest in pediatric age group• 50 % mortality

Frequency A.Parker etal, BJH 149; 675 (2010)

R.E.Curtis etal, Blood 94 ; Nr.7, 2208 (2009)

C.Mackall, BMT 44: 457 (2009)

O.Landgren etal,Blood 113; 4992 (2009)

Jaffe et al -2001

A

BC

D

PERSISTENT EBV INFECTION• INFECTIOUS MONONUCLEOSIS

• HEPATITIS

• PNEUMONITIS

• GASTROINTESTINAL INFECTIONS

• HAEMATOLOGICAL MANIFESTATIONSLeucopenia Thrombocytopenia, Hemolytic anemia Hemophagocytosis

Pathogenesis - PTLD • B cell proliferation induced by EBV infection

• Cytotoxic T cells keep EBV-infected B cells in check

• Anti T cell Rx or T cell depletion is therefore a risk factor for PTLD

• EBV-driven polyclonal proliferations leading to EBV(+) or EBV(-) lymphomas of predominantly B-cell or less often T-cell type

D.A.Thoreley-Lawson, NEJM: 350;1328 (2004)

Pathogenesis

Three types of EBV-related PTLD

a)Benign polyclonal proliferation /Early lesion• Inf. Mononucleosis -like syndrome (55%)• Normal cytogenetics• Seen 2-8 weeks after starting

immunosuppression or after anti-rejection Rx• Tend to regress with reduction in

immunosuppression• EBV +

b) Polyclonal B cell proliferation (30%)(with evidence of early malignanttransformation)• Similar presentation• Clonal cytogenetic abnormalities and/or • Ig gene rearrangements• EBV +• May not regress with reduction in

immunosuppression

c) Monoclonal B cell proliferation (15%)(with malignant cytogenetics and Ig gene

rearrangements)• Often extra-nodal• Various histologies possible: • DLBCL, diffuse immunoblastic, MALT, Burkitt’s-like, Plasmacytoma, HIV

associated

EBV-negative PTLDPresent much later (median 50-60mo vs 6-10 mo)

Monomorphic

Poor outcomes , poor response to therapy( mean survival of 1 month vs 37 months)

Increasing in frequency

Clinical featutes

• >50% present with extranodal masses

• Involved organs include solid organs and the allograft itself

• MC (20-25% )with CNS disease (higher than in general population)

• 15% have allograft involvement leading to allograft dysfunction

Diagnosis1) EBV viral load (high sensitivity, variable

specificity)2) Imaging3) Tissue biopsy (pref excisional node biopsy)• Confirm EBV positivity by immunostaining LMP1 – latent membrane protein 1 EBER- EBV-encoded RNA• Histological grade• Immunophenotyping (CD 20 exp)• Cytogenetics

Diagnostic Criteria 2 out of three features in combination with a lymphoid tumor- a)Disruption of underlying tissue architecture by a lymphoproliferative process

b) Presence of mono- or oligoclonal cell population

c) EBV infection of many cells

Paya et al, Transplantation 1999

Therapy

1)REDUCTION OF IMMUNOSUPPRESSION

2)ANTIVIRAL AGENTS (Ganciclovir, Acyclovir,Maribavir)

3) SURGERY and RADIOTHERAPY (localized)

4)RITUXIMAB (clinical low risk- Preemptive)

5) RITUXIMAB + CHEMOTHERAPY

6) EBV DIRECTED T-CELLS (CTL) – in clinical trials

Reduction in immunosuppressionSeverely ill with extensive disease: Reducing prednisolone to a maintenance dose of 7.5 to 10 mg/day and stopping all other immunosuppressive agents. Less severely ill with only limited diseaseReduction by at least 50 percent of CsA (or tacrolimus) and prednisone, and the d/c of azathioprine and mycophenolate.After 2 weeks, another 50% reduction can be considered if necessary.

PTLD CNS RIS LOCALISED

RADIO MULTIFOCAL RADIOOR CHEMO OR LOCAL EXCN LOW HIGH RISK RISK

RITUX RITUX + CHEMO

BCSH & BTS Guidelines:A.Parker etal, (2010)

THERAPY OF PTLD with T Cells

A.Moosmann etal, Blood 115 (14); 2960 (2010)

Outcomes

EBV – MONITORING

AT LEAST WEEKLY FOR 3 MONTHS• FOR ALLO-SCT • AFTER HIGH RISK SCT• LONGER MONITORING FOR - GVHD - PREVIOUS EBV REACTIVATION J.Styczynski etal, BMT 43; 757 (2009)

Prevention

1) IV ganciclovir to high-risk pts for a min of 100 days

2) Oral acyclovir in low risk patients

2) Lower target tacrolimus levels (2-5 ng/mL )

McDiarmid et al, Transplantation 1998