Post Transplant Lymphoproliferative Disease

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Post Transplant Lymphoproliferative Disease

• Paediatric Case Studies
• RXH GSH Transplant Service

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Patient MVDOB 28/06/1984

• Polycystic Kidney Disease with Liver dis.
• Renal Osteodystrophy with 3 HyperPTH
• Renal Tx May 2001 Immunosuppression
• CSA/Aza/Pred Low Wcc
• CSA/Pred Rejection
• FK/Pred Insulin Dependant Diabetes
• FK(levels 2-5)/Rapamycin(5 10)/Pred 2.5 alt
• Hypercholesterolaemia Atorvostatin
• Delayed Puberty Missed years of school

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Progress

• Creatinine 80 100umol/l
• Teenage wobblies
• IDDM tricky to control HbA1c 9 11
• Osteotomies knees 5cm growth
• Puberty induction testosterone injections
  growth improved even more
• Back _at_ college completing Grd 11 12
• Regular monthly clinic attender

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New Problem

• Presented 29/3/2004 _at_ Renal clinic
• Swelling L groin x 2 weeks
• No fevers minimal weight loss
• L inguinal area
• firm non-tender lymph node 4 x 3cm
• 2nd smaller associated node 1 x 2cm
• No other palpable nodes

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Current Medication

• Immunosuppression
• FK 2mg BD level 1.9
• Rapa 5mg dly level 7.6
• Pred 2.5mg alt days
• Other drugs
• Atorvostatin, Folate, PO4, Enalapril
• Insulin, Sustinon hormonal injections

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Investigations

• Node Biopsy Post Transplant Lymphoma
• Non Hodgkins Diffuse large B cell type
• Strongly CD 20
• CD 10 membrane positivity, CD 15 30 neg
• Bone Marrow Clear
• LP cytospin normal no malignant cells
• CT Chest No LAD
• CT Abd L inguinal node 1.5cm
• Also 1.5cm L para-aortic node lt1cm retrocaval
  node

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Progress

• Immunosuppression
• Stopped FK
• Reduce Rapamycin 2mg dly - Level 5 7
• Pred 2.5mg alt days
• Creatinine stable around 90S
• Gancyclovir IVI daily X 3 weeks
• Rituximab x 4 doses

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EBV titres
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Current Clinical Status

• Clinically remains well
• No intercurrent infections
• Submandibular node appeared prior to Rx now
  disappeared after Ritux
• But Inguinal node still large 6 x 8cm
• Chemorx.
• X 6 courses low WCC GCSF
• Polygam infusions
• Wait See no current lymphadenopathy

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Baby SMDOB 01/03/2002

• Neonatal Hepatitis/ Biliary Atresia
• Liver tx June 2003 2 yrs 5mths
• CMV IgG pos EBV IgG pos
• Discharged home well
• Rx
• Tacrolimus 4mg BD level 7 - 11
• Medrol 4mg

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Readmitted 1 year later

• Failure to thrive Loss of weight
• No fevers
• No evidence of TB
• Mantoux neg. ELI spot neg.
• Severe acute Upper Airway Obstruction
• EBV PCR 2 000 000
• Arrested and Obstructed in CT scanner

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Investigations

• CT upper Neck
• Soft tissue asymmetry and prominence of post
  nasal space
• Submandibular nodes also around larynx
• CT Chest
• R sided tracheal nodes and R lung nodules in
  lower lobe
• R wedge-shaped area in lung
• CT Abd
• Thickened bowel loop LIF but No lymph nodes

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Histology

• Ts As / R neck lymph node biopsy
• Polyclonal PTLD CD 20 positive
• EBV gt 10 000 000
• Bone Marrow
• Few plasma cells. No PTLD
• CSF
• No cells. Fair amount lymphs histiocytes.
• EBV positive.
• Chest Node Biopsy
• PTLD

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Progress

• Immunosuppression
• Reduced FK to 0.5mg BD level 2 4
• Medrol 4mg daily
• LFTs stable
• Gancyclovir IVI daily X 3 weeks
• Rituximab x 4 doses

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EBV titres
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Follow-up investigations

• Clinically NO snoring
• EBV 40 400 000 then neg
• Repeat Chest and Abd CT
• Still one enlarged area in lung but rest MUCH
  improved
• Continue to watch

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Rx of PTLD

• Review

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Rx of PTLD

• Controlling B cell proliferation and facilitating
  development of appropriate EBV-CTL response
• Reduction of immunosuppression
  polyclonal/monoclonal
• Antiviral/Immunoglobulin
• Local therapy surgery/radiotherapy
• Anti-B cell antibodies anti-CD20
• ChemoRx

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Rx of PTLD

• Reduction of Immunosuppression
• Prediction of Non-response to reduction
• LDH gt 2.5 x Normal
• Organ dysfunction
• Multiple visceral sites of disease
• Patients lacking all these risk factors had 89
  response rate
• Graft rejection in 39 with reduction of I/S
• EBV status does not predict response to reduction
  
• response achieved even in EBV ve tumours
• EBV ve tumors have 50 66 response
• Starzl Lancet 1998

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Rx to control B cell proliferation

• Anti B cell antibody therapy neutralises B-cells
  expressing CD 20 aborts lytic replicative phase
  of EBV driven lymphoproliferation
• Predictors for poor response to Rx
• Multivisceral disease
• Late onset PTLD (gt1 year post tx)
• CNS involvement
• Kopf Ped Nephrol 2004
• Rituximab human/mouse chimeric monoclonal
  anti-CD20 antibody

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Rituximab Pescovitz Ped Tx 2004

• Anti-CD 20 monoclonal antibody
• Binding to CD 20 antigen expressed specifically
  on normal infected B cells but not expressed on
  other immune cells
• Dose 375mg/m2 ivi over many hours
• Weekly for 4 weeks
• Monitor EBV PCR and Tumour size

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Rituximab - Side effects

• Correlated with number of circulating CD20 cells
• Anaphylaxis chimeric murine/human
• Fever and rigors
• Orthostatic hypotension bronchospasm
• Neutropaenia thrombocytopaenia
• Pre-existing cardiac problems recurrence
  arrthymia angina
• Respond to interruption of infusion
  recommencement _at_ slower rate
• Usually with first infusion
• No long term toxicities
• COST

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Rx with Rituximab

• Rapid sustained depletion of circulating
  tissue based B cells
• Within first 3 doses
• Sustained depletion for 6-9mths in 83 patients
• B cell recovery began _at_ 6 mths following Rx
• Normal levels by 12 mths
• Sustained significantly reduced IgM G levels

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Rituximab other uses

• Renal
• Allosensitization in dialysis
• Acute / Chronic Rejection
• Non malignant diseases
• Chronic refractory ITP
• Myasthenia Gravis
• Rheumatoid Arthritis
• Cold Agglutinin Disease
• Problems prolonged depletion of B-cells
  hypogammaglobulinaemia x 6/12

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Second line treatment

• Anti-CD 21 and 24 with remission rates of 80 and
  46 in polyclonal monoclonal disorders
• Interferon alfa stimulates host immune response
  to reject PTLD but also high risk of rejection
• Chemotherapy especially monoclonal or frank
  malignant changes CHOP anthracycline based
  chemorx 70 disease free _at_ 20 mths Swinnen
  Blood 1995

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Second line(cont)

• Cyotoxic T-cells
• Passive immunisation using in vitro expanded EBV
  specific cytotoxic T-lymphocytes(CTL)
• Used in Bone Marrow txs using donor derived EBV
  specific CTLs
• More difficult in solid organ but UK trial for
  liver renal tx Haque Lancet 2002
• Rapamycin antiproliferative action inhibits
  primary and metastatic tumor growth Nature
  Medicine 2002

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Rejection Issues Serinet J Ped Gastro
Nutrition 2002

• 6 Ped Liver tx received Rituximab
• 1 CNS tumour
• 5 Acute rejection I/S re-introduced
• 2 Complete Remission
• But 3 continued Fatal Chronic Rejection
• Does not prevent cerebral localisation
• Rapid resumption of I/S may be required to
  prevent lethal chronic liver rejection

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Withdrawal of I/Suppression Hurwitz Ped Tx
June 2004

• 50/355 paeds liver tx PTLD / EBV
• 80 lt 2 yrs
• I/S discontinued in 38
• 21 Required re-institution (mean 107/-140days)
• Acute rejection - BIOPSY proven
• Steroids /- CNI responsive
• Overall survival 84
• But lt 2yr olds do worse 77
• Ongoing EBV infection not necessarily protective
  against rejection

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Dual Sequential Monoclonal Antibody Therapy
Venzke Ped Tx 2003

• Cessation of Immunosuppression
• Antiviral therapy Cidofovir
• B cell depletion with Rituximab effect lasted 3
  mths
• Quantitative EBV PCR monitoring neg
• Ivi Immunoglobulin 500mg/kg/dose if IgG lt 6mg/dL
• Basiliximab 10mg/dose every 3 weeks for 12 weeks
  blocking activated T cells
• Then CSA (level 100ng/ml) Pred 10mg/m2

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Outcome

• 44 of PTLD survivors had 1 organ involvement
• 57 fatal cases if 3 or more organs involved

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Mx of PTLD using EBV PCR screening

• Shroff Rees Ped Nephr 2004

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routine EBV PCR surveillance post transplant
If positive, quantitative PCR
pre Tx EBV-ve
pre Tx EBV ve
high viral load low viral load
antiviral therapy
reduce immunosuppression symptomatic
asymptomatic-no action
very low viral load falling but significant
high viral load
continue monitoring reduce immunosuppression
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persistence or development of symptoms
histological diagnosis is necessary
reactive hyperplasia or polymorhic PTLD
monomorphic PTLD
progressive steady reduction of immunosuppression
with monitoring of T cell response
response
no response
maintain on low dose of immunosuppression
cytotoxic T cells, Rituximab, chemotherapy
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Take Home Message

• Very topical at present
• PTLD may soon become commonest type of lymphoma
  in children
• High level of vigilance
• EBV PCR monitoring