MOHAMED ABDELMONIEM

1. Update of protocol for management of PTLD in
renal transplant recipients
Mohamed AbdelMonem
MD,MRCP
110 November 2019

2. EBV
 Family: Herepesviridae.
 Subfamily: Gamma
herpesvirinae.
 Genus: Lymphocryptovirus
 Enveloped.
 Nucleocapsid.
 The viral genome is ds-DNA.
 Replicate in the nucleus.
 Remain latent in B- cells.
210 November 2019

3. Time of presentation of common viral illnesses post-
transplant.
Weikert B C , and Blumberg E A CJASN 2008;3:S76-S86
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4. EBV in B Cell
Infectious mononucleosis
X-Linked Lymphoproliferative
Disease
Chronic active EBV
Hodgkin Disease
Burkitt Lymphoma
Lymphoproliferative disease
EBV in Other Cells
Nasopharyngeal carcinoma
Gastric carcinoma
Nasal T/NK cell lymphomas
Peripheral T cell lymphomas
Oral hairy leukoplakia
Smooth muscle tumors in transplant
patients
Diseases Associated with EBV
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5. EBV Viral Load is Increased in Patients with
PTLD
Riddler, Blood 1994
Viral Load Used to Monitor Transplant Patients:
Increased EBV load at onset of LPD
Used to initiate preemptive therapy
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6. PTLD
 Is a well recognized complication of both SOT and HSCT
 One of the most common post transplant malignancies
 Associated with EBV infection of B cells
Reactivation of the virus post tx.
Primary infection
May be acquired from donor
Less commonly from environmental exposure
 T cell lymphoproliferative disorder not associated with EBV infection occur
after SOT and HSCT the vast majority of B cell proliferation
 Most of cases occur within the first year post transplant
 It may present as localized or disseminated disease
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7. Clinical presentation of PTLD
 Includes :
Fever (57%).
Lymphadenopathy (38%).
Gastrointestinal symptoms (including obstruction [27%].
Infectious mononucleosis–like syndrome (19%).
Pulmonary symptoms (15%).
CNS symptoms (13%).
Weight loss (9%).
 Involvement of the allografted tissue can cause declining organ function. This
organ failure may be the presenting symptom.
 A rising blood level of EBV viral load by (PCR) measurement in this clinical
setting should raise concern for PTLD.
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8. Clinical presentation of PTLD
 The most common sites :
lymph nodes, liver, lung, kidney, bone
marrow, small intestine, spleen, CNS, large
bowel, tonsils, and salivary glands.
 Less common sites :
oral cavity and skin or subcutaneous lesions.
 T-cell lymphoproliferative disorders not associated with EBV
infection tend to occur at extra nodal sites
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9. Diagnosis of PTLD
 Is made by histopathological evidence of lymphoproliferation
commonly with the presence of EBV DNA ,RNA or protein detected in
the tissue
 Complete history and physical examination
 CBC,EBV,LDH (not diagnostic)
 EBV status of the recipient (pre Tx)
 Primary EBV infection (EBV IgM are elevated )
 Reactivation of EBV infection is characterized by 4 fold rise in EBV IgG-
No change in titer suggests past infection
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10. Diagnosis of PTLD
 Histologic WHO classification system
Early lesion
Polymorphic PTLD
Monomorphic PTLD
Classic Hodgkin lymphoma
 Immunohistologic staining of paraffin embedded tissue
 Clonality of the lesion
Monoclonal
Oligoclonal
Polyclonal
Or mixed
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11. WHO classification of PTLD
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12. Diagnosis of PTLD
 Imaging:
 CT or MRI scan of the neck ,chest ,abdomen, pelvis and head.
 PET scan is still under evaluation
 Procedures:
 BM aspirate and biopsy
is appropriate to determine whether marrow is involved in the
disease process
 CNS involvement
LP CSF examination for malignant cells
EBV DNA (PCR) in CSF
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13. Histopathologic subtypes of PTLD
 AST has recommended that the term PTLD also applied to :
Post transplantation infectious mononucleosis
Plasma cell hyperplasia
Neoplastic disease
 The WHO classification 4 major histopathologic subtypes of
PTLD:
Early hyperplastic lesions
Polymorphic lesion (which may be polyclonal or monoclonal)
Monomorphic lesions
Classic Hodgkin type lymphomas
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14. Pathophysiology of PTLD
 The initial stages of PTLD proliferation is polyclonal
 Mutation and selective growth the lesion becomes oligoclonal and later
monoclonal
 The activity of natural killer cells is reduced several months following tx,
contributing to the impairment of the most important regulator of
proliferation and cellular immune response
 The mechanism that cause EBV negative PTLD are not well understood
 It has a more aggressive course than EBV positive PTLD suggesting that, it may
have a different pathophysiology
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15. Pathogenesis of EBV Infection
Cohen NEJM 2000
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16. Prevalence of PTLD post renal tx
 Higher rates in heart, heart-lung and small bowel tx than in kidney and liver tx
 A French kidney transplant registry (adult patients)
1998-2007
Incidence of PTLD after 5 years 1%
Incidence of PTLD after 10 years 2.1%
 Organ Procurement and Transplantation Network(OPTN)
Incidence 0.6-1.5%
In 2012 incidence rates 1.58%
In Pediatric 4.4-6.9%
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17. Risk for EBV PTLD
 Primary infection- higher viral loads, no memory T
cells to EBV.
 CMV infection.
 Polymorphisms corresponding to low production of
IFN-, TNF-; high levels of IL-10.
 Level of intensity of T cell immunosuppression.
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18. Prognosis
 All PTLD, irrespective of histology is potentially life threatening
 Poor prognostic features
Performance status
Increase sites involved
Primary CNS
T- cell origin
Monoclonality
Non detection of EBV in the tumor
Treatment based on chemotherapy
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19. Management of PTLD
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20. Prophylaxis
 Minimize upfront immunosuppression
 Although Antiviral therapy has not proven to be an effective treatment
for PTLD
 Administer IVIG or CytoGam to maintain high titers of anti-EBV
antibodies that may help prevent the development of EBV PTLD.
 Arising EBV viral load in a high-risk patient may warrant preemptive
reduction in immunosuppression, while continuing to monitor closely
for allograft dysfunction
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21. Reduction in Immunosuppression
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 Limited disease: a 25% reduction in immunosuppression;
 Extensive disease and critically ill: stop all agents except
prednisone 7.5–10 mg/d;
 Extensive disease not critically ill: decrease ciclosporin/tacrolimus
by 50%, discontinue azathioprine/mycophenolate and maintain
prednisone 7.5–10 mg/d.
 European guidelines: recommending steroid maintenance alone
or reducing calcineurin inhibitors e.g, ciclosporin by 50% and
stopping all other agents e.g. mycophenolate or azathioprine.

22. Management PTLD
 Role of antiviral therapy in PTLD:
 Acyclovir,ganciclovir or fosacarnet
 In the absence of RI is not considered effective ttt for PTLD
 Often used together with RI as a first step in management
Role of antibody therapy in PTLD:
Reported in 1991 by Fischer etal
26 patients with B cell lymphoproliferative disease were treated with anti
CD 21 anti CD 24 monoclonal antibodies
Conclusions : could be effective for diffuse oligoclonal lymphoproliferative
CNS is not responded
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23. Management PTLD
 Benkerrou etal
58 patients with PTLD
Complete remission 61%
Relapse rate 8%
Long term survival 55% (SOT)
35%(HSCT)
Role of Interferon alpha in treatment of PTLD:
Mechanism of action
Inhibit the outgrowth of EBV transformed B cells and it
decreases the oropharyngeal shedding of EBV.
Inhibit T helper cells which release cytokines (IL4,6,10) that
promote B cell proliferation
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24. Management PTLD
 Role of IVIG :
 IVIG or anti-cytomegalovirus CMV immunoglobulin most commonly
used in conjunction with antiviral therapy as prophylaxsis
 May provide some protection against developing PTLD
 Role of Rituximab:
 Milpied etal 2000,
32 patients post SOT or HSCT with PTLD
Treated with riruximab
Response rate 69%
 Another several studies
Respose rate 50%
 International multicenter prospective phase II trial found rituximab
followed by CHOP 90% complete response
 9% mortality rate of toxicity
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25. Rituximab Response Rates
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26. Prospective studies of first-line rituximab monotherapy in adult PTLD
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27. Prospective studies of first-line rituximab monotherapy in adult PTLD
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28. Role of antineoplastic agents in treatment of
PTLD
 Mechanism of action:
These agents disrupt DNA replication or cell division inhibiting cell
growth and proliferation e.g.
Cyclophosphamide
Doxorubicin
Vincristine
Etoposide
Bleomycin
Methotrexate
Fludarabine
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29. Management PTLD
 Role of chemotherapy:
 SOT are often not able to tolerate full dose owing to end organ toxicity
or risk of allograft dysfunction
 Cyclophosphamide is piloted in 36 children with PTLD
Response rate 83%
2 patients died of ttt related toxicity
Relapse rate 19%
 Another study,Children Oncology Group phase II trial of low dose
cyclophosphamide and prednisolone:
54 patients with PTLD
The majority had monomorphic disease
Response rate 69%
2 year free survival rate 71%
one death due to infection during therapy
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30. Studies of first-line CHOP or CHOP-like chemotherapy in adult PTLD
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31. Studies of first-line CHOP or CHOP-like chemotherapy in adult PTLD
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32. Management PTLD
 Treatment of CNS involvement in PTLD:
 Poor response
 High dose of methotrexate
 Intrathecal therapy is considered because many systemic chemotherapy
and monoclonal antibodies do not cross the blood –brain barrier
adequately
 Radiotherapy remains an effective modality for treatment of CNS PTLD
 Role of surgery :
 Is rarely the sole mode of therapy
 Only for single nodal or extra nodal site
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33. Radiation therapy
 Localized disease
 Central nervous system involvement, involved field radiation therapy, alone or
in combination, may be beneficial .
 Data regarding efficacy is largely extrapolated from studies of radiation
therapy in localized diffuse large B cell lymphoma and in primary central
nervous system lymphoma.
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34. Guidelines
 NCCN guidelines (Diagnosis):
 Adequate immunophenotyping by immunohistochemistry
 EBV evaluation by EBV LMP1 or Epstien Barr encoding region in situ
hybridization (EBER-ISH) in case of EBV LMP1 is negative EBV evaluation by
Southern blot
 BCL gene mutation is associated with poor RI
 NCCN guidelines (Treatment):
 Patient with complete response reescalation of immunosuppression
should be individualized with monitoring of EBV viral load by PCR and graft
organ function
 Patients with persistent or progression second line ttt with
Rituximab
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35. Guidelines
 AST (Diagnosis):
 CMV staus
 EBV viral load
 CT scan total body
 Immunophenotyping (CD20)
 Molicular genetic markers of antigen receptor genes to assess clonality
 Donor vs recipient origin
 AST (Treatment):
 Monomorphic PTLD(B-cell type):
RI with or without one of the following :
Rituximab
Rituximab as part of a concurrent or
sequential chemotherapy regimen
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36. Guidelines
 AST (Treatment):
 Polymorphic PTLD
Localized disease :
RI plus one of the following
Rituximab
Radiation therapy with or
without rituximab
Surgery with or
without rituximab
Systemic disease:
RI plus one of the following
Rituximab
Rituximab as part of concurrent or sequential
chemoimmunotherapy regimen
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37. KDIGO Guidelines
EPSTEIN-BARR VIRUS AND POST-TRANSPLANT
LYMPHOPROLIFERATIVE DISEASE
We suggest monitoring high-risk (donor EBV seropositive/recipient
seronegative) KTRs for EBV (2C)
once in the first week after transplantation (2D)
Then at least monthly for the first 3– 6 months after transplantation (2D)
Then every 3 months until the end of the first post-transplant year (2D)
Additionally after treatment for acute rejection. (2D)
We suggest that EBV-seronegative patients with an increasing EBV load have
immunosuppressive medication reduced. (2D)
We recommend that patients with EBV disease, including PTLD, have a
reduction
or cessation of immunosuppressive medication .(1C)
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38. Mortality/Morbidity
 In a retrospective review of 32 adult and pediatric patients with PTLD,
the 5-year survival rate was 59%.
 Nearly half of the patients were diagnosed within the first year
following transplantation. Six of 8 patients surgically treated remain
alive and disease free.
 A series of adult kidney transplant recipients reported by Wasson et al
had a mortality rate of 26.6%.
 Similarly, a more recent report of pediatric kidney transplant patients
also found a 25% mortality rate related to PTLD.
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39. PROGNOSIS
 Overall survival rates ranging between 25 to 35 percent
 Mortality with monomorphic PTLD has been reported
to be as high as 80 percent .
 T cell lymphomas have an extremely poor prognosis .
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40. RETRANSPLANTATION
 In the largest cohort study based upon the OPTN/UNOS
database, outcomes were reported among 69 transplant
recipients who survived PTLD and underwent retransplantation .
 The retransplant surgery for 27 kidney. Average time for the
period from PTLD to retransplant, time from transplant to
retransplant, and time for patient survival after retransplant
were approximately 2.6 years.
 At follow-up, overall patient and allograft survival was 86%.
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41. RETRANSPLANTATION
One retrospective study reported the outcomes of six patients with
kidney retransplantation after cure of EBV-related monoclonal B
cell lymphoma .
Five of six patients had the PTLD confined to the graft, with all six
undergoing allograft nephrectomy in addition to their other
treatment.
The subsequent time interval from PTLD to retransplant was
longer, ranging from 4.1 to 10.6 years.
At 24 to 47 months, all patients had functioning grafts without
recurrent PTLD.
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42. Conclusion
 Declining viral load may suggest a response to treatment
 Management of PTLD remain a balancing act between
eradicating and cure of the disease and preservation of graft
function
 Reduction or withdrawal if IS has to be tailored accordingly after
multidisciplinary discussion
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43. Home Message
 Improved methods for early detection of PTLD.
 Safer and cost-effective PTLD therapy.
 Better understanding of long term outcomes of chronic EBV viremia of
patients treated for PTLD.
 Effective and safe immune modulatory regimens that decrease the
risk for PTLD while preserving allograft health.
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44. THANK
YOU
4410 November 2019