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Post-transplant
lymphoproliferative disorder remains a rare but highly significant complication
following both stem cell and solid organ transplantation. The highly variable
clinical presentation may result in significant diagnostic delays requiring
close supervision and vigilance of patients at high risk of developing the
condition. Treatment of established disease becomes a clinical challenge due to
the fine balance required in reducing immunosuppression to control the disease
while safeguarding allograft function. Despite major advances made in overall
management to improve outcomes, the associated morbidity and mortality remains
high.
Keywords: Kidney transplant,
Lymphoma, Malignancy, Lymphoproliferative disorder, Chemotherapy
INTRODUCTION
Post-Transplant Lymphoproliferative Disorder (PTLD) is a rare but
well-recognized, potentially fatal complication of both solid organ
transplantation (SOT) as well as haematopoietic stem cell transplantation
(HSCT). PTLD is the commonest post-transplant malignancy among children and
second commonest among adults after non-melanoma skin cancer. It is a
heterogenous clinical entity with a wide disease spectrum, ranging from
indolent lymphoid proliferation to aggressive lymphoma. Despite numerous
therapeutic measures, the overall mortality remains high around 50% [1].
INCIDENCE AND RISK
FACTORS
The incidence of PTLD following SOT varies according to the organ
transplanted. The incidence is highest following heart, heart-lung, intestinal
and multi-organ transplants (8-25%), while it’s relatively low following renal
transplants (1-3%) [1,2]. The highest incidence has been reported in the first
year after transplantation. However, the cumulative risk increases with each
passing year, demonstrating a steady increase with the progression of time
post-transplant, compared to a matched non-transplant population [3].
Pediatric recipients, especially
those transplanted before 10 years of age, have been consistently shown to have
a higher risk of PTLD. According to the Organ Procurement and Transplantation
Network (OPTN) database (2012), the reported cumulative incidence of PTLD after
renal transplantation was 4.4-6.9% among children, compared to 0.6-1.5% among
adults (10). Similarly, the risk is also higher among elderly recipients
(>60 years), possibly due to decreased immune surveillance in old age [11,12].
Some reports have also implicated donor-recipient mismatch of other viral serologies as a potential risk factor for PTLD. Cytomegalovirus (CMV) sero-negative recipients, receiving a sero-positive donor organ can have up to a seven-fold increased risk of PTLD. Other reports have also implicated Hepatitis C and Herpes Virus-8 infection as possible risk factors, especially when coinciding with EBV infection [13,14]. Smith et al. [15] also demonstrated that Caucasian ethnicity carried a higher risk compared to other ethnicities while there was no demonstrable difference in incidence between the two genders (Table 1).
PTLD affecting the T-cell
lineage is rare where only 30% are EBV related. This is in contrast to the
B-cell lineage PTLD where over 80% are related to EBV infection. EBV-related
PTLD is caused by anti-viral resistant ‘latent-type’ infection as opposed to
anti-viral sensitive ‘lytic-type’ infection [9,16]. As discussed later, this
becomes relevant in the management of PTLD and associated EBV infection.
Post-transplant immunosuppression results in suppression of the host T-cell
function which includes the ability to destroy EBV infected B-cells. This results
in uncontrolled proliferation of EBV-infected B-cells, which become immortal,
culminating in B-cell hyperplasia or frank lymphoma. The initial proliferation
is polyclonal and is often responsive to immunosuppression reduction while as
the disease progresses; it becomes monoclonal, with poor response to therapy.
The exact pathophysiology of
EBV-negative PTLD is poorly understood. The postulated mechanisms include EBV
infection that is no longer detectable or other non-EBV viral infections that
cause antigenic stimulation. EBV-negative PTLD has a distinctly different
clinical course with late onset, more aggressive disease compared to
EBV-positive PTLD. The impact of EBV status on overall survival is unclear.
While most historical studies reported poor survival with EBV-negative disease,
Luskin et al. [17] followed up 176 SOT recipients and demonstrated no
significant difference in overall survival based on EBV status.
CLINICAL PRESENTATION
Clinical presentation of PTLD is
heterogeneous, ranging from non-specific symptoms to features of advanced organ
failure. The common presentation is with non-specific B-symptoms such as fever,
night sweats, anorexia and weight loss requiring a high index of clinical
suspicion and a low threshold for further investigation.
While peripheral lymphadenopathy
is rare, extra-nodal involvement may be common, affecting the gastro-intestinal
tract (GIT), bone marrow, lungs, skin and central nervous system (CNS-PTLD).
Extra-nodal disease results in symptoms related to the relevant affected
system. Accordingly, GIT disease can present with nausea, vomiting, diarrhea
and abdominal cramps. Pulmonary involvement may result in cough, shortness of
breath and reduced air entry. CNS-PTLD may result in features such as
confusion, hallucinations and altered consciousness.
Following renal transplantation,
commonest affected organ is the GIT. Approximately 15% may present with GIT
related emergencies such as perforation and intestinal obstruction [18].
Rarely, fulminant PTLD disease can present with features mimicking septic
shock.
Diagnosis and evaluation
The highly variable clinical
presentation requires a high degree of clinical suspicion and low threshold for
targeted investigation. Basic blood biochemistry may reveal cytopenia, elevated
lactate dehydrogenase (LDH), hyperuricemia and hypercalcemia. Definitive
diagnosis is by histological confirmation of lympho-proliferation with
demonstration of EBV-DNA, RNA, or protein in biopsy tissue. Needle aspiration
cytology is often inadequate and requires image-guided tru-cut biopsy or
excision biopsy for histological confirmation of lymphoid proliferation.
Positron emission tomography
(PET) may be used in specific instances but lacks definitive data of benefit
over CT. Bone marrow aspiration or lumbar puncture to evaluate cerebrospinal
fluid (CSF) may be required to exclude CNS-PTLD [2]. CSF examination can be
used to examine for the presence of malignant cells as well as for the presence
of EBV proteins.
MANAGEMENT
Management of PTLD requires a
multi-disciplinary approach with a team including transplant clinicians,
surgeons, radiologists, histopathologists and oncologists. Management aim
should be successful regression of disease while safeguarding graft function.
The exact management approach
should be individualized to the patient. This depends on several factors
including; general health condition, clinical and pathological stage of
disease, function and necessity of the graft and local availability of
expertise in the management.
REDUCTION OF IMMUNOSUPPRESSION (RIS)
Reduction of Immunosuppression
(RIS) or complete withdrawal of immunosuppression remains the first-line
approach and mainstay in management. An initial reduction of 25-50% of baseline
as tolerated should be followed by complete withdrawal with minimal steroid
maintenance, if response is poor or in the critically ill [19]. Response to
treatment is monitored by resolution of constitutional symptoms, drop in LDH
levels and tumor size reduction on imaging. Tsai et al. [20] have defined
possible indicators of poor response to RIS. These include raised pre-treatment
LDH levels, multi-organ involvement and pre-treatment allograft dysfunction.
Poor response within 2-4 weeks
should prompt second-line therapy. RIS alone has shown response rates of 90% in
low-grade PTLD without multi-organ involvement [20]. However, it carries the
risk of allograft rejection and needs to be carefully weighed against the
dangers of PTLD progression. Where the immunosuppression cannot be reduced
beyond 50% of the baseline as in life-preserving grafts (heart and lung
transplants), an early decision needs to be made regarding second line therapy.
Conversion to m-TOR inhibitor
(sirolimus or everolimus) maintenance therapy with their ‘anti-tumor’ effects
has been studied with conflicting reports. While some studies have shown
successful PTLD regression with sirolimus, others have shown higher incidence
of PTLD with its use [3,21-23]. Several small volume studies including in vitro experiences have shown possible
tumor regression potential in PTLD with the use of mTOR inhibitors. Both
sirolimus and everolimus have been shown to possess an inhibitory effect on
PTLD cell line growth, thereby inhibiting tumor progression as well as inducing
tumor regression. Pascual [24] reviewed the limited pooled data from European
centers with experience of using mTOR inhibitors in post-renal transplant PTLD.
There were 19 recipients with post renal transplant PTLD converted to sirolimus
or everolimus. Calcineurin inhibitors (CNIs) were either completely withdrawn or
minimized. Concomitant PTLD treatment was carried out with rituximab or
chemotherapy in some of the recipients. Fifteen patients demonstrated complete
remission of PTLD.
Rituximab
Rituximab is an anti-CD-20
monoclonal antibody with demonstrated efficacy against CD-20 positive PTLD.
Rituximab has been postulated to cause destruction of pathological malignant
cells by several mechanisms including; antibody dependent cytotoxicity,
complement dependent cytotoxicity, direct programmed cell death (apoptosis) and
adaptive immune mechanisms (Figure 3).
Rituximab is considered second line therapy for those who fail to respond to
RIS alone or where complete immunosuppression withdrawal in not possible [25].
It may be used as stand-alone therapy or in combination with systemic
chemotherapy. Rituximab monotherapy has reported response rates between 50-60%
in CD-20 positive PTLD [26]. However, it has a higher risk of relapse and
slower response rate in aggressive disease, requiring combination therapy.
Hence, it is most often used in combination with systemic chemotherapy to
achieve early disease remission and lower relapse rates. Factors linked to poor
rituximab response are CNS-PTLD, late-onset detection and multi-visceral
disease.
SYSTEMIC CHEMOTHERAPY
Chemotherapy with CHOP
(cyclophosphamide, hydroxy-doxorubicin, vincristine, prednisolone) regime and
its modifications remain an effective treatment for disseminated PTLD [19].
Chemotherapy may be considered either as stand-alone therapy or in combination
with rituximab as discussed above. The overall response rates are higher than
rituximab monotherapy with 1 year survival rates >65% [28] while sequential
treatment with rituximab has shown response rates of 90% [29]. However, the
chief drawback and limiting factor has been the drug toxicity with treatment
related morbidity. Some studies have reported systemic chemotherapy induced
infection related mortality to be as high as 30-50% [30]. Chemotherapy related
infectious morbidity and mortality can be successfully reduced with the
prophylactic use of granulocyte colony stimulating factor (G-CSF), antibiotics,
antifungals and antivirals. This strategy has shown to reduce chemotherapy
induced infection related mortality rates to <30% [31].
In CNS-PTLD, the treatment
options are limited, and the overall prognosis remains poor. Standard systemic
chemotherapy regimens do not cross the blood brain barrier, thus limiting their
efficacy in CNS-PTLD. Hence, higher doses of methotrexate or direct intrathecal
therapy have been used with limited success. However, radiotherapy remains the
best available therapeutic modality in established CNS-PTLD.
ADOPTIVE IMMUNOTHERAPY
Adoptive immunotherapy is a
novel approach and has been used especially in HSCT recipients where
conventional therapies for PTLD have failed. It aims at increasing EBV-specific
cytotoxic T-cells (EBV-Tc) by either donor derived infusions (DDI) or banked, in vitro expanded “third-party” EBV-Tc [32,33].
The use of DDI is limited by the risk of graft-versus-host disease and slow
response compared to third-party EBV-Tc.
DDI of cytotoxic T-cells as
adoptive immunotherapy has been reported with success rates as high as 68%
without significant risk of graft versus host disease. However, these successes
have been largely limited to HSCT and have not been reproduced in PTLD
following SOT (Figure 4).
SURGICAL CARE AND RADIOTHERAPY (RT)
Surgery in PTLD is mainly useful
in diagnosis to obtain tissue for histological confirmation.
Surgical excision can rarely be
therapeutic in well-localized PTLD or during surgical emergencies such as
GIT-related PTLD causing intestinal perforation, obstruction or bleeding [19].
In PTLD after renal
transplantation, where the graft itself is affected by the disease, graft
nephrectomy with RIS can be considered as first-line therapy.
Local radiotherapy has been used
following surgical excision for peripheral PTLD while it remains a primary
treatment modality in CNS-PTLD [34].
Antivirals
PTLD is primarily caused by
‘latent-type’ EBV infection where antivirals are considered ineffective. Hence,
the place of anti-viral therapy in the management of PTLD is limited to
pre-emptive treatment of patients who demonstrate rising EBV antibody titres
during post-transplant surveillance.
Addition of arginine butyrate
with ganciclovir increases the drug efficacy against EBV infected cells that
are otherwise resistant to ganciclovir therapy, and has been with limited
experience [35].
Interferon (IFN-alfa)
IFN-alfa has shown efficacy in
direct destruction of EBV-infected B-cells and blunting the activity of
T-helper cells, which promote B-cell proliferation [36]. However, there is no
definitive prospective studies comparing its safety and efficacy in PTLD and it
remains largely experimental based on few anecdotal reports.
Post-treatment surveillance
Surveillance with EBV viral
loads and renal functions provide valuable information regarding disease
response, progression, recurrence and allograft function. Serial imaging with
CT is also being done to assess disease recurrence.
Prophylaxis
The Seville expert workgroup
consensus (2012) has published recommendations regarding the prevention of PTLD
[37]. The summary of these recommendations are as follows:
·
The EBV serology
status of both donor and recipient should be established prior to all
transplants.
·
EBV
sero-negative recipients should ideally be preferentially allocated EBV
sero-negative donor organs.
·
Minimize
overall immunosuppression so as to minimize the risk of PTLD while maintaining
allograft function and avoiding rejection.
·
Consider
periodic EBV viral load measurement in those deemed at high risk for PTLD.
·
A documented
rise in EBV viral load (10 to 50 fold rises above baseline or a rise over short
time duration) should prompt possible pre-emptive RIS. Furthermore, these
patients may be considered for immunosuppression conversion to sirolimus or
everolimus.
PROGNOSIS
Despite all the advances in
management of PTLD have improved overall outcomes compared to several decades
ago, reports still indicate fairly high rates of disease related mortality.
Most current studies have reported PTLD related mortality after SOT between
22-26% [38].
Despite numerous attempts to standardize a prognostic scoring system for PTLD, there is no consensus in this regard. Factors included in the International Prognostic Index for Non-Hodgkin Lymphoma in non-transplant setting have not been found to correlate accurately with prognosis of PTLD. Different study groups have attempted to define possible poor prognostic indicators based on their individual patient cohorts. Some of the identified poor prognostic indicators are poor general health, EBV-ve disease, hypoalbuminaemia, CD-20 positive disease, primary CNS disease, graft involvement and monomorphic pathology [16,39,40] (Figure 5).
CONCLUSION
PTLD is one of the commonest
malignancies following transplantation. Despite numerous advances in diagnosis
and treatment, the associated mortality remains high. The presentation is
highly variable and requires a high degree of clinical suspicion to avoid fatal
delays in diagnosis. Treatment should be individualized with inputs from a
multi-disciplinary team aiming at reversal of disease progression while
preserving allograft function. While immunosuppression reduction remains the
cornerstone in management, numerous novel therapeutic options have also been
explored in an effort to safeguard graft function while achieving disease
remission. Further studies will be needed to verify the efficacy and safety of
such novel approaches with a view to reducing the associated mortality.
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