Nephrology Dialysis Transplantation 2007 22(Supplement 1):i27-i35; doi:10.1093/ndt/gfm088
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Post-transplant lymphoproliferative disorder—the potential of proliferation signal inhibitors
Julio Pascual
Servicio de Nefrología, Hospital Ramón y Cajal, 28034 Madrid, Spain
Correspondence and offprint requests to: Julio Pascual, Servicio de Nefrología, Hospital Ramón y Cajal, Carretera de Colmenar km 9,100, 28034 Madrid, Spain. Tel: +34 91 3368018; Fax: +34 91 336 8800; Email: julpascual{at}gmail.com
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Abstract
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Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous
group of diseases characterized by abnormal lymphoid proliferation
following transplantation. These lymphomas, in particular, have
been shown to have a higher incidence in renal transplant recipients
compared with the general age-matched population. The effect
of different immunosuppressive regimens on the incidence of
PTLD has been assessed in a number of studies. Although there
are conflicting data on the role of calcineurin inhibitors (CNIs)
in promoting the development of PTLD, an increase in risk is
described in most studies and is usually related to the aggressiveness
of immunosuppression. The proliferation signal inhibitors (PSIs),
everolimus and sirolimus, have both immunosuppressive and antiproliferative
actions and pre-clinical data suggest that everolimus has an
inhibitory effect on the growth of PTLD-derived cell lines.
There is currently limited clinical data on the use of PSIs
in the management of PTLD, therefore, clinical experience from
nine European Transplant centres has been pooled and analysed
to assess their potential. Conversion to PSIs and subsequent
minimization or withdrawal of CNIs was analysed in 19 renal
transplant recipients with PTLD and remission was observed in
15 patients. These data suggest that PSIs may assist with the
management of PTLD following renal transplantation.
Keywords: post-transplant lymphoproliferative disorder; post-transplant malignancy; proliferation signal inhibitors/mammalian target of rapamycin inhibitors; renal transplant recipients
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Introduction
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Renal transplant recipients carry an increased risk of developing
malignancies. Of these, post-transplant lymphoproliferative
disorder (PTLD) is a serious complication of solid organ transplantation,
occurring at an increased risk compared with both the general
population and patients on transplant waiting lists [
1]. Notably,
non-Hodgkin lymphoma (NHL) in transplant recipients has a more
aggressive clinical course, with involvement of sites beyond
the primary lymph node and poorer outcomes [
2–4]. Here,
we review the issue of PTLD for reducing long-term patient survival
following renal transplantation, highlighting the potential
impact of immunosuppressive therapies on the incidence and pathogenesis
of the disease.
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Pathogenesis
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PTLD represents a heterogeneous group of diseases associated
with abnormal lymphoid proliferation that occurs after organ
transplantation [
5]. The World Health Organization classification
of PTLD is one of the most commonly used, dividing PTLD into
three categories: early lesions (hyperplastic PTLD), polymorphic
PLTD and monomorphic PTLD (
Figure 1) [
5]. The majority of PTLD
is B-cell derived and is frequently associated with Epstein–Barr
virus (EBV) infection [
2], although some T-cell derived cases
have been reported [
6]. There is evidence that immunosuppression
of cytotoxic T-lymphocyte function in transplant recipients
enables proliferation of EBV-transformed B cells, although the
role of specific immunosuppressant agents remains controversial
[
4].
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Epidemiology
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In an analysis of the Collaborative Transplant Study (CTS) database,
Opelz and Döhler [
4] reported the incidence of NHL in
200
000 solid organ recipients, including 145 104 renal transplant
recipients. An age-, sex- and location-matched normal population
was generated to enable estimation of the risk of PTLD compared
with the expected risk of lymphoma in the general population.
The analysis showed that the cumulative incidence of NHL in
renal transplant recipients between 1985 and 2001 was significantly
increased compared with the expected rate in the matched population
(
Figure 2). The incidence of NHL was generally highest in the
first year after transplant, after which the cumulative incidence
increased steadily over the 10-year period. During that time,
the relative risk of lymphoma was 11.8 compared with the general
population (
P < 0.0001), with no significant difference between
recipients of a first transplant (relative risk, 11.7) or subsequent
transplant (relative risk, 12.1) [
4]. An association of PTLD
incidence with time was also observed in an analysis of 89 260
US renal transplant recipients, which confirmed that the highest
rates of lymphoma occur within the first 12 months after transplantation,
particularly in Caucasian patients under the age of 25 years
[
7]. In this patient group, the relative risk of lymphoma in
the first 6 months after transplantation was 13.8, which decreased
to 3.46 between 2.5 and 3 years after transplantation.
A number of factors have been identified that predispose transplant
recipients to PTLD, of which the most important is primary EBV
infection. Other risk factors include younger age at transplantation
and infection with hepatitis C, as well as factors relating
to immunosuppression, which will be discussed subsequently [
8].
Recipient EBV seronegativity at the time of transplantation
is thus an important risk factor. In an analysis of 381 consecutive
non-renal transplant recipients at a US clinic, the risk of
PTLD was 24 times higher in EBV-seronegative recipients than
in those seropositive for EBV at the time of transplantation
[
9]. Additional risk factors, including use of the monoclonal
antibody OKT3 and a cytomegalovirus (CMV)-seropositive donor,
increased the overall risk of fatal or central nervous system
PTLD by a factor of 654. There also appears to be geographical
variation in the incidence of PTLD, with approximately double
the incidence observed in North America compared with Europe
[
10], perhaps related to the different practices of induction
immunosuppressive regimens. There also appears to be a lower
incidence of PTLD in Asia compared with Western countries and
a lower incidence in recipients from particular ethnic groups,
including Arabic, Jewish, Black and Mediterranean individuals
[
10]. A difference in the incidence of PTLD between Caucasian
and Black individuals has also been observed in the USA, with
Caucasian transplant recipients at double the risk of PTLD compared
with Black patients [
7]. There was not, however, any difference
in the incidence of lymphoma between men and women.
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Immunosuppressive regimens and PTLD
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The roles of different immunosuppressive agents in the risk
of PTLD have been assessed in numerous studies. For example,
analysis of data from the CTS showed no significant difference
in the 5-year incidence of lymphoma or rate of lymphoma development
between patients receiving ciclosporin (CsA; with or without
azathioprine and steroids) and those receiving azathioprine
and steroids only [
4]. Conversely, tacrolimus use was associated
with a significant increase in the risk of PTLD in renal transplant
recipients compared with CsA, as were the monoclonal antibodies
OKT3 and anti-thymocyte globulin (ATG). Interestingly, OKT3
and ATG appeared to increase the risk of lymphoma only in the
first year after transplant, with a subsequent PTLD risk similar
to that in patients who did not receive antibody therapy [
4].
Induction therapy with anti-interleukin (IL) 2 antibodies was
not associated with any increase in the risk of PTLD [
4]. Similar
results were obtained in a study of 25 127 Medicare patients
in the USA, showing that OKT3 and ATG were associated with an
increased risk of PTLD, particularly when used as anti-rejection
therapy [
11]. Tacrolimus was also associated with an increased
risk of PTLD, which was not observed with anti-IL-2 antibodies
and sirolimus, whereas azathioprine and mycophenolate mofetil
(MMF) were associated with a reduced risk of PTLD. A reduced
risk of PTLD in patients receiving MMF was also observed in
studies of the Organ Procurement and Transplantation Network/United
Network for Organ Sharing, in which there was a trend towards
a lower risk of malignancy in patients receiving MMF and the
CTS databases, in which time to malignancy was significantly
increased in patients receiving MMF [
12]. Some studies have,
however, produced conflicting results regarding the role of
some immunosuppressants in the risk of PTLD. For example, a
randomized, controlled study of tacrolimus in 412 renal transplant
recipients showed no increase in CMV infection or PTLD compared
with CsA [
13]. A retrospective study carried out in a transplant
centre in Denmark, including 667 patients, showed no increase
in the incidence of PTLD after the introduction of CsA, OKT3
or ATG [
14]. The time to occurrence of PTLD did, however, decrease
with the use of CsA, OKT3 or ATG, and, again, MMF was associated
with a decrease in the incidence of PTLD. The type of immunosuppressive
agent is not the only factor associated with the incidence of
post-transplant malignancy. The duration and intensity of immunosuppressive
therapy both have an impact on the development of malignancy
and is therefore an important consideration post-transplantation.
The relationship between the intensity of immunosuppression
and an increased risk of skin cancer has been observed in a
number of studies [
15–17]. This finding has been supported
by the increased incidence of lymphoma in transplant recipients
who generally receive higher immunosuppressive doses and require
more aggressive therapy, such as heart or heart–lung recipients
[
4]. Data from the CTS, in which >50 000 renal and heart
transplant recipients were reviewed, confirmed a higher incidence
of NHL in heart transplant recipients than in renal transplant
recipients [
18]. The rate of NHL was especially high during
the first year post-transplantation, but slowed over subsequent
years. This probably results from the intense immunosuppressive
regimen given to these patients to avoid the detrimental consequences
of acute rejection early post-transplantation. The risk of lymphoma
was also increased in patients who received rejection prophylaxis
with anti-lymphocyte antibodies and in patients who received
combination immunosuppressive therapy that included CsA and
azathioprine [
18]. This further supports the conclusion that
NHL risk is related to the aggressiveness of immunosuppression.
A retrospective review of 478 renal transplant recipients receiving
either triple immunosuppressive therapy (CsA, azathioprine and
prednisone) or quadruple immunosuppressive therapy (CsA, azathioprine,
prednisone and anti-lymphocyte globulin as induction immunosuppression)
showed that the risk of developing NHL was increased in patients
using quadruple immunosuppressive therapy and prophylaxis for
acute graft rejection [
19].
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Conversion to proliferation signal inhibitors (PSIs)
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Whereas specific immunosuppressants increase the incidence of
malignancy post-transplantation, pre-clinical
in vivo and
in vitro studies have demonstrated that PSIs inhibit tumour growth
and progression; therefore, they may have the potential to prevent
malignancy in this at-risk population. Everolimus was found
to have an inhibitory effect on the growth of PTLD-like or -derived
cell lines
in vitro while delaying the progression, and inducing
regression, of established tumours in an
in vivo experimental
model (
Figure 3) [
20,
21]. Sirolimus also has a potent anti-proliferative
effect on
in vitro PTLD-derived cell lines and has been shown
to inhibit the growth of solid tumours in a mouse model of PTLD
[
22]. The anti-tumour potential of sirolimus was demonstrated
in a case study of a patient with PTLD who was converted to
sirolimus and prednisolone after discontinuation of tacrolimus
and MMF therapy [
23]. Renal function improved and a tomographic
scan showed rapid malignancy regression, which was maintained
after 1 year of follow-up [
23].
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Fig. 3. Effect of low-dose everolimus on in vivo growth of PTLD-derived cells. Mice implanted with PTLD-1 cells were treated with everolimus at either 0.25 or 0.5 mg/kg BID for the entire experiment or remained untreated [21]. The number of mice per experimental group is shown in parentheses. (Reprinted with permission from Lippincott, Williams and Wilkins) PTLD, post-transplant lymphoproliferative disorder; BID, twice daily.
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Since there are very limited published data on the role of conversion
to a PSI in patients with PTLD, patient data from centres across
Europe were pooled (
Table 1). This analysis only included renal
transplant recipients who were converted to PSIs following the
development of PTLD. Nineteen renal transplant recipients who
developed PTLD at a mean time of 117 months following renal
transplantation were converted to PSIs (sirolimus
n = 16, everolimus
n = 3). Calcineurin inhibitors (CNIs) were withdrawn in 18 patients
and minimized in one patient. Concomitant rituximab therapy
was used in six patients and chemotherapy with CHOP (cyclophosphamide,
doxorubicin, vincristine and prednisone) was also administered
to six patients. In 15 patients, there was complete remission
of PTLD, which was maintained for between 6 and 156 months.
Stable renal function was observed in 10 patients, with proteinuria
reported in three cases and chronic allograft nephropathy reported
in two cases. Sirolimus blood levels were generally maintained
from 4 to 10 ng/ml and everolimus blood levels were maintained
at 3–5 ng/ml. Two patients experienced recurrence of PTLD
at 5 and 24 months post-conversion, respectively and both of
these were receiving sirolimus 6–10 ng/ml. One patient
received further treatment by anti-CD20 and CHOP and is currently
in remission receiving an immunosuppressive regimen of corticosteroid
therapy. The other patient who experienced recurrence of PTLD
suffered multi-organ failure leading to death. Two other patients
died (one due to advanced tumour and one due to severe concomitant
heart failure). These data suggest that conversion to PSIs with
a subsequent minimization or withdrawal of CNIs may hold potential
for the management of PTLD following renal transplantation.
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Table 1. Clinical experience of PSIs in post-transplant lymphoproliferative disorder from eight European Transplant centres
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Summary
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PTLD is an important complication following renal transplantation.
Given the impact of immunosuppressive therapies on the incidence
of PTLD, consideration of immunosuppressive regimens could be
targeted towards those with potential anti-cancer benefits,
such as PSIs, in order to minimize the impact of the disease.
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Acknowledgements
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Data on PTLD was collected from the following centres:
Division of Nephrology and Dialysis, Internal Medicine III, Medizinische Universität Wien, Vienna, Austria; Hôpital Hotel Dieu, CHU de Nantes, Service du Pr Soulillou, Nantes, France; Cologne General Hospital, Merheim Medical Center, Germany; Universitätsklinikum Charite, Abeteilung fur Nephrologie, Berlin, Germany; Department of Nephrology and Transplantation, Laiko Hospital, Athens, Greece; Renal Unit, Kidney Transplantation Center, ‘Leonardo Sciascia’ Civic Hospital, Palermo, Italy; Nephrology Department, Hospital Universitario de Bellvitge, Barcelona, Spain; Servicio de Nefrología, Hospital Ramón y Cajal, Madrid, Spain; Renal Unit, Department of Nephrology, Hospital Clínic, University of Barcelona, Spain
Editorial assistance was provided by Ogilvy 4D.
Conflict of interest statement. The author received an honorarium from Novartis Pharma AG for participation in the workshop in Rome, March 2006, on the role of everolimus in the management of post-transplant malignancies in renal transplantation.
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J. M. Campistol, J. Albanell, W. Arns, I. Boletis, J. Dantal, J. W. de Fijter, S. A. Mortensen, H.-H. Neumayer, O. Oyen, J. Pascual, et al.
Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance
Nephrol. Dial. Transplant.,
May 1, 2007;
22(suppl_1):
i36 - i41.
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Abstract
Introduction
