Annals of Oncology 11 (Suppl. 1): S45-S48. 2000.
© 2000 Klimer Academic Publishers. Primed in the Netherlands.
Symposium article
Diagnosis and treatment of transplant-related lymphoma
L. J. Swinnen
Department of Medicine. Division Hemawlogy/Oncology, Loyola University Chicago, IL, USA
Summary
Immunodeficiency-related B-cell disorders are seen after organ
transplantation and in congenital and acquired immunodeficiency states. Post-transplant lymphoproliferative disorders
(PTLD) comprise a histologic spectrum ranging from hyperplastic appearing lesions to frank non-Hodgkin's lymphoma
or multiple myeloma histology. Multiple clones may co-exist,
representing a uniquely different mechanism for lymphomagenesis. The incidence varies from 1% in renal recipients to 8%
in lung recipients, but can be markedly increased by the use of
anti-T-cell therapies, or by T-cell depletion in bone marrow
transplantation. Pre-transplant EBV seronegativity increases
risk to as high as 30%-50%. More than 90% of tumors are
EBV-associated. Mechanisms for viral lymphomagenesis remain incompletely defined; LMP-1 may function as an oncogene and coprecipitates withTRAF, BCL-2 overexpression has
also been identified. A possible direct tumorigenic effect has
recently been suggested for cyclosporine. PTLD has a highly
variable clinical picture, certain patterns are however seen.
Reversibility of PTLD with reduction in immunosuppressives
Introduction
Post-transplant lymphoproliferative disorder (PTLD)
remains an often devastating complication of immunosuppression. The pathogenesis, presentation, clinical
course, and management differ significantly from those of
lymphomas seen in the immunocompetent population.
The Epstein-Barr virus is central to the pathogenesis
of PTLD, and is reviewed extensively in this issue.
Deliberate partial suppression of T-cell function to prevent graft rejection is believed to result in uncontrolled
EBV-driven proliferation of B cells. As proliferation
continues, B-cell clones with structural alterations enabling autonomous growth and escape from immune
control emerge. Although the exact mechanisms underlying the appearance of a clinical lymphoproliferative
disorder are still being elucidated, this model is capable
of explaining many of the unusual clinical and pathologic features of the disease.
Incidence
The reported incidence of PTLD has varied according
to the type of organ transplanted, the individual series of
has long been recognized. Predicting reversibility has been
difficult. The presence or absence of BCL-6 mutations has
recently been identified as being of predictive value. Surgical
resection can be curative. Cytotoxics, although problematic,
can also be curative. Long term remission has been achieved
with anti CD21 and CD24 antibodies; efficacy has been reported anecdotally for interferon alpha and for rituximab. In
vitro expanded EBV-specific T cells have been effective as
treatment and as prophylaxis in the setting of bone marrow
transplantation. EBV viral load measured in blood appears to
correlate with the emergence of PTLD and may facilitate
prophylactic studies.
PTLD is a model of immunodeficiency related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic
insights gained from the study of PTLD are likely to be
applicable to other immunodeficiency states and to EBVrelated lymphoid neoplasia in general.
Key words: EBV, immunosuppression, LMP-1, non-Hodgkin's
lymphoma, post-transplant lymphoproliferative disorders
(PTLD)
patients, the immunosuppressive regimens used, and the
proportion of pediatric transplant recipients. Using data
collected by the multi-center European and North
American Collaborative Transplant Study, Opelz et al.
reported on PTLD incidence among 45,141 renal recipients and 7634 cardiac recipients. Incidence was highest
in the first post-transplant year. During that first year,
0.2% of renal and 1.2% of cardiac recipients developed
PTLD, rates that were calculated to be 20 and 120 times
higher than those seen in the general population. In a
subsequent report, analyzing 14,284 heart recipients and
72,360 kidney recipients, a cumulative incidence of 5%
by 7 years follow-up was noted in heart recipients, and
slightly more than 1% by 10 years of follow-up in renal
recipients [1].
The incidence of PTLD is however much higher in
patients who are EBV seronegative prior to transplant,
with rates as high as 30%-50% being reported [2, 3].
Most seronegative patients are children. The true risk
for seronegative patients is difficult to determine from
small series, but is clearly significantly greater than for
seropositives.
The nature of the immunosuppressive regimen used
can also significantly influence risk. A particularly high
incidence of PTLD was noted following the introduc-
46
tion of CsA, which diminished when blood levels were
monitored and lower doses of the drug were used. The
immunosuppressive antibody OKT3 has has been associated with an especially high risk for PTLD, particularly
when used for protracted courses [4]. Further underscoring the effect of T-cell depletion on risk are observations
made in the setting of allogeneic bone marrow transplantation. The disease is surprisingly uncommon (< 1%),
unless a monoclonal anti T-cell antibody was used (14%)
or donor marrow was T-cell depleted (12%, 24%) [5].
Clinical features
Patients may present with B symptoms, symptoms localized to anatomic sites of involvement, or with incidental
clinical or radiologic findings. Although the disease is
extremely variable, some general clinical patterns can be
recognized. An infectious mononucleosis-like presentation, with prominent B symptoms and rapid enlargement of the tonsils and cervical nodes, is often the case
for PTLD presenting early after transplantation - less
than about a year from the time of transplant [6]. Highly
immunosuppressed patients may present with widespread
disease, diffusely infiltrative multiorgan involvement,
and systemic sepsis, within weeks of transplantation,
and pursue a fulminant clinical course difficult to distinguish from sepsis [7].
PTLD presenting later than about a year after transplantation is likely to be more circumscribed anatomically, manifest fewer systemic symptoms, and follow a
more gradual clinical course. Extranodal disease and
visceral nodal involvement are characteristic. Gastrointestinal involvement is a frequent finding in PTLD.
The transplanted organ itself may be affected in up to
20% of cases, at times resulting in a mistaken diagnosis
of rejection. Despite these generalizations, it should be
stressed that PTLD is very variable, and not always
easily recognized clinically. Prompt diagnosis and intervention are likely to improve outcome.
The diagnosis is best established histologically rather
than cytologically, in view of the challenging morphology
often encountered and the importance of ancillary
studies. A surgical or core needle biopsy is often necessary. Clonality can be determined by demonstration of
clonal immunoglobulin gene rearrangement, or on the
basis of clonal EBV in the tumor. The presence of tumorassociated EBV can be determined by DNA analysis, or
by immunohistochemical staining for EBERS or LMP-1.
Finding EBV or a clonal population is strong supportive
evidence for the lesion being PTLD.
Treatment
There is no clear standard approach to the treatment of
PTLD, and the literature on this subject has been largely
anecdotal. Some general principles can however be inferred. Anatomically localized PTLD can be eradicated
by surgical resection (or irradiation of unresectable,
strictly localized lesions). Reduction in immunosuppression has been shown to result in permanent resolution of
PTLD in a proportion of cases. Chemotherapy results in
more frequent and more severe toxicity than in the
general population, mainly due to infection, and has
been viewed as a treatment of last resort.
The likelihood of response to reduction in immunosuppression has been linked to the interval since transplantation. In one series of heart recipients, more than
80% of patients presenting at less than one year following transplantation responded to reduction in immunosuppression, while less than 10% presenting at more
than one year did so [8]. More variable results with
reduced immunosuppression have been reported in other
series [7, 9]. Rejection is a concern, as is disease progression. A clinicopathologic classification fully capable
of predicting disease behavior and the likelihood of
response to a reduction in immunosuppression remains
elusive [6, 10]. A trial of reduced immunosuppression is
therefore considered justified as the initial approach to
all cases [8,11]. The extent and duration of a reduction in
immunosuppression for recipients of a vital organ remains poorly defined and highly subjective. If remission
is achieved by this means, immunosuppressives will need
to be re-instituted before the onset of rejection. Based
on the model of PTLD as a disease of over-immunosuppression, immunosuppressive agents have often been
re-instituted at moderately reduced dosage. Data regarding the level of subsequent immunosuppression required
remain anecdotal. A means for predicting whether a
given PTLD will be responsive to reduced immunosuppression would be highly desirable. Rejection and rapid
disease progression are both significant risks that might
thereby be avoided. With this in mind, Cesarman et al.
studied 36 PTLD patients for the presence of mutations
in the BCL-6 proto-oncogene, using single-strand conformation polymorphism and sequence analysis [12]. In
33 patients this could be related to clinical outcome. No
BCL-6 mutations were identified in cases classified as
plasmacytic hyperplasia (Knowles-Frizzera Classification). Mutations were found in 43% of polymorphic
lesions and in 90% of PTLD's classified as immunoblastic lymphoma or multiple myeloma. BCL-6 mutations
were predictive for lack of response to reduced immunosuppression. Although the association was statistically
significant, the correlations were retrospective and treatment was variable. Nonetheless, this study represents the
strongest data and the clearest predictor for response to
reduced immunosuuppressives to date. The techniques
used unfortunately do not lend themselves to real time
clinical testing.
Local therapies such as resection or limited field
irradiation have resulted in long-term remission in anatomically limited PTLD. That approach has also been
reported to be effective for a limited number of residual
lesions after a partial response to reduced immunosuppression has been achieved [8].
Although regression of lymphoproliferations has been
47
described following the use of high-dose acylovir in a
small number of cases, the value of acyclovir remains
very unclear [13].
Durable complete responses have been reported anecdotally with interferon-a-2b. The mechanism of action is
not defined at present. The drug might exert an antiviral
and/or an antitumor effect; both early polyclonal proliferations and late-presenting monoclonal lesions have
responded [14]. Liebowitz has reported the largest series
to date. Eighteen patients, primarily liver transplant
recipients,were treated with interferon-a-2b and simultaneous reduction in immunosuppression. The overall
response rate was 83% (77% complete response, 6%
partial response). Rejection and life-threatening infection was noted in 50% of patients, and median survival
was only six months [15]. Since immunosuppressives
were reduced concurrently, it is unclear to what extent
both response and toxicities might have been attributable
to that intervention alone. Although experience remains
very limited, resumption of immunosuppressives and a
trial of interferon-oc-2b appears reasonable in patients
who have failed to respond to reduced immunosuppression and who are not candidates for local therapies,
before proceeding to cytotoxic chemotherapy.
A mixture of anti-CD21 and anti-CD24 anti-B-cell
monoclonal antibodies has been shown to be effective in
a European multicenter trial involving both organ and
bone marrow transplant recipients with PTLD [9]. An
update on this series of patients was recently reported
[16]. Fifty-eight patients with PTLD (27 following bone
marrow and 31 following organ transplantation) were
treated. The overall complete response rate was 61%.
The relapse rate was low at 8%. The long-term overall
survival was 46% (BMT 35%, organ transplant 55%) at
a median follow-up of 61 months. The likelihood of
complete response was influenced by several factors:
presentation more than or less than one year post-transplant (22% vs. 82%); multivisceral disease as opposed to
localized disease (34% vs. 82%); monoclonal as opposed
to polyclonal or oligoclonal proliferations (46% vs.
80%); and whether there was CNS involvement or not
(29% vs. 71%). Toxicity was mild, consisting of transient
fever, hypotension and neutropenia. The antibodies used
are not currently clinically available. The majority of
PTLD express CD-20. Anecdotal observations of efficacy for the humanized murine anti-CD20 antibody
rituximab have been made. A retrospective study of 32
patients is reported in this issue by Milpied et al. The
CR rate was 54%. This antibody is commercially available, and represents a reasonable treatment option. The
risks of prolonged B-cell depletion in immunosuppressed
individuals remain unknown. A North American prospective phase II study in adult and pediatric patients
with PTLD refractory to reduced immunosuppression is
currently in progress.
Chemotherapy has been viewed as a treatment of last
resort for PTLD refractory to a reduction in immunosuppression. A mortality of 70% has been reported for
patients presenting at more than one year post trans-
plant [8, 17]. Septic and other complications of chemotherapy have been the major problem in some centers,
while others have found refractory disease to be common [9, 11, 17]. Those poor results have been obtained
with a variety of regimens, frequently CHOP. More
encouraging results have been achieved in a small series
of cardiac recipients treated predominantly with ProMACE-CytaBOM [7]. Mortality during chemotherapy
was 25%, (sepsis, refractory disease); the surviving patients all achieved complete remission. No patient has
relapsed, at a median follow-up of 64 months. The factors
responsible for this favorable outcome are not clear. The
regimen used may play a role, in that it allowed the
discontinuation of all other immunosuppressives for
the duration of chemotherapy and minimized exposure
to doxorubicin. No rejection episode occured during
ProMACE-CytaBOM chemotherapy. Standard ProMACE-CytaBOM dosages, dose reductions, and treatment delays were used. The cardiac allograft appeared
to be more sensitive to doxorubicin than the native
heart. Doxorubicin was discontinued after a mean
cumulative exposure of 63 mg/m2 (range 37-76 mg/m2)
in those patients. Despite those changes, none experienced clinical heart failure [7].
EBV-specific immunocompetence has been rapidly
restored in T-cell depleted allogeneic bone marrow
recipients by the infusion of a limited number of peripheral blood leukocytes from the donor [18]. Highly
selective adoptive transfer of T-cell immunity has been
achieved using in vitro expanded EBV-specific cytotoxic
T cells as treatment and prophylaxis for PTLD following allogeneic bone marrow transplantation [19]. Using
such approaches in the organ transplant setting will
require some adaptations, in view of the MHC-restricted
nature of the T-cell response and the fact that the vast
majority of PTLD's arise from recipient rather than
donor lymphocytes [20].
At this point in time reduction in immunosuppressives appears to be the best initial treatment for all
patients. Surgical resection or irradiation should be pursued for anatomically limited disease if that will produce
complete remission. If those initial measures prove
unsuccessful, a trial of interferon alfa (3 million units/
m2/day) is often attractive, in that it may obviate the
need for cytotoxics. Finally, chemotherapy can be used
successfully if other measures have failed. This is the
approach taken by the currently accruing phase II intergroup study SWOG/ECOG 9239. Rituximab may be a
reasonable alternative to interferon in this treatment
algorithm. Further progress in the treatment and prevention of this disease will require prospective clinical
trials and standardized treatment.
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Correspondence to:
L. J. Swinnen, MD
Department of Medicine
Division Hematology/Oncology
Loyola University Chicago
Bldg 112, R m . 245
2160 S. First Avenue
Maywood, 1L 60153
USA
E-mail' [email protected]