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Blood, Vol. 91 No. 8 (April 15), 1998:
pp. 3079-3083
Risks of Developing Epstein-Barr Virus-Related Lymphoproliferative
Disorders After T-Cell-Depleted Marrow Transplants
By
Geoff Hale and
Herman Waldmann for CAMPATH Users
From the Sir William Dunn School of Pathology, University of Oxford,
Oxford, UK.
 |
ABSTRACT |
T-cell depletion of bone marrow for allogeneic transplantation is
known to increase the risks of Epstein-Barr virus-driven lymphoproliferative disorders that may result in fatal lymphoma, especially with transplants from unrelated or mismatched donors. Over
the past 15 years, we have monitored the outcome of 2,582 transplants
using CAMPATH-1 (CD52) antibodies to deplete lymphocytes from donor
and/or recipient to prevent graft-versus-host disease or
rejection. Unlike many other methods of T-cell depletion, CAMPATH-1 antibodies also deplete B lymphocytes. The actuarial risk of
lymphoproliferative disease using CAMPATH-1 for depletion of donor
lymphocytes was up to 1.3%, hardly different from reported figures for
conventional nondepleted transplants. In contrast, the risk in a small
group of patients transplanted from unrelated donors using E-rosette depletion was as high as 29%, comparable to other reports of specific T-cell depletion. We conclude that the additional depletion of B cells
is beneficial, possibly because it reduces either the virus load or the
virus target until the time when T cells begin to regenerate.
| |
INTRODUCTION |
B-CELL LYMPHOPROLIFERATIVE disorders
(BLPD) related to infection with Epstein-Barr virus (EBV) are a
well-recognized complication of intensive immunosuppression for organ
transplantation1-3 and a comparatively infrequent
complication of allogeneic bone marrow transplantation
(BMT).4-8 Latent EBV is present in the majority of patients
and donors and causes uncontrolled proliferation of B cells under
conditions of intense immunosuppression. This can rapidly lead to a
progressive and highly lethal lymphoma. Risk factors include severe
graft-versus-host disease (GVHD), HLA incompatibility between donor and
recipient, T-cell depletion of the donor bone marrow, and especially
the use of certain anti-T-cell monoclonal antibodies.5,9-12 Treatments such as discontinuance of
immunosuppression or administration of antivirals (eg, acyclovir),
interferon, or monoclonal antibodies have had only limited
success,4,5,11,13,14 but in recent years it has been shown
that infusions of modest numbers of donor T cells can be extremely
effective in bringing the B-cell proliferation under
control.15,16
A recent report12 described 65 children who received
non-HLA-identical BMT at one institution. Nine of them (14%) suffered from BLPD, in contrast with none of 77 children who received
HLA-identical BMT. BLPD was associated with a particular regimen that
included monoclonal antibodies (CAMPATH-1G and anti-LFA1) for
conditioning the recipients, together with T depletion by E-rosetting.
These results are consistent with other reports of a particularly high incidence of BLPD after transplantation of T-depleted bone marrow from
non-HLA-identical donors.5,10
The majority of EBV lymphomas occur in donor B cells.9,17
Latently infected donor B cells may be a significant source of
infection,18 but there are cases of lymphoma in B cells
from a seronegative donor, indicating that virus already present in the
recipient may cause proliferation of donor B cells.5 It is
also possible that EBV may come from an exogenous third-party source
(eg, blood transfusion). Whatever the origin of virus, we wondered
whether removal of donor B cells would diminish the risk of BLPD after
T-cell-depleted BMT. The CD52 monoclonal antibodies CAMPATH-1M (IgM)
and CAMPATH-1G (IgG) have been widely used for T-cell
depletion,19-21 but they also recognize and deplete B cells equally as well.22 We have reviewed the records of
transplants performed by CAMPATH users to identify possible cases of
BLPD.
| |
MATERIALS AND METHODS |
CD52 antibodies.
CAMPATH-1M (rat IgM) and CAMPATH-1G (rat IgG2b) monoclonal antibodies
were produced by the Therapeutic Antibody Centre and supplied to BMT
centers for a variety of physician-initiated trials to prevent GVHD
and/or transplant rejection.20 CAMPATH-1M was used
with human complement in vitro for depletion of T cells to prevent
GVHD. CAMPATH-1G was used in three different ways: (1) in vitro
(without complement) to opsonize donor T cells, marking them for
destruction in vivo; (2) in vivo before the transplant to deplete
recipient T cells to prevent rejection; and (3) in vivo at or just
after the transplant to deplete donor cells and prevent GVHD.
Combinations of these modes of antibody treatment were used in
different trials as described more fully in Hale et al.20
Informed consent was obtained for participation in study protocols and
submission of data to the CAMPATH registry according to the normal
procedure at each center.
Statistical analysis.
A database is maintained with details and outcome of all BMTs using
these antibodies. We believe it is comprehensive, because it correlates
with the antibody distribution records. Between July 1982 and May 1996, a total of 2,578 transplants were recorded, and all of them were
reviewed to identify any suspect cases of BLPD. The collaborating
transplant centers were contacted with a written questionnaire to
obtain confirmation of the suspect cases and to discover whether there
were any others that had not been reported. Replies were received from
46 of 54 centers, representing 97% of the patients in the database.
Eight new cases were identified from the survey, but 4 of them occurred
since May 1996 and were therefore not included in this analysis because
we do not yet have details of all patients transplanted in this period
(approximately 3 to 400 patients). The results were analyzed by the
method of T-cell depletion and the match between donor and recipient.
Statistical comparisons were performed using the  2 test,
log rank survival analysis, or Mann-Whitney U test, as appropriate.
| |
RESULTS |
Cases of EBV-associated lymphoproliferative disease.
A total of 20 possible cases of BLPD were identified (Table
1). The distribution with respect to
patient's original disease, age, year of transplant, donor or
recipient gender, and occurrence of graft rejection or graft failure
was unremarkable. All cases occurred within the first year
posttransplant (which is typical), with the exception of case no. 2, a
patient who died at 17 months posttransplant of secondary lymphoma. In
this case, there was no positive diagnosis of EBV, and it was
considered possible that the lymphoma represented progression of the
original malignancy (chronic myeloid leukemia [CML]).
However, it has been included as a case of possible BLPD for the
purpose of this analysis. Most of the cases occurred before the era of
therapy with donor lymphocyte infusions and progression was generally
very rapid. Sometimes the diagnosis was only made postmortem. However,
case no. 20 has been successfully treated with donor T-cell infusions.
Analysis according to transplant protocol.
The frequency of BLPD was analyzed according to the relationship
between donor and recipient and according to the method of T-cell
depletion (Table 2). Transplants from
HLA-identical siblings were considered in one group and all other
transplants (mismatched family donors and unrelated donors) in another.
Most patients received marrow depleted of T and B cells with CAMPATH-1
antibodies either in vitro (marrow was treated with CAMPATH-M or
CAMPATH-1G before infusion) or in vivo (the patient was treated with
CAMPATH-1G on and/or after the day of transplant). Many
patients also received CAMPATH-1G and occasionally other monoclonal
antibodies as part of the conditioning regime to prevent rejection. The
number of patients who received antibody therapy for rejection
prophylaxis is shown in Table 2. Some of the patients who received
lymphocyte-depleted bone marrow also received infusions of small
numbers of donor lymphocytes (T-cell addback), sometimes at the time of
transplantation23 and sometimes during the
following 3 months.24 The dose was typically in the range
of 104 to 106 per kilogram. These patients have
been analyzed separately.
View this table:
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Table 2.
Analysis of Lymphoma and Lymphoproliferative Disease
According to Type of Match and Method of T-Cell Depletion
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Smaller groups of patients had no T-cell depletion or received bone
marrow depleted of T cells by E-rosetting25 or by an alternative methodology (12 with T-cell-specific antibodies plus rabbit complement, 2 with elutriation, and 2 with CD34 selection). In
all these cases, CAMPATH-1G was used as part of the conditioning regimen.
There was no case of BLPD in the 144 nondepleted transplants. Among 20 patients transplanted from mismatched or unrelated donors with
E-rosette depletion, there were 5 cases of BLPD (actuarial risk,
29% ± 16% at 2 years). In 2,401 transplants in which donor T
cells were depleted with CAMPATH-1M or CAMPATH-1G, there were 15 patients who suffered from BLPD and/or secondary lymphoma
(actuarial risk, 1.1% ± 0.4% at 2 years). There was no
significant difference between sibling and nonsibling donors, and we
could not detect an association with the use of antibody for rejection
prophylaxis or any particular antibody protocol. There were no cases of
BLPD in the subset of 303 patients who received T-cell addback, but this is still not a large enough number to be significantly different from the patients with complete T-cell depletion.
The median age of the E-rosette cases (7 years) was less than that of
the CAMPATH cases (36 years), but this simply reflects the difference
in the populations treated by the two methods.
Time to onset of BLPD.
Diagnosis of BLPD was earlier among patients transplanted from
unrelated donors or mismatched family donors (median, day 85) compared
with HLA-identical sibling donors (median, day 238;
P < .001, Mann-Whitney test). This difference is still
significant if we exclude the doubtful case no. 2 (P < .005) or analyze days of survival rather than days to
diagnosis (P < .001) or exclude the E-rosette patients
(P < .005). Among the nonsibling donors, diagnosis was also
earlier in the patients who received E-rosette-treated marrow (median,
day 59) compared with CAMPATH-1-treated marrow (median, day 116;
P < .003). However, this difference is no longer significant if we compare survival times. Because all the E-rosette patients were children treated at a single center, we surmise that BLPD
might have been diagnosed sooner than in the disparate group of
CAMPATH-1 patients observed at many different centers.
Measurement of residual T cells.
The percentage of residual T cells in bone marrow treated by CAMPATH-1M
and complement was estimated by E-rosette analysis or flow cytometry
and reported for a large proportion of the patients (828/1,267). For
HLA-matched siblings, the median total nucleated cell dose was 2.1 × 108/kg and the median proportion of residual T cells was
0.4%, giving a dose of approximately 8 × 105 T cells/kg
infused. For other donors, the median total nucleated cell dose was 3.6 × 108/kg and the median proportion of residual T cells
was 0.2%, giving a dose of approximately 7 × 105 T
cells/kg infused. It is very likely that these figures are an
overestimate of the number of functional donor T cells, because lymphocytes coated with CAMPATH-1M antibody that escaped lysis in vitro
may still be lysed when they encounter additional complement in vivo.
By the same token, it is not possible to measure the extent of cell
lysis with CAMPATH-1G, because complement was not added in vitro and
much of the cell lysis would occur after infusion of the marrow.
Residual numbers of T cells were not reported for the bone marrow
depleted by the E-rosette method.
| |
DISCUSSION |
The risks of BLPD after lymphocyte depletion with CAMPATH-1 are not
substantially different from those reported for conventional BMTs in
which there was no T-cell depletion. For example, Zutter et
al5 report 5 cases among 1,868 HLA-identical sibling
transplants (0.45%) and 3 among 386 HLA-mismatched transplants
(1.4%). However, the frequency of BLPD seen by CAMPATH users is
substantially lower than that described in many other protocols of more
specific T-cell depletion, whether using E-rosettes or other monoclonal
antibodies where actuarial risks up to and exceeding 20% have been
reported.4,10,12,15,26
A group of 20 patients who received marrow depleted by albumin gradient
and E-rosette treatment were reported by one center to the CAMPATH
users registry. These patients all received CAMPATH-1G as part of the
conditioning regimen and were included in the 65 patients previously
reported in Gerritsen et al.12 We observed that they
suffered an exceptionally high incidence of BLPD (29%). This group was
not directly comparable with the rest of the CAMPATH-1-depleted patients for several reasons: (1) the average age was significantly lower (all were children), (2) all were transplanted from unrelated donors (18) or parents (2), and (3) a unique conditioning regime was
used including a CD11a (LFA-1) antibody as well as
CAMPATH-1G.12 It is not possible to directly compare the
levels of T-cell or B-cell depletion achieved by the different methods
in the clinical cases, because data were not reported for the
E-rosette-depleted marrow and a significant amount of cell lysis may
occur in vivo with the CAMPATH-1 antibodies, especially CAMPATH-1G.
However, there are numerous published data that show that both methods can give a profound degree of T-cell depletion when measured by functional analysis such as limiting dilution. For example, Frame et
al27 found 99.4% depletion of T cells by CAMPATH-1M plus complement, compared with 99.8% by soybean agglutinin plus E-rosettes. Jabado et al26 compared the depletion measured by
immunophenotyping with limiting dilution analysis. By staining with
anti-CD3, they found a mean of 3.1 × 105 T cells/kg
infused after CAMPATH-1M depletion and 1.6 × 105 after
E-rosette depletion. However, the number of viable T cells estimated by
limiting dilution analysis was more than 10-fold lower for the
CAMPATH-1M-depleted samples.
The most conclusive evidence for the extent of T-cell depletion
achieved with CAMPATH-1M or CAMPATH-1G is the effective prevention of
GVHD that is achieved in the absence of posttransplant
immunosuppression in both HLA-matched and mismatched
transplants.19-21 It is conceivable that a few T cells are
spared, particularly if they are CD52 ,28 and
perhaps these are sufficient to control any emerging B cells. More
likely, we think that the CAMPATH-1 will have depleted the donor B
cells and thus removed both a potential reservoir of latent virus and
its immediate target.
If donor B cells are preserved (eg, by E-rosette depletion), but
CAMPATH-1G was administered to the recipient (to prevent rejection), we
anticipate the highest risk; indeed, this is borne out by other
reports.12,26
It has often been remarked that the risk of BLPD is higher for
mismatched transplants than for transplants from HLA-identical donors.4,10,12 It would not be surprising if mismatched
patients were at greater risk due to higher levels of immunosuppression and relatively impaired recovery of T-cell immunity. However, this
effect was not seen in the CAMPATH-1-depleted transplants. Possibly
the depletion of donor B cells by CAMPATH-1 is sufficient to overcome
the other risk factors (eg, see Gerritsen et al12). Most
of the patients also received CAMPATH-1G in vivo for prevention of
rejection. This would have depleted any residual recipient B cells as
well, and we cannot exclude a beneficial effect by this mechanism.
However, it seems less likely, because we saw no association between
the incidence of BLPD and the use (or not) of CAMPATH-1G in vivo.
T-cell depletion is currently enjoying a renaissance of interest after
the success of transplants with peripheral blood stem cells. The
ability to infuse large numbers of stem cells may overcome any problems
of graft rejection or delayed engraftment that were previously seen
with T-cell-depleted bone marrow. The possibilities of storing
cryopreserved donor T cells or harvesting fresh ones may enable
effective treatment of relapse and of viral infections including
cytomegalovirus and EBV.29 We suggest that the
recipient EBV status should be checked before transplantation and that
a negative result should be taken into account in deciding future management. However, if donor B cells can be removed from the transplant along with the T cells, the risks of developing
lymphoproliferative disease would appear to be substantially reduced.
| |
FOOTNOTES |
Submitted July 28, 1997;
accepted November 21, 1997.
Supported by the UK Medical Research Council, The Kay Kendall Leukaemia
Fund, The Gilman Foundation, Wellcome Foundation Ltd, LeukoSite Inc,
and the EP Abraham's Trust.
Address correspondence to Geoff Hale, PhD, Therapeutic
Antibody Centre, Old Road, Headington, Oxford, OX3 7JT, UK.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors greatly appreciate the contributions of many BMT teams who
contributed data for this report. The participating centers are listed
in Hale et al.20 We thank the reviewers A and B for their
constructive comments on this paper.
| |
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Abstract
Introduction
Abstract