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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4581-4590
Improving the Outcome of Bone Marrow Transplantation by Using CD52
Monoclonal Antibodies to Prevent Graft-Versus-Host Disease and Graft
Rejection
By
Geoff Hale,
Mei-Jie Zhang,
Donald Bunjes,
H. Grant Prentice,
David Spence,
Mary M. Horowitz,
A. John Barrett, and
Herman Waldmann
 |
ABSTRACT |
Graft-versus-host disease (GVHD) is a major cause of mortality and
morbidity after allogeneic bone marrow transplantation, but can be
avoided by removing T lymphocytes from the donor bone marrow. However,
T-cell depletion increases the risk of graft rejection. This study
examined the use of CD52 monoclonal antibodies to eliminate T cells
from both donor marrow and recipient to prevent both GVHD and
rejection. Seventy patients receiving HLA-identical sibling transplants
for acute myelogenous leukemia (AML) in first remission were studied.
An IgM (CAMPATH-1M) was used for in vitro depletion of the graft and an
IgG (CAMPATH-1G) for in vivo depletion of the recipient before graft
infusion. No posttransplant immunosuppression was given. Results were
compared with two control groups: (1) 50 patients who received bone
marrow depleted with CAMPATH-1M, but no CAMPATH-1G in vivo; and (2) 459 patients reported to the International Bone Marrow Transplant Registry
(IBMTR) who received nondepleted grafts and conventional GVHD
prophylaxis with cyclosporin A (CyA) and methotrexate (MTX). The
incidence of acute GVHD was 4% in the treatment group compared with
35% in the CyA/MTX group (P < .001). Chronic GVHD was also
exceptionally low in the treatment group (3% v 36%; P < .001). The problem of graft rejection, which had been frequent in
the historic CAMPATH-1M group (31%), was largely overcome in the
treatment group (6%). Thus, transplant-related mortality of the
treatment group (15% at 5 years) was lower than for the CyA/MTX group
(26%; P = .04). There was little difference in the risk of
leukemia relapse between the treatment group (30% at 5 years) and the
CyA/MTX group (29%). Survival of the treatment group at 6 months was
better than the CyA/MTX group (92% v 78%), although at 5 years the difference was not significant (62% v 58%) and
neither was the difference in leukemia-free survival (60% v
52%). We conclude that T-cell depletion is a useful strategy to
prevent GVHD, provided that measures are taken to ensure engraftment. Using CAMPATH-1G to deplete residual host lymphocytes is a simple and
practical method to do this. At least in AML, the beneficial reduction
in GVHD can be achieved without an increased risk of relapse.
| |
INTRODUCTION |
HIGH-DOSE CHEMOTHERAPY and radiotherapy
followed by transplantation of allogeneic hematopoietic stem cells can
cure patients with leukemia. However, allografts have several adverse effects, the most serious of which is graft-versus-host disease (GVHD).
It can result in severe damage to skin, liver, and gut, frequently
leading to death or chronic disability. To control GVHD,
immunosuppressive drugs such as cyclosporin A (CyA), methotrexate (MTX), and corticosteroids are administered
posttransplant.1,2 However, even with combined cyclosporin
and methotrexate, GVHD remains the single most common cause of death
after allogeneic transplants.
For many years it has been known that GVHD can be prevented by
depleting T lymphocytes from the donor bone marrow and a variety of
methods were developed to accomplish this.3-8 One of the
most widely used has been the monoclonal antibody (MoAb) CAMPATH-1M, a
rat IgM antibody that recognizes the CD52 antigen.9 CD52 is
abundantly expressed on all human lymphocytes and is an exceptionally good target for cell lysis by antibody with human complement; this
provided a simple method for purging the donor T cells.10 Prior studies demonstrated the efficacy of T-cell depletion and consequent reduction in GVHD.6,11-14 However the benefit
was offset by an increased risk of graft rejection by residual host T
cells,15,16 and some patients suffered an increased risk of
leukemia relapse due to the loss of graft-versus-leukemia effects contributed by donor lymphocytes.12,17 Animal
models18,19 and clinical experience20,21 showed
that graft rejection might be overcome by increasing the
immunosuppression of the recipient before transplantation. One way of
delivering this, without adding to the toxicity of the conditioning
regimen, is to use MoAbs to deplete residual host T
cells.22 A rat IgG2b CD52 antibody, CAMPATH-1G, effectively
depletes human lymphocytes in vivo.23 Like CAMPATH-1M, it
can activate human complement, although this is not sufficient for
systemic T-cell depletion. Rat IgG2b also binds human Fc receptors and
engages cellular killing mechanisms.24
A combined strategy using CAMPATH-1M to T-cell-deplete donor bone
marrow and intravenous CAMPATH-1G to ablate residual host immunity has
been used in more than 600 transplants worldwide, primarily in
transplants from unrelated donors.13,14,25,26 We report
here results of 70 HLA-identical sibling transplants for acute
myelogenous leukemia (AML). We compare the results first to a
historical group receiving CAMPATH-1M-treated marrow but no
intravenous CAMPATH-1G and second to a matched group of concurrently treated patients reported to the International Bone Marrow Transplant Registry (IBMTR) who received unmanipulated transplants and
posttransplant cyclosporin plus methotrexate for GVHD prophylaxis.
| |
MATERIALS AND METHODS |
MoAbs.
CAMPATH-1G27 was prepared from the culture supernatant of
hybrid myeloma cell culture in a hollow-fiber fermentor (Acusyst-Jr; Cellex, Minneapolis, MN). It was purified by affinity
chromatography on protein A sepharose, followed by ion exchange
chromatography on S-sepharose, and formulated in phosphate-buffered
saline. CAMPATH-1M10 was prepared from hybrid myeloma cells
using three methods: (1) ascitic fluid fractionated with ammonium
sulphate, (2) hollow-fiber culture supernatant fractionated with
ammonium sulphate, and (3) culture supernatant from stirred fermentors
purified by affinity chromatography on protein A sepharose (this was
performed by Wellcome Biotech [Beckenham, UK], who
provided some of the antibody for this study). Batches prepared by each
method were tested in a variety of analytical systems. All had
comparable potency for complement-mediated cell lysis and insignificant
effect on colony-forming cells.28,29 Process (1) was used
for the historic controls, process (2) was used for the study patients
at London and Riyadh, and process (3) was used for the study patients
at Ulm.
In vitro T-cell depletion of bone marrow.
A similar depletion procedure was used for all transplants, as
described previously.11,25 Donor bone marrow was
harvested in the usual way and processed using a cell separator to
prepare a cell concentrate in balanced salt solution (containing
Ca2+) that was free from plasma and depleted of red blood
cells and granulocytes. The volume of the mononuclear cell suspension
was adjusted so that the cell density did not exceed 5 × 107/mL, and CAMPATH-1M was added to give a final
concentration of 0.1 mg/mL. The mixture was incubated for 10 to 20 minutes at room temperature, and then donor serum was added to a final
concentration of 25% (vol/vol). It was then incubated for a further 20 to 45 minutes at 37°C. The treated bone marrow was washed once
before infusion. Experiments had shown that differences in antibody
batch or incubation timing did not materially affect the efficacy of T-cell depletion (G.H., unpublished work). The fraction of
residual T cells was measured using standard methods, according to the practice in each center, either by E-rosettes or by
fluorescence-activated cell sorting (FACS) analysis using
appropriate T-cell-specific mouse MoAbs. (All of the study patients
were assessed by FACS analysis using CD3 antibodies to enumerate T
cells.)
In vivo administration of CAMPATH-1G.
Patients were treated with 20 mg/d of CAMPATH-1G over a period of 5 days at the beginning of the pretransplant conditioning therapy. Each
dose was diluted in 250 mL normal saline and infused intravenously over
3 hours. To minimize the expected systemic first dose reaction, most
patients received medication before the first antibody infusion, either
0.5 to 1 g prednisolone (Ulm) or 100 mg hydrocortisone plus 50 mg
diphenhydramine (Royal Free, Riyadh), followed by 3× 1 g
paracetamol daily.
Patients: Study group.
Three transplant centers participated in the study: Ulm University
Hospital (Ulm, Germany), Royal Free Hospital (London, UK), and King
Faisal Hospital (Riyadh, Saudi Arabia). The original plan was to
include all patients over 13 years with acute leukemia in first
remission transplanted from HLA-matched siblings with the intent of
comparing results in acute lymphoblastic leukemia (ALL)
and AML. Because very few patients with ALL were recruited, this
analysis focuses on patients with AML. (Inclusion of the ALL patients
would not significantly affect the results.) The conditioning regimen
was determined according to the standard protocol of each center. All
included cyclophosphamide plus total body irradiation (TBI), which was
administered as a single dose in 23% patients (at the Royal Free) and
multiple fractions in the others (at Ulm and Riyadh). Additional
chemotherapy (busulphan) was administered in 6% of patients (Royal
Free only). None of the patients received any additional lymphoid
irradiation and none received posttransplant immunosuppression. There
was no selection of patients according to cytogenetic risk group and
data on risk groups were not reported systematically. Each center
recruited consecutive patients provided that they gave informed
consent. The numbers of patients and conditioning regimens at each
center are shown in Table 1.
Patients: Historic CAMPATH-1M controls.
A database is maintained by GH of all transplants using CAMPATH-1
antibodies. It contains information on the patient and donor characteristics and transplant outcomes. It is a condition of antibody
supply that data are regularly reported to the CAMPATH users database.
Controls were selected using the following criteria: (1) patients more
than 13 years of age, (2) transplants for AML in first remission, (3)
HLA-identical sibling donors, (4) conditioning regimens based on
cyclophosphamide and TBI, (5) no lymphoid irradiation, (6) no
intravenous CAMPATH-1G or other antibody, (7) T-cell
depletion with CAMPATH-1M, and (8) no posttransplant immunosuppression. Fifty patients meeting these criteria were identified; 26 were transplanted at the same three centers as the 70 study patients.
Patients: IBMTR controls.
A second control group of patients receiving non-T-cell-depleted
transplants between 1984 and 1995 was selected from the IBMTR database
using the same criteria described above, except that patients from the
three study centers were excluded and GVHD prophylaxis was with
combined CyA and MTX.30 IBMTR is a voluntary study group of
over 300 transplant centers worldwide that contribute detailed data to
a Statistical Center at the Medical College of Wisconsin. Participants
are required to report all consecutive transplants. The IBMTR database
includes 40% to 45% of allogeneic transplant recipients since 1970. Computerized error checks, physician review of submitted data, and
on-site audits of participating centers ensure data quality. Selection
of the control group proceeded as follows: patients with AML,
transplanted in CR1 from 1984 through 1995 (inclusive), N = 2,940;
exclude the three study centers, N = 2,759; select patients
transplanted from HLA-identical siblings, N = 2,429; select
cyclophosphamide + TBI with no ATG for conditioning, N = 1,307; select
MTX plus CyA for GVHD prophylaxis, N = 512; and select patients more
than 13 years of age at transplant, N = 459.
These 459 cases were reported to the IBMTR by 95 transplant centers.
Statistical analysis.
Characteristics of the treatment groups were compared using the
 2 test for categorical variables and the Wilcoxon
two-sample test for continuous variables. Comparing outcomes between
the treatment groups required adjustment for the differences in
baseline characteristics of the patients. First, associations between
outcomes and potential prognostic variables were evaluated in each
group separately using Cox proportional hazards regression with a
forward stepwise approach.31 The outcomes considered were
rate of engraftment (days to reach 0.5 × 109
neutrophils/L), graft failure, transplant-related mortality (TRM; defined as death in continuous complete remission), relapse, survival, and leukemia-free survival. Variables considered were age at
transplant, recipient gender, donor gender, and year of transplant.
Variables significantly associated with the outcome in any treatment
group were included as covariates in subsequent comparisons. Possible interactions between significant covariates and the type of treatment were tested. The proportionality assumption of the Cox model was tested
by adding a time-dependent covariate for each covariate.32 The proportionality assumption did not hold for treatment effects on
survival, indicating that the relationship between treatment and
survival outcomes differed over time. To determine regions of the
treatment period where the relative risk of mortality between different
treatments was a constant, a series of Cox models with different
cut-off time points for time-dependent treatment effects were
fitted.32 The final model chosen was the one giving the largest partial likelihood. In this model, treatment was considered as
a time-dependent covariate with different coefficients from 0 to 6 and
greater than 6 months since transplantation. The adjusted relative
risks (95% confidence intervals and P values) of the study
group versus historic group and study group versus MTX/CyA group were
calculated for each outcome. Where appropriate, confidence intervals
were calculated based on a log transformation.
| |
RESULTS |
T-cell depletion in vitro by CAMPATH-1M.
Several methodologies were used over the years to estimate the fraction
of residual T-cells in treated marrow
(Table 2). The measured fraction of
residual T cells in the study group (median, 0.4%) was less than in
the historic control group (median, 1.0%; P = .024), but the
result must be treated with caution owing to the potential variability
in the measurement of small numbers of cells. The total number of
mononuclear cells infused varied significantly between each of the
three study centers and between the study group (median, 1.0 × 108/kg) and the historic control group (median, 2.15 × 108/kg; P < .001). Consequently, the
calculated numbers of T cells infused differed significantly between
the study group (median, 0.2 × 106/kg) and the
historic group (median, 1.7 × 106/kg; P < .001).
Lymphocyte depletion in vivo by CAMPATH-1G.
CAMPATH1G treatment was started before other components of
the conditioning regimen, so that antibody effects could be determined. All patients had rapid and profound depletion of blood lymphocytes. The
number of clonable T cells that could be recovered from recipient blood
samples obtained 1 to 2 days after the CAMPATH-1G infusions was reduced
by 2.5 to 3 logs compared with pretreatment samples.33 As in other studies with CAMPATH-1G or CAMPATH-1H, there was
generally a first-dose effect of fever, often with rigors and nausea,
which is related to a release of cytokines.34,35 In two
patients the reaction was severe, and it was decided to discontinue
CAMPATH-1G. (These patients are still included in the analysis.) All
other patients had diminished reactions to the second and subsequent doses.
Effect of year of transplant.
To determine whether patients transplanted before 1990 could be
included in comparative analyses, we examined the IBMTR dataset for
differences between patients transplanted in 1984 through 1989 compared
with 1990 through 1995. There were no statistically significant
differences in the actuarial risks of transplant-related mortality
(26% v 27% at 4 years), relapse (26% v 33% at 5 years), survival (57% v 58% at 5 years), or leukemia-free
survival (54% v 49% at 5 years). Therefore, all data from
1984 through 1995 were pooled for subsequent analyses.
Comparison of prognostic features of the study and control groups.
Characteristics of the study and control groups are shown in
Table 3. The most significant difference
was in age. The median age of the study group (36 years) was
significantly higher than the historic control (30 years; P = .003) or the CyA/MTX group (31 years; P = .03). There was also
a difference in the gender of patients between the study group (57%
male) and the historic control (38% male; P = .04), but not
the CyA/MTX group (50% male). The potentially confounding effect of
patient age on the outcome has been adjusted in a multifactorial model
(see below).
Comparison of outcome for study and control groups.
Univariate analyses of outcome are shown in
Table 4. Engraftment was significantly
slower in both CAMPATH groups compared with the CyA/MTX group
(Fig 1). Even disregarding patients who did
not engraft at all, there was a delay of 1 day in the median time to
reach 0.5 × 109 neutrophils/L for the historic
CAMPATH group and 5 days for the study group. There was a significant
variation in time to engraftment among the three study centers. The
median time to reach 0.5 × 109 neutrophils/L at Ulm
was 23 days, whereas at the Royal Free and Riyadh, the median was 30 days (P = .001). Platelet engraftment was not reported in this
study.
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| Fig 1.
Speed of engraftment. Note the cross-over between study
and control groups. The study group engrafts more slowly, but a higher
proportion of patients eventually engraft.
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The study group had a significantly lower risk of rejection than the
historic group (6% v 31%; P = .0003) but a higher
risk than the CyA/MTX group (2%; P = .03;
Fig 2). The incidence of both acute and
chronic GVHD was significantly lower in the study group compared with
either of the two control groups. Only 3 of the 70 study patients
developed grade 2 acute GVHD and 2 developed mild/moderate chronic
GVHD; there were no more severe cases.
Transplant-related mortality was significantly lower in the study group
than in the historic group (15% v 58%; P < .0001) and also less than in the CyA/MTX group (26%; P = .04;
Fig 3). Relapse was similar in the three
groups. Survival and leukemia-free survival were significantly higher
in the study group than in the historic group, but similar to that in
the CyA/MTX group (Figs 4,
5, and 6).
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| Fig 3.
Probability of transplant-related mortality (death in
continuous complete remission). Note the significantly reduced
mortality of the study group in the first 6 months.
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Outcome after graft failure/rejection.
Primary failure of engraftment was documented in 9 of the historic
control group (18%) and 3 of the study group (4%). Late graft
rejection occurred in 6 of the historic group (12%) and 1 of the study
group (1%). It was not possible to determine the cause of graft
failure in every case, but it is likely that most, if not all, were due
to immunological rejection. Therefore, both early and late graft
failure were analyzed together. Patients were treated by reinfusion of
stored autologous marrow (5 historic control and 1 study) or by a
second transplant of unfractionated allogeneic marrow from the original
donor (6 historic control and 3 study). In 11 cases, these rescue
procedures resulted in successful engraftment, but many of the patients
suffered further complications and eventually 12 of 15 patients died in
the historic group (9 from graft failure) and 4 of 4 patients died in
the study group (all from relapse).
Multivariate analysis.
The results were further analyzed using the Cox proportional regression
model to test for interactions with prognostic factors that might have
affected the results of univariate analyses
(Table 5). Variables used in building the
model were age, year of transplant, patient gender, donor gender, and
treatment group. Outcomes were rate of engraftment, graft failure,
transplant-related mortality, relapse, survival, and leukemia-free
survival. There was a significant association between age and
transplant-related mortality. The relative risk of transplant-related
mortality for patients more than 30 years of age was 1.53 times that
for patients under 30 years (95% confidence interval, 1.08 to 2.15;
P = .02). However, the relationship between patient groups and
outcome was similar for young and old patients. In the final model,
allowing for the effect of age, there was less than half the risk of
transplant-related mortality in the study group compared with the
CyA/MTX control (relative risk, .45; P = .02). Tests for
proportionality indicated that the effect of the study treatment on
survival differed at different times after the transplant. In the first
6 months after the transplant, survival of patients in the study group
was significantly higher than the control groups; among patients
surviving 6 months, subsequent survival was similar in the study group
versus the two control groups. It is not surprising that no significant
difference in long-term survival could be shown, because the size of
the study did not give it sufficient power to demonstrate even a 10% difference.
Causes of death.
The underlying causes of death in each patient group are reported in
Table 6. Because of the small numbers in
the study and historic control group and the difficulties inherent in
assigning a single cause of death to some patients, we did not attempt
formal statistical analysis. The most frequent cause of death in the study group was relapse (15 patients), followed by infection (7 patients). There were 3 deaths from infection in the study group after
6 months: 1 varicella zoster + aspergillus (day 191), 1 varicella
zoster + hepatitis C (day 858), and 1 unknown organism (day 387).
| |
DISCUSSION |
Since the early clinical trials of T-cell depletion, it was realized
that graft rejection by residual host T cells was a major problem that
negated much of the clinical benefit of avoiding GVHD. Graft rejection
could be reduced, but not eliminated, by giving extra whole
body20 or total lymphoid irradiation21 or by
administering posttransplant CyA.13 Animal experiments showed that anti-T-cell MoAbs could be used to escalate the
immunosuppression without toxicity, and this prompted the collaborative
CAMPATH users group to begin a number of pilot studies using CAMPATH-1G to deplete residual host T cells.13,14,25,26 These studies gave encouraging results, but it was possible that other improvements in transplant protocols over time might have influenced the outcome. Therefore, we performed the present comparison with a large
contemporaneous control group of patients selected from the IBMTR
database. A second problem associated with T-cell depletion is the loss
of beneficial graft-versus-leukemia effects. This is well documented for patients with chronic myeloid leukemia (CML), but it
is not clear whether there is a significant effect in patients with
acute leukemia. In this analysis, we evaluated relapse in patients
transplanted for AML in first complete remission.
This study convincingly demonstrates the effectiveness of the combined
CD52 antibodies in dramatically reducing the risk of acute and chronic
GVHD, without posttransplant immunosuppression. There were no cases of
severe acute or chronic GVHD in the study group. Similar results have
been reported when the same antibody protocol was used in other
transplant indications.14,26 The addition of CAMPATH-1G in
vivo pretransplant resulted in lower GVHD rates than those seen in the
historic controls, which might be due to additional depletion of donor
T cells in vivo by residual CAMPATH-1G at the time of
transplant. The measured extent of T-cell depletion by
CAMPATH-1M was greater for the study patients than the
historic controls, but the significance of this is hard to assess due
to the technical difficulties in accurate measurement of small numbers
of T cells and the fact that actual depletion is likely to have been
greater than measured, because residual T cells would be coated with
CAMPATH-1M antibody and lysed when they encounter fresh complement
after infusion of the bone marrow.
Importantly, the study group also had a significantly lower risk of
graft failure than the historic control (6% at 12 months). This is
still higher than in the non-T-cell-depleted group (2%), but
acceptable, given the much lower risk of GVHD. Possibly graft failure
would be reduced still further if larger numbers of stem cells were
infused, as is now possible using peripheral blood harvests. Despite
the improvement in overall engraftment, the speed of engraftment, as
measured by the time to reach 0.5 × 109
neutrophils/L, was significantly slower in the study group compared with either control group (after excluding graft failure). The most
likely explanation for this delay is the comparatively small number of
mononuclear cells infused in the study group, especially because the
greatest delay was observed at the two centers where the smaller
numbers of cells were infused (Table 2). Experimental models have shown
that speed of engraftment is related to total stem cell
dose,36 and this has been confirmed in a recent
multifactorial analysis of the whole CAMPATH users database (G.H. and
S.P. Cobbold, unpublished work). Rapid engraftment has
been reported with CAMPATH-1-treated stem cells from peripheral
blood.37
The relative risk of transplant-related mortality was significantly
lower in the study group compared with the CyA/MTX group (15%
v 26%). This is most likely due to reducing the incidence and
severity of GVHD, although we cannot rule out a benefit due to the
avoidance of toxicity of the immunosuppressive drugs themselves or
consequent infection risks. One of the most important parameters in the
long-term follow-up was the risk of relapse, because it has been shown
that T-cell depletion increases relapse risk substantially for
CML,17,38 and it is suggested that there could be a modest increase in risk for acute leukemias. In contrast, we found no significant difference between the study group (30% risk of relapse at
5 years) and the CyA/MTX group (29%), supporting the concept that the
impact of T-cell-mediated graft-versus-leukemia reactions is minimal
in patients transplanted for acute leukemia in first remission.13 Overall survival was significantly better in
the study group compared with the CyA/MTX group up to 6 months;
subsequent survival and leukemia-free survival were slightly, but not
significantly better.
Prospective randomized studies are often thought to be the gold
standard in evaluating new treatments, but their application in
transplantation is hindered by the relative infrequency of the diseases
treated and the fact that only a minority of patients have suitable
donors. This makes accrual of sufficient patients difficult, if not
impossible. We were primarily interested in measuring differences in
the risk of graft failure, where the expected results were in the range
of 2% to 15%. Hundreds of patients would be required to give an
adequate power. Fortunately, a better alternative is available. Large
clinical databases, such as the one maintained by the IBMTR, contain
data on a large proportion of transplant recipients worldwide with
details of prognostic and treatment factors that allow application of
sophisticated statistical techniques to adjust for differences between
groups and exploit the power of large numbers.39 In the
current study, we identified 459 suitable controls receiving the most
common approach to GVHD prophylaxis against which the combined antibody strategy could be compared. Unlike many prospective randomized trials,
in which significant differences are sometimes attributed to unusually
poor performance of the control group, we can be sure that our CyA/MTX
control group is truly representative. The accuracy of the control data
are confirmed by published results from the European Transplant
Registry on an overlapping set of patients, where the
outcomes are superimposable.40 However, it might be argued
that the three study centers shared some favorable factor in common
other than the treatment protocol. In fact, the three centers were more
remarkable for their diversity in approaches to transplantation.
Furthermore, this idea is negated by the published comparison from one
center (Ulm) of study patients compared with their own CyA/MTX control
group.25 The results are very similar to those presented
here, except of course for the smaller numbers of control patients. The
limitations of our analysis should be recognized, particularly the
difficulty of allowing for possible differences in relapse risk
according to AML subtype, prior therapy, and conditioning regimen, but
we can be confident that the control group is representative of
contemporary clinical practice.
Immune reconstitution was not specifically studied here, but results
for marrow transplants depleted with CAMPATH-1M have been reported
previously.41-43 All of these reports agree that lymphocyte
recovery, particularly of CD4+ cells, is slow compared with
T-replete transplants. There does not appear to be a substantial
long-term mortality as a result of opportunistic infections, but this
requires continued surveillance. Some groups report an early increase
in the frequency of cytomegalovirus (CMV) reactivation,
although this did not necessarily lead to severe clinical
disease.44 The cellular distribution of the CD52 antigen
may be fortuitous in this regard. NK cells are relatively spared by
CAMPATH-1,41,45 and it has been suggested that they may
play a role in control of CMV disease and have an antileukemia effect.46-51 However, B cells are efficiently depleted.
Elsewhere, we have reported that T-cell depletion with CAMPATH-1
antibodies does not give rise to an excess of B-cell
lymphoproliferative disorders, in contrast to some other methods of
T-cell depletion.52 We believe this is because depletion of
donor B cells removes both a potential reservoir of virus and its major
target.
In this trial, CAMPATH-1G was used as a form of monoclonal
antilymphocyte globulin to achieve the additional depletion of recipient lymphocytes required to permit engraftment of
T-cell-depleted bone marrow. The positive outcome is in accord with
animal experiments, confirming that graft failure was caused by
lymphocyte-mediated rejection. The logical development is to use the
IgG antibody CAMPATH-1G (or its humanized equivalent CAMPATH-1H) for
depletion of both donor and recipient T cells, and current trials are
aimed at developing the simplest and most effective way to administer it either in vivo before and after the transplant14,53,54 or as a single dose, mixed and infused with the donor bone
marrow.13,55 This study confirms that T-cell depletion is
the best way to prevent GVHD. Our approach largely avoids graft
rejection and does not result in an increased risk of relapse, at least
in AML patients. The disease-free survival achieved is at least as good
as with conventional regimens, but with the following important
advantages: (1) posttransplant immunosuppression is no longer needed
and (2) almost complete elimination of acute and chronic GVHD should
translate into a substantially better quality of life for the
survivors.
| |
ACKNOWLEDGMENT |
The authors are indebted to many colleagues who played an important
part in the production of antibodies, care of patients, data
collection, and analysis, including Jenny Phillips and the staff of the
Therapeutic Antibody Centre (Cambridge, UK), Marcus Wiesneth, Bernd
Hertenstein, Renate Arnold (Ulm, Germany), Mike Hamon, Ian MacDonald,
Grazyna Galatowicz, Chris Collins (Royal Free, London, UK), Hugh Clink,
Andrew Padmos, Peter Ernst, and Kirtikant Sheth (Riyadh, Saudi Arabia)
as well as the following transplant teams throughout the world who
contributed to the registry data. Australia: Royal Prince
Alfred Hospital, Camperdown; Alfred Hospital, Prahran; Westmead
Hospital, Westmead; Austria: Univ. Klinik fur Innere Medizin I,
Vienna; Belgium: A.Z. Sint-Jan, Brugge; Cliniques
Universitaires Saint-Luc, Brussels; University Hospital Gasthuisberg,
Leuven; University of Liege, Liege; Brazil: Hospital de
Clinicas, Curitiba; Centro Nacional de Transplate de Medula Ossea-CEMO,
Rio de Janeiro; Canada: Ontario Cancer Instute, Princess Margaret Hospital, Toronto; China: Bei Tai Ping Lu Hospital,
Beijing; Croatia: Centar za Transplataciju Kostane Srzi,
Zagreb; Cuba: Institute de Hematologia e Immunologia, Ciudad de
la Havana; Czech Republic: Institute of Hematology and Blood
Transfusion, Praha 2; Finland: Helsinki University Central
Hospital, Helsinki 29; Turku University Central Hospital, Turka 52;
France: CHRU, Angers; Chu Clemenceau, Caen; Hopital A. Michallon, Grenoble; Centre Hospitalier Regional de Lille, Lille;
Institut J. Paoli I. Calmettes, Marseille; Hopital Saint Louis, Paris;
Hopital Saint-Antoine, Paris; Hotel Dieu de Paris, Paris; Groupe
Hospitalier du haut Leveque, Pessac; Hopital Jean Bernard, Poiters;
Center Henri Becquerel (C.R.L.C.C.), Rouen; Hopital de Purpan,
Toulouse; Hopital D'Enfants, Vandoeuvre Les Nancy; Germany:
Universitatsklinikum Rudolf Virchow, Berlin; Zentrum fur Knochenmark
Transplantation, Hamburg; Medizinische Hochschule Hannover, Hannover;
Christian-Albrechts-University, Kiel, Kiel; Universitat Munchen,
Munchen; Ulm University Hospital, Ulm; Hungary: National
Institute of Hematology, Budapest; Ireland: St. James's
Hospital, Dublin; Italy: Spedali Civili-Brescia, Brescia; Ospedale San Martino, Genoa; Centro Trapianti Midollo Osseo via fonte
Romana, Pescara; Ospedale San Camillo, Roma; Ospedale Molinette, Torino; Japan: Chiba University School of Medicine, Chuo-Ku;
Osaka Medical Centre for Cancer & Cardiovascular Diseases, Osaka:
Korea: Catholic University Medical College, Yongdungpo-Gu;
New Zealand: University of Auckland Hospital, Auckland;
Canterbury Health Laboratory, Christchurch-NZ; Russia: Clinical
Hospital Number 6, Moscow; Saudi Arabia: King Faisal Hospital,
Riyadh; Spain: Hospital General Vall d'Hebron, Barcelona;
Hospital Sant Pau, Barcelona; Postgraduate School of Haematology,
Barcelona; Hospital de la Princesa, Madrid; Hospital Puerta de Hierro,
Madrid; Hospital Marques de Valdecilla, Santander; Hospital La Fe,
Valencia; Sweden: Huddinge Hospital, Huddinge; University
Hospital of Lund, Lund; Switzerland: Kantonsspital, Basel;
Kantonsspital Zurich, Zurich; Taiwan: Veteran's General Hospital-Taipei, Taipei; The Netherlands: Leiden University
Hospital, Leiden; Turkey: Ankara University Medical School,
Ankara; United Kingdom: Birmingham Heartlands Hospital,
Birmingham; The Queen Elizabeth Hospital, Birmingham; The Royal
Infirmary of Edinburgh, Edinburgh; Glasgow Royal Infirmary, Glasgow;
St. James University Hospital, Leeds; Royal Infirmary, Leicester;
Imperial College School of Medicine, London; Royal Free Hospital,
London; Royal Marsden Hospital, London; The London Clinic, London;
Westminster Hospital, London; The Royal Victoria Infirmary, Newcastle
Upon Tyne; Nottingham City Hospital, Nottingham; United States:
Egleston Hospital for Children at Emory University, Atlanta, GA;
Roswell Park Cancer Institute, Buffalo, NY; Medical University of South Carolina, Charleston, SC; University of Virginia Charlottesville, Charlottesville, VA; Children's Hospital Medical Center, Cincinnati, OH; De University Medical Centre, Durham, NC; University of Florida, Gainesville, FL; St. Francis Medical Centre, Honolulu, HI; MD Anderson
Cancer Center, Houston, TX; Indiana University Medical Center & Outpatient Center, Indianapolis, IN; University of Kansas Medical
Center, Kansas City, KS; UCLA Center for Health Sciences, Los Angeles,
CA; University of Louisville, Louisville, KY; University of Wisconsin
Hospital & Clinics, Madison, WI; University of Minnesota Hospital & Clinics, Minneapolis, MN; Louisiana State University Medical Center,
New Orleans, LA; University of Oklahoma Health Sciences Center,
Oklahoma City, OK; University of Nebraska Medical Center, Omaha, NE;
St. Joseph's Hospital & Medical Center, Paterson, NJ; Intermountain
Health Care, Inc, LDS Hospital, Salt Lake City, UT; Wilford Hall
Medical Center, San Antonio, TX; Mayo Clinic Scottsdale, Scottsdale,
AZ; George Washington University Medical Center, Washington, DC;
Georgetown University Medical Center, Washington, DC.
| |
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A. G. S. Buggins, G. J. Mufti, J. Salisbury, J. Codd, N. Westwood, M. Arno, K. Fishlock, A. Pagliuca, and S. Devereux
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[Abstract]
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P. Klangsinsirikul, G. I. Carter, J. L. Byrne, G. Hale, and N. H. Russell
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V. T. Ho and R. J. Soiffer
The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation
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Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease
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[Abstract]
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H. Matsue, K. Matsue, M. Kusuhara, T. Kumamoto, K. Okumura, H. Yagita, and A. Takashima
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Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I-II study
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[Abstract]
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N. Rufer, T. H. Brummendorf, B. Chapuis, C. Helg, P. M. Lansdorp, and E. Roosnek
Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation
Blood,
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[Abstract]
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N. A. Marshall, J. G. Howe, R. Formica, D. Krause, J. E. Wagner, N. Berliner, J. Crouch, I. Pilip, D. Cooper, B. R. Blazar, et al.
Rapid reconstitution of Epstein-Barr virus-specific T lymphocytes following allogeneic stem cell transplantation
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[Abstract]
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E. Roux, F. Dumont-Girard, M. Starobinski, C.-A. Siegrist, C. Helg, B. Chapuis, and E. Roosnek
Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity
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[Abstract]
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Anthracyclines Trigger Apoptosis of Both G0-G1 and Cycling Peripheral Blood Lymphocytes and Induce Massive Deletion of Mature T and B Cells
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Children With Acute Lymphoblastic Leukemia Who Receive T-Cell-Depleted HLA Mismatched Marrow Allografts From Unrelated Donors Have an Increased Incidence of Primary Graft Failure but a Similar Overall Transplant Outcome
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[Abstract]
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Top
Abstract
Introduction
