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Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2240-2245
CLINICALOBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Increased transplant-related morbidity and mortality in
CMV-seropositive patients despite highly effective prevention of CMV
disease after allogeneic T-cell-depleted stem cell transplantation
Annoek E. C. Broers,
Ron van der Holt,
Joost
W. J. van Esser,
Jan-Willem Gratama,
Sonja Henzen-Logmans,
Vibeke Kuenen-Boumeester,
Bob Löwenberg, and
Jan J. Cornelissen
From the Department of Hematology, Department of Statistics,
Department of Immunology, and Department of Pathology, University
Hospital Rotterdam/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
 |
Abstract |
We evaluated the efficacy, toxicity, and outcome of preemptive
ganciclovir (GCV) therapy in 80 cytomegalovirus (CMV)-seropositive patients allografted between 1991 and 1996 and compared their outcome
to 35 seronegative patients allografted during the same period. Both
cohorts were comparable with respect to diagnosis and distribution of
high- versus standard-risk patients. All patients received a stem cell
graft from an HLA-identical sibling donor, and grafts were partially
depleted of T cells in 109 patients. Patients were monitored for CMV
antigenemia by leukocyte expression of the CMV-pp65 antigen. Fifty-two
periods of CMV reactivation occurring in 30 patients were treated
preemptively with GCV. A favorable response was observed in 48 of 50 periods, and only 2 patients developed CMV disease: 1 with esophagitis
and 1 with pneumonia. Ten of 30 treated patients developed GCV-related
neutropenia (less than 0.5 × 109/L),
which was associated with a high bilirubin at the start of GCV therapy.
Overall survival at 5 years was 64% in the CMV-seronegative cohort and
40% in the CMV-seropositive cohort (P = .01). Increased treatment-related mortality accounted for inferior survival. CMV seropositivity proved an independent risk factor for developing acute
graft-versus-host disease, and acute graft-versus-host disease predicted for higher treatment-related mortality and worse overall survival in a time-dependent analysis. We conclude that, although CMV
disease can effectively be prevented by preemptive GCV therapy, CMV
seropositivity remains a strong adverse risk factor for survival following partial T-cell-depleted allogeneic stem cell transplantation.
(Blood. 2000;95:2240-2245)
© 2000 by The American Society of Hematology.
 |
Introduction |
Cytomegalovirus (CMV) infection is an important cause
of morbidity and mortality in recipients of allogeneic stem cell
transplantation (SCT).1,2 CMV can cause primary infections
or may be reactivated in CMV-seropositive recipients and
CMV-seronegative recipients receiving a graft from a seropositive
donor.3 If untreated, CMV pneumonia may develop in up to
50% of bone marrow transplant (BMT) recipients showing virus
reactivation.1 The mortality of CMV pneumonia has remained
high despite the use of CMV-specific immunoglobulins and potent
antiviral agents such as ganciclovir (GCV).4-6 Therefore,
preventive measures are considered of utmost importance and have
received a great deal of interest. It has been shown that prophylaxis
with GCV effectively prevents CMV disease following allogeneic
transplantation.7-9 However, GCV prophylaxis administered
for a prolonged period after BMT has been complicated by severe
neutropenia, which itself is associated with an increased risk of
opportunistic infections and enhanced treatment-related mortality
(TRM).7-9 Alternatively, GCV may also be administered as
preemptive therapy based on the identification of CMV in blood or
bronchoalveolar lavage (BAL). Randomized and retrospective studies have
shown a significant reduction of CMV disease and enhanced survival in
CMV-seropositive donor-recipient pairs receiving GCV as preemptive
therapy while avoiding severe neutropenia.10-16 However, it
is still unclear how the outcome of HLA-matched sibling BMT in
CMV-seropositive patients receiving GCV preemptively compares to the
outcome of BMT in seronegative patients.
We set out to evaluate the efficacy, toxicity, and possible risk
factors of the preemptive use of GCV in CMV-seropositive patients,
initiated at first evidence of CMV antigenemia. Furthermore, survival,
TRM, and incidence of graft-versus-host disease (GVHD) in the
CMV-seropositive cohort were evaluated and compared to a cohort of
CMV-seronegative patients with a seronegative donor allografted during
the same period. The aim was to determine whether and how prior CMV
disease affects transplant outcome if GCV is used as preemptive therapy.
 |
Patients and methods |
A total of 115 consecutive patients, who received an HLA-identical
sibling hemopoietic SCT at the Daniel den Hoed Cancer Center in
Rotterdam between 1991 and 1996, were included in the study. Two groups
of patients were defined: a group of 35 patients who were
CMV-seronegative before transplantation and received a graft from a
CMV-seronegative donor, hereafter designated as "CMV-seronegative patients," and a group of 80 patients in which either the
donor or the patient or both were CMV-seropositive (Table
1), hereafter designated as
"CMV-seropositive patients."
Patients who received a graft from an unrelated or mismatched related
donor were not included in the analysis. Patients were considered
"standard risk" in case of a diagnosis of acute myelogenous leukemia in first complete remission, acute lymphoblastic leukemia in
first complete remission, chronic myeloid leukemia in first chronic
phase, or untreated aplastic anemia. All other diagnoses were
considered high risk.
Transplantation
The conditioning regimen consisted of cyclophosphamide (Cy) (120 mg/kg of body weight) and total-body irradiation (6 Gy on each of 2 successive days with partial shielding of the lungs, for a
total lung dose of 2 × 4.5 Gy). Alternatively, if patients had
received locoregional irradiation before, the conditioning regimen
consisted of oral busulfan (4 mg/kg of body weight on each of 4 successive days) and Cy (120 mg/kg of body weight) (Table 1). Partial
T-cell depletion (TCD) was performed by sheep erythrocyte rosetting in
standard-risk patients, and few high-risk patients (n = 6) received
an unmodified graft. All patients received additional GVHD prophylaxis
with cyclosporine (3 mg/kg of body weight) from 3 days until 100 days after BMT. Cyclosporine was combined with methotrexate (15 mg/m2 on day 1; 10 mg/m2 on days 3, 6, and 11)
in case of an unmanipulated graft. The source of hematopoietic stem
cells was bone marrow in 105 patients and peripheral blood stem cells
in 10 patients. The institutional review board approved the protocols,
and patients provided informed consent. Graft characteristics are
presented in Table 1. Acute GVHD was graded according to the Glucksberg
criteria. Patients were considered evaluable for GVHD if they showed
neutrophil recovery and survival beyond day 21. Patients with grades
2-4 GVHD were treated with prednisone, 1 mg/kg of body weight twice
daily for 7 to 10 days, which was then tapered according to clinical
response. Grade 1 GVHD was treated with topical steroids. Patients were considered evaluable for chronic GVHD if they engrafted and survived beyond day 100. Chronic GVHD was treated with the combination of
cyclosporine and prednisone according to clinical response.
Supportive care
Erythrocyte and platelet blood products for transfusion were
filtered to remove leukocytes and subsequently irradiated (25 Gy). All
patients who were herpes simplex-seropositive before transplantation
received acyclovir (200 mg, 4 times a day) until discharge.
Furthermore, infection prophylaxis consisted of oral ciprofloxacin (500 mg, twice daily), oral itraconazole (200 mg, twice daily), and
intravenous penicillin during the first 14 days after BMT. Itraconazole
was continued until day 90 after BMT. Prophylaxis for encapsulated
bacteria and Pneumocystis carinii was prescribed for up to 6 months after BMT and consisted of cotrimoxazole (480 mg, once daily),
which was initiated after neutrophil recovery (> 0.5 × 109/L) and cessation of
ciprofloxacin. Patients were hospitalized in (reverse) isolation and
rooms with high-efficiency particulate air-filtered air. All patients
received food with a low microbial count until discharge, and
parenteral alimentation was given in case of severe mucositis.
Diagnostic tests for CMV reactivation and CMV disease
The presence of CMV lower matrix protein pp65-positive leukocytes in
peripheral blood or BAL fluid was analyzed as
described.17,18 In short, cytospin preparations were
prepared and incubated with pp65-specific monoclonal antibodies: 1 slide with clone 1C3/A-YM-1 (Biogenesis, Bournemouth, UK) and another
slide with clone C10/C11 (Biotest, Seralco, Brussels, Belgium). In
addition, 1 cytospin slide was used as a negative control, and slides
with CMV-infected granulocytes served as positive controls. Staining
was performed using the alkaline phosphatase-antialkaline
phosphatase method (dilution 1:50; Serotec, Oxford, UK).
CMV disease was diagnosed on the basis of an inflammatory process due
to CMV, confirmed either by the immediate early antigen
(IEA) assay or CMV cultures, and preferably combined with the presence
of typical cytopathic effects in histologic preparations if biopsies
were available. All biopsies or leukocytes obtained by BAL were
cultured for CMV for 14 days. Histologic examination of tissue biopsies
included immunohistochemical analysis for CMV using pp65-specific
monoclonal antibody clone 1C3 (Biogenesis). Pneumonia was classified as
idiopathic when (multiple) biopsies of lung tissue showed interstitial
inflammation but without any positive indication of viral, bacterial,
parasitic, or fungal causes upon specific culture and
immunohistochemical analysis.
Ganciclovir therapy
CMV-seropositive patients were monitored weekly from transplantation
until day 150 for CMV antigenemia. Test results were considered
positive in case of at least 1 positively staining leukocyte. Patients
with a positive antigenemia test were monitored twice weekly.
Preemptive GCV therapy was initiated (5 mg/kg of body weight
intravenously, twice daily) if 4 or more positive leukocytes were identified by the IEA assay. Treatment was
discontinued after 2 successive negative test results, which was
considered a favorable response, if no CMV disease had developed during
that time. That specific protocol of preemptive therapy was chosen to
avoid GCV treatment in patients with low-grade antigenemia, who may
resolve their antigenemia spontaneously, and to avoid GCV treatment in
false-positive antigenemia and thereby prevent GCV-associated
neutropenia while preserving effective prevention of CMV disease.
CMV disease (eg, pneumonitis and esophagitis) was treated with a
combination of GCV- and CMV-specific immunoglobulins.5 Neutropenia associated with GCV therapy was defined by a neutrophil count of less than 0.5 × 109/L,
appearing during or shortly (less than 10 days) after GCV therapy, in
patients with a neutrophil count of at least
1.0 × 109/L and with no other apparent
cause of neutropenia.
Statistical analysis
Patients were analyzed for response of CMV reactivation to GCV
treatment. Patient characteristics in the 2 cohorts were compared using
Pearson's 2 test or the Wilcoxon rank sum test,
whichever was appropriate. All reported P values are 2-sided,
and a significance level of = .05 was used. Overall survival was
measured from transplantation until death from any cause. Patients
still alive at the time of analysis were censored at the last follow-up
date. TRM was determined from the date of transplantation until death
related to the transplantation. Patients who died from other causes
were censored at the date of death. Time to acute GVHD grades 2-4 was
calculated from date of transplantation until occurrence of acute GVHD.
Patients who died before day 100 posttransplant without having suffered
from acute GVHD were censored at the date of death. Patients without GVHD and still alive at day 100 were then censored. Time to acute GVHD
grades 2-4, overall survival, and TRM were estimated by the Kaplan-Meier method. The following variables were included in the
analysis of prognostic factors: sex, age, risk status, CMV serostatus
of the patient/donor (both negative vs at least 1 positive), and graft
characteristics (number of nucleated cells, CFU-GM
[granulocyte-macrophage colony-forming units] and CD3+ T
cells infused). Univariate survival analysis was performed using the
log-rank test to see whether there was a difference in survival between
the subgroups, and univariate Cox regression was used to determine
whether the relation was monotonous. The variables that appeared
significant in the univariate Cox regression were also used in a
multivariate Cox regression. Moreover, a Cox regression analysis, with
occurrence of acute GVHD grades 2-4 included as a time-dependent
covariate, was performed to examine whether acute GVHD predicted for
higher TRM and worse overall survival.
 |
Results |
A total of 115 consecutive HLA-identical sibling BMTs were
evaluated. Patient characteristics are presented in Table 1. Two cohorts of patients are presented: a CMV-seronegative cohort and a
seropositive (donor, recipient, or both) cohort. Thirty-five patients
and their donors were CMV-seronegative. Eighty recipient-donor pairs
were CMV-seropositive (the so-called "CMV-seropositive
patients"), including 68 seropositive recipients and 51 seropositive
donors. In 39 cases, both donor and recipient were seropositive.
High-risk patients were distributed equally among the CMV-seronegative
and CMV-seropositive cohorts, and diagnoses did also not differ between the 2 cohorts. The median age of the CMV-seropositive cohort was 43 years and exceeded that of the seronegative cohort, which was 37 years
(P = .02). Median numbers of mononuclear cells, CFU-GM, and T
cells infused did not differ between the CMV-seronegative and
CMV-seropositive cohort. Partial TCD of the graft was applied in 109 patients, and 6 patients received an unmanipulated graft because these
patients suffered from high-risk disease and were considered to be at
high risk for relapse. Alternatively, they received cyclosporine and
methotrexate for prevention of GVHD.
Ganciclovir treatment
A total of 47 patients developed CMV antigenemia as defined by at
least 1 pp65-positive peripheral blood leukocyte. Thirty of these
patients showed an increase in the number of positive leukocytes up to
4 or more positive leukocytes, which was the threshold for
initiating GCV treatment. Fifty-two periods of CMV antigenemia
occurring in these 30 patients were treated with GCV. Two of these 30 patients were CMV-seronegative before transplantation but received a
graft from a seropositive donor. Seventeen patients developed so-called
low-grade antigenemia their IEA test results showed less than 4 positive leukocytes and, by protocol, these patients were
not treated with GCV. None of them developed CMV disease.
CMV-seropositive patients with versus without CMV antigenemia did not
differ with respect to their graft characteristics (mononuclear cells,
CFU-GM, T cells), age, sex, underlying disease, or risk status (results
not shown). Results of the 30 patients treated with GCV are presented
in Table 2. Two patients died before the effects of GCV could be evaluated. The median duration of GCV treatment
was 10 days (range, 2-38 days). A favorable response (2 consecutive
negative antigenemia test results and no signs of CMV disease) was
observed in 48 of 50 (96%) evaluable treatment courses. One patient
developed a CMV pneumonia that was lethal, and another patient
developed a CMV esophagitis necessitating the addition of CMV-specific
immunoglobulins combined with a prolonged course of GCV therapy.
Recurrence of CMV antigenemia was observed 22 times in 12 patients.
These recurring episodes of antigenemia all responded favorably to a
second, third, fourth, or fifth course of GCV. In addition
to the 2 aforementioned patients with CMV pneumonia and esophagitis, 1 other patient developed a CMV pneumonia, which was not preceded by
peripheral blood CMV antigenemia. No CMV disease was observed after day
100.
Ten patients developed GCV-related neutropenia (neutrophils less than
0.5 × 109/L). The median number of
neutropenic days was 10 (range, 2-36), and the median nadir was
0.255 × 109/L neutrophils (range, less
than 5-450). Opportunistic infections during these periods of
neutropenia were observed in 7 cases, including 1 case of lethal sepsis
and pneumonia caused by Pseudomonas aeruginosa. Several risk
factors were evaluated for their possible contributory role to
GCV-related neutropenia. Graft characteristics were not associated with
neutropenia. An elevated bilirubin level, but not impaired kidney
function, at the onset of GCV therapy strongly correlated with the
appearance of GCV-related neutropenia (P = .03).
Survival, TRM, and GVHD
Overall survival of these 115 patients was 64% ± 4% at 1 year and 47% ± 5% at 5 years posttransplant. The
median follow-up for patients still alive was 43 months
(range, 9-95 months). Survival was not significantly affected by
diagnosis, risk status, sex, and graft characteristics (such as numbers
of CFU-GM, T cells, and mononuclear cells infused). In univariate
analysis, both positive CMV serology (of donor or recipient) and older
age predicted for inferior survival. However, only CMV serology
significantly affected survival (P = .03) in multivariate Cox
regression analysis. The seropositive cohort included also 12 "-/+" patients those who were seronegative before SCT but
received a graft from a positive donor. Overall survival was
45% ± 9% in these 12 patients at 36 months after SCT, which did
not differ from 39 +/+ patients and 29 +/- patients, who completed the
CMV-seropositive cohort (Table 1). In contrast, overall survival was
70% ± 8% in the seronegative group at 36 months after SCT
(Figure 1).

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| Fig 1.
Overall survival from transplantation in CMV-seronegative
patients (n = 35) versus CMV-seropositive patients (donor or
recipient CMV-seropositive) (n = 80).
Median follow-up was 43 months. The survival difference was significant
(P = .01) by log-rank analysis.
|
|
Excess mortality in the CMV-seropositive cohort (Figure 1) was not due
to relapse but appeared to be due to increased TRM. The variables age,
CMV serology, diagnosis, risk status, sex, and graft characteristic
were also evaluated for a possible association with TRM. Of these, only
positive CMV serology significantly predicted for increased TRM
(P = .03). TRM was 35% ± 5% for all 115 patients at 5 years posttransplant and 18% ± 7% versus 42% ± 6%,
respectively, for CMV-seronegative and CMV-seropositive patients
(Figure 2) (P = .03). In
contrast, these figures were 30% ± 6% and 40% ± 8% for
younger and older patients, which was not statistically significant
(P = .5). We also evaluated whether CMV antigenemia would
quantitatively predict for increased TRM. The median number of
IEA-positive leukocytes was 10 (range, 4-130). A trend
toward a higher TRM was observed for patients with more than 10 positive leukocytes as compared to patients below that
median number: TRM was 46% ± 14% versus 29% ± 12%,
respectively, which was not significant. In addition, when evaluated as
a continuous variable, the IEA number yielded a hazard ratio of more
than 1 but remained not significant. Specific causes of death are
presented in Table 3. Excess mortality in
the CMV-seropositive cohort included pneumonia/adult respiratory
distress syndrome (n = 12), idiopathic pneumonitis (n = 9), GVHD
(n = 3), and CMV (n = 2). All patients with lethal idiopathic pneumonitis were evaluated by BAL and subsequent IEA analysis as well as viral cultures. Test results were CMV-negative in 8 and confirmed by further histologic evaluation of biopsies in 7 of
these 8 patients. One patient with peripheral blood CMV antigenemia
showed IEA-positive leukocytes in her BAL. A diagnosis of CMV pneumonia
was, however, rejected, because cultures as well as IEA staining of an
open lung biopsy (performed 2 days later) were found negative and
histology did not show the typical histologic features associated
with CMV. Apart from these 9 lethal cases of idiopathic pneumonitis, 6 other patients also developed pneumonitis, which was considered
idiopathic after thorough evaluation. Corticosteroid treatment
resulted in a favorable response in all of them.

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| Fig 2.
Probabilities of developing transplant-related
mortality in CMV-seropositive patients (n = 80)
versus CMV-seronegative patients (n = 35).
P = .03 by log-rank analysis.
|
|
The actuarial probability of developing acute GVHD grades 2-4 was
33% ± 4% by 100 days posttransplant. A higher incidence of
acute GVHD grades 2-4 was observed in CMV-seropositive patients (42%
versus 14%, P = .01; Figure 3).
Again, several risk factors were evaluated for a possible association
with the probability of developing acute GVHD. Both univariate and
multivariate analysis showed that positive CMV serology remained an
independent risk factor (Figure 3). In addition, the number of
CD3+ T cells in the graft was also associated with
increased acute GVHD grades 2-4 (P = .01). Following the
observation of more GVHD and enhanced TRM in CMV-seropositive patients,
we subsequently analyzed whether patients suffering from acute GVHD
would develop an increased risk for TRM and reduced overall survival.
Cox regression analysis was performed using acute GVHD grades 2-4 as a
time-dependent covariate and TRM and overall survival as endpoints.
Hazard ratios for overall survival and TRM were 2.0 (95% confidence
interval [CI], 1.2-3.4; P = .01) and 2.5 (95% CI, 1.3-4.8;
P = .007), respectively, which remained significant in
multivariate analyses. Fifteen patients developed limited chronic GVHD,
and 9 patients were treated for extensive chronic GVHD. The probability
of developing limited or extensive chronic GVHD was 23% ± 8% at
12 months after SCT in CMV-seronegative patients and 27% ± 6%
in the seropositive group; the difference appeared
insignificant.

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| Fig 3.
Time to acute GVHD grades 2-4 in CMV-seropositive
patients (n = 80) versus CMV-seronegative patients (n = 35)
calculated from date of transplantation expressed by Kaplan-Meier
curves.
P = .01 by log-rank analysis.
|
|
 |
Discussion |
In this study, we show that CMV seropositivity continues to
represent a major adverse risk factor for transplant-related morbidity and mortality despite the very efficient prevention of CMV disease by
preemptive GCV therapy in patients receiving a partial TCD graft.
Increased TRM accounted for inferior survival observed in
CMV-seropositive patients versus CMV-seronegative patients. Furthermore, an increased incidence of acute GVHD was observed in
CMV-seropositive patients, and the development of acute GVHD strongly
predicted for TRM and overall survival. Thus, CMV disease prior to
transplantation does not affect transplantation outcome by CMV disease
itself but, rather, by increasing the incidence of acute GVHD.
Prerequisites for preemptive therapy are sensitive and specific methods
for early diagnosis, such as the CMV antigenemia test, as well as the
ability to identify patients at risk. Several risk factors have been
identified, including pretransplant serostatus, GVHD, and TCD of the
graft.1,2,14-16 The CMV-seropositive patients presented in
our study can be considered at high risk for CMV disease because of
these risk factors and the relative high percentage of older patients
with advanced disease. Our CMV-seropositive donor-recipient pairs were
monitored weekly for CMV antigenemia, which permitted an early
detection and early institution of GCV treatment. The approach resulted
in an almost complete prevention of CMV disease in this cohort of
patients who were at high risk for CMV infection and disease. Our
results compare well to earlier findings with respect to prevention of
CMV disease by preemptive GCV.9-16
GCV may effectively prevent CMV disease if given prophylactically or as
preemptive therapy.7-16 Preemptive therapy for a short time
is to be preferred because continued GCV prophylaxis is frequently associated with neutropenia and opportunistic infections, which then
may offset the beneficial effects of GCV.7-9 Our approach of a limited course of preemptive therapy did not prevent the occurrence of GCV-associated neutropenia. Ten of 30 patients receiving 1 or more cycles of GCV therapy developed severe neutropenia, which was
complicated by opportunistic infections in 7 patients. The probability
of developing neutropenia did not correlate with renal function, low
graft cellularity, or numbers of CFU-GM in the graft. However,
hyperbilirubinemia at the start of GCV therapy was significantly
associated with neutropenia, which compares well to findings recently
reported by Salzberger et al.19
Studies evaluating preemptive GCV therapy in HLA-identical sibling BMT
also suggested that TRM in CMV-seropositive patients can be reduced to
what can be achieved in CMV-seronegative patients, although no formal
comparison has been reported so far. Our results indicate that survival
remains inferior in these patients as compared to transplants in
seronegative pairs. Reduced survival was predominantly due to increased
infectious mortality, which was not caused by CMV itself (Table 3).
Relapse mortality was not different among the 2 cohorts of patients,
but TRM accounted for the observed survival difference. GCV-associated
neutropenia contributed to TRM, but the latter effect did not explain
the difference of survival among seropositive and seronegative patients.
If not by CMV disease itself, nor by the adverse effects of the drug
needed for prevention, how does CMV affect transplant outcome so
strongly? Increased susceptibility for opportunistic infections and
subsequent TRM may come from an enhanced incidence of GVHD. We observed
a significantly higher incidence of acute GVHD in CMV-seropositive
patients, which could not be explained by other risk factors, such as
age, risk status, or number of T cells in the graft. How do CMV and
GVHD relate? Established GVHD is immunosuppressive itself, and the
immunosuppressive drugs needed to treat GVHD add even more suppression.
Conversely, CMV may also play a role in the development of GVHD.
Several studies have shown an association between pretransplant
seropositivity and the probability of developing GVHD after
transplantation.20-25 Experimentally, murine CMV infection
enhanced the ability of parental spleen cells to induce
GVHD.26 In addition, latent human CMV can be detected in
most organs, including the liver, the spleen, and the
endothelium.27 CMV-infected endothelial cells have been shown to produce inflammatory cytokines such as interleukin-6, resulting in leukocyte adhesion, which may play a role in the initial
phases of initiating a graft-versus-host reaction.28 Lichtman et al have shown that interleukins such as interleukin-1, tumor necrosis factor, and interleukin-6 play a pivotal role in the
initial phase of T-cell activation before T cells are specifically activated by recipient allo-antigens.29 The inflammatory
response evoked by CMV in recipient endothelium could thereby
contribute to the initiation of GVHD. We evaluated whether the
appearance of acute GVHD would predict for enhanced TRM by using GVHD
as a time-dependent covariate in a Cox regression analysis. It was shown that development of acute GVHD at that time significantly increased the risk for both higher TRM and reduced overall survival. These findings indicate that the adverse effects of CMV seropositivity are mediated via an enhanced incidence of acute GVHD and subsequent increased TRM.
Our results were observed in patients receiving a stem cell graft that
was partially depleted of T cells. That particular mode of graft
manipulation may, on one hand, reduce the ability to mount an immune
response toward CMV and, on the other hand, may still be associated
with acute GVHD, which may contribute to TRM in CMV-seropositive
patients. Most of our patients received more than 105 CD3 T
cells per kilogram of body weight, which seems to be the threshold for
acute GVHD.30 The incidence of chronic GVHD was, however,
significantly less compared with unmanipulated SCT, and no late CMV
disease was observed, which may be one of the opportunistic infections
associated with chronic GVHD. It remains to be established whether the
reduction of chronic GVHD outweighs an adverse effect on TRM in
CMV-seropositive patients who receive a stem cell graft that is
partially depleted of T cells. Preferably, a comparative study should
answer that question.
In conclusion, CMV serostatus before HLA-matched allogeneic TCD sibling
SCT remains an independent adverse risk factor despite efficacious
prevention of CMV disease by preemptive GCV therapy. Additional
approaches are needed to prevent CMV reactivation and antigenemia
following allogeneic TCD sibling SCT. First, GCV prophylaxis instead of
preemptive therapy may more effectively control CMV infection. Second,
apart from prolonged high-dose acyclovir,9,31 new antiviral
drugs such as cidofovir and benzimidavir might prove to inhibit the
virus more potently.32 Third, adoptive CMV-specific immunotherapy might prove beneficial in CMV-seropositive
patients.33-35 Reconstitution of CD8 CMV-specific T cells
have been shown to be decisive for control of CMV after
BMT.36 Supplementation of such T cells after
transplantation, especially in the setting of TCD transplantation,
should be further explored for control of CMV reactivation and its
associated complications.
 |
Footnotes |
Submitted May 21, 1999; accepted December 1, 1999.
Reprints: J.J. Cornelissen, Daniel den Hoed Cancer Center,
Department of Hematology, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
 |
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