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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Donor CMV serologic status and outcome of CMV-seropositive recipients after
unrelated donor stem cell transplantation: an EBMT megafile analysis
Per Ljungman, Ronald Brand, Hermann Einsele, Francesco Frassoni, Dietger Niederwieser, and Catherine Cordonnier
Cytomegalovirus (CMV) has been a major
cause of morbidity and mortality after
allogeneic stem cell transplantation (SCT).
The importance of the recipient’s serologic status is paramount. However, the
importance of the donor’s serologic status in CMV-seropositive recipients is controversial. We analyzed the influence of
the donor’s CMV status in a large cohort
of patients. A total of 7018 patients seropositive for CMV reported to the European Group for Blood and Marrow Transplantation (EBMT) were included; 5910
patients had undergone HLA-identical sibling SCT and 1108 patients had undergone unrelated donor SCT. Univariate and
multivariate proportional hazards models
were constructed for survival, event-free
survival, transplant-related mortality, and
relapse incidence. Patients receiving
grafts from CMV-seropositive HLA-identical sibling donors had the same survival
as patients grafted from seronegative donors (hazard ratio [HR], 1.04; P ⴝ .37;
95% confidence interval [CI], 0.95-1.14).
However, unrelated donor stem cell (SC)
transplant recipients receiving grafts from
CMV-seropositive donors had an improved 5-year survival (35% versus 27%;
HR ⴝ 0.8; P ⴝ .006), an improved eventfree survival (30% versus 22%; HR ⴝ 0.8;
P ⴝ .01), and a reduced transplant-related mortality (49% versus 62%;
HR ⴝ 0.7; P < .001). There was no influ-
ence on the relapse incidence. The effects of donor CMV status remained in
multivariate analyses. The effect of donor
status was different among different disease categories. In patients with chronic
myelogenous leukemia (CML), T-cell
depletion abrogated the beneficial effect
of donor status, suggesting that the effect is mediated through transfer of donor
immunity. Our data suggest that donor
CMV status influences outcome of unrelated SCT. For a CMV-seropositive patient, a seropositive donor might be preferable. (Blood. 2003;102:4255-4260)
© 2003 by The American Society of Hematology
Introduction
Cytomegalovirus (CMV) has for many years been an important
cause of morbidity and mortality after allogeneic hematopoietic
stem cell transplantation (SCT). There have been major advances
in antiviral prophylactic strategies1-3 and development of new and
more sensitive diagnostic techniques that allow better monitoring
of patients and early intervention by antiviral therapy.4-6 These
advances have reduced the risk of CMV as a direct cause of
mortality in HLA-identical sibling transplant recipients, although it
is still substantial in patients receiving transplants from HLAmismatched or unrelated donors. However, the patient’s CMV
serologic status still has a strong influence on outcome.7 The
influence of the donor’s serologic status on outcome of transplantation of a CMV-seropositive patient has been controversial.8,9
The aim of this analysis was, therefore, to analyze the influence
of donor seropositivity on outcome of allogeneic stem cell transplantation in a large population of CMV-seropositive patients.
Patients and methods
Patients
The European Group for Blood and Marrow Transplantation (EBMT) has
collected data on patients since the 1970s. Patients were selected from the
From the Department of Hematology, Huddinge University Hospital,
Stockholm, Sweden; Department of Medical Statistics, Leiden University
Medical Centre, Leiden, The Netherlands; Department of Medicine, University
Hospital, Tübingen, Germany; Department of Hematology, Ospedale San
Martino, Genova, Italy; Department of Haematology/Oncology, University of
Leipzig, Germany; and Department of Hematology, Hôpital Henri Mondor,
Creteil, France.
Submitted November 1, 2002; accepted June 27, 2003. Prepublished online as
Blood First Edition Paper, August 21, 2003; DOI 10.1182/blood-2002-10-3263.
BLOOD, 15 DECEMBER 2003 䡠 VOLUME 102, NUMBER 13
EBMT megafile, who were seropositive for CMV and for whom the donor
CMV status was known (n ⫽ 7895). Syngeneic (n ⫽ 87) and non–HLAidentical family donor transplantations (n ⫽ 627) were excluded as were 50
patients for whom the donor type was unknown, incorrectly coded, or coded
as multiple donor. Thus, 7018 patients were included in the study; 5910
patients had HLA-identical sibling donors and 1108 had unrelated donors.
Patient characteristics of the study population are shown in Tables 1 and 2.
Statistics
These data were analyzed by univariate and multivariate proportional
hazards models. In all cases the proportionality assumption was verified for
the final models. All stepwise model fitting procedures were carried out
with a backward approach. Main effects with a log-rank (LR) test P greater
than .05, and interaction terms with a LR test P greater than .10 were
removed from the models except for the main effects (interaction terms,
respectively) under study. Models were chosen with the specific goal of
confirming or rejecting a plausible biologic mechanism and enhancing an
understanding of the data. Hence the explicit incorporation of the main
factors “donor CMV serologic status” and, when appropriate, the main term
“T-cell depletion” as well as the interaction term “donor CMV serologic
status”*“T-cell depletion.” “Age,” “calendar year of transplantation,”
“donor sex,” “stage,” and “mismatch” were used to minimize their
confounding effects on the risk factors under study. Stage in acute leukemia
was defined as “CR1 (first complete remission) or CR2” versus “other” and
Supported by the Swedish Cancer Society.
Reprints: Per Ljungman, Department of Hematology, Huddinge University
Hospital, SE-14186 Stockholm, Sweden; e-mail: [email protected].
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.
© 2003 by The American Society of Hematology
4255
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4256
BLOOD, 15 DECEMBER 2003 䡠 VOLUME 102, NUMBER 13
LJUNGMAN et al
Table 1. Patient characteristics of HLA-identical sibling
transplantations (n ⴝ 5905)
Characteristic
Donor CMVseropositive (%)
N ⴝ 4451
Donor CMVseronegative (%)
N ⴝ 1454
Year of transplantation
Table 2. Patient characteristics of unrelated donor
transplantations (n ⴝ 1108)
P*
.41
Characteristic
Donor CMVseropositive (%)
N ⴝ 566
Donor CMVseronegative (%)
N ⴝ 542
Year of transplantation
1992 or before
1697 (38.1)
581 (40.0)
1992 and before
61 (10.8)
54 (10.0)
1993-1996
1506 (33.8)
468 (32.2)
1993-1996
208 (36.7)
204 (37.6)
1997 and after
1248 (28.1)
405 (27.8)
1997 and after
297 (52.5)
284 (52.4)
32 (14)
30 (14)
26 (15)
27 (15)
Male
310 (54.8)
308 (56.8)
Female
256 (45.2)
234 (43.2)
494 (87.3)
445 (82.1)
Peripheral blood
35 (6.2)
45 (8.3)
Other
37 (6.5)
52 (9.6)
Age, y
Patient sex
.31
Male
2536 (57.0)
805 (55.4)
Female
1915 (43.0)
649 (44.6)
⬍.01
Stem cell source
Bone marrow
⬍.01
3562 (80.0)
1185 (81.5)
Peripheral blood
731 (16.4)
187 (12.9)
Other
158 (3.6)
82 (5.6)
Patient sex
.05
Diagnosis
.21
Acute leukemia
2207 (49.6)
803 (55.2)
Acute leukemia
261 (46.1)
268 (49.4)
CML
1135 (25.5)
203 (14.0)
CML
183 (32.3)
149 (27.5)
Other
1109 (24.9)
398 (27.4)
Other
122 (22.6)
125 (33.1)
Early stage
271 (66.4)
241 (61.8)
Advanced stage
137 (33.6)
149 (38.2)
474 (83.7)
433 (79.9)
92 (16.3)
109 (21.1)
148 (26.2)
147 (27.1)
Stage
Early stage
Advanced stage
.44
2479 (77.7)
789 (78.9)
710 (23.3)
211 (21.1)
T-cell depletion and
T-cell depletion
ATG
Stage
.17
HLA A, B, DR␤1
⬍.01
ATG
721 (16.2)
214 (14.7)
48 (1.0)
10 (0.7)
Neither
2470 (55.5)
940 (64.6)
Missing data
1212 (27.3)
290 (20.0)
Early stage indicates first complete remission, second complete remission, or
first chronic stage.
*Chi-square test is used for categorical variables; if ordered, a trend version was
used; t test was used for continuous variables.
in CML as “CP1 (chronic phase 1)” versus “other.” To verify whether the effect
of CMV donor seropositivity has itself changed over the years, we added an
interaction term “calendar year”*“donor CMV serologic status” to all models.
Separate models were constructed for patients who received transplants
for acute leukemia (acute myeloid leukemia [AML], acute lymphoblastic
leukemia [ALL]; n ⫽ 529), chronic myelogenous leukemia (CML; n ⫽ 332),
and other diseases (n ⫽ 247). This construction was due to the finding that
the effect of donor CMV serologic status differed so that inclusion of the
disease category in the models would have resulted in a violation of the
proportional hazard assumption.
Information regarding donor age was available for only 457 patients.
Because in many of the patients the donor age was not known, a yes/no variable
was created, indicating whether or not donor age was known in a patient. For all
outcomes this variable was added to the Cox models evaluated. A confounding
effect by selection bias is assessed by comparing the hazard ratio (HR) of donor
CMV serologic status and other risk factors before and after adjustment for this
dichotomous variable. Each model was fitted once more using the actual donor
age on the subset of patients with a known donor age.
The causes of death in the EBMT database are coded as multiple
response variables, allowing analysis of more than one contributing causes
of death. For this study, the contributing causes of death were combined into
viral causes, other infectious causes, and noninfectious causes of death,
leading to a 3-group classification. The risk of chronic graft-versus-host
disease (GVHD) development was assessed in patients alive at day 100
after transplantation by logistic regression.
Match
Mismatch
.27
.56
Stem cell source
Bone marrow
⬍.01
Diagnosis
Age, y
P*
.86
.10
T-cell depletion and
ATG
T-cell depletion
ATG
Neither
Missing data
.91
57 (11.1)
59 (10.9)
294 (51.9)
281 (51.8)
67 (11.8)
55 (10.2)
Early stage indicates first complete remission, second complete remission, or
first chronic stage.
*Chi-square test was used for categorical variables; if ordered, a trend version
was used; t test was used for continuous variables.
death, 1.04; 95% confidence interval (CI), 0.95-1.14; P ⫽ .37). The
estimated 10-year survival (Kaplan-Meier) was 42% (⫾ 3%) for
patients with CMV-positive donors and 46% (⫾ 3%) for patients
with CMV-seronegative donors (Figure 1). There was no effect of
donor CMV status on the risk of acute GVHD, whereas patients
alive at day 100 with CMV-positive donors had a higher risk of
chronic GVHD than patients with seronegative donors (38.5%
versus 33.3%; P ⫽ .01).
Results
HLA-identical sibling donor transplant recipients
Univariate analysis. Donor CMV serologic status had no significant effect on the outcome after HLA-identical sibling SCT (HR for
Figure 1. Kaplan-Meier estimates of overall survival in patients undergoing
HLA-identical sibling SCT with CMV-seropositive or -seronegative donors.
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BLOOD, 15 DECEMBER 2003 䡠 VOLUME 102, NUMBER 13
DONOR CMV STATUS AND OUTCOME OF UNRELATED SCT
4257
Multivariate analyses. The hazard ratio for death comparing
CMV-seropositive and -seronegative donors was 1.04 (95% CI,
0.95-1.14; P ⫽ .40) after adjusting for age, calendar year of
transplantation, donor sex, and diagnostic group. Similarly, the HR
for transplantation-related mortality (TRM) was 1.04 (95% CI,
0.93-1.17; P ⫽ .46). In the different diagnostic subgroups the HRs
for death were 1.01 (95% CI, 0.90-1.14; P ⫽ .83) for acute
leukemia, 1.11 (95% CI, 0.89-1.39; P ⫽ .34) for CML, and 1.07
(95% CI, 0.89-1.29; P ⫽ .50) for patients with other diseases.
Patients with CML with CMV-seropositive donors who had
survived for more than 100 days had significantly higher risk of
chronic GVHD (odds ratio [OR], 1.7; 95% CI, 1.2-2.4; P ⬍ .05),
whereas there was no difference in patients with acute leukemia
(OR, 1.0; 95% CI, 0.8-1.3). However, this finding did not result in
any no survival difference in either group.
Unrelated donor transplant recipients
Univariate analysis. There was no difference in the mean age
between patients with CMV-seropositive (26.2 ⫾ 15.2 years) and
-seronegative donors (27.2 ⫾ 15.2 years). Patients receiving grafts
from seropositive donors had improved survival (Figure 2; log
rank, P ⫽ .006), and the 5-year survival estimates were 35%
(⫾ 5%) for CMV-seropositive donors and 27% (⫾ 5%) for CMV
seronegative donors.
Patients receiving grafts from CMV-seropositive donors had an
improved event-free survival (log rank, P ⫽ .01; survival estimates
30% ⫾ 5% and 22% ⫾ 5%) and a decreased treatment-related
mortality (Figure 3; log rank, P ⬍ .001; estimates 49% ⫾ 5% and
62% ⫾ 6%, respectively) compared with patients receiving grafts
from CMV-seronegative donors. There was no effect of the donor
CMV serostatus on the relapse incidence (log rank, P ⫽ .50;
estimates 62% ⫾ 7% and 63% ⫾ 8%, respectively). There was no
effect of the donor CMV serostatus on the risk of acute GVHD or,
in patients alive at day 100, for chronic GVHD.
Multivariate analyses. A multivariate model was constructed
that included donor CMV serologic status, age, calendar year of
transplantation, donor sex, and mismatched grafts (A, B, DR␤1
match versus mismatch; Table 3). Patients receiving a graft from a
CMV-seropositive donor had a lower risk of death, resulting in
improved overall survival. The hazard ratio for death was 0.82
(95% CI, 0.70-0.97). Similarly, patients receiving grafts from
CMV-seropositive donors had a lower risk of transplantation-
Figure 3. Kaplan-Meier estimates of transplantation-related mortality in patients undergoing unrelated SCT with CMV-seropositive or -seronegative
donors.
related mortality (HR, 0.74; 95% CI, 0.61-0.89). Graft type (bone
marrow versus peripheral stem cells) had no affect on either the
survival or the transplantation-related mortality.
There was no effect of donor CMV serologic status on the risk
of relapse (HR, 1.08; P ⫽ .76). There was no confounding effect of
the stage of disease on the effect of CMV donor seropositivity.
CMV donor status had no influence on the risk of developing
chronic GVHD in patients alive at day 100 (OR, 1.4; 95% CI,
0.9-2.1; P ⫽ .13). Donor CMV status did not have any effect on
survival in patients alive at day 100.
Causes of death
HLA-identical sibling transplant recipients. Of 4451 patients,
1860 died in the CMV-seropositive donor group compared with
589 of 1454 in the CMV-seronegative donor group. We found that
721 (16.1%) patients in the CMV-seropositive donor group and 223
(15.3%) in the CMV-seronegative donor group died of infectious
causes (P ⫽ NS).
Unrelated donor transplant recipients. Analysis shows that
294 patients died in the CMV-seropositive donor group compared
with 303 in the CMV-seronegative donor group. We found that 218
patients died of transplantation-related causes and 76 (26%) of
relapse in the CMV-seropositive donor group compared with 244
of transplantation-related causes and 59 (20%) of relapse in the
CMV-seronegative donor group. Patients who died in the
Table 3. Risk factors for survival, transplantation-related mortality,
and relapse in patients receiving unrelated donor transplants
Hazard ratio
95% CI
P
Donor CMV status
0.82
0.70-0.96
.02
Patient age
1.01
1.00-1.02
.001
Year of transplantation
0.95
0.92-0.97
.001
Overall survival
Donor sex
0.99
0.84-1.16
.87
Mismatch graft
1.29
1.04-1.60
.02
Donor CMV status
0.74
0.61-0.89
.001
Patient age
1.01
1.01-1.02
⬍.001
⬍.001
Transplantation-related mortality
Figure 2. Kaplan-Meier estimates of overall survival in patients undergoing
unrelated donor SCT with CMV-seropositive or -seronegative donors.
Year of transplantation
0.92
0.88-0.95
Donor sex
1.03
0.85-1.23
.77
Mismatch graft
1.33
1.03-1.71
.03
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4258
LJUNGMAN et al
CMV-seronegative donor group were, therefore, more likely to
have died of transplantation-related causes than those having
received grafts from CMV-seropositive donors (P ⫽ .06). An
analysis of the different transplantation-related causes showed that
patients receiving grafts from CMV-seronegative donors were
more likely to die of infections (150 [27.6%] of 542 versus 130
[23.3%] of 556; P ⫽ .07). There was no difference in the risk of a
viral cause of death (68 of 542 [12.5%] versus 55 of 566 [9.7%];
P ⫽ .15) or of death in interstitial pneumonia (29 [5.3%] of 542
versus 38 [6.7%] of 566; P ⫽ .37).
When the patients were divided into diagnostic subgroups
(acute leukemia, CML, other diseases), there was a significant
increase in the risk of death from noninfectious causes (relapse of
original disease, venoocclusive disease, GVHD) in patients with
acute leukemia compared with CML (233 of 529 versus 124 of 332;
P ⫽ .05), but there was no difference between the groups regarding
infectious causes of death (data not shown).
Effects of original disease. Donor CMV serologic status had
no independent effect in patients who received transplants for acute
leukemia either on survival (HR, 1.03; 95% CI, 0.82-1.30;
P ⫽ .70) or TRM (HR, 0.91; 95% CI, 0.68-1.21; P ⫽ .60). Factors
with significant influence on the survival and the TRM were age
(P ⬍ .001) and calendar year of transplantation (P ⬍ .001). In
contrast, donor CMV serologic status was independently associated with survival (HR, 0.65; 95% CI, 0.48-0.89; P ⫽ .006) and
TRM (HR, 0.61; 95% CI, 0.44-0.86; P ⫽ .004) in patients who
received transplants for CML. Donor CMV serologic status was
also independently associated with survival (HR, 0.69; 95% CI,
0.49-0.96; P ⫽ .028) and TRM (HR, 0.60; 95% CI, 0.41-0.88;
P ⫽ .009) in the group that included patients who received
transplants for other diseases. There was no effect on the relapse
incidence in the groups of patients who received transplants for
acute leukemia or CML. The protective effect of donor CMV
serologic status was significant in patients with CML in chronic
phase, but a similar trend was seen also in more advanced stages.
HRs associated with the variable that indicated whether donor
age was unknown or known were close to 1.0 for survival in acute
leukemia (HR ⫽ 1.2, P ⫽ .12) and CML (HR ⫽ 0.9; P ⫽ .50) but
significant for the patient group with other diseases (HR ⫽ 1.5;
P ⫽ .02). However, adjusting for donor age known/unknown did
not change the HRs of any other risk factor in the model by more
than a few percent. Thus, the effect of donor CMV serologic status
was not biased by the absence of information on donor age in a
large group of the patients. In the subgroup of patients with known
donor ages, we included donor age in all Cox models as a
continuous covariate. A significant detrimental effect of donor age
on survival and TRM can be detected in the data for the patients
with CML, but the HR of donor CMV serologic status was almost
identical whether we adjusted for donor age.
Effects of T-cell depletion. One possible hypothesis for the
effect of donor CMV serologic status on outcome is that the effect
is mediated by CMV-specific T cells. If this hypothesis is correct,
T-cell depletion would reduce the favorable effect of donor CMV
seropositive status. This possibility was analyzed in patients with
CML through construction of a multivariate model that added
“T-cell depletion, ATG (antithymocyte globulin), or neither” as a
discrete covariate. Apart from the main effect, interaction terms
were added to test for effect modification (ie, a possible dependence of the effect of donor CMV seropositivity on the presence or
absence of T cells or ATG). The overall interaction effect was
significant (P ⫽ .02), indicating that the effect of donor CMV
serologic status is not the same in the 3 categories. The HR for the
BLOOD, 15 DECEMBER 2003 䡠 VOLUME 102, NUMBER 13
donor CMV serologic status was different in the T-cell–depleted
subgroup compared with the other 2 groups. Moreover, the hazard
ratios among the neither and ATG group did not differ significantly.
These data show an estimate for the HR for overall survival of
donor CMV serologic status of 0.49 (95% CI, 0.32-0.75) in the
neither plus ATG subgroup and a HR of 1.22 (95% CI, 0.75-2.0) in
the T-cell–depleted group. Hence, the positive effect of CMV
seropositivity was completely abrogated by T-cell depletion, both
concerning the nontreated subgroup and the ATG patients. Similar
results were found for TRM. The HR was 0.43 (95% CI, 0.27-0.69;
P ⬍ .01) for neither plus ATG subgroup, and it was 1.3 (95% CI,
0.75-2.2; P ⫽ .37) in the T-cell–depleted group.
Discussion
CMV has been a major cause of transplant-related mortality in
allogeneic SC transplant recipients.10-12 One of the key risk factors
has been patient CMV serologic status, especially in unrelated
donor transplant recipients.7,8,13-15 CMV-seropositive patients have
a poorer outcome than CMV-seronegative patients despite improvement in preventive strategies against CMV disease such as antiviral
prophylaxis and preemptive therapy.7,15 CMV is immunosuppressive and in solid organ transplant recipients has been associated
with an increased risk of bacterial and fungal infections,16 and
prevention of CMV can result in a lower risk of bacterial and fungal
infections16,17 and decreased mortality in infectious complications
after SCT.2
The influence of the donor CMV serologic status to a CMVseropositive patient has been controversial. An early study in
T-cell–depleted patients receiving grafts from HLA-identical donors suggested that outcome could be improved by the use of a
CMV-seropositive donor.9 This finding has not been verified in
other studies.13 In this study, we found no influence by CMV
serologic status on overall survival and transplantation-related
mortality in patients receiving grafts from HLA-identical donors.
However, there was a strong influence by donor CMV serologic
status on outcome in unrelated donor transplantations. Patients
receiving grafts from CMV-seropositive unrelated donors had
improved survival, event-free survival, and reduced transplantationrelated mortality. That a possible effect would be stronger in
unrelated donor transplant recipients than in HLA-identical sibling
graft recipients fits with the results showing that CMV-associated
mortality and the risk of other infectious causes of transplantrelated mortality were higher after unrelated than HLA-identical
sibling transplantation.10,14,18 Disease stage was, of course, a highly
significant predictor of mortality. Other factors significant in the
multivariate analysis were patient age, calendar year of SCT, and
the use of HLA-mismatched unrelated donors. These factors are
well recognized from earlier studies.
How was this effect by donor CMV status mediated? The most
likely explanation would be death in CMV disease by itself in
patients receiving grafts from CMV-seronegative donors. However,
although there was a slight trend in this direction with lower risks
of death in interstitial pneumonia, this cannot be the entire
explanation. CMV has been shown to be immunosuppressive and
to increase the risk of bacterial and fungal infections in transplant
recipients. Indeed, by preventing CMV replication, a reduction in
mortality as a result of all types of infections can be achieved.2 This
hypothesis is supported by our data because there was a strong
trend for an increased risk of death from infections in patients
receiving grafts from CMV-seronegative donors.
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BLOOD, 15 DECEMBER 2003 䡠 VOLUME 102, NUMBER 13
We have not looked at acute GVHD’s effect on outcome in this
study because the aim was to evaluate factors known before
transplantation, thereby allowing a choice of the best donor.
However, we could find no effect by CMV donor status on the risk
of acute GVHD. Analyses of CMV donor status on the risk of
chronic GVHD gave different results. There was no effect in
patients who received transplants from unrelated donors, but we
could find a significant increase of the risk of chronic GVHD in
patients with CML who received transplants from CMV-seropositive sibling donors. In neither group, landmark analysis of patients
alive at day 100 showed any influence of donor CMV status on
survival. Thus, the effect on survival and TRM occurs before day
100 at the time when most infectious deaths do occur and is
independent of acute and chronic GVHD.
Recently, Kollman et al19 in a very large study from the National
Marrow Donor Program reported that increasing donor age was a
significant risk factor for decreased survival in unrelated donor
transplantations but no effect of CMV donor serologic status could
be found. There was a difference in how disease categories were
analyzed in the 2 studies. We found that the CMV donor status
effect was different in patients who received transplants for
different diseases; therefore, it was not possible to adjust for
disease categories as a covariate because the adjustment resulted in
a violation of the proportional hazard assumption, whereas Kollman et al19 adjusted for diagnosis. However, to allow comparison
with the study by Kollman et al,19 we reran all models in a similar
manner as in their study. It should be stressed that this is, of course,
statistically incorrect. However, with this limitation, as well as the
limitation of missing data regarding donor age, having a CMVseropositive donor still had a positive effect on survival also when
diagnosis was entered into the models.
In our different disease models, there were strong CMV donor
status effects in patients with CML and in a mixed group of patients
who received transplants mainly for myelodysplastic syndrome
(MDS), aplastic anemia, and lymphoma, whereas there was no
significant effect in patients with acute leukemia. The effects were
mediated through a lower TRM in both groups. It should be noted
that there was a trend for lower TRM also in patients with acute
leukemia who had CMV-seropositive donors, but this trend did not
translate into an improved survival. There are several different
possible explanations to these different effects in different patient
categories. Patients with acute leukemia are more likely to die of
relapse; therefore, the effect of reducing transplantation-related
mortality is less. A second possibility is that patients with acute
leukemia as a result of previous chemotherapy might be more
prone to die of transplantation-related causes unrelated to infections. A third possibility for the different effect in patients who
DONOR CMV STATUS AND OUTCOME OF UNRELATED SCT
4259
receive transplants for acute leukemia and CMV is the large
difference in age between patients with acute leukemia (mean age,
23.9 years) and CML (mean age, 33.7 years). This age difference is
mainly due to the presence of many young children in the acute
leukemia group. The likely mechanism for a negative effect by
using a CMV-seronegative donor is the lack of transfer of mature
CMV-specific effector T cells or the transfer of T-cell precursors
able to multiply and reconstitute T-cell immunity. A key element in
immune reconstitution after transplantation is thymic function, and
children have a better posttransplantation thymic function than
adults20-22 and might, therefore, better be able to mount a CMVspecific immune response.20,23 All 3 explanations might contribute
to the different effect of donor CMV serologic status in the different
diagnostic subgroups, although none of the possibilities can alone
explain the differences.
One way to look at the influence of specific immunity would
have been to look at the rates of CMV replication in patients
receiving grafts from CMV-seropositive and -seronegative donors
preferably with measurements of the viral load by quantitative
methods.5 This approach unfortunately was not possible because of
a limitation of such data in our database. Furthermore, the
monitoring techniques have varied over time and at different
centers. We, therefore, choose to analyze the influence of T-cell
depletion. The results support the hypothesis of specific T cells as
the key controlling factor. The protective effect by a CMVseropositive donor was abrogated by T-cell depletion so that the
overall survival and the risk of transplantation-related mortality
became the same in patients receiving grafts from T-cell–depleted
CMV-seropositive or -seronegative donors.
Our results indicate that a CMV-seropositive donor might
improve outcome of a CMV-seropositive patient undergoing an
unrelated donor transplantation. That the proportion of seronegative versus seropositive donors differs significantly between CMVseropositive patients who receive transplants with identical sibling
donors and unrelated donors suggests that instead the selection of a
seronegative donor has been favored by transplantation physicians. Although our study leaves some unresolved questions, it
at least questions this practice and rather suggests that, if
possible, a CMV-seropositive donor should be chosen for a
CMV-seropositive patient.
Acknowledgments
P.L. designed the study and wrote the paper. R.B. performed the
statistical analyses. H.E., F.F., D.N., and C.C. gave intellectual
input into the paper regarding analysis and interpretation.
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From www.bloodjournal.org by guest on July 28, 2017. For personal use only.
2003 102: 4255-4260
doi:10.1182/blood-2002-10-3263 originally published online
August 21, 2003
Donor CMV serologic status and outcome of CMV-seropositive
recipients after unrelated donor stem cell transplantation: an EBMT
megafile analysis
Per Ljungman, Ronald Brand, Hermann Einsele, Francesco Frassoni, Dietger Niederwieser and
Catherine Cordonnier
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