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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4029-4035
Increased Incidence of Cytomegalovirus Disease After Autologous
CD34-Selected Peripheral Blood Stem Cell Transplantation
By
Leona A. Holmberg,
Michael Boeckh,
Heather Hooper,
Wendy Leisenring,
Scott Rowley,
Shelly Heimfeld,
Oliver Press,
David G. Maloney,
Peter McSweeney,
Lawrence Corey,
Richard T. Maziarz,
Frederick R. Appelbaum, and
William Bensinger
From the Clinical Division, Fred Hutchinson Cancer Research Center,
Department of Medicine, University of Washington School of Medicine and
Puget Sound Oncology Consortium, Seattle, WA.
 |
ABSTRACT |
High-dose therapy with autologous peripheral blood stem cell (PBSC)
rescue is widely used for the treatment of malignant disease. CD34
selection of PBSC has been applied as a means of reducing contamination
of the graft. Although CD34 selection results in a 2 to 3 log reduction
in contaminating tumor cells without significantly delaying
engraftment, many other types of cells are depleted from the
CD34-enriched grafts and immune reconstitution may be impaired. In the
present study, 31 cytomegalovirus (CMV)-seropositive patients who
received myeloablative therapy followed by the infusion of CD34-selected autologous PBSC were assessed for the development of CMV
disease in the first 100 days posttransplant. Seven patients (22.6%)
developed CMV disease and 4 patients (12.9%) died from complications
of their infection. In a contemporaneous group of 237 CMV-seropositive
patients receiving unselected, autologous PBSC, only 10 patients
(4.2%) developed CMV disease, with 5 deaths (2.1%). In a multivariate
logistic regression analysis, the use of CD34-selected autologous PBSC
after high-dose therapy was associated with a marked increase in the
incidence of CMV disease and CMV-associated deaths.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HIGH-DOSE THERAPY followed by autologous
transplantation of peripheral blood stem cells (PBSC) improves initial
response rates and overall survival for several categories of cancer
patients.1-3 However, the major cause of treatment failure
remains relapse. Because PBSC products frequently contain detectable
contaminating tumor cells,4,5 investigators have attempted
to reduce the incidence of relapse by selecting the CD34+
cells, thereby depleting tumor cells. A number of phase I, II, and III
studies6-13 have been conducted with CD34-selected PBSC infused after myeloablative therapy. Because these studies demonstrate effective hematopoietic recovery and a reduction in the number of
contaminating tumor cells in the PBSC product, an increasing number of
patients are being offered treatment with autologous CD34-selected PBSC.
The issue of infectious complications and immune reconstitution after
the infusion of CD34-selected PBSC has been less completely studied.
There are suggestions that immune reconstitution may be delayed with
CD34 selection with an associated increased risk for infections. This
increased risk may be due to the removal of T cells, natural killer
(NK) cells, and monocytes. Among CD34-selected allogeneic
transplant recipients, a higher incidence of infectious complications,
including cytomegalovirus (CMV) disease,14-16 has been
reported. Additionally, case reports have described CMV disease, cryptosporidiosis, and other serious opportunistic infections among
patients receiving autologous CD34-selected PBSC.17-20
However, no systematic review of common opportunistic infections such
as CMV has been reported for autologous CD34-selected PBSC.
CMV disease is a well-described infection in patients with T-cell
deficiencies, including allogeneic stem cell transplant recipients and
human immunodeficiency virus (HIV)-infected
individuals.21-24 However, CMV disease is relatively
uncommon after conventional autografting with unmodified bone marrow or
PBSC and is reported to occur in only 2% to 9% of such
patients.25-28 Little has been published about the impact
of CD34 selection on the incidence of CMV infections after autologous transplantation.
In this report, we describe our experience with CMV disease among
CMV-seropositive autologous PBSC transplant patients who received
CD34-selected stem cell products. Thirty-one patients transplanted for
hematological or nonhematological diseases received CD34-selected
autologous PBSC after myeloablative therapy and were assessed for the
development of CMV disease during the first 100 days posttransplant.
These patients were compared with a nonrandomized control group of 237 CMV-seropositive patients who were contemporaneously transplanted with
unselected PBSC.
| |
MATERIALS AND METHODS |
Study design.
Between April 1995 and November 1998, 268 CMV-seropositive patients
underwent a myeloablative conditioning regimen followed by infusion of
autologous PBSC. According to the specific protocol active at the time
of patient enrollment or at the discretion of the attending physician,
31 patients received CD34-selected PBSC. The remaining 237 patients
received unselected PBSC. Of the CD34-selected patients, 25 were
treated at the Fred Hutchinson Cancer Research Center (FHCRC; Seattle,
WA) or an affiliated academic center (University of Washington and
Veteran's Affairs Medical Center, Seattle, WA) and 6 patients were
treated at Oregon Health Sciences (Portland, OR) or Swedish Medical
Center (Seattle, WA) under the auspices of the Puget Sound Oncology
Consortium (Seattle, WA). Of the patients receiving
unselected PBSC product, 187 patients were treated at the FHCRC,
Veteran's Affairs Medical Center, or University of Washington, and 50 patients were treated at either the Oregon Health Sciences or Swedish
Medical Center. After we had obtained informed consent, all patients
were treated on an FHCRC or Puget Sound Oncology Consortium protocol
approved by the institutional review board of the hospital where the
therapy was administered. Patients were prospectively evaluated for the first 100 days posttransplant for the development of CMV infection or
disease. The data used for patients in the present report were information available as of March 30, 1999.
Patient characteristics.
Of the 31 patients who received CD34-selected PBSC, 23 (74.2%) were
transplanted for a hematological malignancy, 3 (9.7%) for an
autoimmune disease, and 5 (16.1%) for a solid tumor. Of the 237 patients who received unselected PBSC, 90 (38%) were transplanted for
a hematological malignancy and 147 (62%) for a solid tumor. As
Table 1 shows, all patients treated for
autoimmune disorders, chronic lymphocytic leukemia (CLL), and acute
lymphoblastic leukemia (ALL) received CD34-selected PBSC. A similar
percentage of both selected and unselected PBSC recipients received 1 to 2 mg/kg methylprednisolone steroid therapy posttransplant for
regimen-related toxicities.
Mobilization, collection, and cryopreservation of PBSC.
For CD34 selection, PBSC were mobilized with either recombinant
granulocyte colony-stimulating factor (G-CSF; Amgen, Thousand Oaks, CA)
alone (n = 6) or intermediate-dose chemotherapy followed by either
G-CSF (n = 23) or recombinant granulocyte-macrophage colony-stimulating
factor (GM-CSF; Immunex, Seattle, WA) (n = 2). Second mobilizations
were required in 7 patients because of either tumor contamination (n = 4) or insufficient number of stem cells collected (n = 3).
For the patients receiving unselected grafts, PBSC were mobilized with
either G-CSF alone (n = 33) or intermediate-dose chemotherapy followed
by G-CSF (n = 198) or GM-CSF (n = 6). Nineteen patients required more
than 1 mobilization either because an insufficient number of cells were
collected (n = 8) or because there was tumor contamination of the
product (n = 11). All PBSC collections were performed using the COBE
Spectra (COBE BCT, Lakewood, CO) and all products were cryopreserved
with dimethyl sulfoxide (DMSO) as previously described.29
CD34 selection.
The Baxter 300 Isolex System (Baxter, Inc, Irvine, CA) was used to
select the CD34+ cells in 19 cases,30 and the
Cellpro Ceprate System (Cellpro, Seattle, WA) was used in 12 cases.13 Both systems were used according to the
manufacturer's specifications. Two of 12 patients whose cells were
separated with the Cellpro system also underwent an initial B-cell
purging of their PBSC product. For the B-cell purging technique, the
collected cell products were incubated with a combination of
biotinylated antihuman CD19 and CD20 antibodies and then passed through
a column of avidin-conjugated gel to bind the CD19/20-positive cells.
The unbound cells were then sequentially incubated with avidin and
biotin solutions to prevent any CD19/20 antibody-labeled cells that
remained from rebinding in the CD34 selection process.
Transplant conditioning.
Patients in both groups were transplanted with a variety of high-dose
myeloablative regimens. As compared with recipients of unselected PBSC
grafts, a higher proportion of patients in the CD34-selected group
received total body irradiation (TBI)-based conditioning regimens.
Fourteen of the 31 (45.2%) CD34-selected patients received a TBI-based
conditioning regimen, compared with only 34 of the 237 (14.3%)
unselected PBSC patients (Table 1).
Supportive care.
After myeloablative therapy, all patients received prophylactic
intravenous antibiotics when the absolute neutrophil count (ANC)
decreased to less than 0.5 × 109/L and were treated
with additional antibiotics when neutropenic fever occurred. Patients
who were serologically positive for herpes simplex virus received
prophylactic low-dose acyclovir. Because of limitations in drug
availability, prophylactic intravenous Ig was administered to only 6 of
the 10 CLL and multiple myeloma (MM) patients who received
CD34-selected PBSC and 15 of 26 MM patients who received unselected
PBSC, despite the administration of prophylactic Ig being the usual
practice for these patients. At the discretion of the attending
physician or per protocol, 9 of the 31 (29%) CD34-selected patients
received posttransplant growth factor until engraftment, either G-CSF
at 5 µg/kg/d subcutaneously (SC; n = 7), G-CSF at 10 µg/kg/d SC (n = 1), or GM-CSF at 500 µg/m2/d SC until 14 days
posttransplant, followed by G-CSF at 5 µg/kg/d SC (n = 1). Twelve of
the 237 (5.1%) patients transplanted with unselected PBSC product
received G-CSF at 5 µg/kg/d SC until engraftment.
CMV screening.
Per institutional policy, patients treated at the FHCRC and the
Veteran's Affairs Medical Center had weekly CMV screening studies
performed, including the CMV pp65 antigenemia assay (CMV Brite; Biotest
Diagnostic Corp, Denville, NJ) and viral blood culture testing weekly
from day 10 posttransplant until day 100 or discharge home, as
previously described.28 The CMV antigenemia kit was used
according to the manufacturer's instructions. Patients with a
quantitative antigenemia test ( 5 cells/slide) received antiviral
therapy with ganciclovir.28 No screening was used for
patients transplanted at the other 2 institutions.
Definitions.
CMV infection was defined as either evidence of any level of
quantitative pp65 antigenemia or a positive blood or mouth culture. CMV
disease was defined as a positive CMV shell vial or conventional culture of bronchoalveolar lavage fluid, lung biopsy, or
gastric/duodenal biopsy in association with symptoms.31
CMV-associated death was defined as death that occurred within 6 weeks
of documented CMV disease, other than death due to progression of
underlying disease.31 The day of onset of CMV disease was
defined as the date of performance of a diagnostic procedure
(bronchoscopy, open lung biopsy, or esophagogastroduodenoscopic biopsy)
to evaluate symptoms suggestive of disease. Neutrophil engraftment was
defined as the first of 3 consecutive days on which the ANC exceeded
0.5 × 109/L after the nadir. Platelet transfusion
independence was defined as the first of 3 consecutive days on which
the platelet count exceeded 20 × 109/L without transfusion.
Statistical methods.
Summary statistics such as median and range values of continuous valued
and tabulation of categorical valued patient characteristics were
reported. Comparisons between the group of patients receiving CD34-selected PBSC and those receiving unselected PBSC were made using
 2 statistics or the Wilcoxan rank sum test. Cumulative
incidence curves32 for CMV disease were generated.
Univariate and multivariate logistic regression analyses were performed
to evaluate the impact of various factors on the risk of CMV disease
and on CMV infection. The odds ratio (OR) and their associated 95%
confidence intervals (CI) were reported. Because we were primarily
interested in determining whether the inclusion of additional
covariates modified the effect of CD34 selection on the outcome, any
factors that changed the coefficient estimate by more than 10% were
included in multivariate models.33
| |
RESULTS |
Engraftment.
Neutrophil engraftment was reached at a median of 10 days (range, 8 to
21 days) for those patients receiving CD34-selected stem cells and 11 days (range, 8 to 72 days) for those treated with unselected PBSC
(P = .20, Wilcoxan rank sum test). Platelet transfusion
independence occurred a median of 11 days (range, 7 to 47 days) for
selected patients and 11 days (range, 4 to 96 days) for those treated
with unselected PBSC (P = .12, Wilcoxan rank sum test).
The absolute number of peripheral blood lymphocytes at 30 days after
stem cell infusion were markedly different between the 2 groups. In
patients alive at day 30 after transplant, lymphocyte counts were
available in 228 unselected and in 29 CD34-selected patients.
Lymphocyte counts were significantly higher in the unselected group
(P = .03).
Incidence of CMV disease.
Figure 1 displays the cumulative incidence
of CMV disease within 100 days of transplant for CD34-selected and
unselected patients. Overall, 7 of the 31 (22.6%) CD34-selected
patients developed CMV disease within 100 days posttransplant, and 4 (12.9%) died as a result of their infection. In these 7 patients, CMV
disease occurred a median of 26 days (range, 16 to 76 days) after
transplant.
View larger version (11K):
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| Fig 1.
Cumulative incidence curves for CMV disease in
CD34-selected and unselected PBSC autologous transplant patients.
|
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Details of the characteristics of CMV disease in the CD34-selected
patients are shown in Tables 2 and
3. CMV screening was performed in 19 of the
31 (61.3%) CD34-selected patients. Three of these screened patients
developed CMV pneumonia in the first 100 days posttransplant. Two of
these 3 patients had no evidence of CMV antigenemia before the
development of CMV disease. Both of these patients developed CMV
disease early after transplant and began treatment on days 16 and 21, respectively. One of these patients died from their pneumonia. Only 1 of these 3 patients received a TBI-based conditioning regimen. Among
the 12 patients who did not have CMV screening performed, 4 developed
CMV disease. Three patients developed pneumonia and all died. One
patient developed enteritis and survived. All 7 patients developing CMV
disease had an underlying hematological malignancy.
Of the 237 unselected PBSC recipients, 10 patients (4.2%) developed
CMV disease and 5 (2.1%) died (Tables 2 and 3). Among these 10 patients, CMV disease occurred a median of 29.5 days (range, 12 to 51 days) posttransplant. Three of these 10 unselected patients had an
underlying hematological malignancy. Only 5 of the 172 (2.9%) patients
screened for CMV developed disease. Two patients developed pneumonia
and both died. Three patients developed enteritis, and 1 of these died.
Only 2 of these patients displayed evidence of low CMV antigenemia, ie,
less than 5 cells/slide before developing disease. Five of the 65 (7.7%) patients who had undergone no CMV screening studies performed
developed disease. Three patients developed CMV pneumonia and 2 died.
Two patients developed enteritis and recovered after antiviral therapy.
Incidence of CMV infection.
CMV infection (without disease) was detected in an additional 5 of the
19 (26.3%) CMV-screened, CD34-selected patients and in 30 of the 172 (17.4%) patients treated with unselected PBSC who were screened. These
5 CD34-selected patients developed low levels of antigenemia, with less
than 5 cells/slide between days +12 to +38 posttransplant (Table 2).
Three of these patients received antiviral therapy and subsequently
became CMV antigenemia negative. A fifth patient was noted to have low
levels of CMV antigenemia on days +31 and +38 posttransplant and had a
positive upper respiratory tract culture on day +33. This latter
patient had no evidence of lower tract CMV disease and antiviral
therapy was not initiated.
Among the 30 patients receiving unselected PBSC who developed CMV
infection, 20 (11.6% overall) of these patients had a low level of CMV
antigenemia (<5 cells/slide) and did not receive antiviral therapy.
Ten patients (5.8%) had significant antigenemia (>5 cells/slide),
and 9 were treated with antiviral therapy. Four additional patients
were noted to have either a positive blood culture (n = 2) or oral
culture (n = 2) and were not treated.
Risk for developing CMV infection or disease.
Univariate and multivariate logistic regression analyses were performed
to assess risk factors for the development of CMV infection or CMV disease.
As can be seen in Table 4A, CD34 selection
alone was significant for the development of CMV disease with an OR of
6.62 (CI, 2.3 to 19.0; P < .001). Other variables, including
age at transplant, posttransplant steroid therapy, underlying disease,
number of CD34 cells infused, and treatment with TBI-based conditioning regimen, were not significant.
Evaluating combinations of factors together in multivariate logistic
regression models showed that inclusion of conditioning with a
TBI-based regimen and dose of CD34 cells infused amplified the effect
of CD34 selection and increased the OR to 11.76 (CI, 3.1 to 44.8;
P = .0004) for the development of CMV disease. In the
multivariate model, conditioning with a TBI-based regimen was not
significantly associated with CMV disease, but the dose of CD34 cells
as well as CD34 selection were significant. In patients receiving less
than 8.56 × 106 cells/kg CD34 cells/kg, the OR was
4.13 (CI, 1.1 to 15.5; P = .04), compared with an OR of 0.68 (CI, 0.1 to 4.1; P = .67) for 8.56 × 106
CD34 cells/kg infused. Other factors did not modify the effect of CD34
selection on CMV disease and were not included in this model.
Table 4B describes the evaluation of risk factors for CMV infection (as
opposed to disease) in univariate logistic regression. Steroid use
posttransplant was highly significant for the development of CMV
infection, with an OR of 3.00 (P = .003). CD34 selection was
also noted to be significant, with an OR of 2.69 (P = .04). There was a trend for the development of CMV infection in patients who
carried a diagnosis for either an autoimmune disorder or hematological malignancy relative to patients with a solid tumor, with an OR of 1.98 (P = .06). Other variables, including the age at transplant, number of CD34 cells infused, or treatment with a TBI-based regimen, did not sig- nificantly contribute to the risk of developing CMV infection.
In multivariate logistic regression analyses for the risk of CMV
infection, the final model included CD34 selection, steroid use, and
underlying disease. With the inclusion of these additional covariates,
the OR for CD34 selection was slightly decreased over that in the
univariate model (OR, 1.81; CI, 0.7 to 15; P = .27), and it was
not statistically significantly associated with CMV infection. In this
model, steroid use was still highly significant (OR, 3.00; CI, 1.5 to
6.3; P = .003), and underlying disease was no longer
significantly associated with the risk of CMV infection (OR, 1.85; CI,
0.8 to 4.1; P = .12).
Incidence of CMV disease and infection in non-Hodgkin's lymphoma
(NHL), Hodgkin's disease (HD), and MM patients.
Because all patients in the CD34-selected group and 3 of 10 patients in
the unselected group who developed CMV disease had received an
autologous transplant as treatment for NHL, HD, or MM (Table 3), an
additional subset analysis of these patients was performed to compare
the risk for developing CMV disease and CMV infection
(Table 5). As seen in Table 5A,
CD34-selected MM, HD, and NHL patients had a significant chance of
developing CMV disease, with an OR of 17.0 (CI, 3.8 to 76.7; P < .001). In this subset of patients, the median day to CMV disease
among CD34-selected and unselected patients was 26 days (range, 19 to
41 days) and 26 days (range, 16 to 76 days), respectively. This subset
analysis, although significant in univariate analysis, contained too
few events in the unselected group to perform multivariate analysis.
| |
DISCUSSION |
In this study, recipients of autologous, CD34-selected PBSC had an
increased incidence of CMV disease. Seven of 31 (22.6%) CMV-seropositive patients who received CD34-selected PBSC developed CMV
disease, and 4 patients (12.9%) died from complications of their
infection. In contrast, among 237 CMV-seropositive patients undergoing
an autologous transplant during the same time period who received
unselected PBSC, only 4.2% developed CMV disease, and 2.1% died from
complications of their CMV infection. Using univariate analysis, only
CD34 selection was significant for the development of CMV disease, with
an OR of 6.62 (P < .001). Multivariate adjustment for other risk factors, such as TBI-based conditioning regimen and cell dose (5.0 to 8.55 × 106 cells/kg),
amplified this effect (OR, 11.8; P < .001).
A subset analysis of patients diagnosed with HD, NHL, and MM and
transplanted with either CD34-selected PBSC and unselected PBSC showed
a significant increased risk for developing CMV disease in those
patients who were treated with CD34-selected PBSC (OR, 17; P < .001; Table 5A). Seven of the 17 (41%) MM, HD, and NHL patients in
the CD34-selected PBSC group developed CMV disease. In comparison, 76 of the 237 CMV-seropositive patients who received unselected PBSC had
MM, NHL, and HD. Of these 76 patients, 3 patients (3.9%) developed CMV
disease and 2 patients died. This incidence of CMV disease was not
significantly increased from the incidence seen in the whole unselected
group (4.2%) or in the patients without hematological malignancies
(4.6%).
CD34-selected PBSC are increasingly used with the hope of reducing
relapses by decreasing the number of tumor cells infused with the
autograft. Data supporting an actual improvement in disease-free survival for these patients are not yet available.10,13 To date, CD34-selected autologous PBSC have been administered mainly to
patients with breast cancer, lymphoma, or MM. The published data with
CD34-selected autografts do not report an increased incidence of CMV
disease among CD34-selected autograft patients. The initial pilot
studies using CD34-selected autologous PBSC in patients with MM
described 8 episodes of interstitial pneumonia resulting in 4 deaths in
74 transplanted patients.6-9 Unfortunately, the number of
CMV-seropositive patients that were treated is not documented. If one
assumes a 50% incidence of CMV-seropositive patients and that all of
the cases of interstitial pneumonia occurred in CMV-seropositive
patients, then the number of pulmonary complications due to CMV would
be similar to the present report. Recently, Vescio et al13
reported the outcome of a multicenter phase III trial evaluating
patients with MM who received CD34-selected or unselected autologous
PBSC. There were approximately 60 patients in each arm. They reported
no significant difference in terms of infections between the 2 groups.
However, a high number of patients in each arm (56%) developed an
infection in the first 100 days. Data were not provided on the type of
infections that developed, the use of prophylactic Ig therapy, or the
CMV serostatus of the patients. In 1 phase III study conducted in
patients with breast cancer, patients were randomized to receive either
CD34-selected marrow grafts (n = 42) or standard buffy coat bone marrow
grafts (n = 47).10 There was no significant difference in
the incidence of infection in either arm: 52% infection in the
CD34-selected patients and 47% infection in the standard marrow graft
patients. The actual etiology of these reported infections was not described.
Whether there are real differences between the present report and other
studies evaluating CD34 selection on the incidence of CMV disease is
uncertain. Because CMV disease is uncommon after conventional
autografting with unselected PBSC,25-28 it may not have
been suspected in the patients who received a CD34-selected autograft
and developed symptoms of CMV disease. In addition, incomplete virology
studies of bronchoscopy samples, biopsy, and autopsy samples may have
been performed and could result in an underestimation of the true
incidence of CMV disease.34 Finally, patients with
hematological malignancies may be more immunocompromised not only
because of their underlying disease, but also because they are more
heavily treated with chemotherapy before transplant and are thus at
increased risk for CMV disease when CD34-selected PBSC are administered
(Table 5A).
CD34 selection results in a 2 to 3 log depletion of lymphocytes. The
impact of this depletion on immune reconstitution and susceptibility to
infectious complications such as CMV has not been described in detail
after autologous transplantation. In the phase III study evaluating
CD34 selected marrow grafts in breast cancer patients, immunological
reconstitution for both arms of the study was assessed at 100 days, 6 months, and 1 year after transplant.10 By
immunophenotyping, the number of NK and suppressor cells was normal by
day 100 in both groups. However, the number of CD4 cells in the
CD34-selected group did not reach normal levels until 1 year
posttransplant. These data were confirmed in the phase III study
evaluating CD34-selected PBSC autografts in patients with
MM.13 Vescio et al13 report a significantly lower CD4 lymphocyte count at day 100 posttransplant in patients receiving CD34-selected autografts that persisted until 1 year posttransplant. Additionally, Lemoli et al35 studied immune reconstitution in 13 patients with MM who received a CD34-selected autologous product. They noted that the posttransplant absolute CD4
count in these patients was significantly lower than pretreatment levels, with rapid recovery of total number of lymphocyte and NK cells.
Finally, Bomberger et al36 reported that the
restoration of normal numbers of both T and B cells were delayed during
the first 2 months after infusion of CD34-selected PBSC. Mainly
CD4 CD8+,  / TCR+,
CD45RO+, and CD45 RA cells were noted to
be circulating. Thus, there appears to be a loss of the diversity after
infusion of CD34-selected cells that is normally seen in the T-cell
repertoire after infusion of unselected cells. In our study, the
patients who received CD34-selected PBSC and survived beyond 30 days
had significantly lower numbers of circulating lymphocytes at 30 days
posttransplant (P = .03) as compared with patients treated with
unselected PBSC. This may indicate delayed recovery of CMV-specific
cytotoxic and helper T cells.
Nothing is yet known about immune reconstitution to CMV after infusion
of autologous CD34-selected PBSC. Indeed, little is known about immune
reconstitution to CMV after an unselected autologous transplant.
Recently, Reusser et al37 studied the reconstitution of
CMV-specific CD8+ cytotoxic T lymphocytes (CTL) and
CD4+ T-helper (Th) cells in 15 CMV-seropositive autologous
transplant patients who received autologous bone marrow or unselected
PBSC. They found that CMV-specific CD8+ CTL and
CD4+ Th responses were restored in the majority of patients
within the first 3 months and that the presence of CD8+ CTL
activity afforded protection from CMV infection. Brugger et
al38 have speculated that a higher incidence of viral
infections within the first 3 months after autologous transplant may be
a result of these T-cell defects. Preliminary data in our laboratory show that the patients who developed CMV disease after infusion of
CD34-selected PBSC had the lowest number of CD3, CD4, and CD8 cells in
their stem cell product. All of these studies point to the existence of
more profound immunodeficiency early after the infusion of
CD34-selected PBSC as compared with unselected autologous PBSC.
Unfortunately, this study was a retrospective analysis and data were
not available on the immune reconstitution of these patients after transplant.
Studies in patients receiving an allogeneic transplant have shown that
administration of ganciclovir or foscarnet after documentation of CMV
excretion in blood, urine, or throat can prevent the occurrence of CMV
disease. More recently, earlier detection in blood by CMV antigenemia
or polymerase chain reaction (PCR) assays may allow prompt intervention
to prevent disease in recipients of allogeneic transplants.28,31,39-41 In this situation, plasma PCR of
CMV DNA appears to be both sensitive and specific.42 In the
present study, 2 patients who received CD34-selected autologous PBSC
developed CMV disease despite weekly testing for CMV antigenemia. This
may indicate that, in patients receiving CD34-selected PBSC, the
standard CMV screening test for infection is too insensitive just
before or immediately after engraftment, perhaps due to low numbers of circulating leukocytes during this period. We believe that, given this
increased incidence of CMV disease among CD34-selected autologous stem
cell recipients, close monitoring and anti-CMV preventive therapy are
needed in seropositive patients receiving autologous CD34-selected
PBSC. We have instituted a policy at the FHCRC that incorporates early
monitoring by plasma PCR followed by antigenemia testing after
engraftment and antiviral treatment for those patients with positive
results. Because the definitive benefits of CD34 selection on survival
have yet to be demonstrated, future studies using CD34-selected
autologous PBSC should require close patient monitoring for the
development of infections, including CMV. In some patients, risks from
pronounced immunodeficiency could reduce any potential therapeutic
gains from the infusion of CD34-selected cells.
| |
ACKNOWLEDGMENT |
The technical support of Elizabeth Soll, Sue Tracy-Waisanen, and Chris
Davis is greatly appreciated. We express our gratitude to all members
and staff of the Puget Sound Oncology Consortium who enrolled their
patients on study and provided us with follow-up.
| |
FOOTNOTES |
Submitted June 7, 1999; accepted August 5, 1999.
Supported by Grants No. CA18029, CA47748, CA18221, CA15704, and HL35444
and the Jose Carreras Foundation Against Leukemia.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Leona A. Holmberg, PhD, MD, Fred Hutchinson
Cancer Research Center, 1100 Fairview Ave N, PO Box 19024, MS D5-390,
Seattle, WA 98109-1024.
| |
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ABSTRACT
INTRODUCTION