Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 369-371
CORRESPONDENCE
 |
To the Editor: |
Cytomegalovirus infection and disease after autologous
CD34-selected peripheral blood stem cell transplantation for multiple
myeloma: no evidence of increased incidence based on
polymerase-chain-reaction monitoring
Recently, Holmberg et al reported an increased
incidence of cytomegalovirus (CMV) disease following autologous
CD34-selected peripheral blood stem cell transplantation
(PBSCT).1 We have also been interested in the possibility
of delayed immune reconstitution following autologous CD34-selected
PBSCT, especially after the development of an EBV-lymphoma in one of
our patients.2 We have performed 44 CD34-selected
autologous PBSCT procedures at our institute in patients with
plasma cell dyscrasias (42 multiple myeloma, 1 relapsed solitary
plasmacytoma, 1 POEMS syndrome). In 13 cases the patient
was CMV seronegative, and none had evidence of CMV disease after
transplantation. Details of the 31 transplantation procedures in CMV
seropositive patients are shown in Table
1. In our experience, the absolute
T-cell count (× 105 cells) in the CD34-purified
fraction from the 3 different devices used for selection was 72 (54-184), 25 (10-184), and 0.3 (0.2-31) for the CellPro Ceprate, Baxter
Isolex 300i, and Miltenyi CliniMacs, respectively, corresponding to 3, 3.6, and 5.7 logs of T-cell depletion.3 Patients routinely
received low-dose prophylactic aciclovir but not intravenous
immunoglobulin (IVIG). We have seen only one case of CMV disease
(interstitial pneumonia) in these patients. This case was treated
successfully with ganciclovir and IVIG. The study by Holmberg et al
suggested that the use of lower doses of CD34+ cells with a
TBI-based conditioning regimen increased the risk of development of CMV
disease. The lower rate of CMV disease (3.2%) in our study compared to
that of Holmberg et al (22.6%) cannot be explained by differences in
these parameters, because we administered lower doses of CD34-positive
cells (median 2.8 × 106/kg versus
4.8 × 106/kg) and more of our patients received
TBI-based conditioning regimens (71% versus 45.2%). Furthermore, all
of our patients also had an underlying diagnosis of plasma cell
dyscrasia, a subgroup noted to have an increased risk for the
development of CMV disease by Holmberg et al (4 of their 6 patients
with multiple myeloma developed CMV disease).
Of the CMV seropositive patients, 12 were monitored
prospectively for CMV infection by whole blood polymerase chain
reaction (PCR). Surveillance was performed weekly while they were
inpatients; then it was performed at outpatient follow-up until 3 months after transplantation. Results up to 3 months are also available
on 5 unselected procedures performed on patients with multiple myeloma. The results are shown in Table 2.
Although the numbers are small, there is no apparent difference in the
rates of CMV PCR positivity between the selected patients (5 of 12) and
the unselected patients (3 of 5). These rates of CMV positivity are
similar to those previously reported in unselected autologous bone
marrow or PBSC transplants (42.2%).4 Only one patient had
more than 2 positive results on consecutive weeks. The positive results
were coincident with "fever of unknown cause." The patient did
not have bronchoalveolar lavage performed because of the lack of
respiratory symptoms but was treated with ganciclovir with resolution
of the pyrexia. All patients with a single documented positive result
remained asymptomatic and received no treatment.
We have therefore found that a single CMV PCR result has a low positive
predictive value for the development of CMV disease in CD34-selected
PBSC transplants. Quantitative PCR may be a more informative test,
although to date there are no published studies using this technique in
the setting of CD34 selection. The negative predictive value of the
test is of interest in view of the finding of Holmberg et al that 2 of
the 3 patients who developed CMV pneumonia in the pp65 antigenaemia
screened group did not have preceding CMV
antigenaemia.1 CMV PCR has been reported to have a negative predictive value of 100% in unselected autologous bone marrow and PBSC
transplants.4 Although we have not seen any cases of CMV
disease without preceding PCR positivity, the low rate of CMV disease
in our population does not allow us to comment further on the negative
predictive value in the setting of CD34 selection. In summary, we have
not seen an increase in CMV disease in patients with multiple myeloma
after autologous CD34-selected PBSC transplantation despite some of our
patients receiving apheresis products with up to 2 logs greater T-cell
depletion than achieved with the Ceprate/Isolex selection devices used
in the recent study of Holmberg et al.
Karl S. Peggs
Stuart J. Ings
Panagiotis D. Kottaridis
Kwee Yong
Catherine D. Williams
Anthony H. Goldstone
Stephen Mackinnon
Department of Haematology
University College London
London,
England
| |
References |
1.
Holmberg LA, Boeckh M, Hooper H, et al.
Increased incidence of cytomegalovirus disease after autologous CD34- selected peripheral blood stem cell transplantation.
Blood.
1999;94:4029-4035[Abstract/Free Full Text].
2.
Peniket AJ, Perry AR, Williams CD, et al.
A case of EBV-associated lymphoproliferative disease following high- dose therapy and CD34-purified autologous peripheral blood progenitor cell transplantation.
Bone Marrow Transplant.
1998;22:307-309[Medline]
[Order article via Infotrieve].
3.
Watts MJ, Ings SJ, Chavda N, Mackinnon S, Devereux S, Linch DC.
Evaluation of clinical scale CD34+ cell purification devices [abstract].
Br J Haematol.
1999;105(suppl.1):58[Medline]
[Order article via Infotrieve]
4.
Hebart H, Schroder A, Loffler J, et al.
Cytomegalovirus monitoring by polymerase chain reaction of whole blood samples from patients undergoing autologous bone marrow or peripheral blood progenitor cell transplantation.
J Infect Dis.
1997;175:1490-1493[Medline]
[Order article via Infotrieve].
| |
Response: |
Increased incidence of cytomegalovirus infection and
disease after autologous CD34-selected PBSC
transplantation
Unlike the work of Peggs et al, our paper reported
on the incidence of cytomegalovirus (CMV) disease and infection in CMV seropositive patients with a number of different diseases who received
a transplant with autologous CD34-selected peripheral blood stem cells
(PBSCs).1 Overall, 7 out of 31 (22.6%) CD34-selected patients developed CMV disease within 100 days after
transplantation. In a univariate analysis, CD34 selection alone was
significant for the development of CMV disease, with an odds ratio (OR)
of 6.62 (confidence interval [CI], 2.3-19; P < .001). By
evaluating combinations of factors together in a multivariate logistic
regression model, the inclusion of conditioning with a TBI-based
regimen and the dose of CD34 cells infused amplified the effect of CD34 selection. With respect to the development of CMV infection, CD34 selection and steroid use were highly significant in a univariate analysis: OR was equal to 3.0 and 2.69, respectively. Because all
patients in our CD34-selected group and 3 out of 10 patients in the unselected group who developed CMV disease had
received a transplant for multiple myeloma or lymphoma, an additional
subset univariate analysis was performed. In this analysis,
CD34-selected patients had a significant chance of developing disease,
with an OR of 17, (CI, 3.8-76.7; P < .001).
We are not the only group to report an increased incidence of CMV
disease associated with CD34 selection. Recently, Stocherl-Goldstein et
al2 presented their results. In 40 multiple myloma patients who received CD34-selected cells, there were 4 (10%) patients who
developed CMV disease.
In our cohort of patients, there were 6 patients with multiple myeloma
who received CD34-selected cells and 26 who did not. Four of the 6 CD34-selected patients developed CMV disease, as compared to 1 of the
26 unselected.
As mentioned in the discussion section of our paper, we believe that
differences in the reported incidence of CMV disease are due to
differences not only in the evaluation of patients but in the
immunologic function of the patients at risk. In our 6 multiple
myeloma patients who received CD34-selected PBSC, all were
mobilized with intermediate dose chemotherapy for stem cell collection. The number of regimens the patients received
prior to their mobilization chemotherapy were 1, 2, 2, 2, 2 and 3, thus making our multiple myeloma patients probably more
heavily treated than the group treated by Peggs et al, which
received a median of 1 chemotherapy regimen. In addition, 3 of
our 6 CD34-selected multiple myeloma patients received
steroid therapy after transplantation. In general, we have found the
following differences in the median number of immune cells infused in
the CD34-selected and unselected stem cells product: CD3, 8.8 vs
1273; CD4, 4.2 vs 518; CD8, 6 vs 246;
CD3+/CD56
, 10.8 vs 865;
CD3+/CD56+, 0.79 vs 123; and
CD3/CD56+, 2.55 vs
158 × 106. Patients who developed CMV disease after
the infusion of CD34-selected cells had the lowest
number of immune cells infused, with a median of 2.5 CD3, 3.1 CD4, 4.6 CD8, 7.6 CD3+/CD56, 0.49 CD3+/CD56+, and
2.2 × 106 CD3/CD56+.
At present, we are in the process of retrospectively
determining the number of specific T cells that recognize CMV that
were infused in the different patient populations.
We agree with Peggs et al that CMV antigenemia is not helpful, because
2 of 3 of our patients who developed CMV disease had no evidence of CMV
antigenemia. In addition, the median day to developing disease among
our CD34-selected patients was 26 days (range, 16-76 days). Thus the
early onset of CMV disease may make it hard to follow patients by CMV
antigenemia testing because their white blood cell count may be too
low. We also agree with Peggs et al that PCR by itself may not be
the best monitoring for risk for CMV infection and disease and that
quantitative PCR may be more informative. To date, because there are no
published studies using quantitative PCR in the setting of CD34
selection, we have adopted a policy at our institution of screening all
patients prior to initiation of transplant conditioning with a
quantitative PCR. All patients who have at least 100 copies of CMV in
their blood are treated with prophylactic antiviral therapy during
conditioning. Weekly after the infusion of CD34-selected PBSC, all
patients are screened also by CMV PCR. A level of at least 100 copies
of CMV results in the initiation of antiviral therapy.
Leona A. Holmberg
William I. Bensinger
Fred Hutchinson Cancer Research Center
University of
Washington School of Medicine
Seattle, WA
| |
References |
1.
Holmberg LA, Boeckh M, Hooper H, et al.
Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation.
Blood.
1999;94:4029-4035.
2.
Stockerl-Goldstein KE, Brown JM, O'Brien RM, et al.
Increased transplant-related mortality following high-dose sequential chemotherapy and autologous hematopoietc cell transplantation (AHCT) using the Ceprate SC stem cell concentration system for multiple myeloma (MM) [abstract].
Blood.
1999;94:608a.
