Blood, 1 October 2002, Vol. 100, No. 7, pp. 2674-2675
CORRESPONDENCE
To the editor:
Chimerism induction and delayed onset of
cytomegalovirus (CMV) infection after allogeneic reduced-intensity stem
cell transplantation (RIST)
Although cytomegalovirus (CMV) infection has been identified as
one of the primary causes of morbidity and mortality after allogeneic
stem cell transplantation (SCT), very little is known about the
characteristics of this disease after reduced-intensity stem cell
transplantation (RIST). Junghanss et al1 recently reported that the onset of CMV disease was significantly delayed after
nonmyeloablative transplantation (NST) compared with myeloablative SCT.
They speculated that host T cells, which remained after NST, help to
protect recipients from CMV disease in the early phase of SCT. Their
"true" NST-conditioning regimen consisted of low-dose (2 Gy) total
body irradiation with or without fludarabine (Flu), which may allow
most host cells to survive to provide overlapping immunity against CMV
infection along with engrafted donor-derived cells. In our RIST study
framework using Flu (180 mg/m2) or cladribine (0.66 mg/kg)
plus busulfan (8 mg/kg), with or without antithymocyte globulin (ATG),
achievement of donor T-cell chimerism was delayed when ATG was
omitted.2 In this situation, we evaluated the correlation
between the induction of T-cell chimerism and CMV infection by
analyzing the medical records of 63 CMV-seropositive patients who
underwent RIST between September 1999 and November 2001 from an
HLA-matched (n = 49) or -mismatched (n = 14) related donor.
Twenty-four patients underwent RIST without ATG, whereas 39 underwent RIST with ATG. T-cell donor-host chimerism analysis was
performed with CD3+ cells by the polymerase chain reaction
(PCR)-based amplification of polymorphic short tandem repeat (STR)
regions, as previously described.2 Mononuclear cells
(MNCs) were separated by the Ficoll-Hypaque method and then by
magnetic cell sorting (MACS), using anti-CD3 monoclonal antibody
combined with immunomagnetic beads, to give CD3+ and
CD3
cells as final products. CMV infection was monitored
at least once a week after engraftment by a commercially available kit using the monoclonal antibody HRP-C7 (Teijin, Tokyo, Japan) as previously described.3 The initially published
data3 were updated and follow-up chimerism analysis showed
that host T cells were present up to day 60 after RIST without
ATG, but eventually disappeared by day 90. Positive CMV antigenemia was
observed in 14 patients (58%) after RIST without ATG, and in
21 patients (54%) with ATG (P = .57, log-rank test).
However, there was a significant difference in the median number of
days to show positive antigenemia between RIST with and without ATG
(P = .01, Mann-Whitney U test).
Thus, the data obtained with this more homogenous cohort, in terms of
the cytoreductive regimen and CMV seropositivity, appear to further
support the impact of residual host T-cell immunity against CMV, as
suggested by Junghanss et al. Nevertheless, this still needs
to be clarified in a future study. In contrast to the findings
of Junghanss et al, in this series of high-risk patients who were
managed with our preemptive therapy,3 only 2 patients developed CMV disease. Hence, our experience highlights the importance of close monitoring of CMV antigenemia even to the late phase after
RIST, as suggested by Junghanss et al.
Kunihisa Nakai, Shin Mineishi, Masahiro Kami, Yoshinobu Kanda, Ryuji Tanosaki, and Yoichi Takaue
Correspondence: Yoichi Takaue, Stem Cell Transplant Unit,
National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo
104-0045, Japan; e-mail: ytakaue{at}ncc.go.jp
References
1.
Junghanss C, Boeckh M, Carter RA, et al.
Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study.
Blood.
2002;99:1978-1985[Abstract/Free Full Text].
2.
Niiya H, Kanda Y, Saito T, et al.
Early full donor myeloid chimerism after reduced-intensity stem cell transplantation using a combination of fludarabine and busulfan.
Haematologica.
2001;86:1071-1074[Abstract/Free Full Text].
3.
Kanda Y, Mineishi S, Saito T, et al.
Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan.
Bone Marrow Transplant.
2001;27:437-444[CrossRef][Medline]
[Order article via Infotrieve].
Response:
Risk of cytomegalovirus infection after transplantation with
nonmyeloablative and reduced-intensity conditioning regimens
Nakai et al report cytomegalovirus (CMV) results in a cohort of
hematopoietic stem cell transplant (HSCT) recipients who
received HLA-matched or -mismatched related grafts following a
reduced-intensity conditioning with fludarabine or cladribine and
busulphan with and without antithymocyte globulin (ATG). Similar to our
results, Nakai et al report persistence of host T-cell chimerism in the early posttransplantation period. There seemed to be a difference in
the incidence of CMV antigenemia between regimens that did and did not
contain ATG. Patients who received ATG had a prolonged time to
clearance of CMV antigenemia. This is in line with our data, in which a
trend toward a shorter time to CMV clearance was observed in
nonmyeloablative recipients compared with myeloablative recipients
without mixed donor-host T-cell chimerism.1 Nakai et al
raise the question whether the observed effects in nonmyeloablative HSCT recipients are due to persistent host immunity or due to donor-derived lymphocytes. Our data in non-T-cell-depleted patients suggest that persistent host immunity is the likely reason because controlling for donor CMV serostatus did not change the
results.1 However, in T-cell-depleted patients the
situation may be different. Data in myeloablative recipients who
received T-cell-depleted grafts indicate that donor serostatus is an
important parameter of posttransplantation CMV risk.2 This
suggests that CMV-specific donor T cells may be important in this
setting. We agree that more laboratory studies are needed to define the
relative impact of host and donor immunity in nonmyeloablative
transplant recipients who are conditioned with regimens with and
without in vivo T-cell depletion. Recently developed technology should
be helpful to perform these experiments.3,4
Nakai et al also show incidence estimates of 3% for CMV disease using
a preemptive therapy approach and conclude that this figure is lower
than that reported in our study. The time of follow-up was not reported
in the letter. In our study, the incidence of CMV disease in
CMV-seropositive HSCT recipients was 6% (2/34 recipients) during the
first 100 days after transplantation with a similar preemptive therapy
approach.1 Recently we updated the data on CMV disease
among related HLA-matched donor nonmyeloablative HSCT
recipients.5 In this update, no new cases of CMV disease had occurred, resulting in an overall incidence of CMV disease of 4%
(2/51 recipients) among CMV-seropositive HSCT recipients during the
first 100 days after transplantation. Thus, the results appear to be
similar. We also described an increasing incidence of late CMV disease
among nonmyeloablative transplant recipients and emphasized that weekly
CMV surveillance and preemptive therapy should be continued for at
least 1 year in patients who had graft-versus-host disease and/or CMV
reactivation before day 100.1 Thus, the risk for late CMV
disease appears to be similar to that observed after myeloablative
transplantation,6 and similar prevention strategies should
be applied.
Christian Junghanss, Rainer Storb, and Michael Boeckh
Correspondence: Michael Boeckh, Fred Hutchinson Cancer Research
Center, 1100 Fairview Ave N, D3-100, PO Box 19024, Seattle, WA
98109-1024; e-mail: mboeckh{at}fhcrc.org
References
1.
Junghanss C, Boeckh M, Carter RA, et al.
Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation; a matched control study.
Blood.
2002;99:1978-1985[Abstract/Free Full Text].
2.
Gor D, Sabin C, Prentice HG, et al.
Longitudinal fluctuations in cytomegalovirus load in bone marrow transplant patients: relationship between peak virus load, donor/recipient serostatus, acute GVHD and CMV disease.
Bone Marrow Transplant.
1998;6:597-605.
3.
Peggs K, Verfuerth S, Pizzey A, et al.
Characterization of human cytomegalovirus peptide-specific CD8+ T-cell repertoire diversity following in vitro restimulation by antigen-pulsed dendritic cells.
Blood.
2002;99:213-223[Abstract/Free Full Text].
4.
Hebart H, Daginik S, Stevanovic S, et al.
Sensitive detection of human cytomegalovirus peptide-specific cytotoxic T-lymphocyte responses by interferon-gamma-enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation.
Blood.
2002;99:3830-3837[Abstract/Free Full Text].
5.
Junghanss C, Boeckh M, Carter RA, et al.
CMV infections in nonmyeloablative hematopoietic stem cell transplant (HSCT) recipients: a comparison between related and unrelated donor transplants[abstract].
Blood.
2001;98:S1662.
6. Boeckh M, Leisenring W, Riddell SR, et al. Late cytomegalovirus disease
and mortality in allogeneic marrow transplant recipients: importance of
viral load and CMV-specific T-cell immunity. Blood. In
press.
