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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1627-1630
CORRESPONDENCE
To the editor:
Strategies for management of cytomegalovirus (CMV)
infection after allogeneic bone marrow transplantation: the
"doubling of baseline CMV pp65 antigenemia" and the
"cidofovir as rescue treatment" approaches
Recently 2 papers dealing with strategies for management of
cytomegalovirus (CMV) infection in patients receiving bone marrow transplantation (BMT) have made interesting
suggestions,1,2 but we would like to make some comments. Nichols et al1 found that a more than 2-fold increase of
CMV pp65 antigenemia (as compared to baseline) occurring during preemptive anti-CMV treatment should be managed by induction or reinduction doses of antiviral drugs. But we think that the description of this strategy should be clarified. It is, in fact, unclear whether
the definition of "baseline" pp65 refers to the levels that were
observed when the patients first became positive or whether it refers
to levels observed when they became positive again during maintenance
treatment, although after a complete clearance (reactivation).
Therefore, if they mean "baseline" as the first test with
positive result, then considering the 2-fold increase seen in some
patients, the reported levels of antigenemia ranging from 0.5 to 1382 cells/slide could reach levels ranging from 1 to 2 but also from 1382 to 2764 (including all the possible intermediate values). We cannot
wait for such levels to be reached before changing the antiviral drugs. Ljiungman et al2 dealt with cidofovir administration for
management of pp65 antigenemia. In this paper, they reported a 66%
efficacy of cidofovir in patients who failed or relapsed after previous
preemptive therapy. Unfortunately, the authors did report which
strategies were adopted strategies in the one-third of patients who
failed after cidofovir "rescue." We recently treated 2 pediatric patients receiving matched
unrelated donor BMT whose CMV pp65 antigenemia increased during preemptive or maintenance therapy. The time course of CMV antigenemia, the treatment administered, and its "efficacy" are shown in Figure 1.
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| Figure 1.
Time course of CMV pp65 antigenemia and antiviral drugs
administered.
(A) patient 1; (B) patient 2. The 4 arrows refer to each single dose of
cidofovir.
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In our first case (Figure 1A), since other antiviral drugs proved to be
ineffective, cidofovir was administered to the patient.2 When relapse occurred during cidofovir maintenance therapy, we used the
same drug after doubling of antigenemia levels, though unsuccessfully.
But the same patient responded to ganciclovir, as already reported in
another case.3 In the second case (Figure 1B), we observed
an increase in pp65 antigenemia despite association therapy with
ganciclovir and foscarnet.4 A spontaneous decrease in
antigenemia was then observed in this patient without making any
changes in immunosuppressive and antiviral therapy. In both of the patients, in agreement with Nichols et al1
we observed that the role of antiviral resistance is probably not very
important in determining the time course of pp65 antigenemia in
allogeneic BMT recipient. Other unknown factors should likely be
considered pivotal in the outcome of these patients. From our experience, we believe that some clarifications, such as a
more clear definition of "baseline" and of "2-fold increase" levels in the first paper,1 and a description of
treatment administered in patients who failed to respond to cidofovir
administration in the second one,2 would be useful for
studying the best strategies for management of relapsing pp65 antigenemia.
Elio Castagnola, Maurizio Miano, Giuseppe Morreale, Emilo Cristina, Maura Chierici, and Edoardo Lanino
Correspondence: Elio Castagnola, Infectious Diseases Unit, G. Gaslini Children's Hospital, Largo G. Gaslini 5, Genova, Italy
References
1.
Nichols WG, Corey L, Gooley T, et al.
Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes.
Blood.
2001;97:867-874[Abstract/Free Full Text].
2.
Ljiungman P, Lambertenghi Deliliers G, Platzbecker U, et al.
Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients.
Blood.
2001;97:388-392[Abstract/Free Full Text].
3.
Castagnola E, Cristina E, Dallorso S, Lanino E, Giacchino R.
Failure of cidofovir to reduce CMV-antigenemia in a child transplanted from a matched unrelated donor.
J Chemother.
2001;13:100-101[Medline]
[Order article via Infotrieve].
4.
Bacigalupo A, Bregante S, Tedone E, et al.
Combined foscarnet-ganciclovir treatment for cytomegalovirus infection after allogeneic hemopoietic stem cell transplantation (HSCT).
Bone Marrow Transplant.
1996;18(suppl 2):110-114.
Response:
Cidofovir against cytomegalovirus after allogeneic stem
cell transplantation
It was interesting to see the results from the prospective study
by Kiehl and Basara using cidofovir as a first-line preemptive therapy
against cytomegalovirus (CMV) after allogeneic stem cell transplantation. The results from their study seem to differ very much
from those reported in our recent study.1 But the 2 studies do not differ in the response to full-dose cidofovir (58% in
our study, 76% in Kiehl and Basara's). Instead, the difference is in
a higher relapse rate in the study by Kiehl and Basara. In a recent
study by Reusser et al for the Infectious Diseases Working Party of the
European Group for Blood and Marrow Transplantation (EBMT) comparing
ganciclovir and foscarnet, it was shown that relapse defined as
reappearance of CMV DNA detected by PCR or of pp65 antigenemia is
common also when patients are treated by either of these 2 antiviral
drugs.2 The difference is that in Kiehl and Basara's
study reappearance of CMV DNA occurred during maintenance therapy,
while in the EBMT study the relapse occurred rapidly after
discontinuation of therapy. There are at least 3 possibilities to
explain the differences: First, the risk profile of the patients might differ, such as the type
of transplantations performed, the GVHD prophylaxis used, the grades of
GVHD, conditioning therapy, and types of donors. This cannot be
ascertained by the details given in Kiehl and Basara's letter. But
most of their patients had received unrelated donor transplants,
indicating a high-risk group. Second, the diagnostic procedures used for CMV in the different studies
might be different. All patients receiving cidofovir as first-line
preemptive therapy in our study was monitored by pp65 antigenemia.
Kiehl and Basara's study used PCR and antigenemia for monitoring but
PCR for definition of relapse. In fact, they give no data at all
regarding the results of the antigenemia assay after discontinuation of
cidofovir. Furthermore, it is not stated what the material used for the
PCR was (leukocytes, plasma, or whole blood). It would be interesting
to determine the viral load by quantitative PCR, but viral load
determinations were not performed in our study or in Kiehl and
Basara's. But Bosi et al3 recently presented data at the
recent EBMT meeting, indicating that patients with low viral loads have
a better response to cidofovir than patients with high viral loads. Third, treatment schedules might differ, for example, whether the third
cidofovir dose was given after 2 or 3 weeks from start of therapy (see below). These differences can only be controlled in a prospective and
randomized study. This was proposed in our paper and is supported in
Kiehl and Basara's letter. It is important to point out, however, that
when Kiehl and Basara state that their data contradicts our conclusions, this is an incorrect representation of our conclusions. We
clearly state that "additional studies are needed before cidofovir can be recommended for preemptive therapy"1(p388) and
"we believe that randomized, comparative studies are indicated before
CDV is introduced as an accepted agent for first-line preemptive therapy."1(p391) In our opinion, the most important
result from our study is that cidofovir can be used in allogeneic stem
cell transplant patients with a risk for toxicity, allowing further
studies. This is confirmed by Kiehl and Basara's letter and, thereby,
hopefully will make prospective, randomized studies possible. Castagnola et al ask for the strategies used for patients failing
cidofovir "rescue" in our paper. It is important to note that the
indication for secondary preemptive therapy could be either relapse or
no response to previously given antiviral therapy. Thus, many of the
patients were in fact treated for recurring antigenemia or DNAemia
rather than increasing antigenemia. Unfortunately, due to the
retrospective nature of our study, we do not have the information
requested by Castagnola et al. But we agree that both for patients
followed by pp65 antigenemia and for those followed by qualitative PCR,
low-degree positivity in either of the assays has a low predictive
value after antiviral therapy. Furthermore, it is important to
differentiate between failure of an antiviral agent to turn a positive
test to negative and development of relapse in either antigenemia or
DNAemia after the indicator test has become negative. The former
probably has to do with viral kinetics and the built-in
characteristics of the assay used. The latter is also dependent on the
ability of the patient to mount a long-term immune response to handle
the virus. It is possible that wider usage of true quantitative assays
can give additional important information. There is one other important question regarding cidofovir raised by
both letters. When shall the third cidofovir dose be given? From
Castagnola et al's Figure 1, it seems that the third dose was given 2 weeks after the second dose. This is very different from how we give
ganciclovir or foscarnet when 2 weeks' induction therapy usually is
followed directly by maintenance, although in a lower dose. This means
that a patient has therapeutic levels of cidofovir for approximately 2 weeks and then there is a 1-week interval before the drug is
given again.
Per Ljungman and Catherine Cordonnier, for the Infectious Disease Working Party
of the European Group for Blood and Marrow Transplantation
Correspondence: Per Ljungman, Karolinska Institutet, Department
of Hematology, Huddinge University Hospital, Stockholm SE-14186, Sweden
References
1.
Ljungman P, Deliliers GL, Platzbecker U, et al.
Cidofovir for cytomegalovirus infection and disease in allogeneic stem cell transplant recipients: The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.
Blood.
2001;97:388-392.
2.
Reusser P, Einsele H, Lee J, et al.
Randomized, multicenter, open-label trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Paper presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA; September 26-29, 1999.
3.
Bosi A, Laszlo D, Paci C, et al.
PCR-based preemptive therapy for CMV reactivation in allogeneic stem cell transplant recipients with cidofovir: a preliminary single center experience.
Bone Marrow Transplant.
2001;27:s52.
Response:
Rising cytomegalovirus antigenemia on preemptive therapy:
practical aspects
Our study of 119 allogeneic transplant recipients who developed
pp65 antigenemia early after transplantation demonstrated that host
factors (primarily the dose of corticosteroids administered for
graft-versus-host disease [GVHD]), not resistance to antivirals, explain the phenomenon of rising viral load during the first 1-2 months
of preemptive therapy.1 Thus, we concluded that empiric switches from ganciclovir to foscarnet (to restore activity
against ganciclovir resistant strains of cytomegalovirus
[CMV]) are not usually necessary. Rather, dose intensification
(continued induction dosing or reinduction dosing) should be used as a
first-line strategy in the management of these patients. Castagnola et al raise important issues regarding the practical
application of this strategy. The first issue concerns the precise
definition of increases of greater than twice baseline. As indicated in
"Patients and methods," we defined the "baseline" antigenemia
level as the number of positively staining cells obtained at the first
positive test. An increase from 1 cell (at the first positive test) to
2 cells on any subsequent test was thus defined as an increase
of 2 times baseline. Operationally, this criterion was met
predominantly among patients with low initial antigenemia levels: of 47 patients with greater than 2-fold increases over baseline, 25 (53%) had initial antigenemia levels of no more than 2, and 12 (26%) had initial antigenemia levels of 2.5-10, while only 10 (21%)
had initial antigenemia levels above 10. As discussed in the article,
initial antigenemia levels did not predict CMV disease in this cohort
of patients who were receiving preemptive therapy. Castagnola et al also refer to the time course of the antigenemia
increase. Rising antigenemia was assessed regardless of when the
increase occurred. As presented, however, the majority (90%) of
patients whose antigenemia levels rose on therapy did so within the
first 2 weeks: 43% after 1 week of induction therapy and 47% after 2 weeks of therapy (when the majority had received only 1 week of
maintenance therapy). Thus, in our cohort of non-T-cell-depleted patients, these were events that tended to occur early in the course of
antiviral therapy rather than during prolonged courses of maintenance
therapy. This pattern may be quite different in the patient who
receives ganciclovir prophylaxis,2 T-cell-depleted transplants,3 or salvage therapies for GVHD, all of which
impair the recovery of CMV-specific T-cell immunity. It is difficult to speculate about the possible reasons for
failure in the patients presented by Castagnola et al with the limited
information provided on the exact timing of events, net status of
immunosuppression, and dose regimens of the antiviral drugs. But there
are several factors that could be responsible for the failure of
antigenemia clearance in the first patient (Figure 1A), including the
underlying immunosuppressive regimen or changes thereof, changes in
GVHD status, the dosing interval of cidofovir (1 versus 2 weeks), or
drug resistance. Also, there are reports in HIV-infected individuals
that clearance of CMV from the blood can take a long time with
cidofovir, despite efficacy in the treatment of end-organ
disease.4 The pattern displayed in the second patient
(Figure 1B) is compatible with delayed clearance of antigenemia in the
presence of anti-CMV treatment. This may occur in a small number of
allogeneic stem cell transplant recipients, usually those on intense immunosuppression. Some final words regarding the quantitative nature of the
antigenemia assay are warranted. While the antigenemia assay provides useful data on the quantitative CMV viral load, there are very few data
on the interassay variability of antigenemia quantitation. Variability
of quantitative results is usually much greater at the lower ranges of
antigenemia levels (from 0.5 to 2 cells/slide) when compared to the
upper ranges (more than 10 cells/slide). Thus, multiplicative increases
in antigenemia may be more reflective of "true" increases in viral
load if the initial antigenemia level is higher. Nevertheless, modeling
an increase of twice baseline was most correlated with breakthrough CMV
disease in our retrospective cohort; regardless of the initial level of
antigenemia, rises of twice baseline while on preemptive antiviral
therapy appear to reflect the host's inability to control viral
replication. In subjects with rising antigenemia levels, continuation
of induction dosing or reinduction is now standard practice at our
center for those with twice baseline increases. For those patients with
very high initial antigenemia levels (more than 100 cells/slide),
clinically significant increases may be present even before the cut
point of twice baseline is met, especially in patients who are severely immunosuppressed. But in these cases the determination of what is a
"true" increase must include consideration of the coefficient of
variation of the quantitation method. Since quantitative aspects of
antigenemia testing may vary with assay modifications,5 determination of the coefficient of variation may be required for each
individual assay.
W. Garrett Nichols and Michael Boeckh
Correspondence: Michael Boeckh, Program in Infectious
Diseases, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N,
D3-100, Seattle, WA 98109
References
1.
Nichols WG, Corey L, Gooley T, et al.
Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes.
Blood.
2000;97:867-874.
2.
Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR.
Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis.
Blood.
1994;83:1971-1979[Abstract/Free Full Text].
3.
Hebart H, Brugger W, Grigoleit U, et al.
Risk for cytomegalovirus disease in patients receiving polymerase chain reaction-based preemptive antiviral therapy after allogeneic stem cell transplantation depends on transplantation modality.
Blood.
2001;97:2183-2185[Free Full Text].
4.
Polis MA, Spooner KM, Baird BFB, et al.
Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria.
Antimicrob Agents Chemother.
1995;39:882-886[Abstract].
5.
Boeckh M, Boivin G.
Quantitation of cytomegalovirus: methodologic aspects and clinical application.
Clin Microbiol Rev.
1998;11:533-554[Abstract/Free Full Text].
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