initial low-dose valganciclovir as a preemptive therapy is effective for cytomegalovirus infection...
TRANSCRIPT
ORIGINAL ARTICLE
Initial low-dose valganciclovir as a preemptive therapy is effectivefor cytomegalovirus infection in allogeneic hematopoietic stem celltransplant recipients
Katsuto Takenaka • Koji Nagafuji • Ken Takase • Tomohiko Kamimura • Yasuo Mori •
Yoshikiyo Ito • Yukiko Nishi • Hideho Henzan • Koji Kato • Naoki Harada • Tetsuya Eto •
Toshihiro Miyamoto • Takanori Teshima • Koichi Akashi
Received: 11 February 2012 / Revised: 18 April 2012 / Accepted: 19 April 2012 / Published online: 1 May 2012
� The Japanese Society of Hematology 2012
Abstract Preemptive therapy for cytomegalovirus (CMV)
infection in allogeneic hematopoietic stem cell transplant
(HSCT) patients is effective in decreasing the incidence of
CMV disease. Intravenous ganciclovir is a commonly used
preemptive therapy, but as we have recently shown, oral
valganciclovir (VGC) is a useful alternative. However, the
optimal dose of VGC has not been determined. We prospec-
tively evaluated the efficacy and toxicity of an initial low-dose
of VGC (900 mg QD) as preemptive therapy in 20 patients
with low-level CMV antigenemia following allogeneic
HSCT. Patients were screened weekly for CMV pp65 anti-
genemia after engraftment. Preemptive therapy with VGC
(900 mg QD) was initiated if more than two CMV antigen-
positive cells per 50,000 leukocytes were detected. CMV
antigen-positive cells disappeared from all 20 patients after
14–29 days (median 20 days) of VGC treatment. None of the
patients developed CMV disease nor did they require more
than the conventional VGC dose (900 mg BID). Neutropenia
(\500/lL) developed in three patients who required granu-
locyte-colony-stimulating factor support, but there were no
other significant side effects. These observations suggest that
the initial dose of VGC in preemptive therapy for CMV can be
safely decreased to 900 mg QD for patients with low-level
CMV antigenemia.
Keywords Allogeneic hematopoietic stem cell
transplantation � Cytomegalovirus infection �Preemptive therapy � Low-dose � Valganciclovir
Introduction
Cytomegalovirus (CMV) infection is a major infectious
complication following allogeneic hematopoietic stem cell
transplantation (HSCT). CMV causes multiorgan disease
and remains a significant cause of morbidity and mortality
after allogeneic HSCT despite advances in the treatment of
CMV infection and CMV disease using ganciclovir (GCV)
and/or foscarnet [1–7]. The current strategies to manage
CMV infection use preemptive antiviral therapy with GCV,
valganciclovir (VGC), or foscarnet to prevent or minimize
end-organ disease. Preemptive therapy is typically initiated
before the onset of CMV disease when CMV reactivation
is first detected using the CMV pp65 antigenemia assay or
plasma real-time polymerase chain reaction (PCR) [8–14].
Preemptive anti-CMV therapy is highly effective,
decreasing the incidence of CMV disease in the first
100 days after allogeneic HSCT to\10 % [2, 4, 7, 15, 16].
For Fukuoka Blood and Marrow Transplant Group (FBMTG).
K. Takenaka (&) � Y. Mori � K. Kato � N. Harada �T. Miyamoto � K. Akashi
Department of Medicine and Biosystemic Science,
Kyushu University Graduate School of Medical Sciences,
3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
e-mail: [email protected]
K. Nagafuji
Division of Hematology and Oncology,
Department of Medicine, Kurume University School of
Medicine, Kurume, Japan
K. Takase � Y. Nishi � H. Henzan � T. Eto
Department of Hematology, Hamanomachi General Hospital,
Fukuoka, Japan
T. Kamimura � Y. Ito
Department of Hematology, Harasanshin Hospital,
Fukuoka, Japan
T. Teshima
Center for Cellular and Molecular Medicine, Kyushu University
Hospital, Fukuoka, Japan
123
Int J Hematol (2012) 96:94–100
DOI 10.1007/s12185-012-1087-9
The most commonly used antiviral drug for preemptive
therapy is intravenous GCV (IV-GCV); foscarnet, which is
usually reserved as a second-line drug, is as effective as
GCV, and both drugs are highly effective in decreasing the
incidence of early CMV disease [17–23]. These antiviral
treatments are given intravenously, often require hospital-
ization, are expensive, and are associated with IV-related
complications.
Valganciclovir is an L-valyl-ester of GCV that can be
taken orally and has highly improved bioavailability. VGC
and IV-GCV have similar safety and efficacy in the treat-
ment of CMV retinitis among human immunodeficiency
virus (HIV)-infected patients and in preemptive CMV
treatment among solid organ transplant patients; these uses
indicate that oral VGC is a useful alternative to IV-GCV
even after allogeneic HSCT [24–28]. Several recent studies
have shown that preemptive therapy with VGC *900 mg
BID is as effective as IV-GCV in allogeneic HSCT patients
[29–35]. However, neutropenia and/or thrombocytopenia
are significant side effects, indicating that a lower dose of
VCG should be considered, and the optimal dosage of
VGC in these patients remains to be determined. In the
present study, we used prospective analyses to evaluate the
safety and efficacy of initial low-dose VGC (900 mg QD)
taken orally as preemptive therapy for CMV reactivation in
20 allogeneic HSCT patients.
Patients and methods
Study design
This was a prospective, open-label, single-arm, multicenter
phase II study using initial low-dose VGC as preemptive
therapy for CMV reactivation after allogeneic HSCT. The
study was performed at four medical centers in Japan. The
primary objective was to determine the safety, toxicity, and
efficacy of preemptive therapy for CMV with a low-dose of
VGC to reduce the toxicity associated with the conven-
tional dose of VGC. This study was approved by the
Institutional Review Boards of each institute, and written
informed consent was obtained from each participating
patient.
Patients
The study patients were adults who underwent allogeneic
bone marrow, peripheral blood stem cell, or cord blood
transplantation. Patients were screened for CMV infection
at least once a week after engraftment using a CMV pp65
antigenemia assay. Patients were eligible for preemptive
therapy when 2–10 CMV antigen-positive cells per 50,000
leukocytes were detected. CMV-seronegative patients with
seronegative donors were not eligible for inclusion in this
study. Preconditioning regimens and prophylaxis against
graft-versus-host disease (GVHD) were not defined in our
study protocol; however, patients who had received an-
tithymocyte globulin, alemtuzumab, a T-cell depleted
graft, or CD34-positive selection was excluded. Patients
unable to take oral medication or having impaired renal
function (serum creatinine level [2.0 mg/dL) were ineli-
gible. Patients with CMV disease, patients who had
received antiviral agents other than prophylactic acyclovir
for herpes simplex virus, and patients with greater than
stage 2 gastrointestinal GVHD were also ineligible.
Twenty patients who underwent allogeneic HSCT at
Kyushu University Hospital, Kurume University Hospital,
Hamanomachi General Hospital, and Harasanshin Hospital
between December 2009 and January 2011 were enrolled
(Table 1). High-risk patients were defined as those who
Table 1 Patient characteristics
Number of patients 20
Median age (years) (range) 55 (25–68)
Median body weight (kg) (range) 57 (40–75)
Median body surface are (m2) (range) 1.6 (1.3–1.9)
Diagnosis
Acute myeloid leukemia 12
Non-Hodgkin’s lymphoma 5
Myelodysplastic syndrome 2
Multiple myeloma 1
Stem cell donor
HLA-identical siblings 6
Unrelated donors 6
Cord blood 8
CMV serologic status
Donor?/recipient? 11
Donor-/recipient? 9
Preparative regimens
Conventional 11
Reduced intensity 9
GVHD prophylaxis
Cyclosporine/MTX or MMF 13
Taclorimus/MTX or MMF 7
Acute GVHD prior to CMV reactivation
None 7
Grade I 4
Grade II 7
Grade III 2
Risk for CMV disease
Low-risk 4
High-risk 16
GVHD graft-versus-host disease, MTX methotrexate, MMF myco-
phenolate mofetil
Low-dose VGC as preemptive therapy after allo-HSCT 95
123
received transplantation from other than HLA-identical
siblings, those with grade II–IV acute GVHD, and those
receiving C0.5 mg/kg of methylprednisolone at the initia-
tion of preemptive therapy; the remaining patients were
considered to be at low risk.
CMV antigenemia assay
The CMV antigenemia assay was performed as previously
described [10, 11]. Cells were immunostained with anti-
CMV pp65 monoclonal antibody HRP-C7 (Teijin, Tokyo,
Japan). The number of CMV antigen-positive cells per
50,000 leukocytes was determined visually using light
microscopy; 1 or more CMV antigen-positive cells per
50,000 leukocytes was considered positive, low-level
antigenemia was defined as fewer than 10 positive cells,
and high-level antigenemia was defined C10 positive cells
per 50,000 leukocytes.
Definitions of CMV infection and CMV disease
Cytomegalovirus infection was defined as a positive test
for CMV antigenemia, and CMV disease was diagnosed
according to published recommendations [36]. Biopsies
were collected from patients with clinical manifestations of
CMV disease, such as interstitial pneumonia and gastro-
enteritis in the presence of CMV antigenemia, and ana-
lyzed histopathologically and immunochemically.
Protocol for preemptive therapy with initial low-dose
of VGC for CMV infection
Cytomegalovirus reactivation was monitored using the
antigenemia assay once a week until day 100 after
engraftment and once every 2 weeks thereafter. For
patients of all risk groups, preemptive therapy using initial
low-dose of VGC was initiated when low-level CMV
antigenemia with a CMV antigen-positive cell count of C2
per 50,000 leukocytes developed in any patient (Fig. 1).
VGC was administered orally at a dose of 900 mg QD for
at least 1 week. Following this, the antigen-positive cell
count was re-assessed and the dose of VGC modified if
necessary as follows: the dose was not changed if the
positive cell count was\10 per 50,000 leukocytes, the dose
was increased to 900 mg BID if the positive cell count
reached C10 cells per 50,000 leukocytes, the dose was
decreased from 900 mg BID to 900 mg QD if the positive
cell count returned to\10 per 50,000 leukocytes, and VGC
was discontinued after two consecutive negative results.
Patients who required 900 mg BID VGC for more than
2 weeks were considered to be refractory and were allowed
to receive alternative therapy. The dose was adjusted for
patients with impaired renal function according to the
manufacturer’s recommendation. Acyclovir for herpes
simplex prophylaxis was discontinued when VGC treat-
ment was started. Supplemental immunoglobulin was
administered only if total IgG was \400 mg/dL.
Fig. 1 Study design. Patients
who required valganciclovir
(VGC) at a dose of 900 mg BID
for more than 2 weeks were
considered to be refractory and
received alternative therapy
96 K. Takenaka et al.
123
Endpoints and definitions
The primary endpoint was the rate of complete response
(CR) to the initial low-dose of VGC preemptive therapy for
CMV infection. A CR was defined as the conversion of
positive CMV antigenemia test results to negative and the
cessation of VGC preemptive therapy within 8 weeks after
initiation without developing CMV disease.
Secondary endpoints were the rate of patients requiring
an increased dose of VGC (900 mg BID), safety of initial
low-dose preemptive therapy, incidence of CMV disease
during VGC treatment, and incidence of a recurrent CMV
reactivation after the completion of VGC treatment.
Patients were monitored for CMV using the antigenemia
assay for at least 4 weeks after the completion of the VGC
treatment. Safety analyses were conducted at least weekly,
which included blood counts, liver and renal function tests,
and documenting other unexpected side effects according
to the Common Terminology Criteria for Adverse Events
v3.0. The incidence of CMV disease was evaluated during
the entire study period.
Patients whose antigenemia remained [10 per 50,000
leukocytes for more than two weeks at 900 mg BID VGC
or who developed CMV disease during the preemptive
therapy were considered treatment failures and were
allowed to be placed on alternative therapy such as IV-
GCV.
Results
Patient characteristics and CMV reactivation
The characteristics of the 20 patients with low-level CMV
antigenemia enrolled in this study are shown in Table 1.
Preemptive therapy with an initial low-dose of VGC for
CMV reactivation was initiated after a median of 54 days
(range 14–404 days) following transplantation. The med-
ian number of CMV antigen-positive cells at the initiation
of preemptive therapy was 4 per 50,000 leukocytes (range
2–9 per 50,000 leukocytes). The median age of the patients
at the time of transplantation was 55 years (range
25–68 years). Six patients had received bone marrow or
peripheral blood stem cell grafts from HLA-matched sib-
ling donors, whereas the remaining 14 patients had
received transplants from alternative donors, and eight of
these received cord blood. All patients were CMV-sero-
positive before transplantation. Ten patients received my-
eloablative preparative regimens, and the remaining ten
patients received a fludarabine-based reduced-intensity
conditioning regimen. Prior to CMV reactivation, acute
GVHD developed in 13 patients with severities of grade I
(n = 4), grade II (n = 7), and grade III (n = 2). Twelve
patients received methylprednisolone (C0.5 mg/kg) for
acute GVHD at the initiation of preemptive therapy. Four
patients were in the low-risk group, and 16 patients were in
the high-risk group.
Response to preemptive therapy with a low initial dose
of VGC
All patients became negative for CMV antigen, and pre-
emptive therapy was concluded with a median 20 days of
900 mg QD VGC (range 14–29 days; Fig. 2). No patient
required a higher dose of VGC (900 mg BID), and none
were switched to alternate anti-CMV agents. No patient
developed CMV disease during the preemptive therapy or
in the subsequent 4 weeks after the completion of the VGC
treatment. All patients achieved CR; therefore, the CR rate
was 100 % (95 % confidence interval 86.1–100 %). CMV
infection relapsed in four patients within 4 weeks after the
completion of the preemptive VGC therapy, which was
successfully treated using VGC or IV-GCV.
Adverse events during VGC preemptive therapy
All patients completed the VGC preemptive therapy, and
there were no toxicity issues. Neutropenia (\500/lL)
occurred in three patients, and they were administered
granulocyte-colony stimulating factor (G-CSF) for a med-
ian 3 days (range 2–7 days). There was no febrile neutro-
penia. Three patients required platelet transfusion during
preemptive therapy. Their platelet counts at the initiation of
CM
V a
ntig
en-p
ositi
ve c
ells
50,0
00 W
BC
s
Weeks after VGC treatment
VGC 900mg QD x 20days (range, 14-29)
Fig. 2 Time course of the cytomegalovirus (CMV) antigen-positive
cell count in patients who received preemptive therapy with an initial
low-dose of VGC. The CMV antigen-positive cell count decreased
promptly after initiation of VGC treatment, and all patients completed
preemptive therapy in a median of 20 days (range 14–29 days). CMV
infection relapsed in four of 20 patients within 4 weeks after the
completion of the preemptive valganciclovir (VGC) therapy, and
these patients were successfully treated using VGC or intravenous
ganciclovir (IV-GCV)
Low-dose VGC as preemptive therapy after allo-HSCT 97
123
preemptive therapy were 13.3, 2.6 and 1.6 9 109/lL,
respectively, and recovered to[2.0 9 109/lL by the end of
follow-up.
Elevated serum creatinine levels above baseline indi-
cated renal impairment and was detected in two patients
(grade 1, n = 1; grade 2, n = 1). Other adverse events
included grade 1 liver dysfunction (n = 1), grade 1 nausea
(n = 1), and grade 1 diarrhea (n = 1; Table 2), but none
required VGC to be discontinued.
Discussion
Intravenous ganciclovir is currently the first-line agent for
CMV preemptive therapy and is usually initiated at a dose
of 5 mg/kg BID [5]. Previous pharmacokinetic studies in
HIV-infected or liver transplant patients have shown that
the area under the concentration–time curve for 900 mg
VGC was similar to that for 5 mg/kg IV-GCV [37, 38]. On
the basis of those results, early studies of VGC preemptive
therapy found that an initiation dose of 900 mg BID was as
effective at controlling CMV as the conventional IV-GCV
regimen [29–35]. However, hematologic toxicity was a
significant problem with both treatments, indicating that
additional studies were necessary to clarify the safety and
efficacy of lower dose or short-duration preemptive CMV
therapy. Several studies have evaluated the feasibility of
preemptive therapy using an initial low-dose of IV-GCV;
IV-GCV was initiated at 5 mg/kg QD and was increased to
5 mg/kg BID if the viral load continued to increase. These
studies showed that the initial dose of GCV could be safely
decreased to 5 mg/kg QD in combination with weekly
monitoring of the viral load using CMV antigenemia or
plasma real-time PCR assays [22, 23, 39]. In preemptive
therapy using VGC, Candoni et al. [31] suggested that a
lower VGC dose (900 mg QD) had comparable efficacy to
900 mg BID VGC in clearing CMV antigen-positive cells
in the allogeneic HSCT setting; a similar efficacy was also
found in a non-randomized small study [40]. On the basis
of these findings, we performed a prospective study to
evaluate the feasibility of preemptive therapy of VGC at an
initial dose of 900 mg QD.
Patients in any risk group were enrolled in this study if
they had low-level CMV antigenemia. For safety reasons,
we excluded patients with high-level CMV antigenemia,
and most of them received the conventional IV-GCV
treatment of 5 mg/kg BID. In our previous study, the
number of CMV antigen-positive cells was 4.9 per 50,000
leukocytes (range 3.0–59.4 per 50,000 leukocytes) at first
detection [33], and &70 % of the CMV-positive patients
developed low-level CMV antigenemia. Furthermore,
patients who could not take oral medications were not
enrolled. Approximately 20 % of patients who received
allogeneic HSCT during the study period were included in
this study. Even with these limitations, our data clearly
showed that preemptive therapy using initial low-dose
VGC (900 mg QD) was effective in preventing CMV
disease in patients with low-level CMV antigenemia even
though 80 % of the patients were of the high-risk group.
None of the patients required any increase in the VGC dose
or discontinued VGC because of adverse events. This result
suggested that initial low-dose VGC therapy can decrease
the total dose of VGC and hematologic toxicity of VGC
compared with an initial conventional dose of VGC ther-
apy. However, there still could be a possibility that the
initial conventional dose of VGC results in faster
achievement of CR and that the total dose of VGC may be
less than the initial low-dose regimen. This possibility can
be solved only by performing a randomized controlled
study.
Our data showed that preemptive therapy of an initial
low-dose of VGC completely prevented development of
CMV disease; however, hematologic complications, such
as neutropenia and/or thrombocytopenia, remained a sig-
nificant complication, although these were successfully
managed with G-CSF administration and platelet transfu-
sions. In a randomized crossover trial, Einsele et al. [41]
showed that oral VGC led to a higher exposure to GCV
than IV-GCV in allogeneic HSCT patients with no GVHD
or with grade I–II intestinal GVHD. On this basis, 900 mg
QD of VGC may result in a higher effective dose of GCV
than 5 mg/kg QD of IV-GCV. We have demonstrated the
efficacy of 900 mg QD of VGC as preemptive therapy for
patients with low-level CMV antigenemia, and it may be
possible to reduce the initial dose of VGC to\900 mg QD
(e.g., 450 mg QD), especially in low-risk patients, to
minimize hematologic toxicity. In addition, preemptive
therapy using 900 mg QD of VGC may be feasible for
patients with high-level CMV antigenemia if the viral load
is carefully monitored. An alternative method to minimize
hematologic toxicity may be to decrease the total exposure
to VGC by raising the threshold of CMV antigen-positive
Table 2 Adverse events other than hematological toxicity related to
valganciclovir
Adverse events No. of cases
Gastrointestinal
Nausea/vomit Grade 1 2/20
Diarrhea Grade 1 1/20
Hepatic
AST/ALT Grade 1 3/10
Renal
Serum creatinine Grade 1 1/20
Grade 2 1/20
98 K. Takenaka et al.
123
cells at which VGC is initiated. In the present study, we
used a lower threshold value, 2 cells per 50,000 leukocytes,
because the present study was designed to evaluate the
feasibility of preemptive therapy of a decreased initial dose
of VGC. However, as Kanda et al. [23] suggested from
their prospective study using IV-GCV, a higher threshold
to begin VGC therapy could be applied, especially for low-
risk patients, in future studies.
Cytomegalovirus infection relapsed in four out of 20
patients (20 %) within 4 weeks after the completion of the
preemptive VGC therapy, although they were successfully
treated using VGC or IV-GCV. In our previous study using
an initial conventional-dose regimen, four of 10 (40 %)
patients developed recurrent CMV reactivation after the
discontinuation of VGC treatment, indicating that initial
low-dose therapy may not increase the incidence of
recurrent CMV reactivation [33]. However, the relapse rate
is considerable regardless of the initial dose of VGC.
Additional maintenance therapy of VGC will increase the
total dose of VGC and hematologic toxicity, hence CMV
monitoring for recurrent CMV reactivation should be
continued after completion of preemptive therapy instead
of maintenance therapy.
In conclusion, we have demonstrated that the initial dose
of VGC used in preemptive therapy for CMV can be safely
decreased to 900 mg QD for patients with low-level CMV
antigenemia. However, larger clinical trials are necessary
to determine the optimal dose and duration of VGC therapy
that minimizes or eliminates hematologic toxicity in
patients with different viral loads and risk factors.
Acknowledgments This work was supported in part by a Grant-in-
Aid from the Ministry of Education, Culture, Sports, Science and
Technology in Japan [23591392] and the Cell Science Research
Foundation.
Conflict of interest The authors declare that they have no conflict
of interest.
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