Efficacy of the Mobilization of Peripheral Blood Stem Cells by Granulocyte Colony - Stimulating Factor in Pediatric Donors

[CANCER RESEARCH 59, 3321–3324, July 15, 1999]
Advances in Brief
Efficacy of the Mobilization of Peripheral Blood Stem Cells by Granulocyte Colony-
Stimulating Factor in Pediatric Donors1
Yoshifumi Kawano,2 Yoichi Takaue, Tsutomu Watanabe, Takanori Abe, Yasuhiro Okamoto, Asayuki Iwai,
Tsuyako Iwai, Arata Watanabe, Etsuro Ito, Atsushi Makimoto, Ryuji Nakagawa, Hiroyoshi Watanabe, Junko Sato,
Kentaro Suenaga, Hiroko Suzuya, Toshihiro Ohnishi, Sachiyo Kanamaru, Michiya Kaneko, and Yasuhiro Kuroda
Department of Pediatrics, University of Tokushima, Tokushima 770-8503, Japan [Y. K., T. W., T. A., Y. O., A. M., R. N., H. W., J. S., K. S., H. S., T. O., S. K., M. K., Y. K.]; Stem
Cell Transplantation Unit, National Cancer Center Hospital, Tokyo 104-0045, Japan [Y. T.]; Division of Hemato/Oncology, Kagawa Children’s Hospital, Zentsuji, Kagawa 765-
8501, Japan [A. I., T. I.]; Department of Pediatrics, University of Akita, Akita 010-8543, Japan [A. W.]; and Department of Pediatrics, University of Hirosaki, Aomori 030-8562,
Japan [E. I.]
Abstract
of cancers (10 –12). Against this background, we evaluated the effi-
cacy and kinetics of G-CSF mobilization in healthy children who were
The advantages/disadvantages of the use of peripheral blood stem cells
donating grafts for their siblings. The data were compared with those
(PBSCs) for allogeneic transplantation still need to be clarified, particu-
obtained in healthy adult donors treated at our institutes.
larly in children. We compared the kinetics, efficacy, and safety of PBSC
mobilization by granulocyte colony-stimulating factor (G-CSF) and col-
lection by apheresis between healthy pediatric and adult donors. A total of
Materials and Methods
19 pediatric (median age, 6 years) and 25 adult healthy donors (median
Subjects and Mobilization Protocol. A total of 19 healthy children (9
age, 37 years) were given 10 ?g/kg/day of G-CSF for 5 consecutive days
males and 10 females) who were the related donors for allogeneic PBSCT was
for PBSC mobilization, which were harvested by apheresis on days 5
enrolled into this study. The ranges of their ages were 2–5 years in 6, 6 –10
and/or 6. All of the donors tolerated the whole procedures. Serum trough
years in 4, and 11–16 years in 9 (median age, 10 years). PBSC mobilization
levels of G-CSF determined by ELISA were significantly lower in the 16
was performed by the administration of 10 ?g/kg/day of G-CSF (filgrastim
pediatric donors evaluated than in adults (n ? 16) on days 3 and 4
from Kirin Brewery Co., lenograstim from Chugai Pharmaceutical Co., or
(P < 0.05). Although the WBC counts on days 4 and 5 were significantly
nartograstim from Kyowa-Hakko Kogyo Co., Tokyo, Japan) for 5 consecutive
higher in adults than in children (P ? 0.006 and 0.004, respectively), the
days. Principally, G-CSF was injected s.c. at 9 a.m. each day. Blood samples
numbers of circulating CD34? cells/unit of blood were identical. The
for daily analysis of complete blood count, blood chemistry, colony assay,
number of blood CD34? cells collected per unit of blood processed was
CD34? cell assay, and the serum concentration of G-CSF were drawn imme-
identical in both donor populations. We propose that PBSCs could be
diately before the injection of G-CSF. Data from 25 adult donors (median age,
effectively mobilized and collected in small children so that they could be
37 years; 18 – 49 years: 17 males and 8 females) who were treated with the
donors for adult patients.
same mobilization protocol were also analyzed. All of the adult donors
received prophylactic aspirin (600 –900 mg/day) during G-CSF treatment. A
Introduction
consent form was obtained from a guardian of the pediatric donors or directly
from the adult donors. This trial was approved by the individual Institutional
Allogeneic PBSCT 3 is increasingly used in place of bone marrow
Review Boards.
transplantation (1). Its benefits include faster hematopoietic recovery
PBSC Collection Procedure. On days 5 and/or 6 of the mobilization
and a lower complication rate in the early stage of posttransplantation
protocol, collection of PBSCs was begun at 11 a.m. using a Fenwal CS3000
when an adequate amount of cells (?3 ? 106 CD34? cells/kg) are
Plus (Baxter Healthcare Co, Irvine, CA) with a processing volume of 300
mobilized and harvested (2). In most adult donors, PBSCs are mobi-
ml/kg (maximum, 10 liters) per session. For small donors weighing ?20 kg, a
lized by the 5-day administration of G-CSF (10 –12 ?g/kg/day), and
small volume separation chamber holder was used, and WBC-depleted, irra-
a graft containing ?3 ? 106 CD34? cells/kg can be collected in
diated, washed RBCs were also used for priming the extracorporeal line before
?
blood processing was begun, as reported previously (13). In four small donors,
80% of donor-recipient pairs by a couple of aphereses (3– 6).
a total of 200 ml of previously collected and stored autologous RBCs was used
Although the reported complications related to G-CSF treatment vary
for priming. Principally, blood was drawn from a catheter inserted into a radial
widely, serious complications have been observed only in donors/
artery and given back through an antecubital vein. In the case of small donors
patients with background diseases (7–9). No comprehensive data are
who used autologous RBCs, RBCs left in the apheresis kit were collected for
available regarding the safety and efficacy of PBSC mobilization/
the next procedure. To avoid hypocalcemia due to citrate intoxication, calcium
collection in pediatric donors. In autologous settings, we have estab-
gluconate was administered continuously in a ratio of 1 ml per 200 ml of blood
lished a PBSC mobilization and harvesting protocol with the use of a
processed. For safety, the hematocrit level and percentage of oxygen saturation
continuous blood cell separator in pediatric patients with various types
in the arterial blood were continuously monitored with a Crit-Line (IN-LINE
Diagnostic Corp., UT) in pediatric donors (14).
In the case of adult donors, PBSCs were universally harvested with a
Received 3/8/99; accepted 6/1/99.
standard CS3000 Plus using the combination of a granulocyte chamber and
The costs of publication of this article were defrayed in part by the payment of page
small volume collection chamber, as reported previously (15).
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
Hematopoietic Progenitor Assay. The details of the hematopoietic pro-
1 This work was supported by a Grant-in-aid for Scientific Research (C) (2) from the
genitor assays have been reported previously (16). Briefly, cells were incu-
Ministry of Education, Science, Sports and Culture and by a Grant-in-aid for the Second-
bated in methylcellulose medium supplemented with 20% fetal bovine serum
term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and
(Life Technologies, Inc., Grand Island, NY), 450
Welfare.
?g/ml of human transferrin
2 To whom requests for reprints should be addressed, at Department of Pediatrics,
(Sigma Chemical Co., St. Louis, MO), 2 units/ml of human recombinant
University of Tokushima, 2-50-1 Kuramoto-cho 3, Tokushima 770-8503, Japan. Fax:
erythropoietin (Kirin Brewery Co.), 1% crystallized BSA (Calbiochem 12567;
81-88-631-8697; E-mail: ykawano@clin.med.tokushima-u.ac.jp.
3
Hoechst Japan, Tokyo, Japan), interleukin 3 (20 ng/ml; Kirin), stem cell factor
The abbreviations used are: PBSCT, peripheral blood stem cell transplantation;
(20 ng/ml; Kirin), and G-CSF (20 ng/ml; filgrastim, Kirin). Cells were placed
G-CSF, granulocyte colony-stimulating factor; CFU-GM, colony forming units for gran-
ulocyte/macrophage; MNC, mononuclear cell.
into 24-well culture plates (Corning, New York, NY) in quadruplicate and
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PBSC MOBILIZATION IN PEDIATRIC DONORS
incubated in an ESPEC N -O -CO BNP-110 incubator (Tabai ESPEC Co.,
2
2
2
Osaka, Japan), which maintained a humid atmosphere of 5% carbon dioxide,
5% oxygen, and 90% nitrogen. After 14 days of incubation, the number of
CFU-GM3 was counted using an inverted microscope.
Flow Cytometry Analysis of CD34? Cells. Assay of CD34? cells was
performed exclusively by Ohtsuka Assay Institute (Tokyo, Japan) as a central
laboratory. Sample cells were shipped by air cargo and assayed within 24 h.
Cells that expressed the surface CD34 antigen were identified by flow cytom-
etry analysis. Briefly, 100 ?l of cell suspension were added to a test tube
(Falcon 2052; Becton Dickinson, Lincoln Park, NJ) containing isotype control
(phycoerythrin-mouse IgG1) and phycoerythrin-conjugated CD34 monoclonal
antibody (Anti-HPCA2 antibody; Becton Dickinson) at a concentration of 1 ?g
of antibody/106 cells. Samples were analyzed with a FACScan flow cytometer
(Becton Dickinson). After the function was verified, samples were drawn into
the flow cytometer using forward side scatter and side scatter, as gating
parameters, along with debris subtraction techniques to determine the charac-
teristics of the cells. A total of 20,000 events were counted to identify the
mononuclear cell fraction. The flow cytometric data were analyzed using a
gated analysis via a set of SSC-FL parameters for CD34? cells to calculate the
percentage of positive cells. When the sample was substantially contaminated
with RBCs, they were lysed with a solution consisting of 0.826% (w/v)
NH CL, 0.1% KHCO , and 0.004% EDTA-4Na.
4
3
Fig. 2. The absolute numbers of MNC per microliter of blood in both adult and
Assay of G-CSF Concentration. An ELISA kit for human G-CSF was
pediatric donors. The number of MNCs was calculated as (total WBC counts) ? (% of
purchased from Amersham Life Science (Biotrek ELISA System, Bucking-
monocytes and lymphocytes)/100. There were no differences in circulating MNCs be-
hamshire, United Kingdom). The manufacturer guaranteed the specificity of
tween the two groups during G-CSF treatment, although WBC counts were significantly
the assay by demonstrating that it failed to detect other known cytokines. The
higher in adult donors than in children. The median values were 6.71 ? 109/liter (children)
and 6.49 ? 109/liter (adults) on day 5.
serum G-CSF level was measured by strictly adhering to the manufacturer’s
instructions. In this assay system, the limit of sensitivity for the assay kit was
1.1 pg/ml for G-CSF.
Statistics. The numbers of MNCs were indirectly calculated from the total
number of WBCs and percentages of MNCs (monocytes and lymphocytes)
each day of G-CSF treatment. The circulating number of CD34? cells was
calculated from the number of MNCs and the percentage of CD34? cells in
the MNC fraction. The number of CFU-GM was determined by calculation
using the number of colonies per unit number of MNC. The Mann Whitney U
test and/or unpaired t test combined with the F test were used to analyze
differences in the effect of G-CSF administration. Data were analyzed using
the StatView program (version 4.5; Abacus Concepts, Inc., Berkeley, CA) for
a Macintosh computer.
Results
Mobilization. During G-CSF treatment for mobilization, no de-
tectable adverse symptoms or complaints were documented in
Fig. 3. Serum trough levels of G-CSF in donors receiving G-CSF. The G-CSF levels
in children on days 3 and 4 were significantly lower than those in adults (unpaired t test,
P ? 0.05).
younger pediatric donors (n ? 9, ?10 years), whereas 5 of the 10
older pediatric donors (?10 years) complained of mild headache and
general fatigue and received 10 mg/kg of acetaminophen when re-
quired. In contrast, all of the adult donors (n ? 25) had various
complaints including severe lumbar pain, headache, systemic bone
pain, and general fatigue, despite the prophylactic use of aspirin.
Nevertheless, none of the donors failed to complete the mobilization
and harvesting protocols.
The number of WBCs increased from day 2 of G-CSF treatment (24
h after the first injection) and reached a peak value on day 3 or 4 in
all of the donors. The peak values of WBCs on days 4 and 5 were
significantly lower in pediatric donors than in adult donors (Fig. 1),
whereas there were no differences in MNCs (Fig. 2) or the percentage
Fig. 1. WBC counts in donors receiving G-CSF. The WBC counts in children were
significantly lower than those in adults on days 4 and 5 (Mann-Whitney test, P ? 0.01).
of CD34? cells (children, 0.93 versus adults, 1.04) between the two
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PBSC MOBILIZATION IN PEDIATRIC DONORS
Table 1 Comparison of aphereses after 5 days of G-CSF-mobilizationa
Harvested dose
Harvested dose per unit
Processed
Age
Weight
Times of
volume
MNC
CD34?
CFU-GM
CD34?b
CFU-GMb
CD34?c
CFU-GMc
(yr)
(kg)
apheresis
(liter)
(? 108)
(? 106)
(? 105)
(? 106/liter)
(? 105/liter)
(? 106/kg)
(? 105/kg)
Children (n ? 19)
10
31
3
18
360
305
660
16.9
42.5
8.4
25.0
(2–16)
(12–85)
(1–7)
(9–56)
(95–1,608)
(55–1,170)
(36–3,260)
(5.5–35.4)
(2.9–92.4)
(3.1–17.2)
(1.7–86.8)
Adults (n ? 25)
37
60
3
31
787
463
747
13.3
29.1
7.6
13.0
(18–49)
(50–78)
(2–5)
(16–54)
210–1,480)
(5–6,679)
(55–5,370)
(0.2–247)
(0–199)
(0.1–92.8)
(0.9–74.6)
Statistics
Mann-Whitney U test
(p-value)
0.022
0.501
0.790
0.649
0.378
0.383
0.210
Unpaired t test
0.108
0.306
0.760
0.432
0.849
0.522
0.225
a The data are shown as median values (ranges).
b These values are harvested cell doses/liter of processed blood volume.
c These values are harvested cell doses/kg of the donor’s body weight.
groups. As a result, the absolute numbers of circulating CD34? cells
harvesting protocol should be established for children who will donate
per unit of blood were identical in both groups.
grafts for an older child or adult patient.
Although the levels of hemoglobin and platelet counts did not
In this study, we noted for the first time that the serum kinetics of
significantly change during the G-CSF treatment, a marked decrease
G-CSF differ between adult and pediatric donors undergoing PBSC
in the platelet level (?50 ? 109/liter) developed in two adult donors
mobilization. The trough level of G-CSF tended to become lower in
after plural courses of aphereses (?40 liters of blood processed), in
almost all of the donors as mobilization continued. Watts et al. (19)
whom platelet-rich plasma was required to be given back after the
reported that G-CSF concentrations on day 6 were one-third of those
final step of cell preparation. None of the donors developed a tend-
on day 1 in adult donors. Additionally, there have been reports that
ency to bleed during or after the treatment. All of the blood compo-
G-CSF clearance increases with an increase in the number of absolute
nents recovered to baseline levels in all of the donors within 2 weeks
neutrophil counts in mobilization settings (3, 20). Accordingly,
after the aphereses.
Faulkner et al. (20) suggested that an absolute neutrophil counts-
G-CSF pharmacokinetics could be evaluated in 16 donors from
adjusted G-CSF dosing schedule may improve a PBSC mobilization
each group and showed a wide interdonor variation in the serum
protocol for patients with cancer (20). In this study with normal
trough level of G-CSF, which was significantly lower in pediatric than
healthy donors, we showed that the decrease in the G-CSF concen-
in adult donors on days 3 and 4 (Fig. 3). The trough G-CSF levels
tration was more prominent in pediatric donors compared with adult
became maximal on the second day of treatment in most of the donors,
donors, despite their lower number of absolute neutrophil counts.
with a subsequent decline upon continuing G-CSF administration.
Our pediatric donors also had a lower level of G-CSF than adult
Apheresis Procedure. Three adult patients complained of mild
donors at any point in the evaluation (not statistically significant),
nausea and palpitation during apheresis, which quickly responded to
which might be related to the lower frequency of G-CSF toxicity
the rapid additional injection of 5 ml of calcium gluconate. Conse-
observed in our pediatric donors. Although careful evaluation is still
quently, none of the donors failed to complete apheresis. Crit-Line
required with a larger number of patients within each age range, it
monitoring in selected donors disclosed no significant change in the
appears that G-CSF clearance may change during treatment in differ-
dynamics of circulation. Changes in the values of blood components
ent degrees between children and adults. It has been reported that a
before and after apheresis were not clinically significant in any of the
dose-response effect exists in the use of G-CSF for mobilization.
donors, although several cases required an add-back of platelet-rich
Taken together, these data may indicate that a pharmacokinetically
plasma, as described above. Median numbers of MNC, CD34? cells,
adjusted higher dose of G-CSF may be indicated for effective mobi-
and CFU-GM harvested from pediatric donors were, respectively,
lization from pediatric donors.
360 ? 108, 305 ? 106, and 660 ? 105; a statistically significant
The present results suggest that G-CSF mobilization and harvesting
difference was found only in MNCs, when compared with those in
of PBSCs are safe and effective in pediatric donors, as well as in adult
adults (787 ? 108, 463 ? 106, and 747 ? 105, respectively). As a
donors. Although a long-term follow-up is still required to confirm the
result, the numbers of cells harvested per processed volume (liter) of
safety of G-CSF treatment, children appear to tolerate this drug well
blood or per kg of body weight were equivalent between adult and
while demonstrating the same mobilization effect as adult donors.
pediatric donors (Table 1).
Discussion
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