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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4040-4046
Marginal Benefit/Disadvantage of Granulocyte Colony-Stimulating
Factor Therapy After Autologous Blood Stem Cell Transplantation in
Children: Results of a Prospective Randomized Trial
By
Yoshifumi Kawano,
Yoichi Takaue,
Junichi Mimaya,
Yasuo Horikoshi,
Tsutomu Watanabe,
Takanori Abe,
Yukitoshi Shimizu,
Takeji Matsushita,
Atsushi Kikuta,
Arata Watanabe,
Asayuki Iwai,
Etsuro Ito,
Mikiya Endo,
Nobuyuki Kodani,
Shigeru Ohta,
Kazuo Gushi,
Hiroshi Azuma,
Takao Etoh,
Yasuhiro Okamoto,
Koji Amano,
Hiroyoshi Hattori,
Haruhiko Eguchi, and
Yasuhiro Kuroda for the Japanese Cooperative Study Group of PBSCT
From the Department of Pediatrics, University Hospital of Tokushima,
Tokushima; Stem Cell Transplant Unit, National Cancer Center Hospital,
Tokyo; the Department of Hematology/Oncology, Shizuoka Children's
Hospital, Shizuoka; the Department of Pediatrics, University
Hospital of Yamagata, Yamagata; the Department of Pediatrics,
International Medical Center of Japan, Tokyo; the Department of
Pediatrics, Fukushima Prefectural Medical College, Fukushima; the
Department of Pediatrics, University Hospital of Akita, Akita; Kagawa
Children's Hospital, Kagawa; the Department of Pediatrics University
Hospital of Hirosaki, Aomori; the Department of Pediatrics, Iwate
Medical University, Iwate; the Department of Pediatrics, Matsuyama Red
Cross Hospital, Ehime; the Department of Pediatrics, Shiga Medical
College, Shiga; the Department of Pediatrics, Naha Hospital, Okinawa;
the Department of Pediatrics, Asahikawa Medical College, Hokkaido; the
Department of Pediatric Surgery, Chiba Children's Hospital, Chiba; and
the Department of Pediatrics, University of Kurume, Fukuoka, Japan.
 |
ABSTRACT |
In this prospective trial, a total of 74 children who were scheduled
to undergo high-dose chemotherapy followed by autologous peripheral
blood stem cell transplantation (PBSCT) were prospectively randomized
at diagnosis to evaluate the effectiveness of exogenous granulocyte
colony-stimulating factor (G-CSF) treatment in accelerating hematopoietic recovery after PBSCT. The diagnosis included acute lymphoblastic leukemia (ALL) (n = 27), neuroblastoma (n = 29), and
miscellaneous solid tumors (n = 18). Eligibility criteria included
(1) primary PBSCT, (2) chemotherapy-responsive disease, and (3)
collected cell number >1 × 105 colony-forming
unit-granulocyte-macrophage (CFU-GM)/kg and >1 × 106
CD34+ cells/kg patient's body weight. After applying the
above criteria, 11 patients were excluded due to disease progression
before PBSCT (n = 6) or a low number of harvested cells (n = 5),
leaving 63 patients for analysis; 32 patients in the treatment group
(300 µg/m2 of G-CSF intravenously over 1 hour from day 1 of PBSCT) and 31 in the control group without treatment. Two distinct
disease-oriented high-dose regimens without total body irradiation
consisted of the MCVAC regimen using
ranimustine (MCNU, 450 mg/m2), cytosine
arabinoside (16 g/m2), etoposide (1.6 g/m2),
and cyclophosphamide (100 mg/kg) for patients with ALL, and the
Hi-MEC regimen using melphalan (180 mg/m2),
etoposide (1.6 g/m2), and carboplatinum (1.6 g/m2) for those with solid tumors. Five patients (two in
the treatment group and three in the control group) were subsequently
removed due to protocol violations. All patients survived PBSCT. The
median numbers of transfused mononuclear cells (MNC),
CD34+ cells, and CFU-GM were, respectively, 4.5 (range, 1 to 19) × 108/kg, 8.0 (1.1 to 25) × 106/kg,
and 3.7 (1.2 to 23) × 105/kg in the treatment group (n
= 30) and 2.9 (0.8 to 21) × 108/kg, 6.3 (1.1 to 34) × 106/kg, and 5.5 (1.3 to 37) × 105/kg,
respectively, in the control group (n = 28), with no significant difference. After PBSCT, the time to achieve an absolute neutrophil count (ANC) of >0.5 × 109/L in the treatment group was
less than that in the control group (median, 11 v 12 days; the
log-rank test, P = .046), although the last day of red blood
cell (RBC) transfusion (day 11 v day 10) and the duration of
febrile days (>38°C) after PBSCT (4 v 4 days) were
identical in both groups. However, platelet recovery to >20 × 109/L was significantly longer in treatment group than
control group (26 v 16 days; P = .009) and >50 × 109/L tended to take longer in the treatment group (29 v 26 days; P = .126), with significantly
more platelet transfusion-dependent days (27 v 13 days;
t-test, P = .037). When patients were divided into
two different disease cohorts, ALL patients showed no difference in
engraftment kinetics between the G-CSF treatment and control groups,
while differences were seen in those with solid tumors. We concluded
that the marginal clinical benefit of 1 day earlier recovery of
granulocytes could be offset by the delayed recovery of platelets. We
recommend that the routine application of costly G-CSF therapy in
children undergoing PBSCT should be seriously reconsidered.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
RECENTLY, SOME HEMATOPOIETIC growth
factors have been used clinically in patients undergoing high-dose
chemotherapy with hematopoietic stem cell transplantation, and their
effects in ameliorating the neutropenic period have been
reported.1,2 High-dose chemoradiation therapy and
autologous peripheral blood stem cell transplantation (PBSCT) has
become an established option for the treatment of certain types of
childhood cancer.3 The popularity of PBSCT over bone marrow
transplantation (BMT) is in part due to more rapid engraftment. As a
result of data obtained in BMT studies, the use of growth factors,
including granulocyte-colony stimulating factor (G-CSF), is widespread
in PBSCT procedures, with the anticipation that hematopoietic recovery
will be further accelerated.4-15
Although randomized studies with adult patients have reported
accelerated hematopoietic recovery with the use of G-CSF after PBSCT,1,16 whether this actually provides any practical
clinical benefit remains the subject of debate and needs further
clarification. Routine use of G-CSF in children undergoing PBSCT should
be seriously evaluated, because the stem cell kinetics, hematopoietic
reservoir, and profile of the effects of G-CSF might be quite different
from those in adult patients. Indeed, the results of our retrospective study with pediatric patients suggested that the clinical application of G-CSF after PBSCT did not have a significant clinical
effect.17
We report here the first prospective randomized trial in children to
determine whether engraftment after PBSCT is improved by the addition
of exogenous G-CSF. The dose of infused stem cells should affect de
novo engraftment speed. Hence, patients were randomized at diagnosis to
either receive G-CSF or not, while those from whom a threshold number
of cells could not be collected were excluded. The present results cast
doubt on the benefit of G-CSF treatment in this special setting.
| |
MATERIALS AND METHODS |
Patients.
From December 1993 to December 1996, 74 patients with various types of
cancer were registered into our clinical protocol studies, as reviewed
elsewhere.18,19 The diagnosis included acute lymphoblastic leukemia (ALL) in complete remission (n = 27), neuroblastoma (n = 29),
and miscellaneous solid tumors (n = 18). All of the patients with ALL
and neuroblastoma were uniformly treated according to the protocols of
the Japanese Cooperative Study Group of PBSCT. All of the patients with
ALL were treated for more than 7 months with conventional chemotherapy
and then prepared for PBSC collection. All received central nervous
system (CNS) prophylaxis with a minimum of five courses of intrathecal
administration of methotrexate (15 mg/m2), cytosine
arabinoside (Ara-C; 30 mg/m2), and hydrocortisone (50 mg/m2) at the completion of induction therapy and
immediately before PBSCT. The initial chemotherapy for patients with
other solid tumors varied at participating institutes, although they
were similarly treated with regimens containing cyclophosphamide (CY), vincristine, pirarubicin (THP-ADR), etoposide (VP-16), dacarbazine (DTIC), cisplatinum or carboplatinum (CBDCA). Selected patients underwent delayed primary or second-look surgery and/or
intraoperative radiation treatment (10 to 20 Gy).
To perform an intent-to-treat analysis, all of the patients were
randomly assigned at the time of diagnosis into one of two groups:
treatment group with G-CSF (300 µg/m2) after PBSCT (n = 38) versus control group without G-CSF (n = 36). The registered
patients proceeded to PBSCT when the following criteria were satisfied:
(1) primary case of PBSCT, (2) chemotherapy-responsive disease, and (3)
the numbers of collected cells exceeded 1 × 105
colony-forming unit-granulocyte-macrophage (CFU-GM)/kg and 1 × 106 CD34+ cells/kg patient's body weight. The
protocol was approved by the Institutional Review Board of each
institute and consent was obtained from the patients' guardians.
Harvest of PBSCs.
PBSCs were collected by apheresis in the recovery phase of marrow
function after intensive chemotherapy with G-CSF (filgrastim; Kirin
Brewery Co, Tokyo, Japan), as previously reported.20-22
Briefly, the patients received 50 to 200 µg/m2 of
intravenous (IV) G-CSF from when white blood cell (WBC) count fell to
0.5 × 109/L after chemotherapy to the time of
apheresis. When patients were judged to be in complete remission, PBSCs
were harvested, and the criteria for performing apheresis included WBC
of >3.0 × 109/L and a platelet count of >100 × 109/L. The regimens for mobilization chemotherapy
were high-dose Ara-C (2 g/m2 twice daily for 5 days) plus
VP-16 (100 mg/m2 for 3 days) for ALL, and the
combination of THP-ADR (40 mg/m2), CBDCA (400 mg/m2), and VP-16 (100 mg/m2 for 3 days) for solid tumors. The harvested cells were frozen with a
nonprogrammed freezing method and stored in electric medical freezers
set at  80°C or 135°C (Sanyo Electric Co, Tokyo,
Japan) until use, as previously reported.23
Assay of CD34+ cells.
Assay of CD34+ cells was exclusively performed by Ohtsuka
Assay Institute (Tokyo, Japan) as a central laboratory. Sample cells were shipped by air cargo and assayed within 24 hours. Sample cells
were adjusted to 1 × 106 cells/mL in Iscove's
modified Dulbecco's Medium (IMDM; GIBCO-BRL, Life Technologies Inc,
Grand Island, NY). Aliquots of 0.3 to 0.5 mL were then transferred in a
volume of 1.5 mL of medium with 10% fetal bovine serum (FBS, Filtron
PTY Ltd, Brooklyn, Australia) and stored at 4°C until analysis
within 24 hours. A total of 100 µL of cell suspension was dispensed
into a test tube (Falcon 2052; Becton Dickinson, Lincoln Park, NJ) for
staining and for a control. Staining was performed in the test tube by
adding phycoerythrin (PE)-conjugated CD34 antibody
(anti-HPCA2 antibody; Becton Dickinson) at a concentration
of 1 µg antibodies/106 cells. PE-mouse IgG1
was used as a control. After 30 minutes of incubation in the dark,
cells were washed twice and resuspended in Dulbecco's
phosphate-buffered solution (PBS; Nissui, Tokyo, Japan) containing 1%
bovine serum albumin (BSA; Sigma, St Louis, MO; A-4503).
In the case of substantial contamination of the sample with red blood
cells (RBC), they were lysed with a solution consisting of 0.826%
(wt/vol) NH4CL, 0.1% KHCO3, and 0.004%
EDTA-4Na.
Samples were analyzed with a FACScan flow cytometer (Becton Dickinson).
After function was verified, samples were drawn into the flow cytometer
using forward scatter (FSC) and side scatter (SSC), as
gating parameters along with debris subtraction techniques to determine
the characteristics of the cells. A total of 20,000 events was 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.24
Assay of hematopoietic progenitor cells.
Assays of hematopoietic progenitor cells using shipped frozen samples
were principally performed at the University of Tokushima as a central
laboratory, as previously described.21 Briefly, cells were
thawed using DNase (20 U/mL; Sigma, DN-25) containing medium and washed
three times with PBS. Cells were then resuspended in IMDM for colony
assay. Cells were incubated in methylcellulose cultures supplemented
with 20% FBS, 450 µg/mL of human transferrin (Sigma T-1147), 2 U/mL
of recombinant human erythropoietin (2 × 105 IU/mg
protein, Kirin Brewery Co), 1% crystallized BSA (Calbiochem 12657;
Hoechst Japan, Tokyo), and a combination of recombinant human G-CSF
(Kirin), interleukin-3 (Kirin), and stem cell factor (Kirin). These
factors were used at a final concentration of 20 ng/mL, which was the
prescreened optimal concentration in our laboratory. Triplicate or
quadruplicate cultures were plated in volumes of 0.4 mL in 24-well
tissue culture plates (Corning 258201, New York, NY) and placed in an
ESPEC N2-O2-CO2 BNP-110 incubator (Tabai ESPEC Co, Osaka, Japan), which maintained 5% carbon dioxide, 5% oxygen, and 90% nitrogen in a humid atmosphere at 37°C. Plates were incubated for 14 days and colony-forming units for CFU-GM were
counted using an inverted microscope.
Treatment regimens.
As a cytoreductive therapy before transplant, the MCVAC regimen,
consisting of ranimustine (MCNU, 450 mg/m2), Ara-C (16 g/m2), VP-16 (1,600 mg/m2), and CY (100 mg/kg),
was used for patients with ALL. Patients with solid tumors received a
combination of melphalan (180 mg/m2), VP-16 (1,600 mg/m2), and CBDCA (1,600 mg/m2). These
protocols do not incorporate total body irradiation (TBI) and are
considered marrow-ablative. Thirty-six hours after completion of the
cytoreductive regimen, the cells were rapidly thawed at 37°C and
promptly infused into the patients through a central venous catheter
without additional postthaw washing manipulation. No further specific
antileukemia or antitumor therapy was given after PBSCT. In the
treatment cohort, 300 µg/m2 of G-CSF (filgrastim) were
intravenously given to patients over 1 hour from the day after PBSCT
(day 1) until the absolute neutrophil count (ANC) reached 3.0 × 109/L.
Supportive therapies.
All of the patients had a central venous catheter and were kept in a
protected environment, but with no oral decontamination. When patients
developed fever or any evidence of infection, they were treated with
broad-spectrum antibiotics either with or without intravenous
 -globulin preparations according to the guidelines of the individual
institutes. RBC and platelet transfusions were performed to maintain
levels of 7.0 g/dL and 20 × 109/L, respectively.
Blood components were irradiated and filtered to reduce contaminating
leukocytes.
Statistical analysis.
Because all medical costs related to cancer therapy in pediatric
patients are paid by the government in Japan, the duration of
hospitalization is not a meaningful indicator of clinical benefit. Therefore, the primary end point of this study was the evaluation of
engraftment speed. The day of hematopoietic recovery was defined as the
first day with an ANC of at least 0.5 × 109/L, a
platelet count of 20 or 50 × 109/L without
transfusion for 3 consecutive days. The Mann-Whitney U-test and
Student's t-test were used to analyze the effect of G-CSF
administration. Kaplan-Meier estimates of time to ANC and platelet
recovery were also analyzed using the log-rank test.
| |
RESULTS |
Patients.
Eleven of the 74 registered patients did not proceed to PBSCT; six
patients (three from each group) developed disease progression before
blood cell harvesting. The other five patients (three from the
treatment and two from the control group) were excluded because an
inadequate number of cells was collected. Consequently, 63 patients (32 in the treatment group and 31 in the control group) were finally
evaluated for the benefit of G-CSF after PBSCT. However, two cases in
the treatment group who were administered the incorrect dose of G-CSF
and three in the control group who were given G-CSF were excluded from
the analysis because of protocol violations (Fig 1). The evaluated patients in both
groups were comparable in terms of their clinical characteristics
(Table 1) and the numbers of transfused
cells (Table 2).
Transplant procedure and clinical parameters.
All of the patients who underwent PBSCT showed little evidence of
serious transplant-related complications. After PBSCT, the patients
received G-CSF for a mean number of 15 days (range, 10 to
25), which resulted in an average cost of G-CSF of about $7,500 per
person.
In patients in the control group, the median number of days to achieve
an ANC of 0.5 × 109/L was 12 (9 to 49), while it was
11 (8 to 20) in the treatment group. There was a significant difference
between the two groups, with P values of .034 (t-test)
and 0.046 (log-rank test). On the other hand, the median numbers of
days to achieve platelet counts of 20 and 50 × 109/L
in the control group were 16 (6 to 45) and 26 (11 to 100), respectively, whereas these were 22 (7 to 101) and 31 (13 to 123), respectively, in the treatment group. There was a statistically significant difference in early platelet recovery between the two
groups (20 × 109/L: P = .020 by
t-test and P = .009 by log-rank test). The results of a
Kaplan-Meier analysis with a log-rank test are shown in
Fig 2. Furthermore, the last day of
platelet transfusions in the control group (day 13), occurred
significantly sooner than that in the treatment group (day 27)
(P = .037 by t-test). The numbers of days
with febrile (>38°C) episodes (4 v 4) and the day of the last RBC transfusion (10 v 11) were comparable between the two groups (Table 3).
View larger version (20K):
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| Fig 2.
Kaplan-Meier probability of achieving 0.5 × 109/L of ANC (top graph, P = .046), and those of
20 or 50 × 109/L of platelet counts independent of
platelet transfusions (bottom graph, P = .009 for 20 × 109/L or P = .126 for 50 × 109/L).
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When patients with ALL and solid tumors were analyzed separately, the
engraftment data in G-CSF-treated ALL patients were identical to those
in control ALL patients. However, in patients with solid tumors,
granulocyte engraftment occurred on days 11 and 12, respectively, and
this difference was significant. Although platelet engraftment tended
to be delayed in the treatment group, this difference was not
significant (Table 4).
| |
DISCUSSION |
Despite the widespread use of G-CSF after high-dose chemotherapy with
stem cell support, there have been no comprehensive evaluations of the
clinical benefit of this strategy after autologous PBSCT in pediatric
patients. The presumed reason for the rapid hematopoietic recovery
after PBSCT compared with BMT is the infusion of relatively more early
engrafting committed progenitors.25 We and others have
previously suggested that the enhanced endogenous secretion of
cytokines at least partly contributes to this early recovery.26,27 The enhancement of hematopoietic recovery
after autologous bone marrow transplantation (ABMT) by treatment with CSFs appears to be offset by the finding that further enhancement can
be achieved with G-CSF-primed PBSC support without posttransplant CSF.
The results of recent clinical studies on the value of G-CSF after
PBSCT have been controversial, as summarized in Table
5.1,2,4-16 We believe that the reported degree of
effectiveness does not provide a practical clinical benefit.
Although we could not perform a critical cost analysis, which
considered supportive therapy or hospitalization due to our government-supported insurance policy, G-CSF did not appear to provide
any benefit when used after autologous PBSCT, although this result must
be considered preliminary given the small number of patients studied.
The reason for this marked contrast with adult studies remains unclear,
but is most likely due to differences in the quantity and/or
quality of PBSC in the grafts between the studies. In addition, we
previously presented data suggesting that hematopoiesis is more active
in pediatric than adult populations, and both the reconstituting
potential and quantity of stem cells are superior in
children.28 The guidelines of the American Society of
Clinical Oncology state that treatment with G-CSF is unnecessary in
patients with neutropenia of short duration, while it may benefit those
with prolonged neutropenia.29 Our study excluded 7.4% of
the initially targeted patients due to a small number of cells available for transplantation. These patients with less than the threshold level of PBSC might be suitable candidates for supplemental therapy with G-CSF after PBSCT.
In previous studies with adult patients, we found that hematopoietic
recovery in control groups without G-CSF was generally slower than that
in our clinical trials in a pediatric population. In the current study,
the median time to an ANC >0.5 × 109/L was 12 days
in the control group, which was comparable to the results in
G-CSF-treated groups in most of the adult reports. Panici et
al11 reported that platelet recovery to 50 × 109/L required about 11 days both in the control and
treated groups. Because this speed of recovery was exceptionally fast
compared with other studies, the cytoreductive regimen could not be
considered myeloablative. In the data reported by Klumpp et
al,13 the infused dose of CFU-GM was <1 × 105/kg, which was less than the widely accepted threshold
for performing PBSCT with enhanced hematopoietic recovery. Thus, it is
possible that G-CSF may be effective in a transplantation setting only with the use of fewer stem cells. On the other hand, Reiffers et
al30 reported that G-CSF had its greatest effect in the
treatment of patients with acute myelogenous leukemia
(AML). None of the patients in this study had AML, and
this may explain the difference between the present results and those
in previous studies.
The results in this study suggested that the use of G-CSF was
associated with a delayed recovery of the platelet count after PBSCT.
In patients who underwent autologous PBSCT, Bensinger et al7 reported G-CSF tended to have an adverse effect on the time to platelet independence, but they failed to identify any statistically significant differences. In a multicenter retrospective survey involving 18 centers,31 the use of posttransplant
growth factors were associated with a longer time to platelet recovery in allogeneic marrow transplantations (P = .01). They
speculated that the decreased probability of platelet recovery may be
related to the reasons why growth factors were started rather than to a
true biologic effect on recovery. In this prospective randomized study,
we found a significant difference between the two groups both in the
number of days to achieve a platelet count of 20 × 109/L (P = .009 by log-rank test) and the last day
of platelet transfusion according to Student's t-test
(P = .034). Although the exact cause of this result should be
clarified, it is probable that G-CSF exerts negative effects via
receptors expressed on platelets. The exposure of stem cells to a high
concentration of G-CSF immediately after reinfusion may induce
hematopoietic immature progenitor cells to myeloid committed progenitor
cells, which results in the delayed growth of megakaryocyte progenitors
or platelets. Further investigations on this point are required.
In conclusion, we showed that the use of G-CSF does not provide a
marked clinical benefit in pediatric patients undergoing autologous
PBSCT with more than a threshold level of PBSC, while this expensive
strategy appears to be associated with a tendency for the delayed
recovery of platelets. The benefit of G-CSF therapy, in terms of
enhancing hematopoietic recovery after high-dose therapy, is more
clearly indicated in our patient population in the setting of
mobilization of PBSC.
| |
FOOTNOTES |
Submitted April 9, 1998; accepted July 20, 1998.
Supported by a Grant-in-aid for Scientific Research (C) from the
Ministry of Education, Science, Sports and Culture, and by a
Grant-in-aid for the Second-term Comprehensive 10-year Strategy for
Cancer Control from the Ministry of Health and Welfare.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Yoichi Takaue, MD, Department of Medical
Oncology, Hematopoietic Stem Cell Transplant Unit, National Cancer
Center Hospital, 1-1 Tsukiji 5-Chome, Chuo-ku, Tokyo 104, Japan;
e-mail: ytakaue{at}gan2.ncc.go.jp.
| |
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Abstract
Introduction