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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
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.
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.
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