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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3565-3566
CORRESPONDENCE
Is Filgrastim as Useless After Peripheral Blood Stem Cell
Transplantation for Adults as It Could Be for Children?
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LETTER |
To the Editor:
We read with interest the report by Kawano et al1
concerning the use of granulocyte colony-stimulating factor (G-CSF)
after peripheral blood stem cell transplantation (PBSC) in pediatric patients. The main conclusions of this study are that filgrastim does
not provide a marked clinical benefit in the setting of patients with
more than a threshold level of PBSC infused, despite the existence of a
significantly accelerated neutrophil recovery in the group of
patients that receive G-CSF. Unfortunately, this effect does not imply
fewer infections or lower the transfusion measures (only
registered for red blood cells) for these patients. All of those facts,
with an unfavorable trend for platelet engraftment in the group treated
with G-CSF, move the investigators to recommend a more cautious
use of this expensive treatment strategy in children.
Despite its indubitable interest (as one of the few randomized trials
published to assess the use of G-CSF postransplantation using PBSC in
which a nontreatment group has been included), in our opinion there are
some points in the report that diminish its value. First, this
multicentric study was developed in 14 different institutions, with a
relatively small number of patients recruited for the different
pathologies investigated. Moreover, the supportive measures were not
uniform for all the centers involved, making difficult the
interpretation of possible differences in incidence and type of
infections and number of transfusions between the two groups. Second,
the unfavorable trend for platelet engraftment observed for the
patients treated with G-CSF could be irrelevant, if this fact does not
imply a higher number and severity of hemorrhagic episodes with an
increased number of platelet transfusions (not displayed in the report)
for this group. Finally, other important items to analyze in this field
could not be performed by this study due to the low number of patients
recruited. Among other objectives, we suggest studies of the
economics, the duration of hospitalization, the
possible benefit of G-CSF in patients with lower threshold of
PBSC infused, and the possible impact on incidence of mucositis
or on survival.
In our hospital, to assess the use of G-CSF (Filgrastim) after
autotransplantation, two consecutive prospective and randomized trials
were performed over the last 3 years. Only adult patients with breast
carcinoma, acute leukemia, or lymphoma were recruited. Chemotherapy
conditioning (BuCy2, BEAC, or STAMP-V) and G-CSF mobilization for PBSC
were used in all cases. No other cytokines were used. There were no
statistical differences for age, sex, diagnosis, remission status,
number of mononuclear and CD34+ cells infused by body
weight, platelet count before transplantation, or conditioning used
among the different groups. The observation period analyzed ran from
PBSC infusion to day +100 posttransplantation. Multiple variables in
the evolution of patients posttransplantation were recorded and
analyzed to display any possible difference between the established groups.
In the first trial (from May 1994 to June 1997), the patients randomly
received G-CSF (Filgrastim) at 5 µg/kg subcutaneously from day +2 (36 cases) or +5 (44 cases) after infusion of PBSC. No differences could be
established between these two groups for aplasia time (granulocytes,
<500 × 109/L), time to recover more than 20 × 109/L platelets, days with parenteral nutrition support,
transfusional support, infectious complications, days of
hospitalization, or number of days with fever and any other possible
complications. A substantial economic benefit was obtained with a
delayed use of G-CSF. These results are in accordance with those
published previously by Faucher et al.2
In the second trial (from July 1997), the patients randomly received
G-CSF: one group received G-CSF (Filgrastim) at 5 µg/kg subcutaneously from day +5 and the other received no cytokines. From
the analysis of the data available at the time of this report, with a
total of 62 patients recruited (30 with G-CSF and 32 without it), only
minor differences regarding the use of G-CSF could be inferred. A
faster granulocyte engraftment was evident in the group treated (mean
of 10 v 12 days to achieve >0.5 × 109/L
granulocytes; P < .001), without any differences between
groups in incidence and severity of infections, days of fever, and
duration of antibiotic treatment. As in the report of Kawano et
al1 and that of Berstein et al,3 a subtle
slower engraftment for platelets appeared in our series (mean of 15 days in the group with G-CSF v 12 days in the other group to
achieve >20 × 109/L platelets; P = not
significant), but without differences in incidence and severity of
hemorrhages or platelet transfusion support.4
From our data it could be concluded that a delayed rather than an
early administration of G-CSF post-PBSC transplantation is preferable
(if used) and that there is no clear beneficial impact of its
administration whatsoever.
We believe, as Kawano et al1 suggest for children, that the
use of G-CSF post-PBSC transplantation could be marginal also for
adults. Nevertheless, more ample randomized studies are necessary before condemning or supporting its use in this particular clinical setting.
E. Ojeda
J. Garcia-Bustos
M.J. Aguado
E. Quevedo
R. Arrieta
V. Jimenez
M. Canales
F. Hernandez-Navarro
Servicio de Hematología
Hospital La
Paz
Madrid, Spain
| |
REFERENCES |
1.
Kawano Y, Takaue Y, Mimaya J, Horikoshi Y, Watanabe T, Abe T, Shimizu Y, Matsushita T, Kikuta A, Watanabe A, Iwai A, Ito E, Endo M, Nobuyuki Kodani N, Ohta S, Gushi K, Azuma H, Etoh T, Okamoto Y, Amano K, Hattori H, Eguchi H, Kuroda Y, for the Japanese Cooperative Study Group of PBSCT:
Marginal benefit/disadvantage of granulocyte colony-stimulating factor therapy after autologous blood stem cell transplantation in children: Results of a prospective randomized trial.
Blood
92:4040, 1998[Abstract/Free Full Text]
2.
Faucher C, Le Corroller AG, Chabannon C, Novakovitch G, Manonni P, Moatti JP, Nouyrigat P, Marininchi D, Blaise D:
Administration of G-CSF can be delayed after transplantation of autologous G-CSF primed blood stem cells: A randomized study.
Bone Marrow Transplant
17:533, 1996[Medline]
[Order article via Infotrieve]
3.
Bernstein SH, Nademanee AP, Vose JM, Tricot G, Fay JW, Negrin RS, DiPersio J, Rondon G, Champlin R, Barnett MJ, Cornetta K, Herzig GP, Vaughan W, Geils G, Keating A Jr, Messner H, Wolff SN, Miller KB, Linker C, Cairo M, Hellmann S, Ashby M, Stryker S, Nash RA:
A multicenter study of platelet recovery and utilization in patients after myeloablative therapy and hematopoietic stem cell transplantation.
Blood
91:3509, 1998[Abstract/Free Full Text]
4.
Ojeda E, Garcia-Bustos J, Aguado MJ, Arrieta R, Quevedo E, Jiménez-Yuste V, Martin MP, Canales M, Hernandez-Maraver MD, Jiménez M, Alvarez MT, Morado M, Sevilla J, Hernandez-Navarro J:
A randomized study of filgrastim (G-CSF) after autologous peripheral blood transplantation.
Blood
92:325b, 1998 (abstr, suppl 1)
Response
To the Editor:
The word "transplantation"
does not necessarily imply that targeted patients will always develop
prolonged cytopenia, for which treatment with G-CSF is recommended. It
must be stressed that de novo hematopoietic recovery kinetics after PBSCT versus those after bone marrow transplantation or after transplants with a minimum number of hematopoietic stem/progenitor cells versus after those with more than threshold numbers should be
quite different. It is clear that there are age-dependent differences in stem cell kinetics and the quantity/quality of PBSC in grafts, which
certainly affect the profile of the clinical response to G-CSF. In this
regard, we thank Ojeda et al for revisiting the now widely accepted
clinical procedure of using G-CSF after PBSC transplantation (PBSCT) by
referring to our data published in a recent issue of
BLOOD.1 In that study, we reported the results of a
prospective randomized trial with 74 children who were scheduled to
undergo high-dose chemotherapy followed by autologous PBSCT. In the
data reported by us with children and by Ojeda et al with adult
patients, a 1- or 2-day earlier recovery of granulocytes did not have
any meaningful practical clinical impact. Moreover, we and Ojeda et al
found that the marginal clinical benefit of an earlier recovery of
granulocytes could be offset by the delayed recovery of platelets,
which has been well reported by other groups,2,3 although
the exact mechanism of this phenomenon is unclear.
The quality of our multicenter study might be questioned. However, in a
series of studies we have shown that morbidity and mortality related to
PBSCT are essentially negligible, particularly in pediatric patients.
This makes the biases that originate from differences in clinical
management procedures among the participating institutes less
significant. Indeed, in our intent-to-treat analysis, none of the
patients suffered from serious bleeding episodes or clinically
significant infectious complications. Hence, the value of extending the
analysis to include minor items, such as mucositis, is questionable.
All of the patients with ALL (n = 27) and neuroblastoma (n = 29)
were treated uniformly according to the protocols of the Japanese
Cooperative Study Group of PBSCT. Thus, it is unlikely that the quality
of our multicenter trial and trivial differences in supportive care
systems, if any, greatly affected the outcome of our study. We could
not perform a critical cost analysis, because in Japan all medical
costs related to cancer therapy for children are paid by the
government, not by the family, and decisions regarding drug therapy or
hospitalization depend strongly on social considerations.
There might be another pitfall with G-CSF treatment when used after
transplantation, ie, the administration of G-CSF may further exaggerate
cytokine dysregulation, which frequently occurs in the rapid recovery
phase of hematopoiesis after PBSCT and is clinically recognized as
engraftment syndrome. In addition, a sharp surge of granulocytes in the
circulation may increase the trapping of cells in the microcirculation,
particularly in pulmonary vessels. Consequently, the incidence and
severity of pulmonary complications might be increased in adult
patients, as has been reported after conventional
chemotherapy.4 Considering these points, we agree that the
routine application of this expensive strategy in patients undergoing
PBSCT should be seriously reevaluated in adult patients. Reconsideration of this maneuver also has important implications for
the cost-effectiveness of hematopoietic stem cell transplantation.
Yoshifumi Kawano
Department of Pediatrics
University
Hospital of Tokushima
Tokushima, Japan
Yoichi Takaue
Stem Cell Transplant Unit
National Cancer Center Hospital
Tokyo, Japan
| |
REFERENCES |
1.
Kawano Y, Takaue Y, Mimaya J, Horikoshi Y, Watanabe T, Abe T, Katsuura T, Matsushita T, Kikuta A, Watanabe A, Iwai A, Ito E, Endo M, Kotani N, Ohta S, Gushi K, Azuma H, Etoh T, Hattori H, Okamoto Y, Kuroda Y, (for the Japanese Cooperative Study Group of PBSCT):
Marginal benefit/disadvantage of granulocyte colony-stimulating factor (G-CSF) therapy after autologous blood stem cell transplantation in children: A result of prospective randomized trial.
Blood
92:4040, 1998
2.
Bensinger W, Appelbaum F, Rowley S, Storb R, Sanders J, Lilleby K, Gooley T, Demirer T, Shciffmann K, Weaver C, Clift R, Chauncey T, Klarnet J, Montogomery P, Petersdorf S, Weiden P, Witherspoon Buckner D:
Factors that influence collection and engraftment of autologous peripheral-blood stem cells.
J Clin Oncol
13:2547, 1995[Abstract]
3.
Bernstein SH, Nademanee AP, Vose JM, Tricot G, Fay JW, Negrin RS, DiPersio J, Rondon G, Champlin R, Barnett MJ, Cornetta K, Herzig GP, Vaughan W, Geils G, Keating Jr A, Messner H, Wolff SN, Miller KB, Linker C, Cairo M, Hellmann S, Ashby M, Stryker S, Nash RA:
A multicenter study of platelet recovery and utilization in patients after myeloablative therapy and hematopoietic stem cell transplantation.
Blood
91:3509, 1998
4.
Yokose N, Ogata K, Tamura H, An E, Nakamura K, Kamikubo K, Kudoh S, Dan K, Nomura T:
Pulmonary toxicity after granulocyte colony-stimulating factor-combined chemotherapy for non-Hodgkin's lymphoma.
Br J Cancer
77:2286, 1998[Medline]
[Order article via Infotrieve]
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