Pediatr Drugs 2003; 5 (10): 673-684

THERAPY IN PRACTICE 1174-5878/03/0010-0673/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

The Role of Colony-Stimulating Factors and

Granulocyte Transfusion in Treatment Options
for Neutropenia in Children with Cancer
Der-Cherng Liang
Division of Hematology-Oncology, Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
1. Colony-Stimulating Factors (CSFs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
2. Biology of Recombinant CSFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
2.1 Granulocyte Colony-Stimulating Factor (G-CSF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
2.2 Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
3. Clinical Applications of CSFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
3.1 Primary Prophylaxis in Patients After Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
3.1.1 G-CSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
3.1.2 GM-CSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
3.2 Secondary Prophylaxis in Patients After Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
3.3 Therapy for Neutropenia With or Without Fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
3.3.1 Afebrile Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
3.3.2 Febrile Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
3.4 Chemotherapy Dose-Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
3.5 Adjunct Therapy to Progenitor-Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
3.6 Patients Receiving Concurrent Chemotherapy and Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
3.7 CSF Dosing and Route of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
3.8 Initiation and Duration of CSF Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
3.9 Comparative Clinical Activity of G-CSF and GM-CSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
4. Toxicity and Adverse Effects of CSFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
4.1 G-CSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
4.2 GM-CSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
4.3 Potential of CSFs to Induce Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
5. Granulocyte Transfusion in Severe Neutropenic Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
5.1 Collection and Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
5.2 Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
5.3 Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681

Abstract Children with cancer receiving anticancer therapy always experience neutropenia, and as a result often
develop serious neutropenic infections that cause morbidity and/or mortality. Intensive chemotherapy with
improved supportive care for neutropenia contribute to the recent advances in treatment outcome in children with
674 Liang

cancer. Recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulo-
cyte-macrophage colony-stimulating factor (GM-CSF) can shorten the duration and decrease the severity of
neutropenia, and thus support intensive chemotherapy. Both G-CSF and GM-CSF stimulate proliferation and
maturation of myeloid progenitor cells and are thus used to help mobilization of peripheral blood progenitor
cells, and after stem-cell transplantation.
The American Society of Clinical Oncology 2000 Guidelines recommended that colony-stimulating factors
(CSFs) can be administered as a primary prophylaxis with a chemotherapy regimen if previous experiences with
chemotherapy regimens have shown that the incidence of febrile neutropenia (neutropenic fever) is ≥40%. The
routine use of CSFs for secondary prophylaxis or for patients with afebrile neutropenia is not recommended in
order to avoid the overuse of CSFs. The use of a CSF may be considered in children with febrile neutropenia with
a neutrophil count <100/μL, uncontrolled primary disease, pneumonia, hypotension, multiorgan dysfunction
(sepsis syndrome), or invasive fungal infection. Although these guidelines are generally applicable to children
with cancer, further studies on CSFs are certainly needed in pediatric oncology.
The recent advances in granulocyte collection, using healthy volunteer donor stimulation with G-CSF and/or
dexamethasone to yield large numbers of granulocytes has made granulocyte transfusion a more realistic option.
Granulocyte transfusion has shown promising results in treating children with severe neutropenic infection;
however, controlled trials are warranted to clarify the efficacy and cost-effectiveness of this procedure.

Neutropenia in children with cancer most often results from
anticancer chemotherapy, radiation therapy, or both. Neutropenia
may also be caused by marrow infiltration by leukemic cells or
tumor cells (most commonly neuroblastoma or non-Hodgkin’s
lymphoma). Qualitative defects of neutrophil function are also
common in patients with cancer. These defects include impairment
of superoxide generation, phagocytosis, and microbicidal activity
in vitro. These defects may be due to the underlying malignancy,
chemotherapeutic agents, radiation therapy, or the presence of
viral infections, such as cytomegalovirus.[1]
Bodey et al.[2] first reported the quantitative relationship be-
tween circulating neutrophils and infection in patients with acute
leukemia. The frequency of infection increases progressively as
the neutrophil count decreases below 1000/μL, reaching the high-
est level when the count falls below 100/μL.
Neutropenic infection also correlates with the duration of neu-
tropenia. Patients in whom the process of neutrophil recovery lasts
longer than 10–14 days are at particularly high risk of severe
infections. At the onset of neutropenia, most infections are bacter-
ial. After the first 10–14 days, the spectra of infectious pathogens
expand to comprise fungi and other opportunistic micro-orga-
nisms.[3,4] Neutropenia of long duration is associated with poor
response to antibacterial therapy and prolonged hospital stay.[5]
Febrile neutropenia (neutropenic fever) in patients receiving
chemotherapy should be treated with empiric antibacterials. In
serious infections not responding to antibacterials, granulocyte
transfusions have occasionally been used. Despite remarkable
progress achieved in the treatment of febrile neutropenia with the
use of broad-spectrum antibacterials, morbidity from neutropenic
infections remains considerable, and a threat to life exists. Al-
though antibacterials are generally effective, their efficacy is ulti-
mately often hampered by the potential emergence of drug resis-
tance. Thus, other measures that can reduce the use of antibac-
terials have been sought. Attempts to attenuate neutropenia led to
the development of recombinant myeloid growth factors (MGFs).
Two MGFs, or colony-stimulating factors (CSFs), currently avail-
able for clinical use are recombinant human granulocyte colony-
-stimulating factor (G-CSF) and recombinant human granulo-
cyte-macrophage colony-stimulating factor (GM-CSF). Both
G-CSF and GM-CSF stimulate proliferation, maturation, and mo-
bilization of myeloid progenitor cells.
The treatment options, including G-CSF, GM-CSF, and granu-
locyte transfusion, for neutropenia in children with cancer are
presented and discussed.
1. Colony-Stimulating Factors (CSFs)
The baseline production of neutrophils in the bone marrow is
approximately 1.0 × 1011/day in a healthy adult, which increases
several-fold in infection.[6] After myeloid precursor neutrophils
mature, they are released into the circulation, where they survive

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (10)
Treatment for Neutropenia in Childhood Cancer
for only 6–10 hours. While half of the neutrophils in peripheral
blood circulate freely, the other half remain in the microcircula-
tion, adherent to vascular walls in the marginal pool. Neutrophils
from the microcirculation can be mobilized to circulate by stress or
by medications such as corticosteroids. In contrast, neutrophilia
induced by growth factors occurs mainly through the stimulation
of the myeloid progenitors in the bone marrow to increase neutro-
phil production.
In the process of hematopoiesis, the role of hematopoietic
growth factors is both permissive and instructive.[7] Hematopoietic
growth factors maintain the survival of the early hematopoietic
progenitor cells by preventing apoptosis. They also promote the
proliferation of, and facilitate and direct the differentiation of
myeloid progenitors, and activate effector functions in mature
cells. Although the commitment of multipotent hematopoietic
progenitor cells to a specific lineage is most likely random, further
development depends on the instructional influence of the micro-
environment, in which hematopoietic growth factors serve an
important role.
Hematopoietic growth factors are produced by a variety of
stromal and hematopoietic cells. There are four CSFs: G-CSF,
GM-CSF, macrophage colony-stimulating factor (M-CSF), and
multi-colony stimulating factor (multi-CSF) or interleukin
(IL)-3.[8] All four have been purified and defined genetically. The
first two, GM-CSF and G-CSF, have been manufactured through
recombinant engineering technology and made available for clin-
ical use. The latter two, M-CSF and IL-3, were tested in clinical
trials, but have not been widely used because of undesirable
toxicities.[9] However, a chimeric dual of G-CSF and IL-3 receptor
agonist (leridistim) was shown in vitro to cause more potent
stimulation of hematopoietic proliferation than G-CSF or IL-3.[10]
2. Biology of Recombinant CSFs
2.1 Granulocyte Colony-Stimulating Factor (G-CSF)
Experimental evidence indicates that G-CSF is the cytokine
responsible for maintenance of normal blood neutrophil levels and
for increasing neutrophil release and production seen in infection
and inflammation.[11-13] Human G-CSF is a glycoprotein of ap-
proximately 20kDa.[14,15] It is encoded by a single gene located on
chromosome 17q21-22, and is produced by activated macro-
phages, endothelial cells, fibroblasts, and bone marrow stromal
cells. The G-CSF receptor is a type I membrane protein belonging
© Adis Data Information BV 2003. All rights reserved.
675
to the hematopoietic growth factor receptor family. Expression of
the G-CSF receptor is specifically restricted to neutrophilic pro-
genitor cells, mature neutrophils, and various myeloid leukemia
cells. After stimulation, the G-CSF receptor transduces the signals
for both proliferation and differentiation of myeloid cells.
Human G-CSF is a protein of 174 amino acids. It is glycosylat-
ed in the natural state. The available recombinant human G-CSFs
include a nonglycosylated form synthesized in Escherichia coli
(filgrastim) and a glycosylated form synthesized in Chinese ham-
ster ovarian cells (lenograstim).[11] These two preparations appear
to have identical activity,[16] exerting their effect on cell prolifera-
tion and function by interacting with the specific G-CSF cell
surface receptor.[17,18]
Subcutaneous administration of G-CSF to healthy human vol-
unteers causes a rapid dose-dependent increase in the blood neu-
trophil count, beginning within about 1 hour and peaking at
approximately 12 hours. Repeated daily administration produces
sustained dose-dependent neutrophilia with an increase in neutro-
phil count superimposed on the baseline after each injection.[19]
This acute neutrophilia is most likely attributable to release of the
marrow reserve into circulation. G-CSF also stimulates marrow
myeloid production, increasing the size of the marrow prolifera-
tive pool, and accelerates the transit time of the developing neutro-
phil through the marrow maturational pool into the blood. At a
daily dose of 300μg G-CSF, marrow transit time is shortened from
the usual 6.6 days to approximately 2.5 days.[20] In addition, the
survival of neutrophils is prolonged. After G-CSF is discontinued,
the neutrophil count returns to normal within several days.
Filgrastim conjugated to polyethylene glycol (PEG-rhG-CSF),
with a mean half-life of 59 hours, has a prolonged neutrophil-
proliferating activity enabling fewer administrations than filgras-
tim.[21,22] However, this preparation is not suitable for use in
children with cancer as children require monitoring of neutrophil
count at an interval of usually no longer than 3 days. A new
preparation of lenograstim (stabilizer changed from human serum
albumin to gelatin) can be stored at room temperature.[23]
Treatment with G-CSF also affects cell function. Phagocytic
activity is increased, as is bactericidal and fungicidal ac-
tivity.[11,24,25] Although G-CSF does not cause neutrophils to un-
dergo a respiratory burst, it does prime the cells to exhibit an
enhanced respiratory burst in response to second agonists.[11] The
levels of cell surface receptors, which are important for neutrophil
function, are also altered by G-CSF.[11,26,27] G-CSF induces in-
creased expression of FcγR1(CD64), CD35, and CD14. When
Pediatr Drugs 2003; 5 (10)
676
administered in vivo, G-CSF initially increases the expression of
CD11b. However, continued administration of G-CSF is asso-
ciated with decreased expression of this adherence protein.[26]
Apoptosis of neutrophils is inhibited by exposure to G-CSF,[11,28] a
finding that may explain, in part, the prolonged survival of neutro-
phils in the blood in patients who received G-CSF.[19]
2.2 Granulocyte-Macrophage Colony-Stimulating
Factor (GM-CSF)
Human GM-CSF is a glycoprotein of approximately 22kDa and
has a three-dimensional structure composed of two pairs of an-
tiparallel α helices.[29] The α receptor subunits play an essential
role in the activation of the shared βc subunit, the major signaling
entity. The complete βc extracellular domain forms a stable inter-
locking dimer.[30] The human GM-CSF gene is located on the long
arm of chromosome 5, near other cytokine genes. GM-CSF can be
produced by a variety of cells: T lymphocytes, macrophages,
endothelial cells, fibroblasts, stromal cells, and various malignant
cells. GM-CSF receptors are found on hematopoietic cells and
various nonhematopoietic cells, such as trophoblasts, endothelial
cells, oligodendrocytes, and some cancer cells.[31] GM-CSF recep-
tors have not been found on lymphocytes.
GM-CSF stimulates proliferation and maturation of a bipotent
neutrophil and macrophage progenitor, which leads to the release
of monocytes and macrophages into circulation, in addition to
neutrophils.[32] GM-CSF also enhances the function of mature
neutrophils, monocytes, and macrophages by increasing anti-
microbial activity, chemotaxis, and proinflammatory cytokine re-
lease. GM-CSF has a significant effect on the antigen-presenting
function of antigen-presenting cells. Specifically, in vitro studies
have demonstrated that GM-CSF acts as the major stimulatory
cytokine for the production, differentiation, and viability of den-
dritic cells. Thus, GM-CSF appears to act not only as a stimulant
of peripheral blood neutrophil recovery, but also as an enhancer of
several other components of immune response to infection and
malignancy.[33]
3. Clinical Applications of CSFs
Three basic strategies are applied in the use of CSFs in the
management of patients with malignancy. Primary prophylaxis is
defined as the administration of a CSF during the first chemother-
apy cycle in an attempt to prevent anticipated neutropenic infec-
tious complications. Secondary prophylaxis is to use a CSF to
© Adis Data Information BV 2003. All rights reserved.
Liang
prevent new episodes of neutropenia or delays in the administra-
tion of subsequent cycles of chemotherapy in a patient who has
previously experienced documented neutropenic fever or delay in
therapy. In the therapeutic setting, the use of CSFs is for adjuvant
treatment of established neutropenia with or without fever, or a
documented infection.
Although clinical benefit has been been established for about
10 years, when CSFs were first introduced into clinical practice,
the high cost of CSFs has led to concerns about their appropriate
use. First published in 1994[34] and updated in 1996,[35] the Ameri-
can Society of Clinical Oncology (ASCO) has issued guidelines
for the use of CSFs, based on an expert panel review of the
available data. The most recent version was published in 2000.[36]
The panel stated that although pediatric data are not conclusive,
the guidelines recommended for adult patients are generally also
applicable to children.[35,36]
3.1 Primary Prophylaxis in Patients After Chemotherapy
3.1.1 G-CSF
A variety of studies in children with cancer receiving intensive
chemotherapy have documented that primary prophylaxis with G-
CSF reduces the duration of neutropenia, lowers rates of febrile
neutropenia, decreases use of antibacterials, and diminishes the
need for hospitalization.[37,38] Several larger randomized trials also
have been conducted in children with cancer undergoing chemo-
therapy. Children with high-risk leukemia randomly assigned to
receive G-CSF had a lower incidence of febrile neutropenia and
documented infection, and a shorter duration of antibacterial use
compared with those receiving placebo.[39] Another trial in chil-
dren undergoing chemotherapy showed a reduction in the duration
of neutropenia, hospital stay, and incidence of febrile neutropenia,
as well as antibacterial treatment for patients receiving G-CSF
compared with those receiving placebo.[40]
However, not all studies have shown any benefit from the use
of G-CSF. In 164 children with acute lymphoblastic leukemia
(ALL) undergoing post-remission chemotherapy and randomly
assigned to receive either G-CSF or placebo, no significant differ-
ence was noted between the two groups in the rate of hospitaliza-
tion for febrile neutropenia, event-free survival at 3 years, or
incidence of serious infections. Patients treated with G-CSF did
have shorter hospital stay and fewer documented infections. The
cost of supportive care was similar in those in the G-CSF and
placebo-treated groups.[41] A Pediatric Oncology Group study also
Pediatr Drugs 2003; 5 (10)
Treatment for Neutropenia in Childhood Cancer
disclosed no significant benefit in a randomized trial of G-CSF
versus placebo in children with T-cell leukemia and advanced
lymphoblastic lymphoma.[42] A trial in 149 children and adoles-
cents receiving chemotherapy for non-Hodgkin’s lymphoma also
revealed no significant differences between the two groups in
terms of febrile neutropenia, duration of neutropenia, and total
cost of treatment.[43] Another randomized study evaluated the role
of G-CSF prophylaxis following intensive chemotherapy in a
crossover study with CSF or no CSF in children with ALL or T-
cell lymphoma. The use of G-CSF resulted in a significant reduc-
tion in the rate of rehospitalization for febrile neutropenia. How-
ever, there were no differences in the duration of hospital stay,
hematologic toxicity, neutrophil recovery, or duration of support-
ive care between the two groups.[44] A very recent report also
revealed that G-CSF shortened the duration of severe neutropenia,
but failed to reduce episodes of febrile neutropenia or improve
outcome in children with high risk ALL.[45] In 1996 and 1997 a
panel of European experts developed specific pediatric guidelines
for the use of CSFs in children with cancer. Their established
indications also included the use of CSFs in life-threatening infec-
tion. Less clear indications included primary prophylaxis to sup-
port dose intensification in children with high risk/advanced ma-
lignancies, secondary prophylaxis to prevent neutropenia in pa-
tients with a history of severe neutropenia.[46] A beneficial effect of
G-CSF on platelet levels has not been observed. In fact, several
trials have found that patients treated with G-CSF develop some-
what more severe thrombocytopenia.[37] Amelioration of mucositis
in association with G-CSF has been reported.[47]
It appears that the use of G-CSF should be limited to children
who receive intensive chemotherapy. For malignancies in which
available data do not demonstrate an improvement in survival with
increasing dose intensity, consideration should be made to reduce
chemotherapy doses rather than using a CSF.[48]
3.1.2 GM-CSF
Randomized trials of GM-CSF as primary prophylaxis of feb-
rile neutropenia in children and adults have usually resulted in
decreased duration or severity of neutropenia, but clinical benefits
have not been as consistently positive as those observed with G-
CSF.[37-39] Two prospective studies of children have been reported.
In the first, GM-CSF prophylaxis was randomly used in children
receiving intensive chemotherapy. Although GM-CSF reduced the
severity and duration of the neutropenic nadir, the rates of febrile
neutropenia, hospital stay, antibacterial requirement, dose intensi-
© Adis Data Information BV 2003. All rights reserved.
677
ty, and disease control were not significantly affected. Further-
more, thrombocytopenia was more severe in children receiving
GM-CSF, resulting in greater transfusion requirements.[49] The
other randomized trial of GM-CSF in children also documented a
shortened duration of neutropenia for children receiving GM-CSF,
but the period of thrombocytopenia was longer.[50]
In summary, although the effectiveness of primary CSF admin-
istration has been clearly established in less myelosuppressive
regimens, the cost-benefit of primary prophylaxis for the majority
of initial chemotherapy regimens is unproven. It is recommended
that primary administration of CSFs be reserved for patients
expected to experience an incidence of febrile neutropenia ≥40%.
Thus, for previously untreated patients receiving most chemother-
apy regimens, primary administration of CSFs cannot be recom-
mended.[35,36]
3.2 Secondary Prophylaxis in Patients
After Chemotherapy
No randomized trials have assessed whether secondary prophy-
lactic use of either G-CSF or GM-CSF can prevent new episodes
of febrile neutropenia in pediatric patients with a prior episode,
and encouraging results in adults are limited. A randomized trial of
G-CSF versus placebo in adults with small-cell lung cancer re-
vealed that patients receiving G-CSF as an adjunct to chemother-
apy had a shorter duration and reduced severity of neutropenia,
and a reduction in the rate of febrile neutropenia.[48]
No published regimens have demonstrated disease-free or over-
all survival benefits when the dose of chemotherapy was main-
tained and secondary prophylaxis was given. In the absence of
clinical data or other compelling reasons to maintain chemother-
apy dose-intensity, physicians should consider chemotherapy dose
reduction after neutropenic fever or severe prolonged neutropenia
that occurred in the previous cycle of treatment. The routine use of
G-CSF for secondary prophylaxis cannot be recommended.[36]
3.3 Therapy for Neutropenia With or Without Fever
CSFs are sometimes administered concomitantly with antibac-
terials in patients with febrile neutropenia. Since the response rate
of these children to antibacterial therapy is high, the likelihood of
detecting any therapeutic benefit of CSFs is minimal. Therefore,
the utility of CSF therapy may have to be evaluated in terms of
improved quality of life, shortened durations of hospital stay and
antibacterial use, or decreased treatment costs.
Pediatr Drugs 2003; 5 (10)
678
3.3.1 Afebrile Neutropenia
A series of studies in adults have evaluated the efficacy of
initiating CSF therapy after neutropenia is identified during a
chemotherapy cycle. Three randomized trials failed to detect a
clinical benefit for either G-CSF[51,52] or GM-CSF.[53] Therefore,
CSFs should not be routinely used for patients with neutropenia
who are afebrile.[36]
3.3.2 Febrile Neutropenia
Several randomized controlled trials have evaluated either G-
CSF,[54,55] GM-CSF,[33] or both[38,56] as adjuvant treatment for
adults with chemotherapy-induced febrile neutropenia. In the larg-
est of these trials, 216 patients were enrolled. No significant
difference was noted between the two groups in fever duration,
days of antibacterial use, duration of hospital stay, and mortality
due to infection.[54] In contrast, another prospective, multicenter,
randomized clinical trial involving 210 patients with solid tumors
and at high risk (more prone to be septic) of febrile neutropenia
showed that the addition of G-CSF was associated with shortened
duration of neutropenia, decreased durations of antibacterial ther-
apy and hospital stay, and reduced overall hospital cost.[55] In a
randomized study of GM-CSF versus placebo in 107 adults, GM-
CSF improved the response rate in terms of defervescence, but not
overall survival.[37] However, a meta-analysis of published ran-
domized trials, their methodologic quality assessed by a scoring
system, did not reveal any advantage from the use of G-CSF or
GM-CSF for cancer patients in terms of mortality from febrile
neutropenia.[57]
In a double-blind study, children who had febrile neutropenia
were randomly assigned to receive G-CSF or placebo in addition
to antibacterial therapy. The G-CSF group had a shorter hospital
stay and reduced antibacterial use than those receiving placebo.[58]
In a randomized study, the children given GM-CSF instead of
placebo had a slight reduction in hospital stay.[59] In another
pediatric trial, GM-CSF therapy for febrile neutropenia after inten-
sive chemotherapy shortened the mean duration of severe neutro-
penia from 9 days in the placebo group to 7 days in the GM-CSF
treatment group.[49]
The clinical trials evaluating CSF treatment for febrile neutro-
penia have produced variable results, most likely because of
heterogenous patient groups and treatments involved.
The ASCO 2000 update recommended that the routine use of
CSFs as an adjunct to antibacterial therapy is unnecessary in
patients with febrile neutropenia.[36] Certain patients with febrile
© Adis Data Information BV 2003. All rights reserved.
Liang
neutropenia are at higher risk of infection-associated complica-
tions, and have prognostic factors that are predictive of poor
clinical outcome, e.g. profound neutropenia (neutrophil count
<100/μL), uncontrolled primary disease, pneumonia, hypotension,
multiorgan dysfunction (sepsis syndrome), and invasive fungal
infection.[36] The use of a CSF for such high-risk patients may be
considered, but the benefits in these situations have not been
proven.
3.4 Chemotherapy Dose-Intensity
In the absence of more trials demonstrating a favorable effect
on overall survival, disease-free survival, quality of life, or toxici-
ty, there is no justification for the use of CSFs to enable an
increase in chemotherapy dose-intensity or schedule, or both,
outside of a clinical trial. This application of CSF use remains to
be determined.[36] One of the uses of CSFs is to induce cycling of
leukemic progenitors with the aim of enhancing the cytotoxic
effects; however, the results were generally disappointing.[60,61]
3.5 Adjunct Therapy to Progenitor-Cell Transplantation
As no data in children are currently available, data presented in
this section are from studies in adults only.
Mobilized peripheral blood progenitor cells (PBPCs) have
largely replaced bone marrow cells for use in autologous trans-
plantation, and are being evaluated in allogeneic stem cell trans-
plantation. Adverse effects associated with mobilization and sub-
sequent apheresis are usually limited, and include constitutional
symptoms and a decrease in platelets and other hematopoietic
elements, especially after mobilization with combinations of
chemotherapeutic agents and a CSF. Determining the optimal
doses of CSFs and chemotherapeutic agents is the subject of
ongoing investigations. A higher (10 μg/kg/day) dose of G-CSF
for mobilization of PBPCs may yield a greater amount of CD34+
progenitor cells in the PBPC product, as documented in patients
with hematologic malignancies and patients with rheumatoid ar-
thritis.[62,63] Although the optimal method of mobilization needs
further investigation, especially in heavily pretreated patients,
administration of G-CSF, either alone[64,65] or in combination with
GM-CSF,[62,66] or after the use of chemotherapeutic agents,[67,68]
generates PBPCs, leading to rapid hematopoietic recovery, shorter
hospitalization, and possibly reduced costs.[64,65,67,68] Further in-
vestigations are necessary to assess the potential risks, especially
that of secondary hematologic malignancies associated with the
Pediatr Drugs 2003; 5 (10)
Treatment for Neutropenia in Childhood Cancer
use of combining chemotherapeutic agents and CSFs.[69] The role
of CSF-mobilized donor bone marrow in the autologous transplant
setting is also under investigation.[70] Two episodes of splenic
rupture have been reported in healthy donors after G-CSF based
regimens for the harvest of PBPCs.[71,72] Furthermore, the long-
term safety of G-CSF administration to healthy donors for mobili-
zation of PBPCs or granulocytes (see section 5.1) requires careful
monitoring.[73-75] Following transplantation, delayed initiation of
CSFs until 5–7 days post-transplant is recommended.[76-80] A G-
CSF dose of 5 μg/kg/day appears equivalent to 10 μg/kg/day in
this situation.[81] Alternatively, CSFs may only be given to patients
who receive a suboptimal quality graft. CSFs are recommended to
help mobilize PBPCs, and after PBPC transplantation.[36]
3.6 Patients Receiving Concurrent Chemotherapy
and Irradiation
CSFs should be avoided in patients (including children) receiv-
ing concomitant chemotherapy and radiation therapy, particularly
involving the mediastinum. In the absence of chemotherapy, thera-
peutic use of CSFs may be considered in patients receiving radia-
tion therapy involving large fields, if prolonged neutropenia is
expected.[36]
3.7 CSF Dosing and Route of Administration
In adults, the recommended CSF doses are 5 μg/kg/day for G-
CSF (filgrastim) and 250 μg/m2/day for GM-CSF (sargramostim)
for all clinical settings other than PBPC mobilization. If G-CSF is
used in a PBPC mobilization setting, a dose of 10 μg/kg/day seems
preferable. Outside of this indication, CSF dose escalation is not
advised. Rounding the dose to the nearest vial size is an appropri-
ate strategy to maximize cost benefit.[36] In the absence of conclu-
sive pediatric data, the guidelines recommended for adults are
generally applicable to the pediatric age group; however, optimal
CSF doses have yet to be determined. Further clinical research into
the use of these factors in support of chemotherapy and PBPC
transplantation in the pediatric age group should be given high
priority.[36] Although much of the administration of CSFs in chil-
dren is dictated by protocol requirements, administration is also
influenced by pediatrician preference and available data.[82]
Pharmacokinetic analysis favors subcutaneous administration
rather than intravenous use for both G-CSF and GM-CSF.[83-85]
The comparable pharmacokinetic characteristics of GM-CSF in
children supported single daily subcutaneous administration in
© Adis Data Information BV 2003. All rights reserved.
679
both age groups, instead of intravenous infusion.[83] The same
conclusion was also established in studies in adults receiving GM-
CSF[84] or G-CSF.[85] The ASCO 2000 update recommended that
the preferred route of CSF administration is subcutaneous for both
adults and children.[36]
3.8 Initiation and Duration of CSF Administration
When to start or to stop CSF therapy relative to chemotherapy
has been controversial. Based on available data, it appears that
starting CSF therapy 24–72 hours after completion of chemother-
apy may be optimal.[36] Delayed start of G-CSF from day 4 of
chemotherapy to day 6 might be associated with a similar neutro-
phil recovery, but a further delay to day 8 resulted in a less
favorable recovery.[86] Starting CSF therapy prior to chemotherapy
can lead to more profound neutropenia and should, therefore, be
avoided.[87] Continuing G-CSF until the occurrence of a neutrophil
count of 10 000/μL, or GM-CSF until a neutrophil count 20 000/
μL after the neutrophil nadir, as specified in the G-CSF and GM-
CSF package inserts, is known to be well tolerated and effective.
In our experience, a shorter duration of administration that is
sufficient to achieve clinically adequate neutrophil recovery may
be a practical alternative, considering issues of patient conve-
nience and cost.[35] The optimal timing and duration of CSF
administration are still under assessment. Starting CSFs up to 5
days after PBPC reinfusion is reasonable, based on available
clinical data.[36]
3.9 Comparative Clinical Activity of G-CSF and GM-CSF
A randomized, double-blind, multicenter study comparing the
efficacy of GM-CSF and G-CSF in the treatment of standard-dose
chemotherapy-induced neutropenia revealed no statistically sig-
nificant difference.[88] Compared with G-CSF, GM-CSF is a less
potent inducer of neutrophil production and is less specific in its
activity.[89] GM-CSF has greater adverse effects, which may be
related to the actions of macrophages. In particular, GM-CSF
causes fever in >20% of recipients.[90] The approved clinical
indications in the US for the use of G-CSF or GM-CSF are
mobilization and collection of PBPCs and myeloid reconstitution
after hematopoietic stem cell transplantation (see section 3.5). G-
CSF is also indicated for patients with cancer receiving myelosup-
pressive chemotherapy, following induction or consolidation
chemotherapy for acute myeloid leukemia (AML) and severe
chronic neutropenia. GM-CSF is also indicated in hematopoietic
Pediatr Drugs 2003; 5 (10)
680
stem cell transplantation failure or engraft delay, following induc-
tion chemotherapy for AML, and following autologous PBPC
transplantation. As an adjuvant therapy, GM-CSF may be superior
to G-CSF in treating severe fungal infections.[91] Investigation that
will guide clinical application of these CSFs by addressing issues
of comparative clinical activity, toxicity, and cost-effectiveness is
still warranted.[36] There are some studies exploring the potential
synergy between CSFs.[66,67,92] The potential limitations of the
benefits of CSFs are listed in table I.
4. Toxicity and Adverse Effects of CSFs
The toxicity and adverse effects of CSFs in adults and children
are similar.
4.1 G-CSF
The most common adverse effect of G-CSF is mild-to-moder-
ate bone and/or musculoskeletal pain, which occurs in 20–30% of
individuals.[89,93] Other adverse effects include headache, anemia,
splenomegaly, thrombocytopenia and, rarely, allergic and injec-
tion-site reactions.[89,93] A cutaneous neutrophilic vasculitis
(Sweet’s syndrome) is uncommon. G-CSF is generally well toler-
ated during prolonged treatment in patients with severe chronic
neutropenia.[94]
4.2 GM-CSF
Compared with G-CSF, GM-CSF treatment has been asso-
ciated with a greater frequency of adverse effects in children,
possibly as a result of stimulation of proinflammatory responses in
Table I. The potential limitations of the benefits of colony-stimulating fac-
tors (CSFs)[36]
Cannot affect the outcome of cancer unless infection-related morbidity
and mortality are significant causes of treatment failure
Do not eliminate neutrophil count nadirs
Do not substantially alter the time to recover neutrophil count to ≥100/μL
Are costly
May have adverse effects of musculoskeletal pain, thrombocytopenia,
fever and, uncommonly, Sweet’s syndrome
Potential to increase in the risk of therapy-related myeloid malignancy in
patients treated with leukemogenic agents and CSFs
Frequently, the cost-effectiveness in a special setting is not clear
Clinical trials produced variable results, most likely because of
heterogenous patient groups and the treatments involved
© Adis Data Information BV 2003. All rights reserved.
Liang
monocytes/macrophages. The most frequent adverse effect is fe-
ver, which occurs in >20% of patients and can serve as a con-
founding factor in the evaluation of treatment responses during
infection.[95] Fever is often accompanied by myalgias and an
influenza-like syndrome. First-dose reactions, consisting of flush-
ing, tachycardia, hypotension, musculoskeletal pain, dyspnea,
nausea, vomiting, and arterial oxygen desaturation, have been
reported in 5% of patients receiving GM-CSF.[96] High doses of
GM-CSF have been reported to cause a generalized capillary leak
syndrome in children.[97]
4.3 Potential of CSFs to Induce Malignancy
Concerns have been raised about the use of GM-CSF in patients
with AML. GM-CSF promotes the in vitro proliferation of leuke-
mic blasts, and thus might lead to disease relapse. However,
numerous clinical studies in adults and children have not shown
clinically detectable adverse effect of CSFs on stimulation of
myeloid leukemic cell growth. The complete response and relapse
rates of patients receiving CSFs have usually been the same as, or
better than those in control groups.[98] However, in one trial there
had been at least six cases of secondary AML reported among
2548 patients with breast cancer receiving chemotherapy and
prophylactic G-CSF, which can inhibit apoptotic death of chemo-
therapy-damaged hematopoietic progenitors, and may contribute
to their leukemic transformation.[99,100] Several studies in adults
and children have suggested the potential increase in the risk of
therapy-related myeloid malignancy in patients treated with
leukemogenic agents and CSFs.[100-104] In 412 children with ALL
who all received etoposide, the 6-year cumulative incidence
(standard error) of therapy-related myeloid leukemia or myelodys-
plasia was higher in those receiving G-CSF (11.0% [3.5%] among
the 85 children who received G-CSF but no irradiation, 7.1%
[7.2%] among the 14 children who received irradiation plus G-
CSF, and 2.7% [1.3%] among the 269 children who received
neither G-CSF or irradiation).[105] Further investigations are neces-
sary to assess the potential of CSFs to induce malignancy.
5. Granulocyte Transfusion in Severe
Neutropenic Infection
5.1 Collection and Use
Because of the adverse effects of granulocyte (neutrophil)
transfusion, especially pulmonary reaction, and the lack of appar-
Pediatr Drugs 2003; 5 (10)
Treatment for Neutropenia in Childhood Cancer
ent efficacy, granulocyte transfusion almost disappeared from
clinical practice for several years. Due to an improvement in
technology, the granulocyte yield has improved considerably.
Currently, granulocytes are routinely collected by continuous-flow
centrifugation leukapheresis at most centers.[106] For acceleration
of red cell sedimentation, a sedimenting agent, usually hydroxy-
ethyl starch, with citrated anticoagulant, is added.[106] A meta-
analysis defined that prophylactic transfusion of adequate doses of
compatible leukocytes significantly reduced the relative risk of
infection, death, and death from infection in patients with leuke-
mia or bone marrow transplantation recipients.[107] Recently, the
collection of neutrophils from donors stimulated with G-CSF
600μg and dexamethasone 8mg yielded 82 × 109 neutrophils.[108]
Up until now, this is the most efficient method in the collection of
granulocyte. With the transfusion of such a large amount of
neutrophils, the post-transfusion neutrophil increments are sub-
stantial and are often maintained above baseline for at least 24
hours. Moreover, the function of neutrophils obtained from donors
who have been treated with G-CSF appears to be normal, or near
normal.[109] Currently, granulocytes are transfused as soon as
possible after leukapheresis.
5.2 Clinical Efficacy
In 20 neutropenic stem cell transplant patients (including four
children) with severe bacterial or fungal infection receiving granu-
locyte transfusion from volunteer donors, infection resolved in
eight patients.[107] Although the results are encouraging in some
series, the aggregate experience is not sufficient to draw conclu-
sions about the clinical efficacy of high dose granulocyte transfu-
sion therapy for severe fungal and/or bacterial infection in neutro-
penic patients with cancer, including children.[108]
5.3 Toxicity
Reported transfusion reactions associated with granulocyte
transfusion therapy have generally been mild, and similar to those
observed with the transfusion of other blood products. They in-
clude fever, chills, and minor changes in arterial oxygen desatura-
tion, but these changes were not sufficient to limit therapy.[108]
Human leucocyte antigen incompatibility might also contribute
to transfusion-associated graft-versus-host diseases (GVHD).[110]
Most HLA antigens are found on lymphocytes, but they are also
present on neutrophils. Current standard procedure is to check for
antibodies to ABO blood group antigens, and to test for leukoag-
© Adis Data Information BV 2003. All rights reserved.
681
glutination prior to transfusion.[111] Current practice is to irradiate
granulocyte products with 15–30Gy prior to transfusion to reduce
the risk of potential GVHD.[112]
More severe reactions occur in approximately 5% of granulo-
cyte transfusions, including hypotension, pulmonary infiltrates,
and respiratory distress, especially when granulocytes and ampho-
tericin B are given concomitantly.[113] Animal models suggest that
transfusion-related acute lung injury may be induced by granulo-
cytes that aggregate in the pulmonary microvasculature after acti-
vation by transfusion-derived antibodies or biologically active
lipids.[114]
6. Conclusions
The ASCO 2000 guidelines recommended that primary pro-
phylaxis with CSFs should be used in chemotherapy regimens
with an expected incidence of febrile neutropenia ≥40%. The
routine use of CSFs for secondary prophylaxis, or for patients with
afebrile neutropenia, is not recommended. In patients with febrile
neutropenia with a neutrophil count <100/μL, uncontrolled malig-
nancy, pneumonia, hypotension, multiorgan dysfunction (sepsis
syndrome), or invasive fungal infection, the use of a CSF may be
considered. CSFs are recommended to help mobilize PBPCs, and
after stem-cell transplantation.[36] In general, these guidelines are
also applicable to children with cancer.
Although there have been few data, especially in children, some
clinical trials suggest that granulocyte transfusion may be effective
in treating life-threatening bacterial and fungal infections.[108]
These results must be confirmed in large, controlled, multicenter
clinical trials.[109]
Acknowledgements
Preparation of this manuscript was supported by grant no. 9105 from
Mackay Memorial Hospital. The author has no conflicts of interest directly
relevant to the content of this manuscript.
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Correspondence and offprints: Dr Der-Cherng Liang, Division of Hematolo-
gy-Oncology, Department of Pediatrics, Mackay Memorial Hospital, 92
Sec. 2, Chung-San North Road, Taipei 104, Taiwan.
E-mail: dcliang@ms2.mmh.org.tw
Pediatr Drugs 2003; 5 (10)