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Hematopoietic Management in Oncology Practice

Hematopoietic Management in Oncology Practice

ABSTRACT: Hematopoietic growth factors have transformed the practice of oncology. The two major factors in clinical use are recombinant human (rh) granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) and granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine]). These factors differ significantly in their role in hematopoiesis and the regulation of mature effector cell function. G-CSF regulates both basal and neutrophil production and increased production and release of neutrophils from the marrow in response to infection. GM-CSF mediates its effects on the neutrophil lineage through its effects on phagocytic accessory cells and its synergy with G-CSF, but it does not appear to have a role in basal hematopoiesis. Part 1 of this twopart series focuses on the use of the myeloid growth factors rhG-CSF and rhGM-CSF to shorten the duration of chemotherapy-induced neutropenia and thus prevent infection in cancer patients. In randomized trials, rhG-CSF has consistently decreased the duration of neutropenia during all cycles of chemotherapy and reduced the risk of infection by 50% or more. Trials of rhGM-CSF have not reported consistent results.

One of the first, most important,
and sustained applications of
recombinant DNA technology
in medicine was the cloning and introduction
into clinical practice of several
glycoprotein factors involved in
the regulation of hematopoiesis. In less
than 20 years, hematopoietic growth
factors have transformed the practice
of nephrology, hematology, and oncology.
This review will summarize the
data supporting the clearly established
clinical applications of hematopoietic
growth factors in oncology, discuss
areas of controversy requiring further
study, and indicate some of their more
promising potential future applications
in the care of cancer patients. Part 1
focuses on the myeloid growth factors
and their role in decreasing the duration
of neutropenia and thus preventing
the development of clinically significant
infection in cancer patients.
Part 2, which will appear in the next
issue of ONCOLOGY, discusses the
biology and pharmacology of erythropoietin
and therapy with erythropoietic
agents.

Myeloid Growth FactorsBiology and Pharmacology
Two major factors involved in the
regulation of leukocyte production and
function are currently used in clinical
practice: recombinant human (rh)
granulocyte colony-stimulating factor
(G-CSF, filgrastim [Neupogen]) and
granulocyte-macrophage colonystimulating
factor (GM-CSF, sargramostim
[Leukine]). A thorough, clinically
relevant review of the biology of
these two factors is available.[1,2] It
is often overlooked that G-CSF and
GM-CSF differ significantly in their
roles in hematopoiesis and the regulation
of mature effector cell function,
and hence require individual evaluation
of their clinical utility. Although
human interleukin (IL)-3 and monocyte
colony-stimulating factor have
effects on leukocytes and have been
cloned and introduced into clinical
trials, they are not currently in clinical
use.

  • Granulocyte Colony-Stimulating
    Factor-
    G-CSF is probably the primary
    regulator of both basal neutrophil
    production and increased
    production and release of neutrophils
    from the marrow in response to infection
    ("emergency hematopoiesis") in
    mammals. Endogenous G-CSF levels
    rise during neutropenia or infection,
    and a mechanism for the feedback
    regulation of G-CSF levels by neutrophils
    has recently been described.[3]
    Mature neutrophils have functional
    receptors, and G-CSF induces activation
    and priming of neutrophils in several
    in vitro assays, and increases
    neutrophil migration to tissues without
    increased adhesion to endothelial
    surfaces.[4] G-CSF is also an antiapoptotic
    factor, prolonging neutrophil
    survival.
    Worldwide, two "unmodified"
    forms of rhG-CSF are in clinical use:
    filgrastim, which is expressed in
    Escherichia coli, and lenograstim,
    which is expressed in yeast cells and is
    available outside the United States. Following
    subcutaneous administration,
    rhG-CSF has a terminal serum half-life
    of approximately 2 to 5 hours and is
    associated with a dose-related increase
    in circulating neutrophils due to increased
    production and release from
    the marrow, and to increased neutrophil
    survival.[5,6] Neutrophils produced
    in response to rhG-CSF therapy
    function normally or "supernormally"
    in in vitro function assays.[7]

    Toxicities of rhG-CSF include bone
    pain and rare cases of Sweet's syndrome
    (neutrophilic dermatosis). Several
    cases of steroid-responsive interstitial
    pulmonary infiltrates have been
    reported in rhG-CSF-treated patients
    with hematologic malignancies.[8]
    Recently, a pegylated preparation of
    filgrastim that appears to be cleared
    by neutrophils and their marrow precursors
    and to have a prolonged serum
    half-life (particularly in neutropenic
    patients) has been introduced
    into clinical practice.[9] This preparation
    does not appear to be associated
    with any additional toxicities or
    an increase in the incidence or severity
    of bone pain.

  • Granulocyte-Macrophage Colony-
    Stimulating Factor-
    GM-CSF does
    not appear to be required for basal
    hematopoiesis. In vitro studies suggest
    that at least some of its apparent
    hematopoietic effects on the neutrophil
    lineage are mediated through its
    effects on phagocytic accessory cells
    and synergy with G-CSF.[10,11] Studies
    in knockout mice have demonstrated
    that GM-CSF has a role in
    pulmonary homeostasis, which may
    be due, in part, to a role in the generation
    of antigen-presenting cells in the
    lungs.[12] Serum GM-CSF levels do
    not increase during neutropenia or
    infection. Mature neutrophils, eosinophils,
    and monocyte/macrophages
    have receptors for GM-CSF; in vitro,
    GM-CSF primes neutrophils to
    enhanced performance in function
    assays. Unlike G-CSF, GM-CSF increases
    adhesion of neutrophils to
    endothelial surfaces and inhibits neutrophil
    migration across inflamed endothelial
    surfaces.[4]

    Two rhGM-CSF preparations are
    currently in clinical use: sargramostim,
    expressed in yeast, and molgramostim
    (Leucomax), expressed in bacteria.
    The subcutaneous or intravenous injection
    of rhGM-CSF is associated
    with a dose-related increase in circulating
    eosinophils and neutrophils, and
    a terminal serum half-life of approximately
    2 hours.[13] Circulating neutrophils
    taken from patients treated
    with rhGM-CSF function normally or
    supernormally in in vitro assays. However,
    some evidence suggests that in
    vivo migration of neutrophils to extravascular
    sites is impaired during
    rhGM-CSF therapy-an observation
    that is consistent with in vitro migration
    studies and that may be relevant
    to the efficacy of this factor in the prevention
    of infections.[14]

    Toxicities of rhGM-CSF include
    bone pain, rare cases of Sweet's syndrome,
    fevers, myalgias, serositis, and
    eosinophilic pneumonia.[15] Some
    investigators have concluded that these
    influenza-like symptoms occur more
    frequently when bacteria-derived
    rhGM-CSF is used; however, randomized
    comparative trials of the two
    preparations have not been reported.
    In addition, a transient pulmonary
    leukoagglutination syndrome characterized
    by hypoxia and hypotension
    following the first dose of rhGM-CSF
    has been observed, presumably related
    to the effects of this factor on neutrophil
    adhesion.[16]

Prevention of Infection
During Chemotherapy

By far the most frequent clinical
application of the myeloid growth factors
in oncology is to shorten the duration
of neutropenia in patients receiving
cyclic myelosuppressive chemotherapy.
Three distinct strategies
have been used to achieve that goal:
(1) attempts to lower the risk of infection,
usually measured as the incidence
of febrile neutropenia in patients receiving
already-established doses of
chemotherapy, (2) attempts to accelerate
the recovery of chemotherapy
patients with established neutropenic
infections, and (3) attempts to increase
the dose and/or frequency of administration
of myelosuppressive chemotherapy
to improve antitumor efficacy.

Interest in using rhG-CSF to
shorten the duration of neutropenia
and hence lower the risk of infection
in patients receiving chemotherapy
began when early trials demonstrated
a dose-related decrease in the duration
of neutropenia during chemotherapy
cycles.[17] These data, which included
rhG-CSF doses as high as 60 μg/kg/d,
are still of interest, because they
suggest that one strategy for addressing
the problem of febrile neutropenia
in patients receiving conventional
doses of rhG-CSF may be to increase
the dose in subsequent cycles. Another
strategy is to continue rhG-CSF
therapy and add quinolone antibiotic
therapy in later cycles.[18]

Trials of rhG-CSF
to Prevent Infection

Several randomized trials have
evaluated multicycle chemotherapy
with or without rhG-CSF, usually administered
subcutaneously at a daily
dose of approximately 5 μg/kg before
the onset of neutropenia. In adequately powered studies, the results have been
consistent, with a significant reduction
in the duration of neutropenia for all
chemotherapy cycles and a 50% or
greater reduction in the risk of clinically
significant infections.[19-29]
These results have been observed
when adjustments in chemotherapy
doses were permitted for neutrophil
counts or infection (which may bias
the study against the overall efficacy
of rhG-CSF),[20-22,27] when solid
tumors[19,21,23] or nonmyeloid hematologic
malignancies[20,22,24-28]
were studied (in trials that included
pediatric[24] and elderly[25] patient
populations), and when prophylactic
oral antibiotics were administered to
all study patients.[20]

Moreover, in the only well-powered
randomized comparison of the
efficacy of two myeloid growth factors
for the prevention of infection
during chemotherapy, rhG-CSF was
superior to leridistim, a G-CSF/IL-3
fusion molecule.[30] The consistent
efficacy of rhG-CSF has been matched
by a consistent safety profile, with no
evidence of an increased rate of tumor
progression or stem cell depletion in
clinical trials to date.

Trials of rhGM-CSF
to Prevent Infection

The administraton of rhGM-CSF
has also been associated with a reduction
in the duration of neutropenia
in patients receiving chemotherapy.[
31] However, randomized,
controlled clinical trials of the effects
of rhGM-CSF on the incidence of infection
during multicycle chemotherapy
have been fewer in number and
have generally involved smaller numbers
of patients than those that studied
rhG-CSF. Moreover, the results of these
trials have been inconsistent.[32-38]

Two studies have reported a decreased
incidence of infection associated
with rhGM-CSF therapy-one in
an efficacy-evaluable subset of adult
patients with lymphoma treated with
a daily dose of 400 ?g/d for 7 days
per cycle,[32] and the other, a small
study of 11 children treated for 2
weeks per cycle.[35] Three studies in
adults have reported a decreased incidence
of infection limited to the first
chemotherapy cycle despite continued
rhGM-CSF therapy in subsequent
cycles.[33,34,36] Three trials-one in
adult breast cancer patients[37] and
two in pediatric patients[38,39]-have
failed to detect a difference in the risk
of infection associated with rhGM-CSF
therapy.

These trials have also yielded varying
assessments of the toxicity of
rhGM-CSF in this setting, with four
trials reporting no significant increase
in adverse events,[32,36-38] and other
studies suggesting an increased incidence
of thrombocytopenia[33,35,39]
or of symptoms, including fever,
myalgia, edema, and rash.[33-35] In
one study, 14% of patients required
discontinuation of rhGM-CSF therapy
due to toxicity.[34]

The variations in efficacy and toxicity
results cannot be completely explained
by differences in rhGM-CSF
preparation, dose, or schedule, or in
statistical issues associated with trial
design or analysis. To date, the efficacy
of rhGM-CSF in the prevention
of infection during multicycle chemotherapy
has not been established, and
if it is effective, the optimal dose and
schedule are unknown. One dose-finding
study suggested that 10 ?g/kg/d
would be appropriate for testing in a
randomized trial.[33]

Practical Issues
Although the safety and efficacy of
rhG-CSF has been clearly demonstrated
in this setting, practical issues
remain. First, because rhG-CSF has
not been shown to improve survival,
cost-effectiveness is an important consideration.
For prevention of infection,
the impact of rhG-CSF therapy on cost
depends on the cost of the drug, the
risk of infection without the use of
rhG-CSF, the risk of infection with
rhG-CSF, and the cost of treating the
infections. Several studies that used a
combination of clinical data and
modeled assumptions have concluded
that the break-even point, at which
rhG-CSF therapy becomes less expensive
than leaving patients untreated,
occurs when the risk of febrile neutropenia
is greater than approximately
20%. In addition to assumptions about
patients who have experienced a serious
neutropenic infection during a
prior chemotherapy cycle (secondary prophylaxis) and patients who are initiating
myelosuppressive therapy (primary
prophylaxis), a useful model for
predicting a cost-effective degree of
risk based on neutrophil counts during
previous chemotherapy cycles has
been published.[40]

Some clinicians, in an attempt to
decrease costs, initiate rhG-CSF
therapy only when the neutrophil
count has nadired, and thus, fewer than
one-half of the doses used in all the
positive randomized trials are administered.
No evidence suggests that this
practice provides any decrease in the
risk of infection, and preclinical data
predict that it is ineffective. One randomized
trial has failed to demonstrate
any benefit in terms of infection risk,
antibiotic use, or length of hospitalization.[
41] Paradoxically, this misguided
practice increases overall cost by adding
the cost of rhG-CSF for 5 or 6 days
per cycle without decreasing the risk
or cost of infections.

Some clinicians administer myeloid
growth factors to raise prechemotherapy
neutrophil counts when
they do not meet their established criteria
for initiating the next chemotherapy
cycle. This approach should
be discouraged, because there is no
evidence that temporarily raising neutrophil
counts before administering
chemotherapy provides any benefit to
patients. If the goal of chemotherapy
is cure, and delay of such therapy is
clinically unacceptable, chemotherapy
administered on time, with the growth
factor given beginning 1 day thereafter,
has been shown to reduce the risk
of infection and is a more rational use
of the resource.

Finally, some evidence suggests
that the administration of myeloid
growth factors during chemoradiotherapy
may be associated with increased
thrombocytopenia.[42]

Dose and Schedule Issues
There is still legitimate debate
regarding the most cost-effective dose
and schedule of rhG-CSF. Would a
dose of rhG-CSF other than 5 μg/kg/d
be more appropriate? The results of
one randomized trial suggest that
2 μg/kg/d provides similar results in
terms of neutropenia and infection, obviously
at a cost savings.[43] Another study failed to find any advantage of
μg/kg/d compared to 5 ?g/kg/d in
a population of pediatric patients.[44]
Should rhG-CSF be administered every
day? In one trial, 5 μg/kg/d for
5 days a week provided protection
against infection, with cost and convenience
advantages for patients.[25]
Although daily administration of
5 μg/kg remains the most exhaustively
studied and validated approach to
rhG-CSF use, there may be more costeffective
alternatives.

  • Pegylated rhG-CSF-Further investigation
    of the optimal dose and
    schedule of rhG-CSF has been
    rendered less important by the introduction
    of pegylated rhG-CSF
    (pegfilgrastim [Neulasta]). Because it
    appears to be cleared by mature neutrophils
    and their precursors, this factor
    can be considered "self-regulating"
    and once-per-cycle dosing is effective.
    The efficacy and safety of this preparation
    has been demonstrated in randomized
    trials that compared it to conventional
    rhG-CSF therapy.[45] The
    pegylated preparation is similarly effective
    when administered at a fixed
    dose of 6 mg given 24 hours after chemotherapy
    or when administered using
    weight-based dosing.[46] A substantial
    trend in the data suggests that
    pegylated rhG-CSF may actually be
    superior to rhG-CSF in terms of protection
    against infection. The major
    issues remaining for future study are
    the safety of administering pegylated
    rhG-CSF on the same day as chemotherapy
    and use of pegylated rhG-CSF
    to support every-2-week dose-dense
    chemotherapy.

Treatment of Established
Febrile Neuropenia

Several clinical trials have addressed
the efficacy of myeloid growth
factors in decreasing antibiotic use and
length of hospital stay in patients who
develop febrile neutropenia during
chemotherapy.[47-52] In these trials,
growth factor therapy was started at
the time of hospitalization, usually an
average of 10 days after chemotherapy.
Daily myeloid growth factor
therapy was consistently associated
with approximately a 2-day decrease
in the duration of severe neutropenia;
in some studies, this translated into a
statistically significant, approximately
1- to 2-day decrease in the mean number
of hospital days utilized, in either
a subset of patients[51] or in the overall
planned analysis of the whole population
of enrolled subjects.[48,50] No
trial has demonstrated that growth factor
therapy has an impact on survival,
and in the one study of quality of life,
this outcome was improved in the placebo
group compared to the growth
factor group.[49]

In the absence of demonstrated survival
or quality-of-life benefits, the
impact on cost becomes an important
outcome. Two studies have addressed
this issue, with one concluding that
costs were increased for patients
treated with growth factors,[49] and
the other reporting a trend favoring
decreased costs associated with these
agents.[48] Clinical trials to date do
not consistently demonstrate a benefit
in terms of survival, quality of life, or
resource consumption associated with
rhG-CSF or rhGM-CSF therapy in
patients with chemotherapy-related
febrile neutropenia. In the one trial that
studied the effects of either of the two
factors vs placebo, similar results were
reported when either factor was given
at a dose of 5 &$956;g/kg/d.[48] A recent
meta-analysis of the literature suggested
that treatment of established
febrile neutropenia may decrease hospital
stay and, hence, costs.[52a]

Chemotherapy Dose
Intensification

Myeloid growth factors have been
used to increase the intensity of chemotherapy,
with the goal being an
improvement in tumor response rates
and survival. Multiple studies of either
rhG-CSF or rhGM-CSF have shown
that the dose intensity of chemotherapy
can often be increased by 20%
to 60% depending on the agent used,
the tumor type studied, and whether
the dose intensity was increased via
higher dosing or shorter interdose
intervals.

Randomized trials exploring the
benefit of this level of dose escalation
have more often been negative[53-61]
than positive.[62-64] However, two recent controlled trials of dose-intensified
adjuvant chemotherapy for
breast cancer have been conducted-
one using an increased per treatment
dose intensity and the other, a decreased
intertreatment interval,[65]
with each regimen compared to an
accepted standard. Both approaches
are associated with sufficient risk of
febrile neutropenia to warrant the use
of rhG-CSF or pegylated rhG-CSF,
and these trials currently comprise the
best data documenting a benefit associated
with the use of growth factor-
facilitated dose intensification.

Bone Marrow/Progenitor Cell
Transplantation

The greatest impact of myeloid
growth factors on clinical practice in
oncology has been in the field of bone
marrow transplantation. When unprimed
bone marrow was the only
available source of hematopoietic
support following myeloablative
therapy, either rhGM-CSF[66,67] or
rhG-CSF[68,69] administered daily
following marrow infusion was shown
to decrease the duration of neutropenia,
antibiotic use, length of hospitalization,
and the overall costs of
therapy. In the allogeneic transplant
setting, growth factor therapy was
not associated with increases in
graft-vs-host disease. Unfortunately,
the results of trials using rhG-CSF or
rhGM-CSF to treat graft failure have
been disappointing.

Growth Factor-Mobilized Grafts
A major change began with the recognition
that hematopoietic progenitor
cells circulate in increased numbers
during myeloid growth factor therapy,
followed by the discovery that it was
feasible to harvest sufficient quantities
of these cells with leukapheresis to
provide an alternative and potentially
superior graft compared to traditional
bone marrow. Peripheral blood progenitor
cells (PBPC) harvested during
therapy with rhG-CSF[70-74] or
rhGM-CSF[70,75-78] and used as
hematopoietic support were shown to
be associated with significantly more
rapid neutrophil and platelet engraftment
compared to bone marrow.

This advantage of PBPC over marrow may be due to priming of the
harvested progenitors. Rapid engraftment
profiles have similarly been observed
when rhG-CSF-primed marrow
is employed.[79] The relatively
few published studies comparing engraftment
associated with rhG-CSF-
vs rhGM-CSF-mobilized PBPCs have
suggested that rhG-CSF may be superior
to rhGM-CSF in terms of efficacy
and/or toxicity.[80,81]

The consistency of engraftment is
related to the quantity of CD34-positive
PBPCs infused. Improved yields
are obtained when myeloid growth factors
are administered following chemotherapy,
although chemotherapy is
usually not necessary for adequate
graft acquisition even in heavily pretreated
patients.[82,83] This approach
is not feasible for normal donors in allogeneic
transplantation.

Several trials have addressed the
optimal dose of rhG-CSF dose for an
adequate graft. For patients not receiving
chemotherapy, rhG-CSF at a dose
of 10 μg/kg/d with harvesting commencing
on day 5 may produce better
yields than lower doses.[84] Splitting
the daily dose and administering
rhG-CSF twice daily may[85] or may
not[86] improve the yield of CD34-
positive cells. Very high-dose rhG-CSF
(12 μg/kg twice daily) may be superior
to 10 μg/kg/d.[87] For patients
mobilized with chemotherapy plus
rhG-CSF, 16 g/kg/d is associated with
greater cell yields than 8 g/kg/d, although
the increased cell dose may not
translate into faster engraftment.[88]

Similar dose-finding studies have
not been reported for rhGM-CSF in
PBPC harvesting. The combination of
rhG-CSF and rhGM-CSF is an effective
mobilizing regimen,[89] but no
studies have demonstrated that this
approach is superior to single-factor
mobilization in terms of benefit to
patients. Initial data suggest that
pegylated rhG-CSF is an excellent
PBPC mobilizer, and clinical trials are
in progress.

Graft-vs-Host Disease
Although growth-factor-mobilized
PBPCs are clearly superior to unprimed
marrow for autologous hematopoietic
support, there was initial
concern that PBPCs would not provide the sustained long-term donor engraftment
required for allogeneic transplants
or might change the risk of
graft-vs-host disease in this setting.
Some studies of mobilized PBPCs for
allogeneic transplantation have found
that these grafts are durable and not
associated with increased graft-vs-host
disease.[90-92] However, an increase
in the prevalence of anti-HLA alloantibodies
has been observed among
patients who received PBPC allografts,[
93] and one controlled trial
found an increased incidence of
chronic graft-vs-host disease in this
population.[94]

The use of growth-factor-primed
bone marrow may confer all of the
engraftment advantages associated
with PBPCs without increasing graftvs-
host disease.[95] The use of PBPCs
as opposed to bone marrow in the unrelated
allogeneic transplant setting
has not been associated with increases
in graft-vs-host disease.[96] Although
many large transplant centers now routinely
use PBPCs for allografting, and
there are clear advantages to donors
in terms of morbidity and to recipients
in terms of engraftment kinetics,
controversy remains regarding the
impact of this practice on the severity
of the graft-vs-host reaction.

Posttransplant Growth
Factor Therapy

Are myeloid growth factors beneficial
when administered following
PBPC transplantation? In sufficiently
powered randomized clinical trials,
rhG-CSF, at a daily dose of 5 μg/kg or
less until neutrophil recovery, has
reduced the duration of neutropenia,
and in some cases, decreased the
length of hospitalization and overall
costs.[97-101] It may be possible to
delay the initiation of growth factor
therapy until day 6 posttransplant
without compromising efficacy.[102]
Few data exist on the efficacy of
rhGM-CSF during recovery from
PBPC transplant.

Ongoing Research
The use of myeloid growth factors
continues to transform bone marrow
transplantation. Mobilized PBPCs
have made the procedure safer and less
costly and have replaced marrow as the
preferred source of cellular support.
Equally importantly, the use of this
flexible graft source has made several
promising graft manipulations more
feasible-for example, tumor cell
purging, ex vivo expansion,[103,104]
"split grafts" for multiple cycles of
high-dose therapy, selective removal of
particular effector cells to reduce or
manage graft-vs-host reactions, acquisition
of dendritic cell precursors for
anticancer vaccine therapy,[105] and
gene therapy. Therapy with rhG-CSF
has been reported to produce benefits
similar to those achieved with donor
leukocyte infusions in patients who
relapse following allogeneic transplantation.[
106,107] It is reasonable to expect
one or more of these lines of research
to yield results that will enable
important additions to standard practice
in transplantation.

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