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Hematopoietic growth factors

Hematopoietic growth factors

For years, chemotherapy-associated myelosuppression has represented a major
limitation to a patient's tolerance of anticancer therapy. In addition, the
clinical consequences of chemotherapy-induced myelosuppression (such as febrile
neutropenia, dose reductions, or lengthy dose delays) may have had significant
negative effects on quality of life or even response to treatment.

Before the widespread availability of agents to stimulate host hematopoiesis,
administration of antibiotics, transfusion of blood products, and reductions or
delays in chemotherapy dose have been the major means of combating the
myelotoxicity of chemotherapy. It is now possible to stimulate clinically relevant
production of several formed elements of the blood: neutrophils,
erythrocytes, and platelets.

This chapter summarizes data supporting the clinical activity of several hematopoietic
growth factors. A thorough knowledge of these data will help clinicians
to make judicious, informed decisions about how to use these agents most
responsibly.

Hematopoietic growth factors

Over the past several years, a great deal of progress has been made in understanding
the process of hematopoiesis by which mature cellular elements of
blood are formed. Hematopoietic growth factors are a family of regulatory
molecules that play important roles in the growth, survival, and differentiation
of blood progenitor cells, as well as in the functional activation of mature cells.

Table 1 lists the recombinant human hematopoietic growth factors (also known
as hematopoietic cytokines) that have been approved by the US Food and
Drug Administration (FDA) for clinical use: granulocyte colony-stimulating factor
(G-CSF, filgrastim [Neupogen]); pegfilgrastim [Neulasta]; yeast-derived
granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim
[Leukine, Prokine]); recombinant human erythropoietin (epoetin alfa, EPO
[Epogen, Procrit]); darbepoetin alfa (Aranesp); and interleukin-11 (IL-11,
oprelvekin [Neumega]). In addition, several other hematopoietic cytokines are
under clinical development.

The commercial availability of these recombinant human hematopoietic growth
factors has led to their wide clinical application in oncology practice. However,
the substantial costs of colony-stimulating factor utilization as supportive care
for patients receiving myelosuppressive chemotherapy make it imperative to
identify the optimal settings in which their use can make a significant difference
in patient outcomes.

This chapter discusses the appropriate uses of only the FDA-approved hematopoietic
growth factors/cytokines: G-CSF, GM-CSF, EPO, darbepoetin alfa,
and IL-11. For a more detailed review of recommendations for the use of myeloid
CSFs, readers are referred to the evidence-based, clinical practice guidelines
developed in 1994 (last updated in 2000, with 2005 update pending) by
the American Society of Clinical Oncology (ASCO). The ASCO guidelines
were formulated to encourage reasonable use of CSFs when their efficacy has
been well documented but to discourage excess use when marginal benefit is
anticipated. These clinical practice guidelines have been published and are
most easily accessed at the official web site of ASCO (www.asco.org). In addition,
the National Comprehensive Cancer Network (NCCN) will publish for
the first time guidelines on the use of colony-stimulating factors. Similar clinical
practice guidelines have been developed for the use of EPO (and, by extension,
for darbepoetin alfa) by the American Society of Hematology (ASH) in
conjunction with ASCO (see www.hematology.org).

Myeloid growth factors

Three myeloid growth factors are currently licensed for clinical use in the United
States: G-CSF, pegfilgrastim, and GM-CSF.

G-CSF (filgrastim) is lineage-specific for the production of functionally active
neutrophils. G-CSF has been extensively evaluated in several clinical scenarios.
G-CSF was first approved in 1991 for clinical use to reduce the incidence of
febrile neutropenia in cancer patients receiving myelosuppressive chemotherapy.

This broad initial indication has since been expanded even further, to include
many other areas of oncologic practice, such as stimulation of neutrophil recovery
following high-dose chemotherapy with stem-cell support. In addition,
G-CSF is indicated to increase neutrophil production in endogenous myeloid
disorders, such as congenital neutropenic states.

Pegylated G-CSF (pegfilgrastim) When polyethylene glycol was attached to
the protein backbone of filgrastim, a new molecule (pegfilgrastim) was created
with a longer half-life than the standard human G-CSF. Pegfilgrastim was approved
in 2002 to reduce febrile neutropenia. It has been studied and shown to
be equally efficacious to filgrastim, with the advantage of once-per-cycle dosing
and self-regulating features of clearance of the drug during neutrophil
recovery. Findings have suggested that pegfilgrastim is more effective than
G-CSF in preventing febrile neutropenia, but further study is required. The
use of pegfilgrastim in cycles < 3 weeks has not been approved; however, it has
been studied in 2-week regimens and appears to be safe and effective. In addi-
tion, pegfilgrastim is not currently approved in bone marrow transplantation
(BMT) or in pediatrics, but studies are under way.

GM-CSF (sargramostim), primarily a myeloid-lineage-specific growth factor,
stimulates the production of neutrophils, monocytes, and eosinophils. It has
been extensively evaluated and received a more narrow FDA approval in 1991
for clinical use in patients with nonmyeloid malignancies undergoing autologous
BMT. Since that initial indication, GM-CSF has also been approved for an expanded
range of conditions, such as mitigation of myelotoxicity in patients with
leukemia who are undergoing induction chemotherapy.

To date, no large-scale randomized trials have directly compared the efficacy
of these two CSFs in the same clinical setting. Future comparative trials may
help to determine the optimal clinical utility of these CSFs in different clinical
situations.

INDICATIONSUses to support chemotherapy
CSFs have been used to support both conventional and intensified doses of
chemotherapy. The use of CSFs in this setting can be defined as prophylactic
or therapeutic.

Prophylactic use is defined as the administration of a growth factor to prevent
febrile neutropenia. "Primary prophylaxis" denotes the use of CSF following
the first cycle of multicourse chemotherapy prior to any occurrence of febrile
neutropenia. The term "secondary prophylaxis" is reserved for the use of
CSFs to prevent a subsequent episode of febrile neutropenia in a patient who
has already experienced infectious complications in a previous chemotherapy
cycle.

Primary prophylaxis G-CSF has been evaluated in at least three major randomized
clinical trials in cancer patients receiving chemotherapy. The use of G-CSF
as primary prophylaxis reduced the incidence of febrile neutropenia by approximately
50% in these trials, in which the incidence of febrile neutropenia
in the control group was high (≥ 40%). The value of CSF in patients receiving
less myelosuppressive regimens has not been clearly established, although
studies are ongoing. Several studies presented at the 2004 meetings of ASCO
and the Multinational Association of Supportive Care in Cancer (MASCC)
provide evidence to support the use of colony-stimulating factors in less
myelosuppressive regimens. At the ASCO meeting, Timmer-Bonte and colleagues
reported the results of a prospective, randomized study evaluating
the impact of filgrastim in patients with small-cell lung cancer receiving CAE
(cyclophosphamide [Cytoxan, Neosar], Adriamycin [doxorubicin], and
etoposide) chemotherapy and prophylactic antibiotics. The incidence of febrile
neutropenia in the first cycle and overall was 23% and 30%, respectively,
for those receiving antibiotics and 10% and 18%, respectively, for those
receiving filgrastim.

A second study, reported by Martin and colleagues looked at prophylactic
growth factor support in patients receiving adjuvant TAC (docetaxel [Taxotere],
Adriamycin [doxorubicin], and cyclophosphamide). The study initially did
not include prophylactic growth factor but was amended after a high incidence
of febrile neutropenia was observed. The rates of febrile neutropenia
were 23.8% prior to the amendment and 3.5% after the institution of prophylactic
growth factor.

Lastly, at the 2004 meeting of MASCC, a convincing study was presented by
Schwartzberg; it looked at a single dose of pegfilgrastim vs placebo 24 hours
after chemotherapy in 950 patients with breast cancer receiving docetaxel
(100 mg/m2). This regimen was specifically chosen to try to assess the potential
benefit of growth factor in a setting associated with approximately a 20%
risk of febrile neutropenia. The placebo group experienced a 17% incidence
of febrile neutropenia, compared with a 1% incidence in the pegfilgrastim
group. The results from these three studies suggest a benefit to pegfilgrastim
at least as great or greater than that seen in the previous clinical trials that
evaluated filgrastim in treatment settings where the risk of febrile neutropenia
was higher.

Furthermore, pharmacoeconomic sensitivity analyses have suggested that
CSF use may be cost-effective if the anticipated risk of febrile neutropenia
is > 20%.

Since most standard chemotherapy regimens are designed to induce a risk of
neutropenic fever less than 40%, the ASCO guidelines have suggested that
CSFs should not be used routinely with initial cycles of chemotherapy. Unfortunately,
this places patients at the highest risk of febrile neutropenia, which
occurs during the first cycles. The ASCO guidelines committee is currently
reevaluating this threshold with publication of guidelines expected in 2005.
Also, more emphasis is being placed on the patient at high risk (due to comorbid
disease, age, etc.) than on the regimen.

Secondary prophylaxis Available data indicate that the use of CSFs as secondary
prophylaxis in patients who have had a prior episode of febrile neutropenia
can decrease the likelihood of febrile neutropenia in subsequent cycles of chemotherapy.
It is important to recognize that this conclusion has never been
specifically proven in any randomized clinical trial. Rather, it has been derived
from analyses of subsets of patients who crossed over from the placebo arms of
the initial randomized clinical trials, as well as large clinical experience.

Thus, in clinical settings where maintenance of chemotherapy dose appears to
be important, secondary prophylaxis with CSF to prevent new episodes of
neutropenic fever is appropriate. CSF support can also be considered to maintain
standard dose delivery of chemotherapy when the maintenance of dose
may impact outcome.

Therapeutic use is defined as the administration of a growth factor at the time
when neutropenia or neutropenic fever is documented in a patient who had
not been receiving CSFs previously.

Clinical trials do not support the routine use of CSFs as an adjunct to antibiotics
in the treatment of all patients with uncomplicated febrile neutropenia.
However, in certain high-risk patients who have features predictive of poor
outcome (eg, sepsis syndrome, pneumonia, fungal infection), use of a CSF with
antibiotics may be justified. To conduct appropriate clinical trials to test the
hypothesis that CSF support may improve the outcomes of subsets of patients,
selection of patients based on risk-stratification criteria that have been validated
to predict poor outcomes or delayed recovery from neutropenia will be
critical. Certain trials performed with more selective entry criteria (such as absolute
neutrophil count < 100 cells/L) have, in fact, shown statistically significant
benefits from the use of CSFs as an adjunct to antibiotics in these high-risk
patients with febrile neutropenia. Continued analyses of these data and the
performance of larger scale, confirmatory studies are needed to further assess
the therapeutic use of CSFs.

There are no indications for CSF use to treat uncomplicated neutropenia without
fever. A large-scale randomized clinical trial noted no difference in patients
who had CSF support in whom afebrile neutropenia was detected vs those
patients whose hematologic status was allowed to recover spontaneously without
CSF support. Thus, low neutrophil counts alone do not represent a reason
to prescribe CSF support. One effective way to use CSFs is prophylactically,
24 hours after chemotherapy is completed.

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