Here's an update on G-CSF and GM-CSF:
(from oncolink.upenn.edu )
Update on Colony-Stimulating Factors
Authors: Celeste M. Lindley, PharmD, MS, FCCP, FASHP
Affiliations: University of North Carolina
Last Revision Date: Monday, 15-Sep-97 19:57:52 EDT
Copyright c 1994-1998, The Trustees of the University of Pennsylvania
Celeste M. Lindley is Associate Professor, School of Pharmacy,
University of North Carolina, Chapel Hill.
Reprinted with permission from the publisher
Highlights on Antineoplastic Drugs,. Vol 12, No. 2, 24-31, 1994
Note:
Immunex Corporation has provided us with an Update Regarding
Sargramostim (GM-CSF) which outlines changes since the below
article was first published in 1994.
Abstract
An update is presented on the two colony-stimulating factors (CSFs)
commercially available in the United States: granulocyte CSF and
granulocyte-macrophage CSF. Clinical effects, including adverse
reactions, are briefly described, and issues concerning optimum dosage
and scheduling are discussed with respect to standard-dose
chemotherapy regimens. The usefulness of CSFs in the treatment of
chemotherapy-induced febrile neutropenia is evaluated, and the
economic pressures determining the cost-effectiveness of theseexpensive
cytokines are outlined. Guidelines are currently being formulated that
should prove helpful in clarifying some of these issues.
Table
of Contents
Clinical Effects of G-CSF and GM-CSF
Dosage Guidelines
Optimal Dosage Regimen to Prevent Neutropenia
CSF Dose Issues
CSF Schedule Issues
Use of CSFs in Established Febrile Neutropenia
Economic Considerations
Proliferation, differentiation, and activation of circulating blood
cells are regulated by endogenous substances collectively known
as hematopoietic growth factors. A virtual explosion of
information about the role of hematopoietic growth factors has
occurred during the past several years, and no less than a dozen
distinct interleukins and colony-stimulating factors (CSFs) with
hematopoietic activity on one or more myeloid precursor
populations have been identified. At least six new CSFs are under
development in the United States. Currently, however, only two
members of this group, granulocyte colony-stimulating factor, or
G-CSF (filgrastim), and granulocyte-macrophage
colony-stimulating factor, or GM-CSF (sargramostim), are
commercially available in the United States. These products were
approved in 1991 by the Food and Drug Administration (FDA) to
enhance neutrophil recovery following chemotherapy
administration.
A Medline review identified over 1000 references addressing the
therapeutic use of G-CSF and GM-CSF published between
January 1990 and September 1993. Close to 20% of these
references focused on nonchemotherapeutic uses of CSFs. Both
G-CSF and GM-CSF have been shown to increase neutrophil
number and/or function in a variety of clinical settings (Table 1).
Although the amount of information available is staggering, it does
not adequately answer some of the most basic questions about the
optimal use of G-CSF and GM-CSF for their approved indications.
This article summarizes information regarding clinical effects of
CSFs that are well described in many textbooks and review
articles and focuses on information that has become available
during the last 2 to 3 years on the use of G-CSF and GM-CSF in
cancer patients receiving standard-dose chemotherapy.
Clinical Effects of G-CSF and GM-CSF
G-CSF and GM-CSF are sometimes confused because of
similarities in their scientific names. "Granulocyte CSF" is
actually a misnomer, because G-CSF influences the proliferation
and differentiation of neutrophil precursors only and has little to
no effect on the other granulocytes, which include basophils and
eosinophils. GM-CSF is more appropriately named, in that it
influences the proliferation and maturation of all granulocytes, and
monocytes as well. GM-CSF supports the in vitro growth of
pluripotent stem cells and nongranulocyte myeloid progenitor
cells. Both growth factors function by binding to specific receptors
on hematopoietic progenitor cells and mature blood cells.
The clinical significance of GM-CSF's earlier and broader effect
on hematopoiesis is not entirely clear. Although in theory,
GM-CSF could be expected to increase circulating red blood cells
and platelets effectively, this has been an infrequent finding in
clinical trials. Although it would be logical to assume otherwise,
GM-CSF does not appear to be more effective than G-CSF in
hematologic disorders associated with lesions above the level of
the progenitor cell committed to granulocyte and monocyte
lineage, such as aplastic anemia or myelodysplastic syndromes, in
clinical trials reported to date.
The major clinical effect of both G-CSF and GM-CSF is their
ability to produce a dose-dependent increase in neutrophil
concentration. Numerous randomized controlled trials have
demonstrated an enhanced rise of neutrophil counts in patients
treatedwith CSFs, compared with placebo-treated ones, for both
chemotherapy-induced neutropenia and autologous bone marrow
transplantation (BMT). However, both CSFs also have effects on
mature myeloid cells. G-CSF enhances the effector cell capability
of the neutrophil and functions as a weak chemoattractant for
these same terminally differentiated cells. GM-CSF enhances the
function of mature neutrophils, eosinophils, monocytes, and
macrophages. The effects of GM-CSF on mature effector cells of
several lineages may reflect the wide role of this cytokine in host
defense and inflammatory response.
The most clinically important consequence of GM-CSF's effects
on mature effector cells is that GM-CSF, through its action on
monocytes, induces the release of secondary cytokines. Release
of interleukin-1 (IL-1) and tumor necrosis factor (TNF) from
monocytes is thought to account for the differences in
adverse-effect profiles of the two cytokines. The inflammatory
mediators released from monocytes frequently result in fever and
chills and the generation of high-energy oxygen radicals that
damage the endothelial cells lining the walls of blood vessels and
capillaries. This breakdown in vascular integrity leads to leakage
of intravascular fluids into the extravascular space, and it may
result in hypotension, edema, decreased organ perfusion, and
pleural and pericardial effusions. The toxicity of GM-CSF is
dose-related, so that a higher incidence of these toxicities is seen
with increasing doses. Although controversy exists regarding the
incidence of these effects with the GM-CSF dosages used
clinically, patients who receive more than 10 ug/kg/day of
GM-CSF should be closely observed.
Table 1.--Clinical Uses of Colony-Stimulating Factors
GM-CSF G-CSF
Acquired Neutropenias
Chemotherapy-induced + Approved
Autologous BMT Approved +
Allogeneic BMT + +
Aplastic anemia +/- +/-
Myelodysplastic syndromes + +
Acute myelogenous leukemia + +
AIDS + +
Congenital Neutropenias
Cyclic neutropenia - +
Severe congenital neutropenia - +
(Kostmann's syndrome)
Mobilization of Stem Cells
Preautologous BMT + +
Abbreviations and symbols:
AIDS = acquired immunodeficiency syndrome;
BMT = bone marrow transplantation;
G-CSF = granulocyte colony-stimulating factor;
GM-CSF = granulocyte-macrophage colony-stimulating
factor;
+ = efficacy demonstrated in phase II trials;
- = efficacy not demonstrated in phase II trials;
Approved = indication approved for use in the United States
and Europe.
Adapted from Schriber et al,[3] with permission.
A "first-dose phenomenon" has been described with IV
administration of GM-CSF. This reaction occurs in 15% to 30%
of patients and is characterized by flushing, tachycardia,
hypotension, dyspnea, vomiting, and less commonly, rigors, leg
spasm, and syncope. Direct activation of monocytes and/or
release of secondary mediators is thought to be involved. For this
reason, it is recommended that IV administration of GM-CSF be
done over no less than 2 hours. Additional toxicities related to
GM-CSF's effect on mature cells include decreased granulocyte
migration and responsiveness to chemotactic factors. These
actions of GM-CSF may have consequences in the clinical setting.
GM-CSF is associated with a number of side effects that may be
related to increased neutrophil adhesion to capillary endothelium;
decreased neutrophil movement to skin windows has been
reported in one study.[2]
In addition, GM-CSF has been associated with enhanced
replication of human immunodeficiency virus(HIV) in normal
monocytes and macrophages, as well as in monocytes from
HIV-infected patients, and with potentiation of the anti-HIV
activity of zidovudine by facilitating drug entry and subsequent
phosphorylation. Although the significance of enhanced replication
of HIV is unclear, the use of GM-CSF in HIV-seropositive
patients is discouraged unless there is concomitant use of
zidovudine or didanosine.
The only commonly reported symptom associated with G-CSF is
bone pain. This occurs in 20% to 30% of patients who receive
either GM-CSF or G-CSF; it is typically noted in the lumbar,
sternal, or pelvic areas at the time when granulocyte recovery
begins to occur. Isolated cases of flare-up of pre-existing
inflammatory and autoimmune disorders have been reported with
both GM-CSF and G-CSF.
The sole adverse effect reported with long-term CSF therapy is
splenomegaly in patients having congenital neutropenia managed
with chronic G-CSF. Theoretical concerns with clinical use of
CSFs include acceleration of disease in patients with myeloid
malignancies, biased stem cell commitment, and bone marrow
exhaustion. At present, there is no evidence that these occur.
Dosage Guidelines
Although the two commercially available CSFs are often used
interchangeably in clinical trials, their approved indications and
dosage guidelines are different. Filgrastim (Neupogen) is
indicated for prevention of neutropenic fever in patients who have
nonmyeloid malignancies and are receiving cytotoxic
antineoplastic therapy. An initial dosage of 5 ug/kg/day as a single
daily injection by SC bolus, by short IV infusion (30 minutes), or
by continuous SC or IV infusion is recommended. It is commonly
agreed that SC bolus is the preferred route and method of
administration. The manufacturer recommends that therapy with
filgrastim be continued until the neutrophil count exceeds 10,000
cells/mm3 after the expected chemotherapy-induced neutrophil
nadir.
To date, the only GM-CSF product commercially available is
sargramostim (Leukine). Sargramostimhas a narrower
FDA-approved indication than filgrastim, which is to accelerate
recovery of neutrophils following high-dose chemotherapy and
autologous BMT in patients with lymphoid malignancies. The
recommended initial dosage of sargramostim is 250mg/m2/day for
21 days (or until the absolute neutrophil count [ANC] reaches
20,000) as a 2-hour IV infusion, beginning 2 to 4 hours after the
autologous bone marrow infusion, and not less than 24 hours after
the last dose of chemotherapy and 12 hours after the last dose of
radiation therapy.
Several different GM-CSF proteins have been used in clinical
trials and may soon become available in the United States. The
products are not the same in biologic activity by weight.
Yeast-derived GM-CSF is variably glycosylated and differs from
natural human GM-CSF by one amino acid substitution. Fully
glycosylated GM-CSF is derived from mammalian cell (Chinese
hamster ovary) cultures, and two nonglycosylated Escherichia
coli-derived products are also in development. The qualitative or
quantitative effects of these differences are unclear. Doses cannot
be easily transposed among various GM-CSF preparations, but
the average molecular weight of E. coli GM-CSF is approximately
80% that of yeast GM-CSF.
The recommended dose of G-CSF is expressed in ug/kg, and that
of GM-CSF in ug/m2; however, one will find both weight
expressions for doses of these products in the clinical trials
reported in the literature. Note that a dose expressed in ug/m2
can be divided by 40 to obtain a rough estimate of an equivalent
dose in ug/kg. Thus, the recommended initial dose of GM-CSF(6
ug/kg [~ 240 ug/m2]) is roughly equivalent to that of G-CSF (5
ug/kg).
The dosage guidelines described for filgrastim and sargramostim
are based on specific phase III trials that brought these products
to market for their FDA-approved indications. In the ensuing
years, clinical trials have begun to address questions related to
optimal dose and scheduling of CSFs to prevent febrile
neutropenia following myelotoxic chemotherapy. Some of the
more compelling studies of these questions are discussed below.
Optimal Dosage Regimen to Prevent Neutropenia
The optimal dose and schedule of CSFs may be defined as the
lowest CSF dose administered for the shortest period of time that
results in a relatively "safe" neutrophil nadir (not less than 500 to
100/mm3) for the fewest number of days. Because febrile
neutropeniais the major life-threatening toxicity of chemotherapy,
the optimal dose and schedule of CSFs would be expected to
result in the lowest incidence of febrile neutropenia, which would
also translate into reduced hospitalization and antibiotic use.
In addition, because neutropenia and infection are the major
dose-limiting side effects of chemotherapy, optimal dose and
schedule of CSFs should also lead to improved adherence to the
planned chemotherapy regimen or the potential to deliver higher
doses of chemotherapy, or at least as high a dose but over a
shorter period of time. Because a number of tumors exhibit steep
dose-response curves in vitro, the advent of CSFs has fostered
the hope that much higher doses of chemotherapy could be safely
administered. Thus, the assumed benefit of the optimal dose and
schedule of CSFs would be greater destruction of tumor cells,
more complete remissions, and increased survival.
The optimal dosage regimen for CSFs is highly dependent on the
specifics of the patient, the disease under treatment, and the
planned treatment protocol. For example, the optimal dose of
CSFs for a patient with aplastic anemia, myelodysplastic
syndrome, or AIDS appears to be much lower than doses used to
prevent neutropenia in patients receiving chemotherapy. The
optimal dose and schedule of CSFs to enhance generation of
progenitor cells or to support patients who receive high-dose
chemotherapy with peripheral blood progenitor cell (PBPC)
support may differ from that to accelerate recovery of neutrophils
following high-dose chemotherapy with autologous bone marrow
support. Optimal use of CSFs in these settings is currently being
defined by clinical trials, and no doubt pharmacists will see many
doses and schedules of CSFs emerge in the future. The following
discussion of optimal dosage regimens of CSFs pertains to CSFs
used to prevent febrile neutropenia in patients receiving
chemotherapy without bone marrow or PBPC support.
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