RHuGMCSF and rHuGCSF

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3.5.1. Background

GM-CSF supports the survival, clonal expansion, and differentiation of hematopoi-etic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathway through its interaction with specific surface receptors located on the target cells. It also enhances the phagocytic and antibacterial activity of mature granulocytes and macrophages. GM-CSF has a multilineage effect, and in addition to its effects on cells committed to the macrophage-granulocyte pathway, it can also promote, in conjunction with appropriate and target-specific other HGFs, the proliferation and maturation of megakaryocytic and erythroid precursors. rHuGM-CSF (sargramostim) is produced by DNA technology in a yeast (Saccharomyces cerevisiae)-expressing system. Sargramostim is a glycoprotein that differs from natural occurring human GM-CSF by a leucine substitution at the 23 position of the amino acid sequence and differences in the carbohydrate content. Another rHuGM-CSF (molgramostim) is produced in an E. coli-expressing system and is nongylcosylated. Because it is not clinically available in the United States, it will not be discussed. Information about studies in which other forms of rHuGM-CSF were used is included in the following section.

G-CSF is a lineage-specific glycoprotein produced by monocytes, fibroblasts, and endothelial cells that regulates the production and function of marrow neutrophils by stimulating the proliferation, differentiation, and maturation of neutrophilic precursor and end-cell activation through direct interaction with ligand-specific receptors on the target cells (90). Filgrastim (r-metHuG-CSF) is a nonglycosylated, rHuG-CSF with an N-terminal methionine group produced by DNA technology in E. coli. The molecule is identical to that of endogenous G-CSF in every way except for the N-terminal methionine group (which is required for E. coli expression) and the nonglycosylation. Another form of rHuG-CSF (lenograstim) is glycosylated and is produced in CHO cells. It is not commercially available in the United States and will not be discussed.

A further modification of filgrastim (pegfilgrastim, PEG-r-metHuG-CSF) is derived by adding a 20-kDa monomethoxypolyethylene glycol molecule to the N-terminal residue. The resulting compound has increased size, molecular weight, and prolonged half-life, allowing for less frequent administration than its parent compound (filgras-tim) (91).

Filgrastim and sargramostim are used commonly in normal donors and in patients to mobilize peripheral blood progenitor cells (PBPCs) for harvesting in preparation for bone marrow or stem cell transplantation, in patients with cancer receiving myelosup-pressive or myeloablative chemotherapy, and less commonly for the treatment of patients with severe chronic neutropenia (SCN). Pegfilgrastim has been approved in the United States for use in cancer patients receiving chemotherapy to reduce the risk of neutropenic fever, for neutropenia-induced treatment delays, and in cases of chemotherapy dose reduction (92).

3.5.2. Studies

The adverse events reported in subjects receiving either filgrastim or sargramostim are similar. The most frequently reported adverse events attributed to filgrastim are bone pain, injection site reaction, rash, acute neutrophilic dermatoses, allergic reactions, worsening of inflammatory conditions, and splenic enlargement. For sar-gramostim, they are bone pain, fever, headache, chills or muscle ache, rash or injection site reactions, shortness of breath, and edema or capillary leak (93).

The most common adverse event associated with patients receiving filgrastim relative to placebo-treated patients is bone pain (15-39% vs 0-21%) (93). This dose-related adverse event appears to begin shortly after beginning treatment with filgrastim and may occur again or worsen just before neutrophilic recovery among patients who have previously received myelosuppressive chemotherapy (93). Both filgrastim and sargramostim can cause benign transient increases in serum concentrations of lactic dehydrogenase (LDH), alkaline phosphatase, and uric acid. Although the mechanisms of these increases are poorly understood, they are probably related to increased cell turnover in chemotherapy (94). The administration of sargramostim is associated with heightened activities of several cytokines (such as IL-1, IL-6, tumor necrosis factor-a, and leukotrienes), which may explain some of the asymmetry in that HGF's adverse event profile relative to that of filgrastim. In particular, the presence of fever may confuse the clinician, leading to the conclusion that an active infection may be present when it is not or may result in the fever's being prolonged. There is some evidence that prolonged treatment with molgramostim or filgrastim may cause thrombocytopenia; however, this is evidently not the case for yeast-derived sargramostim (93). One proposed mechanism for the occurrence of rHuGM-CSF-associated thrombocytopenia is the stimulation of Kupffer cells in the liver. Since splenomegaly has been reported to occur with filgrastim treatment, it is not unreasonable to assume a similar mechanism for the thrombocytopenia associated with this agent. Because most patients treated with either filgrastim or sargramostim have either received myelosuppressive chemotherapy or are being prepared for PBPC harvesting, it is impossible to separate the cause of CSF-associated thrombocytopenia from a chemotherapy or leukophoresis effect. Interestingly, 17% of patients with SCN (who were not receiving chemotherapy) had platelet counts < 100 x 109/L while being treated with filgrastim (90). Unfortunately, since one-third of these patients also had pretreatment splenomegaly and pretreatment thrombocy-topenia, it is difficult to determine whether this occurrence represents a worsening of their underlying illness, activation of liver Kupffer cells, or liver macrophage proliferation. Splenomegaly and splenic rupture have been reported to occur with treatment with either filgrastim or sargramostim, although both adverse advents appear to be more common with the former (95-100).

Venous and arterial thrombosis has been associated with both types of HGFs, with the reported cases being more frequent in patients with cancer receiving intravenous sar-gramostim (4.2%) than in those receiving filgrastim (4.2% vs 1.2%; p < 0.01) (101-105). A review of 13 controlled clinical trials involving 838 cancer patients supported an increased incidence of thrombosis with rHuGM-CSF treatment relative to nontreated control patients (6.6% vs 3.6%, p < 0.05). When a pooled meta-analysis was performed on the data from each of these trials, a statistically significant difference in the incidence of thrombosis was noted in rHuGM-CSF-treated patients vs those who did not receive rHuGM-CSF (106). Although the mechanism for these thrombotic episodes is unknown, there is evidence that treatment with rHuGM-CSF results in platelet, endothelial cell, neutrophilic, and surface coagulation activation, which further results in a hypercoagula-ble state that affects both the right and left side of the circulation (107,108).

Acute dyspnea with or without pulmonary infiltrates, fluid retention, and hypotension has been reported to occur with sargramostim (109). Both sargramostim and fil-grastim have been reported to cause a so-called first-dose reaction characterized by dyspnea, rigors, and hypotension, although this adverse event appears to be more commonly associated with the brief intravenous or prolonged subcutaneous administration of rHuGM-CSF than with filgrastim treatment (110-112). This syndrome often disappears with subsequent doses of the CSF and may be in part preventable by primary or secondary prophylaxis with analgesics, antihistamines, and corticosteroids (113). Acute respiratory distress syndrome has also been associated with both drugs and can occur either as a first-dose phenomenon or either immediately before or during neu-trophil recovery from myelosuppressive or myeloablative chemotherapy. The risk is heightened for the development of this serious complication when the patient has received chemotherapeutic agents that can damage the lung or has a known previous lung injury or pulmonary infection and experiences a brisk neutrophil recovery from myelosuppression while receiving filgrastim or sargramostim. It is believed that the CSF-activated neutrophils are retained in the lung vasculature and that either the release of other cytokines or highly oxidizing moieties damage the lung's blood vessels and/or parenchyma (114,115). A review of all the reported cases of pulmonary toxicity associated with rHuG-CSF administration found that few of the cases could be attributed to the CSF alone, since most patients also received chemotherapy that could have caused lung damage (116).

Filgrastim and sargramostim may play a permissive role in the pathophysiology of sickle cell crisis, suggested by increased concentrations of GM-CSF in the plasma of a disproportionate number of patients in sickle cell crisis relative to the proportion of noncrisis sickle cell patients (117). In addition, at least one case has been reported of a patient with breast cancer and sickle cell trait treated with myelosuppressive chemotherapy and filgrastim who developed sickle cell crisis and severe multiorgan failure including the lung (118).

An unusual severe, atypical peripheral neuropathy characterized by the presence of severe neuropathic foot pain and marked motor weakness of the lower extremities without an associated weakness of the upper extremities has been described in patients receiving vincristine-containing chemotherapy for NHL (119). Comparing the frequency of this neuropathy in 54 patients receiving either filgrastim or sargramostim or no CSF, there was a strong association between CSF exposure and the occurrence of the neuropathy (39% vs 4%, p = 0.0024). It is speculated that the relationship between sargramostim exposure and neuropathy may be caused by a chemotherapy-induced modulation of CSF effect on nerve growth or to an alteration in vincristine clearance.

Neutrophilic dermatosis (Sweet's syndrome) and leukocytoclastic vasculitis have been associated with filgrastim and sargramostim (120) in patients with myeloprolifer-ative diseases and various other benign conditions, nonmyeloid cancers, and bullous pyoderma in patients with lung cancer (121,122).

Hyperleukocytosis occurs with treatment with either sargramostim or filgrastim (90,123). Patients with various myeloproliferative disorders and hematologic and non-hematologic malignancies theoretically could be worsened by treatment with either of these CSFs; however, there is little evidence to support this contention (124). The risk of leukemic/myelodysplastic transformation among patients with congenital neutropenia, a heterogeneous group of diseases commonly treated from the time of diagnosis with fil-grastim, has been reported to be approx 1.7% each year. No relationship has been shown between this conversion risk and patient age or duration of exposure to filgrastim. Comparison with a nontreated group of similar patients is not possible, since most die of infections before the third year of life (125). A retrospective review of six prospective trials in which patients with breast cancer received standard chemotherapy or intensified or increased chemotherapy with or without filgrastim or sargramostim support indicated that the risk of developing AML/MDS was greater among those who received increased or intensified chemotherapy, in-breast irradiation, and a CSF (126). A prospective analysis of children with acute lymphoblastic leukemia treated with radiation therapy and intense chemotherapy ± filgrastim demonstrated that the subsequent risk of developing AML/MDS was significantly increased among all groups receiving filgrastim (127).

The development of neutralizing Abs has not been reported in patients treated for prolonged periods with filgrastim (90). Neutralizing Abs have been detected in 2.3% of patients receiving sargramostim by both intravenous and subcutaneous routes; however, because of the patients' underlying illnesses, the effect on endogenous GM-CSF and hematopoietic reconstitution could not be ascertained (123).

A retrospective review of the comparative safety of filgrastim and sargramostim as reported from 10 outpatient chemotherapy centers indicated that fever unexplained by infection was more common with sargramostim compared with filgrastim (7% vs 1%, p < 0.001), as were fatigue, diarrhea, injection site reactions, other dermatologic disorders, and edema (all p < 0.05). Bone pain was more frequent with filgrastim (p < 0.06). Patients initially treated with sargramostim more frequently change to filgrastim as an alternative than vice versa (p < 0.001) (128).

To date, little published information exists about the adverse event profile associated with pegfilgrastim treatment, which is understandable given the recent approval of peg-filgrastim. Adverse events with this growth factor appear to be similar to those observed with its parent compound (filgrastim) (129,130). Mild-to-moderate bone pain that is easily managed with non-narcotic analgesics is the most frequently observed adverse event, being reported by approx 25% of patients receiving pegfilgrastim (129,130). Joint pain, muscle aches, headache, leukocytosis, thrombocytopenia, and heightened liver test, LDH, and uric acid values have been observed (129-131). Hypersensitivity reactions have not been reported with pegfilgrastim; however, since it (like filgrastim) is derived from E. coli, patients who have had hypersensitivity reactions when receiving E. coli-derived proteins should not be offered this drug. Other unusual but life-threatening adverse events that have not been observed with pegfilgrastim treatment but have been seen among patients receiving filgrastim have included adult respiratory distress syndrome, splenic rupture, and sickle cell crisis.

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