Colony Stimulating Factor Therapy

The CSFs are glycoproteins that regulate the proliferation, differentiation, functional activity, and survival of myeloid cells. They were discovered through their capacity to stimulate single myeloid progenitor cells to proliferate in vitro and form clusters and colonies of differentiated cells, particularly neutrophils and monocytes. Basic characteristics of the CSFs rHuG-CSF and rHuGM-CSF are outlined in Table 1.

Several characteristics of the CSFs are of great clinical importance for the management of chemotherapy-induced neutropenia and FN:

1. Both G-CSF and GM-CSF are produced endogenously by many cell types. Amounts of circulating G-CSFs increase markedly with naturally occurring and experimentally induced infections (21,22). In experimental animals, a deficiency of G-CSF is associated with the development of neutropenia (23). Experimental studies indicate that G-CSF is the natural regulator for the blood neutrophil count analogous to erythropoietin (EPO) and thrombopoietin (TPO). In contrast, GM-CSF concentrations are not increased with infection, and a deficiency of GM-CSF does not result in neutropenia (24,25).

2. Receptors for G-CSF and GM-CSF are expressed on primitive and mature myeloid cells, including expression on mature circulating neutrophils. Exposure of neutrophils to G-CSF or GM-CSF primes mature neutrophils for an enhanced metabolic burst when they are exposed to bacteria.

3. Both G-CSF and GM-CSF promote the survival of myeloid cells at all stages in their development; thus, these CSF have an antiapoptotic effect (26).

4. Studies involving normal human volunteers who received either rHuG-CSF or rHuGM-CSF for 14 d showed that rHuG-CSF is more potent than rHuGM-CSF in stimulating neutrophil production (27,28)

5. In vivo administration of rHuG-CSF or rHuGM-CSF increases neutrophil production and accelerates the transit time of developing cells through the bone marrow. Increases in blood neutrophil counts after cytokine administration are attributable to increased numbers of cell divisions, shortened time between divisions, accelerated transit through the postmitotic stage of development, and increased neutrophil survival in the blood (28).

6. Neutrophils made in response to rHuG-CSF or rHuGM-CSF have normal, functional bacteria-killing properties (29).

7. The primary HGF now used for the prevention and treatment of FN is rHuG-CSF because of its greater potency (30) and fewer associated adverse effects (31).

Adverse effects associated with injections of rHuG-CSF are less severe than with rHuGM-CSF (31). Bone pain and headache are the most common adverse effects with rHuG-CSF (30). Myalgias and flu-like symptoms are the most common adverse effects with rHuGM-CSF (30).

The use of rHuG-CSF concomitant with antibiotics for treating FN has been explored in several clinical trials (32-37). One study, early in the development of rHuG-CSF, involved treating 218 patients with cancer who developed fever and neutropenia (neutrophil count < 1.0 x 109/L) after chemotherapy administration (36). Patients were randomized to receive either rHuG-CSF 12 Mg/kg daily, beginning within 12 h of initiation of a standard antibiotic treatment, or standard antibiotic treatment alone. Patients remained on study until their neutrophil count was >0.5 x 109/L and they were afebrile for 4 d. Patients who received rHuG-CSF had more rapid neutrophil recovery than those who did not receive rHuG-CSF, but there was no reduction in overall days of fever or antibiotic treatment. However, patients who were slowest to recover appeared to benefit from rHuG-CSF.

A more recent randomized, controlled trial enrolled 210 patients with a variety of solid tumors treated with standard-dose chemotherapy (32). High-risk patients who developed FN were assigned to receive a standard antibiotic regimen with or without rHuG-CSF 5 Mg/kg daily. High-risk patients had neutrophil counts < 0.1 x 109/L, a short latency period from previous chemotherapy, severe comorbidities, signs of sepsis, or prior inpatient status. Administration of rHuG-CSF shortened the duration of severe neutropenia and hospitalization and reduced the use of antibiotics. Results from a recent meta-analysis (38), including this trial, demonstrate that the therapeutic use of rHuG-CSF for FN is probably beneficial, particularly for high-risk patients. Further investigation is needed to define the benefits of this strategy and the details for optimum management, such as the dose and duration of treatment and optimal antibiotics to use with rHuG-CSF.

Recently, pegylated rHuG-CSF (pegfilgrastim) has been introduced to simplify the management of patients developing neutropenia after chemotherapy. Pegfilgrastim has a much longer half-life than nonpegylated filgrastim, remaining in the body long enough to stimulate complete bone marrow recovery after standard-dose chemotherapy. Pegfil-grastim has otherwise similar effects as the filgrastim. Two randomized, controlled trials were conducted to establish the effectiveness of pegfilgrastim to prevent FN (39,40). Interestingly, in these trials, treatment with pegfilgrastim was associated with a lower incidence of FN, although overall it stimulated a lesser neutrophil response.

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