Recombinant Granulocyte Colony-Stimulating Factor (rG-CSF)

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Abstract
Recombinant granulocyte colony-stimulating factor (rG-CSF) is a glycoprotein hormone which has been produced in mammalian cells and, in a nonglycosylated form, in the bacterium Escherichia coli through recombinant DNA technology. It stimulates proliferation, differentiation and activation of cells of the neutrophil-granulocyte lineage and has been investigated as therapy for patients with various neutropenic conditions, both iatrogenic and disease related. rG-CSF is well tolerated, the most frequently reported adverse effect being mild to moderate bone pain. A major use for rG-CSF therapy will be in ameliorating the neutropenia which follows cytoreductive chemotherapy. rG-CSF accelerates neutrophil recovery after chemotherapy, leading to a reduction in duration of the neutropenic phase. Consequently, infection rate is diminished, as is the associated usage of antibiotics and duration of hospitalisation. The implications are that rG-CSF may allow increased dose intensity and stricter adherence to chemotherapy schedules. The increase in neutrophils produced by rG-CSF renders it a useful treatment for conditions such as congenital, acquired and cyclic neutropenias for which current therapy is not very successful. rG-CSF may be an effective therapy in myelodysplasia, although there is concern about acceleration of the possible rate of conversion of this disease to acute myelogenous leukaemia. It is also likely that rG-CSF will be useful in accelerating the recovery of transplanted bone marrow in patients with leukaemia, lymphoma and solid tumour. Furthermore, there is great potential for expansion of the role of rG-CSF as monotherapy or in combination regimens with other cell factors in various haematological disorders such as aplastic anaemia. In summary, while many aspects of its use remain to be clarified, rG-CSF must be seen as an exciting advance in therapeutics. It should rapidly find an important place as an adjunct to cancer chemotherapy, and also appears to have substantial potential in a number of other neutropenic conditions which are currently difficult to treat. G-CSF (granulocyte colony-stimulating factor) is a human glycoprotein hormone which acts primarily to stimulate proliferation, differentiation and activation of committed progenitor cells of the neutrophil-granulocyte lineage into functionally mature neutrophils. These cells are also further stimulated by G-CSF to show enhanced activity at sites of infection and inflammation. Recombinant human G-CSF (rG-CSF) used clinically is produced by the bacterium Escherichia coli carrying a cDNA encoding the human gene, and by mammalian cells. Both products have the same activity as that of the natural factor. In combination with other stimulating factors, rG-CSF can also act on other cell lineages (in vitro and in animals) within the haematopoietic system. Granulocytosis has been induced in healthy volunteers at intravenous doses of rG-CSF 10 to 40µtg. Neutrophil levels reached about 4.5 times baseline values within 4 to 8 hours after a single rG-CSF 40µg dose, and returned to baseline within 24 to 48 hours. Subcutaneous administration is also effective at the same doses, but peak neutrophil levels occur a few hours later and return to baseline within 24 to 72 hours. In patients with cancer in the absence of chemotherapy, doses of rG-CSF 1 to 60 µg/kg/day intravenously induced increases in neutrophil levels from a baseline of approximately 20 × 109/L to a maximum of 90 × 109/L after 4 to 5 days of treatment. In patients developing neutropenia following chemotherapy, the postchemotherapy neutrophil count nadir occurred up to 5 days earlier than expected, and the duration of leucopenia was reduced dose proportionally from 8 days (rG-CSF 1 µg/kg/day) to 1 day (rG-CSF 30 µg/kg/day). Phase I/II trials in cancer patients who received rG-CSF alone (in the absence of chemotherapy) have demonstrated an initial transient decrease in neutrophil counts (within the first hour after dosing) then a rapid, sustained elevation (within 24 hours after dosing), suggesting release of mature neutrophils and/or demargination. Dose-proportional increases in neutrophil counts have also occurred in patients with congenital agranulocytosis or myelodysplasia. Administered to mice, dogs and monkeys following total body irradiation, with or without bone marrow transplantation, rG-CSF accelerated recovery of neutrophils compared with control animals. Prophylactic or simultaneous administration of rG-CSF (up to 400 µg/kg) to neutropenic mice, hamsters and neonatal rats infected experimentally (with, for example, Pseudomonas aeruginosa or Staphylococcus aureus), increased their rate of survival by up to 100% at 10 days after infection and by 95% at 22 days after infection, compared with 65% in controls. Furthermore, when rG-CSF was combined with antibiotic therapy, the effect on survival in neonatal rats was enhanced at 72 hours after infection (91% survival in the rG-CSF plus antibiotics group compared with 28% in animals receiving antibiotics only, 9% in animals receiving rG-CSF only and 4% in controls). The reduced incidence of infection in animals after rG-CSF administration indicates a potential use for rG-CSF in patients with severe infection. rG-CSF induces differentiation of mouse myeloid leukaemic cell lines, a human promyelocytic leukaemia cell line and some human acute myelogenous leukaemia cells in vitro. However, since rG-CSF induces proliferation of some acute myelogenous leukaemia cells in vitro, there is concern that if rG-CSF is used therapeutically in acute myelogenous leukaemia patients or in patients with myelodysplasia at risk of progression to leukaemia, proliferation may occur in vivo — this concern must be balanced against some favourable findings in patients with acute myelogenous leukaemia (see below). There are limited published data available regarding the pharmacokinetics of G-CSF. However, a few trials have measured plasma concentrations and terminal half-life (t½) of rG-CSF following intravenous or subcutaneous administration. A mean t½ value of 0.75 hours was reported in healthy individuals. In cancer patients a similar value of about 1.3 hours was observed after intravenous doses of 1 and 3 µg/kg, but t½ values of 5 to 7 hours have been reported more consistently by other investigators using higher doses. Peak serum concentrations (Cmax) of rG-CSF are dose proportional for intravenous and subcutaneous routes of administration. At 30 minutes after intravenous infusion of rG-CSF 100 to 800 µg/m2 in 39 patients with advanced pulmonary cancer, Cmax values ranged from 55 to 512 µg/L. Cmax values were maintained for about 40 minutes when G-CSF was given by intravenous infusion and subsequently decreased logarithmically with time. When rG-CSF was administered subcutaneously, Cmax values persisted for up to 6 hours and rG-CSF was eliminated from the serum within 48 hours. Continuous intravenous or subcutaneous infusion of rG-CSF did not lead to accumulation in the serum. When neutrophil levels rose above 30 × 109/L, detectable serum rG-CSF concentrations rapidly decreased despite continuing infusion. G-CSF was initially used therapeutically in limited numbers of patients in an attempt to ameliorate the neutropenia that follows chemotherapy. These studies established an effective dose, route and duration of rG-CSF administration. Results of a pivotal randomised, placebo-controlled trial have now confirmed the findings of phase II trials. In this study of 199 evaluable patients receiving up to 6 cycles of chemotherapy for small-cell lung cancer, the incidence of severe (grade IV) neutropenia was reduced (relative to placebo) in rG-CSF recipients (98 vs 84%), as was the median duration (6 vs 1 day across all cycles). A reduction of 50% occurred in the event rate for infection as manifested by fever with neutropenia; decreases in the rate of culture-confirmed infections, mean number of days of hospitalisation and mean number of days of intravenous antibiotic use were of a similar magnitude. Almost all patients in the early studies responded with a dose-proportional reduction of about 4- to 6-fold in the number of days of neutropenia and a dose-proportional increase in recovery of neutrophil counts. However, the magnitude of patient response varied widely, in part reflecting the heterogeneity of patients in these studies, particularly with regard to prior radiotherapy and chemotherapy. As a consequence of diminished neutropenia, patients experienced a reduction in number of infective episodes and fewer days of hospitalisation and antibiotic treatment, results which have now been confirmed in the above large trial. Importantly, in 1 study the percentage of patients who qualified to receive the next planned cycle of chemotherapy was significantly increased (100 vs 29% with controls) — a finding with potentially positive implications for survival rate, although this has not yet been established. Studies to date have indicated that rG-CSF enhances neutrophil recovery after various chemotherapy regimens, including those which are anthracycline or platinum based. In patients receiving high dose chemotherapy followed by autologous bone marrow transplants in various trials, rG-CSF therapy caused an acceleration in the time to recovery of neutrophils in the bone marrow compared to historical controls. For example, the time for the neutrophil count to reach 1.0 × 109/L was 31 days (mean) for historical control patients and 13 days for rG-CSF-treated patients. Although the incidence of neutropenic fever and mucositis were similar for rG-CSF or control groups, the duration of severe neutropenia and severity of mucositis were improved, and there were reductions in the frequency of bacteraemias and the number of intravenous antibiotics used in different studies. The value of rG-CSF in the treatment of myelodysplasia is not yet established. In 4 patients with myelodysplasia a single intravenous dose of rG-CSF induced an increase in white blood cells within 4.5 hours, levels peaking between 8.5 and 12.5 hours, and returning to pretreatment values within 3 days of stopping 6 days’ therapy. There were increases in WBC of 0.8 × 109/L to 4.5 × 109/L and patient response to different doses of rG-CSF varied widely. Subcutaneous administration of rG-CSF prolonged neutrophil recovery, with levels returning to pretreatment values over 2 to 4 weeks after stopping therapy, and the possible benefits of maintenance therapy were demonstrated, 10 of 11 patients responding with 3.6- to 16.3-fold increases in neutrophil count for up to 16 months. Some anaemic patients also had reduced requirement for red blood cell transfusion. It is not known whether rG-CSF alters the rate of progression of myelodysplasia patients to convert to leukaemia. Patients with established acute myelogenous leukaemia, treated with rG-CSF after undergoing intensive chemotherapy, experienced shortened periods of recovery of neutrophil counts to 0.5 × 109/L (20 days vs 28 days for control patients). In 4 patients in the rG-CSF group, therapy was discontinued due to leukaemic cell regrowth but it was not confirmed whether this was caused by rG-CSF. Patients with congenital neutropenia administered rG-CSF 3 to 60 µg/kg/day had increases in neutrophil counts from approximately 0.1 × 109/L to between 1.3 and 9.5 × 109/L cells. Consequently, the number of infectious episodes was reduced, as was the requirement for antibiotics. Neutrophil counts remained elevated for up to 26 months with maintenance therapy, and rG-CSF may have an important role in such patients. In patients with cyclic neutropenia, rG-CSF 3 to 10 µg/kg caused an increase in mean neutrophil counts, a shortening of cycle duration and a significant reduction in symptom scores. There are insufficient data to draw any conclusions regarding the potential use of rG-CSF in AIDS, aplastic anaemia and hairy cell leukaemia, although some encouraging preliminary findings have been reported. rG-CSF is generally well tolerated. Mild or moderately severe bone pain is the main adverse effect and has occurred in about 20 to 25% of patients who received rG-CSF following chemotherapy in clinical trials. Pain was alleviated with analgesics, disappeared within hours of stopping rG-CSF treatment and almost always resolved even with continued therapy. Rises in serum levels of leucocyte alkaline phosphatase, lactate dehydrogenase and uric acid (⩽ 10 times baseline levels) occurred during treatment, but clinical symptoms have not been reported. Splenomegaly has been observed (using MRI) in all of 6 cyclic neutropenia patients administered rG-CSF, with only 1 palpable spleen tip. Other reported adverse effects possibly related to rG-CSF therapy have been rare, and no serious or life-threatening events were attributable to rG-CSF in the large study. Continuous and short intravenous infusion, or subcutaneous injection or continuous infusion of rG-CSF is effective in elevating neutrophil counts in neutropenic patients. If deemed appropriate, rG-CSF can be self-administered subcutaneously by patients and this is a suitable method for acute and maintenance treatment. The recommended starting dose is 5 µg/kg/day subcutaneously as a bolus or continuous infusion or intravenously by infusion. rG-CSF should not be administered in the 24 hours before or after cytotoxic chemotherapy. rG-CSF may be administered for up to 2 weeks until the neutrophil count is 10 × 109/L following the chemotherapy-induced nadir. Patients with cardiac conditions or sepsis should be closely monitored. Although the increase in neutrophil counts in patients is dose-proportional, the dose of rG-CSF effective in stimulating an initial rise may differ between individuals, so a flexible dosing regimen based on monitoring neutrophil counts and using increments of 5 µg/kg per cycle could be required.

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