Lenograstim: a review of its use in chemotherapy-induced neutropenia, for acceleration of neutrophil recovery following haematopoietic stem cell transplantation and in peripheral blood stem cell mobilization

Lenograstim (Granocyte?, Neutrogin?, Myelostim?) is a glycosylated recombinant human granulocyte colony-stimulating factor. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of lenograstim, mainly focusing on its use in chemotherapy-induced neutropenia, acceleration of neutrophil recovery following haematopoietic stem cell transplantation (HSCT), and peripheral blood stem cell (PBSC) mobilization in patients with cancer and healthy donors. In randomized, multicentre trials in patients with solid tumours, lymphoma or multiple myeloma, the durations of chemotherapy-induced neutropenia, hospitalization for infection and intravenous antibacterial therapy were significantly shorter in patients receiving lenograstim prophylaxis than in those receiving placebo. The time to neutrophil recovery was also significantly shorter in patients with acute myeloid leukaemia or acute lymphoblastic leukaemia who received lenograstim than in those who received placebo or no treatment, according to the results of randomized, multicentre trials. In addition, lenograstim prophylaxis facilitated the administration of dose-intense or dose-dense chemotherapy regimens, with improved clinical outcomes seen in some trials. In patients with cancer undergoing HSCT, lenograstim accelerated neutrophil recovery post-HSCT and shortened the duration of hospitalization, according to the results of randomized, multicentre trials. Lenograstim effectively mobilized PBSCs in patients with cancer, demonstrating generally similar efficacy to filgrastim or molgramostim in five randomized trials (although lower dosages of lenograstim than filgrastim were administered in four of the trials). Lenograstim also provided effective PBSC mobilization in healthy donors and was more effective than filgrastim when both drugs were administered at a dosage of 10?μg/kg/day. The efficacy and safety of lenograstim for PBSC mobilization in healthy donors was supported by the results of a prospective, longer-term study involving almost 4000 healthy donors. Lenograstim was generally well tolerated across a variety of treatment settings, including PBSC mobilization in healthy donors, with bone pain being one of the most commonly reported adverse events. In conclusion, lenograstim remains an important option for use in chemotherapy-induced neutropenia, acceleration of neutrophil recovery following HSCT, and PBSC mobilization.     

Comparison of lenograstim and filgrastim on haematological effects after autologous peripheral blood stem cell transplantation with high-dose chemotherapy

OBJECTIVE: To compare the efficacy of lenograstim and filgrastim on haematological recovery following an autologous peripheral blood stem cell transplantation (PBSCT) with high-dose chemotherapy. METHODS: A retrospective case-controlled study. RESULTS: Absolute neutrophil count (ANC) recovery above 0.5 x 10(9)/l and white blood cell (WBC) recovery above 4 x 10(9)/l for 3 consecutive days was achieved earlier with filgrastim than with lenograstim ((13.2 +/- 8.0 vs 19.0 +/- 10.0 days, p = 0.004), (16.9 +/- 9.7 vs 29.9 +/- 16.6 days, p = 0.001), respectively). The platelet recovery above 20 x 10(9)/l was also achieved earlier with filgrastim than with lenograstim (19.5 +/- 11.6 vs 27.2 +/- 13.8 days, p = 0.006). Furthermore, filgrastim-treated patients received fewer days of granulocyte colony simulating factor (G-CSF) administration (12.5 +/- 7.0 vs 18.6 +/- 8.5 days, p = 0.001) and spent less time in hospital (23.7 +/- 10.9 vs 32.0 +/- 17.6 days, p = 0.009). Duration of antibiotic administration was also significantly shorter in the filgrastim group (13.6 +/- 7.6 vs 29.1 +/- 19.8 days, p = 0.001). CONCLUSION: In patients undergoing PBSCT following high-dose chemotherapy, filgrastim significantly reduced the duration of neutropenia, thrombocytopenia and days of G-CSF administration, and led to earlier hospital discharge compared with lenograstim.     

Mobilization of peripheral blood stem cells by granulocyte-colony stimulating factors: comparison of a standard dose of glycosylated and mutated granulocyte-colony stimulating factor in non-Hodgkin's lymphoma patients following CHOP therapy

The effects of granulocyte-colony stimulating factor (G-CSF) have been studied in several clinical settings. G-CSFs are widely used to stimulate the production of granulocytes and are well known to mobilize peripheral blood stem cells (PBSCs). However, very few studies have examined differences among G-CSFs. The aim of this study was to compare the mobilization of PBSCs induced by a standard dose of two G-CSFs following biweekly cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy. Using a standard dose of G-CSF, we conducted a randomized, crossover trial that compared the efficacy of two kinds of G-CSF, glycosylated [lenograstim (2 micrograms/kg)] and mutated [nartograstim (1 microgram/kg)], on PBSC mobilization in 10 patients with non-Hodgkin's lymphoma after biweekly CHOP chemotherapy. Lenograstim (2 micrograms/kg) was more effective in shortening the duration of neutropenia than nartograstim (1 microgram/kg) (3.8 days vs. 5.0 days, p < 0.05, the number of days for the neutrophil count to reach 5 x 10(9)/l from nadir). The number of CD34+ cells and granulocyte-macrophage colony forming units (GM-CFU) was higher for lenograstim but no statistically significant difference between the two groups was found. Glycosylated G-CSF is more effective than mutated G-CSF in shortening the duration of neutropenia. As for the mobilization of CD34+ cells and the number of CFU-GM, there was a tendency to increase in the lenograstim group but no statistically significant differences were found.     

Use of filgrastim for stem cell mobilisation and transplantation in high-dose cancer chemotherapy

Myeloablative or high-dose chemotherapy regimens utilise doses that are significantly greater than those used in standard treatments. The neutropenia caused by these high-dose therapies can be associated with an increased incidence of bacterial and fungal infections and remains an important clinical issue among patients with advanced-stage cancers. Filgrastim is approved for stem cell mobilisation in both chemotherapy-treated patients and normal donors. Harvested peripheral blood progenitor cells have been used effectively in allogeneic and autologous transplantation, increasing the speed and extent of neutrophil and platelet recovery. Accelerated haematopoietic recovery is associated with a significantly shorter hospital stay and, therefore, leads to a reduction in treatment costs. The contribution of filgrastim to the acceleration of haematopoietic recovery after peripheral blood progenitor cell transplant has been assessed in a number of prospective clinical trials after high-dose chemotherapy. Controversy remains over whether growth factors should be administered shortly after stem cell infusion or after several days. The recently approved, once-weekly form of filgrastim, pegfilgrastim, has been shown to have efficacy comparable to that of the native molecule and can be expected to enhance patient quality of life through the need for fewer injections. This article will review the role of filgrastim for stem cell mobilisation and transplantation in patients receiving high-dose chemotherapy.     

Economic evaluation of lenograstim for prophylaxis of chemotherapy-induced neutropenia in patients with small cell lung cancer

The impact of lenograstim, recombinant human granulocyte colony-stimulating factor, on healthcare costs was evaluated on the basis of the results of a clinical trial of the drug in patients receiving VICE (vincristine, ifosfamide, carboplatin and etoposide) chemotherapy for small cell lung cancer (SCLC). The use of lenograstim resulted in a significant (p < 0.03) increase in the cumulative chemotherapy dose intensity (125% with lenograstim vs 118% without). Lenograstim was found to have no significant impact on the use of healthcare resources for administration of chemotherapy, chemotherapy-induced neutropenia, and associated infections. The cost of healthcare for the lenograstim group (excluding lenograstim acquisition costs) was 700 pounds higher per patient than that for the group not treated with lenograstim (95% CI -930 pounds to 2300 pounds). The use of lenograstim to intensify the chemotherapy dose is likely to increase the costs of treatment for SCLC. However, any increased costs need to be balanced against the potential cost savings associated with the possible long term benefits resulting from chemotherapy dose intensification.     

Comparison of lenograstim and filgrastim on haematological effects after autologous peripheral blood stem cell transplantation with high-dose chemotherapy

SUMMARY

Objective: To compare the efficacy of lenograstim and filgrastim on haematological recovery following an autologous peripheral blood stem cell transplantation (PBSCT) with high-dose chemotherapy.

Methods: A retrospective case-controlled study.

Results: Absolute neutrophil count (ANC) recovery above 0.5?×?10⁹?l^?1 and white blood cell (WBC) recovery above 4?×?10⁹?l^?1 for 3 consecutive days was achieved earlier with filgrastim than with lenograstim ((13.2?±?8.0 vs 19.0?±?10.0 days, p?=?0.004), (16.9?±?9.7 vs 29.9?±?16.6 days, p?=?0.001), respectively). The platelet recovery above 20 x 10⁹/l was also achieved earlier with filgrastim than with lenograstim (19.5?±?11.6 vs

27.2?±?13.8 days, p?=?0.006). Furthermore, filgrastim-treated patients received fewer days of granulocyte colony simulating factor (G-CSF) administration (12.5?±?7.0 vs 18.6?±?8.5 days, p?=?0.001) and spent less time in hospital (23.7?±?10.9 vs 32.0?±?17.6 days, p?=?0.009). Duration of antibiotic administration was also significantly shorter in the filgrastim group (13.6?±?7.6 vs 29.1?±?19.8 days, p?=?0.001). Conclusion: In patients undergoing PBSCT following high-dose chemotherapy, filgrastim significantly reduced the duration of neutropenia, thrombocytopenia and days of G-CSF administration, and led to earlier hospital discharge compared with lenograstim.     

Pegfilgrastim

Pegfilgrastim is a covalent conjugant of filgrastim (a recombinant human granulocyte colony-stimulating factor) and monomethoxypolyethylene glycol. It is administered as a single dose per myelosuppressive chemotherapy cycle to decrease the incidence of infection, as manifest by febrile neutropenia, in patients with nonmyeloid cancer. Pegfilgrastim increases the terminal elimination half-life and decreases the apparent serum clearance of the drug in patients with nonmyeloid cancer. Serum concentrations of pegfilgrastim remain elevated during neutropenia but decline when the neutrophil count increases. In phase III trials in patients with breast cancer and in a phase II trial in patients with non-Hodgkin's lymphoma or Hodgkin's disease, the mean duration of grade 4 neutropenia and the time to absolute neutrophil recovery during cycle 1 of chemotherapy was similar in recipients of single-dose pegfilgrastim or daily filgrastim. In the larger of two phase III trials in patients with breast cancer, the incidence of febrile neutropenia over four cycles of chemotherapy was significantly lower in recipients of single-dose pegfilgrastim than that in recipients of daily injections of filgrastim. Moreover, the mean duration of grade 4 neutropenia in cycles 2 to 4 of chemotherapy was significantly lower in recipients of pegfilgrastim than that in recipients of daily filgrastim. In comparative trials, there were no differences in the incidence and severity of adverse events, including skeletal pain, between single-dose pegfilgrastim and daily filgrastim in patients with nonmyeloid cancer receiving myelosuppressive chemotherapy.     

Overview of the lenograstim pharmacoeconomics programme

Lenograstim is a recombinant colony-stimulating factor that has been shown to be a useful adjunctive agent in cancer chemotherapy. Clinical trials have demonstrated the efficacy of lenograstim in correcting chemotherapy-induced neutropenia and associated complications in inflammatory breast cancer and non-Hodgkin's lymphoma, and in facilitating dose intensification of chemotherapy in small cell lung cancer. To meet increasing demands for economic data on new drug entities, a lenograstim pharmacoeconomics programme was established. This programme involved prospective economic evaluations of lenograstim that were undertaken as part of phase III randomised clinical trials by a combined German/Italian health-economics team (inflammatory breast cancer), a French team (non-Hodgkin's lymphoma), and a team from the UK (small cell lung cancer).     

Granulocytic growth factors and cancer-related neutropenia: limited effects

(1) Cancer chemotherapy often causes haematological complications, in particular neutropenia, which can have grave consequences in terms of the risk of infections (increasing with the degree and duration of neutropenia) and the need for modifications in chemotherapy protocols (longer intervals between cycles or dose reductions). (2) In France, three haematopoietic growth factors are licensed to stimulate leukocyte production: filgrastim (unglycosylated granulocyte colony-stimulating factor (G-CSF)), pegfilgrastim (pegylated filgrastim), and lenograstim (glycosylated G-CSF). (3) The main adverse effects of these three growth factors are joint and bone pain, a flu-like syndrome, and reactions at the injection site. (4) G-CSF has provided disappointing results in primary prevention, and its use is only justified for patients receiving chemotherapy that causes febrile neutropenia in at least 40% of cases: patients with acute leukaemia, elderly patients, and patients with cancer-related neutropenia or poor general status, etc. In these patients, G-CSF reduces the incidence of febrile neutropenia and, possibly, the risk of hospitalisation. A meta-analysis of 11 comparative trials involving about 1500 patients with non Hodgkin's lymphoma showed only a reduction in the incidence of febrile neutropenia and infections. (5) In the prevention of recurrences of neutropenia on continuing chemotherapy, only one trial, involving patients aged over 60 with high-grade non Hodgkin's lymphoma, showed an improvement in survival time with filgrastim (survival rate: 64.3% with filgrastim versus 49% with placebo, after a median follow-up of 40 months). Until these results are confirmed in other clinical trials, reduction in the intensity of chemotherapy (dosage, frequency) is generally recommended. (6) Curative treatment of neutropenia with G-CSF is only warranted for febrile patients with a high risk of severe infections requiring lengthy hospitalisation. Two meta-analyses, one including 8 trials and the other including 13 trials, involving a total of about 1500 patients, only showed a reduction in the length of hospitalisation.     

Filgrastim-mediated neutrophil recovery in patients with breast cancer treated with docetaxel and doxorubicin

STUDY OBJECTIVES: To study the impact of filgrastim 5 microg/kg given once/day through absolute neutrophil count (ANC) recovery on the duration of grade 4 neutropenia (ANC < 0.5 x 10(3)/mm3) and time to ANC recovery. Additional objectives were to study the average number of filgrastim injections/cycle required to achieve ANC recovery and differences in outcome by cycle. DESIGN: Combined analysis of two double-blind, randomized, multicenter trials. PATIENTS: Two hundred twenty-two patients treated for breast cancer. MEASUREMENTS AND MAIN RESULTS: All patients but one were evaluable for efficacy end points. Mean +/- SD duration of grade 4 neutropenia was 1.7 +/- 1.3 days in cycle 1; the duration decreased in cycles 2-4 to between 1.0 and 1.2 days. Fifty percent of patients had ANC recovery to 10 x 10(3)/mm3 or greater by day 11 of the cycle, and 90% by day 13, corresponding to 10 and 12 days of filgrastim administration, respectively. Across all cycles, the mean +/- SD number of filgrastim injections/cycle was 10.51 +/- 1.70, with little variation among cycles. CONCLUSION: When filgrastim is administered as recommended, starting 24 hours after chemotherapy and continuing through an ANC of 10 x 10(3)/mm3 or greater, neutrophil recovery is rapid and predictable. Because the first cycle of chemotherapy has the highest rates of neutropenia and febrile neutropenia, it seems prudent to administer growth factor support preemptively.     

Pegfilgrastim: using pegylation technology to improve neutropenia support in cancer patients

Pegylation of a protein can improve not only its formulation properties, but also both its pharmacokinetic and pharmacodynamic performance. Pegfilgrastim was made by linking a 20-kDa polyethylene glycol molecule to filgrastim, producing a long-acting cytokine requiring less frequent dosing than its parent drug. This review describes the clinical development of pegfilgrastim, and discusses its potential benefits to patients and caregivers in the prophylaxis of chemotherapy-induced neutropenia. Pegfilgrastim has a longer half-life and slower elimination rate than filgrastim, resulting in an increased serum concentration over time. Serum levels of pegfilgrastim are maintained until after a chemotherapy-induced neutrophil nadir and then decline rapidly as the neutrophil count recovers, consistent with a neutrophil-mediated clearance mechanism. In two pivotal phase III studies of women receiving chemotherapy for breast cancer, a single injection of pegfilgrastim per chemotherapy cycle, dosed either by body weight (100 microg/kg) or as a fixed dose (6 mg), was comparable to daily filgrastim (5 microg/kg) for all efficacy parameters, including duration of severe neutropenia and depth of neutrophil nadir. Analysis of pooled data from these studies showed a significantly lower incidence of febrile neutropenia in patients receiving pegfilgrastim compared with filgrastim (11 versus 19%, p<0.05), and a trend towards a lower risk of hospitalization and use of i.v. anti-infectives. The safety profiles of pegfilgrastim and filgrastim were similar. Pegfilgrastim given once per chemotherapy cycle is as effective and well tolerated as daily injections of filgrastim. With its more convenient dosing regimen, pegfilgrastim has the potential to improve quality of life and compliance in patients, and to be more cost effective.     

Pegfilgrastim administered once per cycle reduces incidence of chemotherapy-induced neutropenia

Neutropenia is a common and potentially dangerous adverse effect of cancer chemotherapy. It also often necessitates a reduction or delay in dose, thus compromising efficacy. The human granulocyte colony-stimulating factor filgrastim has been proven to have a good safety profile and to be effective in accelerating neutrophil recovery and reducing the incidence of infections following myelosuppressive chemotherapy. However, its short serum half-life necessitates daily administration. Pegylated filgrastim (pegfilgrastim) was developed by attaching a polyethylene glycol moiety to the filgrastim protein. Pegfilgrastim binds to the same cell surface receptor on neutrophils and their precursors as filgrastim and stimulates the proliferation and differentiation of neutrophils through the same mechanism. However, because of the pegylation, it is minimally cleared by the kidneys and has a much longer serum half-life. Furthermore, its clearance is neutrophil dependent and thus 'self-regulated'. Pegfilgrastim is administered as a single subcutaneous injection per cycle of chemotherapy. In clinical trials it has been shown to be comparable in efficacy to filgrastim in decreasing the incidence of infection as manifested by febrile neutropenia following chemotherapy. Its safety profile and tolerability are similar to those of filgrastim.     

Effect of lenograstim on the cost of autologous bone marrow transplantation. A preliminary communication

High dose chemotherapy and autologous bone marrow transplantation (BMT) can produce prolonged remission in patients with malignant lymphoma or solid tumours. However, neutropenia is a serious complication of treatment in patients with these diseases. In this study, we investigated the costs and effects of using lenograstim, a recombinant human granulocyte colony-stimulating factor, to treat neutropenia in 16 patients with lymphoma or solid tumours. The cost of lenograstim was not included in the calculations. The duration of neutropenia and hospitalisation were both lower in patients who received lenograstim compared with no treatment. The mean cost of autologous BMT was FF142,000 in patients who received lenograstim, compared with FF166,000 in patients who did not. Savings were largely attributable to decreased expenditure on hospitalisation in the lenograstim-treated group. The cost of 14 days' treatment with lenograstim was estimated at FF10,500, based on a daily dosage of 150 micrograms/m2/day.     

Pharmacokinetics and pharmacodynamics of pegfilgrastim

Pegfilgrastim is a sustained-duration form of filgrastim, a recombinant methionyl form of human granulocyte colony-stimulating factor (G-CSF), to which a 20 kDa polyethylene glycol molecule is covalently bound to the N-terminal methionine residue. Similar to filgrastim, pegfilgrastim increases the proliferation and differentiation of neutrophils from committed progenitor cells, induces maturation, and enhances the survival and function of mature neutrophils, resulting in dose-dependent increases in neutrophils. After subcutaneous administration, pegfilgrastim exhibits nonlinear pharmacokinetics and exposure to pegfilgrastim increases in more than a dose-proportional manner, suggesting that the clearance of pegfilgrastim decreases with increased dosing. Filgrastim is primarily eliminated by the kidney and neutrophils/neutrophil precursors; the latter presumably involves binding of the growth factor to the G-CSF receptor on the cell surface, internalization of the growth factor-receptor complexes via endocytosis, and subsequent degradation inside the cells. Pegylation of filgrastim renders renal clearance insignificant, which was demonstrated in bilaterally nephrectomized rats and confirmed in subjects with renal impairment. As a result, the neutrophil-mediated clearance is the predominant elimination pathway for pegfilgrastim. During chemotherapy-induced neutropenia, the clearance of pegfilgrastim is significantly reduced and the concentration of pegfilgrastim is sustained until onset of neutrophil recovery. Pegfilgrastim concentrations are sustained longer in patients with profound neutropenia. Evidence supports the use of a postnadir absolute neutrophil count (ANC) of ≥ 1?×?109/L as a surrogate marker threshold for the clearance of pegfilgrastim to subtherapeutic levels. After repeated administration of pegfilgrastim, the peak concentrations of pegfilgrastim decrease, likely due to increased neutrophil and neutrophil precursor mass. A pharmacokinetic-pharmacodynamic model was developed to describe the pharmacokinetic and ANC profiles of pegfilgrastim; the analysis supported that 100 μg/kg was an adequate weight-based dose of pegfilgrastim and predicted that 6 mg would be an optimal fixed dose of pegfilgrastim to simplify treatment. Data from a pivotal study confirmed that a once-per-chemotherapy-cycle injection of pegfilgrastim at 6 mg was as safe and effective as 11 daily injections of filgrastim at 5 μg/kg in reducing neutropenia and its complications in patients with breast cancer receiving four cycles of doxorubicin/docetaxel chemotherapy. Because of the highly efficient regulation of pegfilgrastim clearance via neutrophils and neutrophil precursors, a single fixed dose of pegfilgrastim can be given once per chemotherapy cycle in conjunction with a variety of myelosuppressive chemotherapy regimens.     

Filgrastim. A reappraisal of pharmacoeconomic considerations in the prophylaxis and treatment of chemotherapy-induced neutropenia

Neutropenia is a frequent and often dose-limiting complication of chemotherapy and is associated with considerable patient morbidity and mortality. Standard treatment in patients who become febrile includes hospitalisation and empirical antibiotic therapy. Filgrastim is a recombinant human granulocyte colony-stimulating factor (rHuG-CSF). It significantly decreases the incidence of febrile neutropenia in patients receiving standard-dose chemotherapy, and shortens the duration of febrile neutropenia in patients undergoing autologous bone marrow transplantation (BMT) or peripheral blood progenitor cell (PBPC) infusion after myeloablative chemotherapy regimens. These effects are usually associated with a decrease in hospitalisation and antibiotic requirements. The contribution of filgrastim therapy to beneficial effects on other clinically important end-points (e.g. quality of life, tumour relapse rate, and short and long term survival) remains to be accurately determined. Pharmacoeconomic data concerning the use of filgrastim as an adjunct to standard-dose chemotherapy are derived largely from the results of phase III trials. Cost analyses based on hospital charges suggest that the cost of providing filgrastim therapy can be fully recouped if the drug is used as primary prophylaxis in previously untreated patients, for whom the risk of developing febrile neutropenia is at least 40%. Reserving filgrastim for use in patients who have developed febrile neutropenia in a previous chemotherapy cycle may result in further cost savings. However, careful patient selection is required, since potential cost savings will vary depending upon the risk of hospitalisation in the absence of filgrastim treatment. Infusion of filgrastim-mobilised PBPCs is emerging as a preferred strategy in patients receiving myeloablative chemotherapy, and promising results have been obtained from cost analyses. From a pharmacoeconomic viewpoint, future research should be directed towards defining optimum dosage regimens and hence improving the cost-effective use of filgrastim. Data evaluating patient quality of life and treatment preferences would help define the cost utility of filgrastim therapy. In the meantime, available pharmacoeconomic data support the use of filgrastim as an adjunct to chemotherapy in selected clinical situations.     

Pharmacokinetics of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) in healthy male volunteers

AIMS: The aim of this open, randomised, crossover, parallel-group study was to compare the pharmacokinetics and neutrophil responses of lenograstim when administered subcutaneously (s.c.) and intravenously (i.v.). METHODS: A total of 27 healthy male volunteers was recruited. Lenograstim doses (0.5, 2, 5, or 10 microg kg(-1)) were administered s.c. or i.v. once-daily for 5 days, and then, after a 10-day washout period, vice versa for a further 5 days. Lenograstim concentrations and absolute neutrophil counts (ANCs) were measured predosing and postdosing on days 1 and 5. RESULTS: Maximum serum concentrations of lenograstim were higher following i.v. dosing (mean 5.2-185.5 vs 0.7-30.0 ng ml(-1) after s.c. dosing on day 1) and attained sooner (median 0.5-0.8 vs 4.7-8.7 h on day 1). However, apparent elimination half-lives of lenograstim were longer following s.c. dosing (mean 2.3-3.3 vs 0.8-1.2 h after i.v. dosing on days 1 and 5). ANCs increased in a dose-dependent manner with both routes of lenograstim, but more prolonged rises and higher ANC peaks were attained following s.c. doses. ANCs peaked on day 6 following 5 microg kg(-1) s.c. doses (mean peak=26.3x10(9) cells l(-1)), but on day 2 after 5 microg kg(-1) i.v. doses (mean peak = 12.4 x 10(9) cells l(-1)). Irrespective of route, the most common adverse events were headaches and back/spine pain; at doses of up to 5 microg kg(-1) these were mild and generally well tolerated. CONCLUSIONS: While supporting the use of both s.c. and i.v. administered lenograstim to treat neutropenia, these results demonstrate that neutrophil responses are more sustained and prolonged with the s.c. route.     

Treatment of breast cancer with chemotherapy in combination with filgrastim: approaches to improving therapeutic outcome

Chemotherapy improves disease-free and overall survival in breast cancer, and its benefit is directly related to the percentage of the planned dose that is actually administered. In all current chemotherapeutic regimens, a substantial proportion of patients have reductions and/or delays in dosage due to side effects. In about half such cases, the delays or reductions are related to neutropenia. Overall, approximately 30% of patients have a reduction to less than 85% of the planned dosage. Women aged > or = 50 years are more likely to experience a reduction or delay in dose. Dose-intense regimens (excluding myeloablative high-dose chemotherapy) which increase the dose of chemotherapy or reduce the interval between cycles, or both, are a promising approach now under investigation. The human granulocyte colony-stimulating factor filgrastim reduces the incidence of neutropenia and facilitates adherence to full dose intensity in both standard and dose-intensified regimens. A model based on the first-cycle absolute neutrophil count nadir has been developed and validated to determine which patients should receive filgrastim. A cost benefit associated with the use of filgrastim in patients with breast cancer has been realised. This may lead to a re-evaluation of the current treatment guidelines.     

Comparison of pegfilgrastim with filgrastim on febrile neutropenia,grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials

ABSTRACT

Background and objective: While head-to-head clinical trials demonstrate pegfilgrastim to be as efficacious as filgrastim in reducing chemotherapy-induced neutropenia, these studies lacked the statistical power to demonstrate better outcomes with one therapy compared to the other. Our objective was to obtain a pooled estimate of the effect of pegfilgrastim compared with filgrastim on incidence of febrile neutropenia (FN), and related outcomes among patients with solid tumors and malignant lymphomas receiving myelosuppressive chemotherapy.

Research design and methods: We searched PubMed and EMBASE for articles published from January 1, 1990 to August 31, 2006 reporting on randomized controlled trials (RCTs) that compared the efficacy and safety of pegfilgrastim versus filgrastim. We only accepted studies in which filgrastim (5 µg/kg/day) and pegfilgrastim (100 µg/kg or a fixed dose of 6?mg) were administered at approved doses indicated on the package insert. Pooled relative risk (RR) was estimated using the conservative random effects, empirical Bayesian method of Hedges and Olkin.

Main outcome measures: Rates of grade IV neutropenia and of FN, time to absolute neutrophil count (ANC) recovery, and bone pain.

Results: We identified five RCTs, with a total of 617 patients, evaluating the efficacy of a single dose of pegfilgrastim per cycle versus daily filgrastim injections. Although only one study had a statistically significant difference in FN reductions favoring pegfilgrastim over filgrastim (relative risk reduction of 50%; p = 0.027), the pooled RR showed a statistically significant favorable result for pegfilgrastim (RR = 0.64; 95% CI, 0.43–0.97). Grade IV neutropenia rates (for cycle 1: RR = 0.99; 95% CI, 0.91–1.08; cycle 2: RR = 0.88; 95% CI, 0.70–1.11; cycle 3: RR = 0.80; 95% CI, 0.47–1.36; cycle 4: RR = 0.90; 95% CI, 0.71–1.13), time to ANC (SMD = 0.11, 95% CI, –0.34–0.56), and incidence of bone pain (RR = 0.95; 95% CI, 0.76–1.19) were similar between the two G?CSFs. The included trials varied in the type of cancer, chemotherapy regimen and type of trial.

Conclusion: A single dose of pegfilgrastim performed better than a median of 10–14 days of filgrastim in reducing FN rates for patients undergoing myelosuppressive chemotherapy.     

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). A review of its pharmacological properties and prospective role in the management of myelosuppression.

Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a polypeptide hormone produced through recombinant DNA technologies in glycosylated (yeast or mammalian expression systems) or nonglycosylated (Escherichia coli expression system) form. It is a multilineage haematopoietin which stimulates proliferation and differentiation of bone marrow myeloid progenitors and increases peripheral white blood cell counts when administered systemically. Treatment is generally well tolerated, although mild to moderate flu-like symptoms are common and rGM-CSF-induced fever and fluid retention may be problematic in occasional patients. rGM-CSF accelerates recovery of peripheral neutrophil counts after bone marrow transplantation, and results of a placebo-controlled randomised trial correlate this with reduced infectious episodes and shortened length of hospitalisation in patients with lymphoid malignancies. A substantial number of patients with graft failure after bone marrow transplantation also respond to rGM-CSF. The duration of myelosuppression secondary to cancer chemotherapy can be significantly reduced by rGM-CSF which has permitted investigation of antineoplastic dose-intensity escalation. In some haematopoietic disorders (e.g. aplastic anaemia, myelodysplasia and neutropenia secondary to HIV infection and antiviral therapy), rGM-CSF produces clinically useful increases in peripheral blood granulocyte counts, although the effect is generally not sustained after drug withdrawal. The potential for rGM-CSF to stimulate proliferation of the abnormal clone in myelodysplasia and in acute myelogenous leukaemia following induction therapy is of concern. Available data suggest, however, that with appropriate monitoring and exclusion of high-risk patients this serious potential risk can be avoided, and that myelopoiesis is enhanced in such patients by rGM-CSF treatment. Recombinant colony-stimulating factors are a new therapeutic modality; hence many aspects of their use remain to be clarified. Nonetheless, as one of a small group of novel agents rGM-CSF has major potential in the management of myelosuppression secondary to cytoreductive therapy with or without bone marrow transplantation, and in amelioration of disturbed myelopoiesis. It represents an important application of biotechnology to a difficult area of therapeutics.     

The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta)

Recombinant protein technology produces drugs for human therapy in unprecedented quantity and quality. Research is now focusing on the relationship between pharmacokinetic and pharmacodynamic properties of molecules, with the aim of engineering proteins that possess enhanced therapeutic characteristics in contrast to being used as simple replacements for the natural equivalent. The addition of a polyethylene glycol (PEG) moiety to filgrastim (rmetHu-G-CSF, Neupogen) resulted in the development of pegfilgrastim. Pegfilgrastim is a long-acting form of filgrastim that requires only once-per-cycle administration for the management of chemotherapy-induced neutropenia. The covalent attachment of PEG to the N-terminal amine group of the parent molecule was attained using site-directed reductive alkylation. Pegylation increases the size of filgrastim so that it becomes too large for renal clearance. Consequently, neutrophil-mediated clearance predominates in elimination of the drug. This extends the median serum half-life of pegfilgrastim to 42 hours, compared with between 3.5 and 3.8 hours for Filgrastim, though in fact the half-life is variable, depending on the absolute neutrophil count, which in turn reflects of the ability of pegfilgrastim to sustain production of those same cells. The clearance of the molecule is thus dominated by a self-regulating mechanism. Pegfilgrastim retains the same biological activity as filgrastim, and binds to the same G-CSF receptor, stimulating the proliferation, differentiation and activation of neutrophils. Once-per-chemotherapy cycle administration of pegfilgrastim reduces the duration of severe neutropenia as effectively as daily treatment with filgrastim. In clinical trials, patients receiving pegfilgrastim also had a lower observed incidence of febrile neutropenia than patients receiving filgrastim.