Granulocyte colony stimulating factor (G-CSF)

Summary
Granulocyte colony stimulating factor (G-CSF) is a glycoprotein which stimulates the survival, proliferation, differentiation and function of neutrophil granulocyte progenitor cells and mature neutrophils. The two forms of recombinant human G-CSF in clinical use (filgrastim and lenograstim) are potent stimulants of neutrophil granulopoiesis and have demonstrated efficacy in preventing infectious complications of some neutropenic states. They can be used to accelerate neutrophil recovery from myelosuppressive treatments. G-CSF decreases the morbidity of cancer chemotherapy by reducing the incidence of febrile neutropenia, the morbidity of high-dose chemotherapy supported by marrow transplantation, and the incidence and duration of infection in patients with severe chronic neutropenia. Other potential applications are being evaluated.

Introduction
Mouse granulocyte colony stimulating factor (G-CSF) was first recognised and purified in Australia in 1983, and the human form was cloned by groups from Japan and the U.S.A. in 1986. The natural human glycoprotein exists in two forms of 174 and 177 amino acids. The more abundant and more active 174 amino acid form has been used in the development of pharmaceutical products by recombinant DNA technology.

The recombinant human G-CSF synthesised in an E. coli expression system is called filgrastim. The structure of filgrastim differs slightly from the natural glycoprotein. Most published studies have used filgrastim and it was the first form of G-CSF to be approved for marketing in Australia.

Another form of recombinant human G-CSF called lenograstim is synthesised in Chinese hamster ovary (CHO) cells. As this is a mammalian cell expression system, lenograstim is indistinguishable from the 174 amino acid natural human G-CSF. No clinical or therapeutic consequences of the differences between filgrastim and lenograstim have yet been identified, but there are no formal comparative studies. G-CSF should not be confused with granulocyte macrophage colony stimulating factor (GM-CSF), which is a distinctly different haemopoietic growth factor also under clinical development.¹

Approved indications
Patients with neutropenia have significant morbidity due to bacterial infections. These infections require treatment in hospital with intravenous antibiotics. The vulnerability of neutropenic patients to infections dictates that antibiotics are given at the onset of fever, before microbiological confirmation, and continued until the neutropenia resolves to prevent recurrent infection. G-CSF is the first treatment available to Australian patients which reliably ameliorates the underlying neutropenia.

Cancer chemotherapy
G-CSF (filgrastim) is indicated for the prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy for non-myeloid malignancies. It reduces the duration and severity of post-chemotherapy neutropenia (Fig. 1). In 3 randomised placebo controlled studies^2-4 of G-CSF (filgrastim) given after chemotherapy to patients with small cell lung cancer or lymphoma, the haematological effects of G-CSF (filgrastim) resulted in a 50% reduction in the number of patients experiencing febrile neutropenia. There were associated reductions in the use of intravenous antibiotics, hospitalisation, and the incidence of microbiologically documented infections. These 3 pivotal studies used significantly myelosuppressive chemotherapy regimens: without G-CSF, the incidence of febrile neutropenia for these regimens was 44-77%.

The recommended dose of G-CSF (filgrastim) for the prevention of febrile neutropenia is 5 micrograms/kg/day, commencing the day after chemotherapy and finishing after 10-14 days, when the post-nadir neutrophil level has reached 10x 10⁹/L. G-CSF is repeated with each cycle of chemotherapy. Concurrent administration of G-CSF and chemotherapy is not recommended as some combinations may increase myelosuppression. Subcutaneous and intravenous G-CSF have equivalent potency, but subcutaneous injection is generally recommended, as it is suitable for outpatients. Educational materials are available to help patients learn how to give themselves subcutaneous G-CSF.

G-CSF (lenograstim)is also approved for use to reduce the incidence of infection associated with established cytotoxic chemotherapy. Similar practical considerations apply to its use as for G-CSF (filgrastim).

Some potentially cost-saving variations to the recommended G-CSF regimen are under investigation. They include lower G-CSF doses (in particular, doses based on vial size rather than body mass) and shorter G-CSF courses (in particular, delayed commencement or earlier cessation of G-CSF). Formal assessments of whether or not these other approaches are as effective as the recommended regimen have not been reported.

At present, G-CSF is not recommended for patients with myeloid malignancies because in vitro data suggest that it may stimulate some myeloid malignancies. The safety and efficacy of G-CSF for infection prevention in patients with myeloid leukaemia is currently under investigation. Other research is investigating if the stimulatory effects of G-CSF on myeloid leukaemias will increase the susceptibility of leukaemic cells to cytotoxic drugs.

The patient should be monitored at least twice per week and the full blood count drawn before that day's G-CSFdose. (In the hour immediately following G-CSF administration, there is a transient reduction in numbers of circulating neutrophils.) All febrile neutropenic post-chemotherapy patients must seek urgent medical attention whether or not they have been receiving G-CSF. General practitioners will probably encounter patients who are self-administering G-CSF during outpatient phases of chemotherapy. They should refer febrile patients urgently to hospital.

The greatest benefit of G-CSF is expected with chemotherapy regimens given with intent to achieve cure or prolonged remission and having an incidence of febrile neutropenia above 40% (e.g. treatment regimens for patients with non-Hodgkin's lymphoma, relapsed Hodgkin's disease, germ cell tumours and acute lymphoblastic leukaemia). The validity of correlating the degree and duration of neutropenia with the risk of febrile neutropenia or infection has been demonstrated for G-CSF-treated patients in the pivotal studies with G-CSF (filgrastim). Since G-CSF has similar haematological effects for a variety of chemotherapy regimens including some with lower incidences of febrile neutropenic episodes, patients receiving other chemotherapy regimens for different tumour types are also expected to benefit clinically from G-CSF therapy. G-CSF (filgrastim and lenograstim) are approved for use in all non-myeloid tumour types.

Bone marrow transplantation
G-CSF (filgrastim) is indicated to reduce the duration of neutropenia and clinical sequelae following high-dose myeloablative chemotherapy supported by autologous marrow transplantation (i.e. re-infusion of the patient's own bone marrow cells). In Australian studies, G-CSF (filgrastim) reduced the duration of neutropenia and antibiotic therapy.5Evidence that the duration of hospitalisation is also reduced has accumulated since the original Australian studies.

The recommended schedule of G-CSF (filgrastim) for this indication is based on the early Australian studies. This involves a starting dose of 20-30 micrograms/kg/day, commencing within 24 hours of the marrow infusion, and tapering the dose according to neutrophil levels during the post-nadir neutrophil recovery.

G-CSF (lenograstim) has been shown to reduce the neutropenia following autologous and allogeneic marrow transplantation (the latter involves infusion of marrow from a genetically non-identical but optimally matched donor, usually a relation), with associated shortening of the durations of infection, antibiotic treatment and hospitalisation.6The recommended dose of G-CSF (lenograstim) in this setting is 5 micrograms/kg/day, until the neutrophil count returns to within the normal range.

There are many new applications of G-CSF in autologous haemopoietic support under investigation in Australia. G-CSF can be used to increase the numbers of circulating haemopoietic precursor cells which are then harvested by leucapheresis and used either as a supplement to or a substitute for aspirated bone marrow cells in autologous haemopoietic cell transplants. This approach has resulted in significantly accelerated platelet recovery in addition to neutrophil recovery. The role of post-transplant G-CSF after these peripheral blood progenitor cell autologous transplants is being reassessed. Community practitioners should be aware of these new approaches to haemopoietic support after myeloablative chemotherapy as these patients are now often managed as outpatients for a significant proportion of the period of haemopoietic reconstitution. The transplant physician should be contacted if any management questions arise regarding the care of these patients.

Severe chronic neutropenia
The early observations of the efficacy of G-CSF in patients with severe chronic neutropenia and recurrent infections have been confirmed in a multi centre randomised study of patients with congenital, idiopathic and cyclical neutropenia.7G-CSF (filgrastim) reduced the incidence and duration of infection-related events and antibiotic use, and the incidence of hospitalisation. G-CSF (filgrastim) is approved for chronic administration to patients with severe chronic neutropenia.

Other applications

Treatment of febrile neutropenia
Not all patients given chemotherapy for cancer receive G-CSF to prevent febrile neutropenia. A randomised placebo-controlled Australian study evaluated the effects of using G-CSF (filgrastim) as an adjunct to empiric intravenous combination antibiotics for post-chemotherapy febrile neutropenia (unpublished data). G-CSF shortened the duration of neutropenia and febrile neutropenia, but did not significantly shorten the duration of fever or hospitalisation, although there were consistent trends towards these benefits. G-CSF halved the relative risk of prolonged hospitalisation. Subset analyses suggested particular benefits for patients with solid tumours and documented infections.

This study supports the hypothesis that there is a real benefit from adding G-CSF to the standard antibiotic management of febrile neutropenia. It seems improbable that this benefit is as significant to patients as the prevention of febrile neutropenia. However, the relative benefit of G-CSF therapy by these two approaches has not been assessed.

Adverse effects and safety
G-CSF has been well tolerated by patients. In the randomised studies of patients having chemotherapy for cancer, the only significant adverse effect of G-CSF has been bone pain, which occurred in 15-20% of patients (approximately twice the incidence of placebo-treated patients). This medullary bone pain is effectively managed with simple oral analgesics such as paracetamol with or without codeine. Stronger analgesics are only very rarely required. Thrombocytopenia may be more pronounced in patients who do not have their chemotherapy dose reduced or delayed because of the effect of G-CSF to ameliorate neutropenia, which permits intended doses of chemotherapy drugs to be administered on schedule without dose reductions. (Chemotherapy doses are usually decreased if there is a delayed recovery of the neutrophil count.) The thrombocytopenia is probably a consequence of continued delivery of the intended chemotherapy doses rather than an effect of G-CSF itself. G-CSF has not been associated with the flu-like symptoms or fever which occur with the administration of other cytokines.

The 'low-grade' adverse events related to G-CSF (filgrastim) administration in the randomised study of patients with severe chronic neutropenia were musculoskeletal and bone pain, headache, rash and asymptomatic increase in spleen size. G-CSF (filgrastim) administration to some of these patients for up to 3 years has remained effective and well tolerated.

Infrequent adverse effects reported include vasculitis, Sweet's syndrome (acute febrile neutrophilic dermatosis) and exacerbation of some pre-existing dermatological conditions. Possible anaphylactoid reactions (incidence <0.001%) have been reported, although these have not been confirmed to be allergic reactions. Antibody formation has not been reported, even during G-CSF (filgrastim) courses of up to 9 months.

Cost and benefit considerations
G-CSF is an expensive drug. The cost of G-CSF (filgrastim) for the recommended minimum 10-day schedule for prevention of febrile neutropenia after cancer chemotherapy is A$1504 or $2407 per cycle depending on which of the two vial sizes (300 and 480 micrograms/vial) is used. G-CSF (lenograstim) costs $1283.60 for 1O vials (263 micrograms/vial), which is sufficient to treat a 53 kg person for 10 days at the recommended dose. The cost per microgram is $0.50 for G-CSF (filgrastim) and $0.49 for G-CSF (lenograstim) (costs as at September 1994). In Australia, a full assessment of the economic impact of G-CSF is difficult because of the different sources of health care funding. A significant proportion of the cost of G-CSF may be offset by the savings to the total health care budget through the reduction in admissions for management of febrile neutropenia. These admissions have a median duration of 8 days and are estimated to cost in the vicinity of A$500-700 per day. Such cost offsetting has been documented within both the private and public health care systems in the U.S.A. For the few patients with severe chronic neutropenia and clinically significant infections for whom there is no reliably effective alternative therapy, the benefits of daily G-CSF administration such as an improved quality of life, the significant reduction in morbidity and the reduced cost of managing infections must be considered in cost-benefit analyses.

G-CSF (filgrastim) is available under Section 100 of the Pharmaceutical Benefits Scheme for outpatient use during treatment of patients with selected tumour types (non-Hodgkin's lymphoma, germ cell tumours, relapsed Hodgkin's disease, acute lymphoblastic leukaemia, Ewing's sarcoma, rhabdomyosarcoma and neuroblastoma), and after autologous marrow transplantation, and in selected patients with severe chronic neutropenia. As of August 1994, G-CSF (lenograstim) also became available as a pharmaceutical benefit for similar uses.

Although G-CSF reduces the morbidity which accompanies neutropenia, it is not known whether G-CSF affects the mortality of neutropenic sepsis. Febrile neutropenia has a mortality of 10%, but occurs only in a proportion of patients and varies with the degree of myelosuppression of the various chemotherapy regimens. Although febrile neutropenia is a serious complication of chemotherapy, large numbers of patients would be required before a statistically significant effect of G-CSF on mortality could be detected.

G-CSF is currently used for the haematological support of cancer patients receiving chemotherapy, but it is not an anticancer treatment. The use of G-CSF allows patients to receive the intended dose of chemotherapy without reductions or an increased dose. However, it is unknown if this will result in a better outcome for the patient.

The future
There are preliminary data suggesting that G-CSF will be useful in the following conditions:

• neutropenia due to infections (such as occurs in viral infections)
• neutropenia due to non-chemotherapeutic myelosuppressive treatments (such as gancyclovir)
• drug-induced agranulocytosis
• primary marrow failure (such as aplastic anaemia)

It will be interesting to see if a role for G-CSF can be demonstrated in non-neutropenic states, such as burns or diabetes (where there are adequate numbers of neutrophils butthey are functionally defective), or in the management of infections in patients with normal neutrophil counts.

Acknowledgement

Dr Lieschke is supported by the John Maynard Hedstrom Research Scholarship of the Anticancer Council of Victoria.

Further reading

Metcalf D, Morstyn G. Colony-stimulating factors: general biology. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Biologic therapy of cancer. Philadelphia: JB. Lippincott Company, 1991:417-44.

Faulds D, Lewis NJ, Milne RJ. Recombinant granulocyte colony-stimulating factor (rG-CSF): pharmacoeconomic considerations in chemothempy-induced neutropenia. PharmacoEconomics 1992;1:231-49.