Granulocyte and granulocytemacrophage colonystimulating factors

Physiology of G-CSF and GM-CSF

G-CSF and GM-CSF are both glycosylated polypeptides in their natural form, which are the main regulators of granulocyte production. The gene for G-CSF is located on chromosome 17q, whereas that of GM-CSF is located on chromosome 5q. Both of these CSFs can be secreted by a variety of cell types, including monocytes/macrophages, T cells, endothelial cells and fibroblasts when appropriately stimulated in vitro. The levels of endogenous G-CSF can increase to detectable levels when there is a demand for increased granulocyte production such as in acute treatment-induced neutropenia, chronic neutropenic conditions and in acute infections in patients with or without underlying haematological disorders. G-CSF in peripheral blood is detected more often and in higher concentrations than GM-CSF, and there appear to be differences in their production and regulation. GM-CSF has more pleiotropic effects than G-CSF and stimulates the production of neutrophils, eosinophils and monocytes, although both have been primarily exploited for their effects on stimulating myelopoiesis. GM-CSF treatment results in the release of IL-1 and tumour necrosis factor from monocytes and hence its administration has been associated with fever.

Clinical uses of G-CSF and GM-CSF

Mobilization of peripheral blood stem cells

The use of CSFs for the mobilization of peripheral blood stem cells (PBSCs) from both patients and donors is recommended in both the BCSH guidelines and also the ASCO recommendations.

Mobilization of PBSC for autologous transplantation It was first discovered in the 1960s that peripheral blood contains a small number of stem cells that can give rise to all three haemopoietic cell lineages. In the resting state, the number of these cells circulating in the peripheral blood is very low, whereas during haemopoietic recovery after myelosuppressive chemotherapy the number of circulating PBSC increases up to 100-fold. The administration of haemopoietic growth factors (G-CSF or GM-CSF) can also lead to a similar increase in the number of circulating PBSCs, and these can be readily collected by the use of continuous-flow cell separation and then used for autologous transplantation and to support high-dose therapy.

The combination of chemotherapy and subsequent administration of a growth factor (G-CSF or GM-CSF) appears to be synergistic and leads to a superior yield of PBSCs as enumerated by flow cytometric analysis of cells expressing the CD34 antigen. The minimum number of PBSCs required for complete and sustained haemopoiesis has been established at a level of 2 X 106 CD34+ cells/kg, with optimal haemopoietic recovery occurring at doses of around 5 X 106/L. Various stem cell mobilization regimens have been employed, either using cyclophosphamide alone in doses ranging from 2 to 7 g/m2 followed by G-CSF, or using combination chemotherapy regimens plus G-CSF, which may give superior yields and also have the advantage of efficacy against the underlying haemopoietic malignancy. Although high doses of cyclophosphamide may be more effective for PBSC mobilization, they are now less frequently used because of the higher toxicity that is associated with them (Figure 18.2).

The rationale behind obtaining PBSCs for autologous transplantation is that a number of studies have confirmed that restoration of haemopoiesis occurs more rapidly using PBSCs as the source of haemopoietic progenitors than when using autologous marrow. The use of PBSCs for autologous transplantation leads to a significant acceleration of neutrophil and platelet engraftment, and this may result in shorter hospital-ization and reduced toxicity of the procedure. One of the early studies by Sheridan et al. (1992) showed a highly significant acceleration of platelet engraftment compared with historical bone marrow controls of 15 versus 39 days. Furthermore, this benefit of PBSC transplantation over bone marrow transplantation in terms of faster haemopoietic reconstitution has been confirmed in a randomized study of lymphoma patients. As a result of these findings, the use of PBSCs for autologous transplantation has become widespread and has virtually replaced autologous marrow in order to achieve rapid restoration of bone marrow function after high-dose therapy.

The efficacy of G-CSF and GM-CSF for autologous mobilization has been reported to be equal in terms of median progenitor cell yield and time to haematological recovery following transplantation. However, in view of the better toxicity profile of G-CSF, its use has generally been favoured for PBSC mobilization. Mobilization of sufficient PBSCs for autografting is not always successful, and factors associated with a failure to mobilize

Figure 18.2 Mobilization of stem cells for autologous transplantation.

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include heavy pretreatment with chemotherapy, especially alkylating agents, and also previous radiotherapy exposure. The use of additional growth factors for these patients, for example IL-3 and SCF, is being evaluated at present.

Mobilization of PBSCs for allogeneic transplantation A number of randomized studies have also shown similar benefits of mobilized PBSCs compared with bone marrow for allogeneic transplantation. There are good data showing significant benefits for G-CSF-mobilized PBSC in terms of neutrophil and platelet recovery. One study has also reported a trend for improved survival and a significant increase in disease-free survival at 2 years for the PBSC recipients. Another has reported a shorter duration of hospitalization for those patients receiving G-CSF-mobilized PBSCs, resulting in a reduction in the total cost of the procedure.

One concern regarding the use of PBSCs for allogeneic transplantation was that there is a theoretical increased risk of graft-versus-host disease (GvHD) compared with the use of bone marrow, as unmodified PBSC grafts contain at least 1 log more T cells. However, this has not been apparent clinically, as a number of studies have not shown an increased risk of acute GvHD, although the incidence of chronic GvHD does appear to be raised.

The mobilization of PBSCs from normal donors has almost entirely been with G-CSF alone, which has an excellent safety record and low toxicity profile compared with GM-CSF, which tends to have more side-effects. In Europe, the usual schedule for G-CSF administration to normal donors has been 10 |ig/kg per day given subcutaneously for four consecutive days. Higher doses of G-CSF have been used (12-16 |g/kg per day), which may result in a higher yield of progenitors, although this may result in greater toxicity. Using the standard dose of G-CSF of 10 |g/kg per day, the number of CD34+ cells in the peripheral blood peaks on days 5-6, reaching levels of between 20 and 140 |L before tailing off. The white cell count (WCC) usually peaks at between 30 and 65 X 109/L. There is no correlation between the WCC and the CD34+ cell count in the peripheral blood; however, a dose reduction of G-CSF is usually recommended if the WCC reaches levels of more than 70 X 109/L. With this regimen, leucapheresis is usually initiated on day 5 (i.e. the day following the fourth G-CSF injection), and the target of > 4 X 106 CD34+ cells/kg recipient weight is usually achieved in one to two collections processing 2.5 times the blood volume (Figure 18.3). For the majority of donors, it is possible to collect PBSCs via the use of peripheral veins, although the use of long lines is occasionally necessary due to poor venous access.

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Figure 18.3 Mobilization of stem cells - sibling donors.

The advantages of PBSC donation for the donor include the avoidance of general anaesthesia, the less invasive procedure and the lack of hospitalization. Using this dose of G-CSF, the procedure is generally well tolerated but it is not a completely risk-free procedure. The commonest side-effects reported include bone pain (83%), headache (39%), fatigue (14%) and nausea (12%), which resolve rapidly with cessation of G-CSF therapy. More serious adverse effects have been reported in small numbers of patients (often using higher doses of G-CSF), including splenic rupture, severe pyogenic infection, exacerbation of ischaemic heart disease and precipitation of vaso-occlusive crisis in a patient with Hb SC disease. A number of relative contraindications of PBSC mobilization have been agreed, which include a history of autoimmune, inflammatory or thrombotic disease. There do not appear to be any long-term sequelae of a short course of G-CSF for PBSC mobilization. Studies investigating the long-term effects of PBSC donation have revealed no significant abnormalities in the blood counts of donors, their general health, the risk of development of leukaemia or other malignancy or any effect on fertility.

Use of colony-stimulating factors following haemopoietic progenitor cell transplantation

The use of CSFs to accelerate haemopoietic reconstitution after autologous and allogeneic progenitor cell transplantation is recommended both by the BCSH guidelines (Table 18.3) and the ASCO recommendations (2000 update) (Figure 18.4 and Table 18.4).

Colony-stimulating factors post autologous transplantation High-dose myeloablative chemotherapy followed by autologous transplantation is a highly effective treatment for a number of haematological malignancies and has been widely used. Apart from the risk of disease relapse, the major complication of this approach is the possibility of procedure-related toxicity. This includes the risks of major haemorrhage, life-threatening infection, delayed or incomplete engraftment and organ damage from the ablative regimen, all of which may lead to prolonged hos-pitalization and increased procedural cost. Measures to reduce any of these potential problems will clearly be of benefit in terms of improved survival and also the cost-benefit of this treatment

Table 18.3 BCSH guidelines on the use of colony-stimulating factors in haematological malignancies.

Primary prophylaxis

Secondary prophylaxis

Adjunctive treatment

Aplastic anaemia

Bone marrow failure Lymphomas

PBPC mobilization PBPC transplantation

Not routinely recommended unless the expected incidence of febrile neutropenia is greater than 40% (level Ila, grade B)

Not routinely justified but indicated for tumours when delay/dose reduction would compromise overall survival (level III, grade B)

Not recommended for patients with uncomplicated febrile neutropenia (level Ib, grade A) but should be considered in patients with poor prognostic factors (level IV, grade C)

Routine use of CSF is recommended after consolidation chemotherapy (level Ib, grade A); CSF is recommended following induction if it reduces hospital stay or antibiotic usage

G-CSF is indicated to reduce the severity of neutropenia following intensive phases of therapy (level Ib, grade A)

CSFs are indicated to reduce the severity of neutropenia in patients receiving intensive chemotherapy (level 1b, grade A). CSFs are also recommended on an intermittent basis for neutropenic patients with infection (level IV, grade C) but continuous prophylactic use is not justified

There is insufficient evidence to make any recommendations and so patients should be given CSFs on an individual therapeutic trial basis (level IV, grade C)

G-CSF is recommended when improvement of the neutrophil count is appropriate (level III, grade B)

Evidence supports the routine use of CSFs to reduce infection, chemotherapy delay and hospitalization especially when the risk of neutropenia sepsis exceeds 40% (level 1a, grade A); there is also evidence of improved survival with G-CSF supported dose intensification in elderly patients with HG NHL (level Ib, grade A); at present this cannot justify a change in policy for all lymphoma patients but elderly patients may benefit from G-CSF support

CSFs are indicated for the mobilization of PBPCs

CSFs are indicated to accelerate reconstitution after allogeneic and autologous transfusion

Figure 18.4 Role of haemopoietic growth factors in progenitor cell transplantation.

PBSC Mobilization (+ chemotherapy)

Autologous PBSCT

5 |g/kg/day until

G-CSF

PBSC Mobilization from normal donors

G-CSF

Allogeneic PBSCT

Delayed engraftment

Table 18.4 Summary of ASCO recommendations (2000 update).

Primary prophylaxis

Secondary prophylaxis

Chemotherapy AML

Lymphomas PBSC mobilization

Post HSC transplantation

Routine use of CSFs not recommended; consider CSFs in high-risk patients, including the elderly Use of CSFs should be considered in patients with complicated febrile neutropenia

CSF treatment after induction therapy should be used if cost-benefits can be shown; CSFs for priming is not recommended outside the setting of clinical trials; CSFs are recommended after consolidation chemotherapy

G-CSF administration begun after completion of the first few days of chemotherapy of the initial induction or first post-remission course is recommended

Intermittent use of CSFs may be considered in patients with severe neutropenia and recurrent infection; prolonged or continuous treatment with CSFs is not recommended

No specific recommendations

No specific recommendations

Use of CSFs is recommended for both patient and donor PBSC mobilization; higher CSF doses may be useful

Use of adjunctive CSFs is recommended post PBSC transplantation and after autologous and allogeneic BMT

approach. The administration of haemopoietic growth factors following autologous transplantation has therefore been introduced in an attempt to shorten the neutropenic period, decrease the frequency and severity of neutropenic septic episodes, and hence reduce the duration of hospitalization and thereby reduce the overall cost of the procedure. A number of randomized controlled trials have confirmed that the use of CSFs after autologous transplantation are beneficial in significantly shortening the duration of neutropenia and hospitalization. This did lead to a mean cost saving in at least one of the studies.

Both G-CSF and GM-CSF have been shown to be effective in hastening haemopoietic recovery following autologous transplantation. No large-scale prospective comparative studies have been performed addressing the relative efficacy of these two CSFs. In addition, the optimal timing, duration and dose of CSFs following autologous transplantation remains to be established.

The ASCO guidelines support the use of G-CSF at a dose of 5 |ig/kg per day and 250 |g/m2 per day for GM-CSF, and the commencement of CSFs up to 5 days after progenitor cell reinfusion. This dose should then be continued until the absolute neutrophil count (ANC) exceeds a minimum of 1 X 109/L. Further modifications to the dosage and scheduling of these growth factors may be possible to reduce costs without impairment of the beneficial clinical effects.

Colony-stimulating factors post allogeneic transplantation The major complications of allogeneic transplantation are similar to those of autologous transplantation with the additional problems of GvHD and graft rejection. Therefore, as for autolog-ous transplantation, the rationale for administration of growth factors following allogeneic transplantation is to accelerate myeloid recovery and reduce the incidence of infection, number of febrile days, antibiotic usage and duration of hospitalization. Available data from a number of studies have confirmed a clinical benefit in terms of neutrophil engraftment kinetics using either G- or GM-CSF following allogeneic transplantation from either sibling or unrelated donors. The degree of acceleration of neutrophil recovery, however, is also influenced by other factors, including the GvHD prophylaxis used and the source of haemopoietic progenitors infused, i.e. G-CSF-mobilized PBSCs versus bone marrow.

It is still not clear whether the enhanced haemopoietic reconstitution seen in patients receiving CSFs post transplant translates into improved transplant-related mortality rates and survival, although this has been suggested by some studies.

Initial concerns about the use of growth factors in the allo-geneic setting leading to an increased risk of GvHD or to an increase in relapse rates for AML have proved to be unfounded despite the effects of growth factors on cytotoxic T cells and myeloid blast cells in vitro. As with autologous transplantation, the optimal cost-effective dose and schedule for the administration of CSFs following allogeneic transplantation remains to be established.

The problem of bone marrow graft failure or delayed haematological recovery (ANC < 0.2 X 109/L by day +28) after transplantation is a problem mainly seen after allogeneic transplantation using unrelated donors, especially when a low cell dose has been infused. When this occurs, it usually results in prolonged hospitalization, increased treatment costs and a higher treatment-related mortality, mainly as a result of infective deaths. Few studies have examined the use of growth factors for the treatment of delayed engraftment, although there are some data to suggest that GM-CSF may be of benefit in this setting. The updated ASCO guidelines recommend a trial of CSFs for patients who experience delayed or inadequate neutrophil engraftment after PBSC transplantation, and suggest using a dose of GM-CSF 250 |g/m2 per day for 14 days, followed by a 7-day break. This can be repeated for up to three courses if there is no effect with a dose escalation to 500 |g/m2 per day for the third course.

Use of colony-stimulating factors to support standard chemotherapy

Neutropenia and neutropenic sepsis are the main dose-limiting complications of chemotherapy, with the risk of infection being directly related to the severity and duration of neutropenia. Although the mortality from neutropenic sepsis is low, such episodes require hospitalization and treatment with broad-spectrum antibiotics. They may also lead to the delay or dose reduction of subsequent courses of chemotherapy, which may have a deleterious effect on the response to treatment.

Primary prophylaxis

Although the addition of CSFs following chemotherapy has been shown to reduce the incidence of febrile neutropenia, this appears only to be cost effective for highly myelosuppress-ive dose-escalated regimens in which the incidence of febrile neutropenia reaches 40%. Routine use of CSFs for primary prophylaxis in patients receiving standard outpatient chemotherapy regimens is not recommended except in high-risk patient populations (e.g. the elderly, patients with AIDS-related non-Hodgkin's lymphoma, patients with pre-existing neutropenia or decreased immune function or patients with active infections).

Secondary prophylaxis

The use of CSFs in patients who have already experienced an episode of febrile neutropenia following a previous course of chemotherapy is justified in order to prevent further infection and also to maintain the delivery of full-dose chemotherapy on schedule.

Use of colony-stimulating factors for neutropenia The routine use of haemopoietic growth factors in patients rendered neutropenic following standard chemotherapy but who remain afebrile cannot be justified. Although the duration of neutropenia may be reduced in patients treated with CSFs, this has not been shown to be of any clinical benefit as in general the neutropenia observed in such patients is profound but short. Even in the presence of neutropenic fever, there is only limited evidence that the addition of growth factors improves clinical outcome in terms of duration of hospitalization and antibiotic use despite a consistent reduction in the duration of neutropenia. Thus, current ASCO and BCSH guidelines recommend the use of CSFs only in febrile neutropenic patients who have adverse prognostic factors such as pneumonia, hypotension, multiorgan failure or invasive fungal infection or who are elderly.

Use of colony-stimulating factors in haematological disorders

A number of studies have investigated the role of haemopoietic CSFs in the treatment of patients with a number of haemato-logical disorders in an effort to maintain chemotherapy dose intensity and to reduce the incidence of neutropenic sepsis.

Use of colony-stimulating factors in AML therapy Randomized trials have shown that the administration of CSFs following acute myeloid leukaemia (AML) induction chemotherapy has consistently reduced the neutropenic period, with concurrent benefits in terms of hospitalization and antibiotic use. Some of these studies have also shown additional benefits in terms of clinical response rate, disease-free or overall survival, although this has not been consistently observed. Importantly, no adverse effects have been observed on the stimulation of leukaemic cell growth or drug resistance in any of these studies despite the fact that CSF receptors may be expressed on myeloid blasts. Elderly AML patients are most at risk from death from neutropenic sepsis, and recommendations at present are that this group should certainly be considered for CSF therapy. The use of CSFs for other AML patients can also be justified if it is considered that the reduction in hospitalization outweighs the cost of the CSF treatment. Comparative studies of G- and GM-CSF have not been performed, but available data seem to suggest that both CSFs are effective in this setting. Delaying the commencement of CSF 2-3 days following the completion of chemotherapy does not appear to reduce the efficacy and may be associated with some cost savings.

Similarly, the use of CSFs in a similar way following consolidation chemotherapy can also be justified as their use in this setting appears to result in a marked reduction in the duration of neutropenia and hospitalization.

The use of CSFs to 'prime' leukaemic blasts in an attempt to enhance their sensitivity to S-phase-specific cytotoxic agents has been investigated. The best-known AML chemotherapy regimen utilizing this approach is the 'FLAG' chemotherapy protocol, which combines fludarabine, cytosine arabinoside and G-CSF. In this case, G-CSF is given before and during the chemotherapy to sensitize the blast cells, and the fludarabine, being scheduled before the cytosine arabinoside, acts synergist-ically to increase the rate of accumulation of Ara-CTP in the blasts and lead to enhanced killing of these cells. No clear benefit in terms of response rates or survival has, however, been demonstrated using such an approach, and at present it is recommended that the use of CSFs in this setting should be restricted to clinical trials.

Myelodysplastic syndromes

Many patients with myelodysplasia suffer from chronic severe neutropenia, and among such patients the incidence of serious infections is high. Studies have demonstrated that administration of CSFs alone to such patients may be effective in improving neutrophil and also eosinophil counts and is well tolerated. Thus, the intermittent use of CSFs in patients with severe neu-tropenia and recurrent infection can be recommended. Indeed, the combination of CSFs together with erythropoietin may also be of benefit in MDS patients who are also anaemic owing to a synergistic effect on Hb. Furthermore, for patients with high-risk MDS who are receiving systemic chemotherapy, the admin istration of CSFs results in a shortening of neutropenia and reduction of the interval between induction and consolidation courses. The theoretical increased risk of transformation to overt AML has not been observed but, in view of this, prolonged or continuous use of CSFs cannot be recommended.

Acute lymphoblastic leukaemia

There is good evidence from randomized trials that G-CSF is effective in reducing the duration of neutropenia by up to 8 days in both adults and children receiving ALL induction chemotherapy. This was associated with a reduction in the number of infections and duration of hospitalization in some of the studies but had no effect on overall or disease-free survival. On the basis of these findings, it has been recommended that G-CSF is commenced after the first few days of induction or first postremission course of chemotherapy.

Aplastic anaemia

There is limited evidence from clinical trials regarding the use of CSFs for patients with aplastic anaemia. There have been a number of sporadic reports of responses to G- and GM-CSF, especially in less severe cases. It also does not appear that the addition of prophylactic CSFs to immunosuppressive therapy reduces the number of infections developing in such patients. Therefore, it is suggested at present that the use of these agents for patients with aplastic anaemia should be restricted to clinical trials. The efficacy of a number of other haemopoietic growth factors is being evaluated at present, both alone and in combination with stem cell factor (SCF), erythropoietin, flt3-ligand and thrombopoietin. The data from these studies are awaited with interest.

Severe chronic neutropenia

Severe chronic neutropenia is defined as an absolute neutro-phil count below 0.5 X 109/L lasting for months or even years. Causes include cyclic, idiopathic and congenital neutropenias, and G-CSF has been shown to be effective in all these categories, leading to durable responses in the neutrophil counts. In the case of inherited bone marrow failure syndromes such as Kostmann's syndrome, Schwachman-Diamond syndrome, Fanconi anaemia and dyskeratosis congenita, G-CSF may be effective in improving neutrophil counts in up to 90% of cases and may also reduce infections and improve survival; these infants previously suffered from severe pyogenic infections and had a median survival of less than 3 years. Adverse effects include mild splenomegaly, mild thrombocytopenia, osteoporosis and possibly malignant transformation.

The fact that some responders with congenital neutropenia have developed myelodysplastic syndromes or AML raises the possibility that G-CSF may play a role in the pathogenesis of these disorders in these patients. The issue is complicated because many of these disorders have a propensity for transformation into AML/MDS as part of their natural history. One registry study revealed a rate of AML/MDS of 12.5% after 8 years of treatment, with no significant relationships found between the age of onset of AML/MDS, patient gender, G-CSF dose or duration of G-CSF therapy. However, the cumulative acquisition of genetic aberrations was observed in the bone marrow cells from patients with Kostmann's syndrome who transformed, including ras mutations, the appearance of clonal cytogenetic abnormalities and the presence of G-CSF receptor mutations. It has been shown in murine models that G-CSF receptor defects may lead to the development of a hyperproliferative response to G-CSF, confer resistance to apoptosis and hence enhance cell survival.

It remains unclear whether G-CSF directly accelerates the propensity for transformation to AML/MDS in the genetically abnormal progenitor cells in these patients with inherited forms of bone marrow failure, especially those with G-CSF and ras mutations, or whether G-CSF simply prolongs patient survival and allows time for the malignant predisposition to declare itself. It is, however, noteworthy that G-CSF has also been shown to be effective in the management of patients with cyclic and idiopathic neutropenia, and in these patients there have been no cases of AML/MDS. Nevertheless, only careful follow-up of these patients will resolve this issue.

Hodgkin's disease and non-Hodgkin's lymphoma Several studies have shown that the addition of G- or GM-CSF as primary prophylaxis in patients receiving chemotherapy for various lymphomas reduces the incidence of neutropenia, neutropenic sepsis, chemotherapy delays and duration of hos-pitalization. Furthermore, G-CSF has been used to permit a reduction in the interval between cycles of CHOP chemotherapy from 3-weekly to 2-weekly, which may translate into improved disease responses and survival. Overall, there is currently insufficient evidence to justify routine addition of CSFs for all patients with non-Hodgkin's lymphoma, but it may be considered in elderly patients.

Use of colony-stimulating factors in the paediatric population

Chemotherapy protocols for the treatment of paediatric malignancies are often considerably myelotoxic, and infants are particularly susceptible to neutropenic sepsis because of the immaturity of their immune systems. In addition, as many childhood cancers are potentially curable, there is a perceived higher cost-benefit ratio for the use of CSFs to support these chemotherapy regimens. As a result, there is generally a higher usage of CSFs for primary and secondary prophylaxis than in the adult population. The use of CSFs for patients with congenital neutropenias has already been discussed, and there are some data to support the use of CSFs in neonatal sepsis. Otherwise, the indications for the use of CSFs are similar to those for adults, and it appears to be that G-CSF is better tolerated than GM-CSF.

Use of GM-CSF as an adjunct to antifungal therapy

Invasive fungal infections have emerged as a cause of serious mortality and morbidity to immunocompromised patients. Host defences including appropriate cytokine responses and intact phagocyte function are necessary to combat opportunistic fungal infections such as candidiasis and aspergillosis. Bronchoalveolar macrophages, which are derived from peripheral blood monocytes, have a particularly important role in this regard, but this mechanism may be severely impaired in patients who are cytopenic following cytotoxic chemotherapy or who are treated with steroids (e.g. dexamethasone) that have a suppressive effect on macrophage function.

A number of CSFs have been investigated and studied in vitro for activity against fungal pathogens. The most promising results have been seen with GM-CSF, which has been shown to augment the antifungal activity of monocytes and macrophages. The main effects of GM-CSF on macrophages and monocytes are to enhance their phagocytic and metabolic functions, including increased synthesis and release of superoxide anions that are directly toxic to microbes, and to release other proinflammatory cytokines. This results in the inhibition and/or killing of Candida albicans, Aspergillus hyphae, Cryptococcus, Pneumocystis, Leishmania and Mycobacteria as well as other intracellular pathogens. GM-CSF has also been shown to block the ability of dexamethasone to suppress the activity of bronchoalveolar macrophages.

There have been several reports on the successful use of GM-CSF in conjunction with antimicrobial therapy in the management of patients with these opportunistic infections. This supports the clinical value of CSFs in this situation, although controlled trials are needed for full evaluation of their efficacy.

The role of G-CSF in the harvesting of granulocytes for transfusion

The development of bacterial and fungal infections continues to be a major complication for neutropenic patients. Despite the use of modern antibiotics and the use of haemopoietic growth factors to reduce the period of post-treatment neutro-penia, infection remains a major cause of morbidity and mortality in these patients. The transfusion of normal granulocytes is a logical approach to the treatment of serious infections in neutropenic patients. Before the introduction of CSFs, initial studies of granulocyte transfusions in the 1960s using buffy coats were disappointing owing to difficulties in collecting adequate numbers of functional granulocytes from donors to raise the ANC in adult recipients by more than a few hundred cells per litre. This dose of cells is probably inadequate to treat an established infection.

More recently, it has been shown that the combined administration of dexamethasone and G-CSF to donors prior to leucapheresis can increase the yield of granulocytes collected up to 10 X 109/L in a single 2- to 3-h procedure using hydroxyethyl starch as a sedimenting agent. These cells appear to be functionally normal by both in vitro and in vivo measurements. This dose of cells can increase and maintain the blood neutrophil count at 0.5-1.0 X 109/L for up to 24 h after transfusion, and several reports have indicated a significant improvement in established infections. Adverse effects experienced by recipients are mainly febrile transfusion reactions, although there are theoretical concerns regarding pulmonary toxicity and HLA sensitization. G-CSF administration to donors is generally well tolerated. Further studies are required to determine the exact role for granulocyte transfusions in neutropenic patients with severe infection.

Exogenous production of colony-stimulating factors by tumours

Tumour-related leucocytosis is a paraneoplastic syndrome that has been reported occasionally in a number of different non-haematological malignancies, including lung carcinoma, mesothelioma, transitional cell carcinoma of the bladder, and renal and hepatocellular carcinomas among others. Autonomous production of haemopoietic CSFs such as G-CSF, GM-CSF and IL-6 by these tumours has recently been demonstrated. Although the mechanism for this aberrant expression of G-CSF m-RNA remains unclear, it appears that in the case of lung cancer this phenomenon is associated with a poor outcome.

Haemopoietic growth factors such as G-CSF and GM-CSF are highly effective at shortening the period of neutropenia following cytotoxic chemotherapy and hence reducing the incidence of infections. Although they are safe and effective, they have a short half-life, being rapidly cleared from the body predominantly through the kidneys. As a result, daily subcutaneous administration is required often for periods of 7-14 days. Attempts have therefore been made to modify these agents to increase their half-life and reduce the frequency of injections. The successful engineering of a sustained-duration G-CSF has now been achieved by the addition of a polyethylene glycol moiety to the G-CSF molecule (pegfilgrastim). This longer-acting cytokine binds to the same receptor and stimulates the proliferation and differentiation of neutrophils by the same mechanism as its shorter-acting counterpart. However, it is minimally cleared by the kidneys and has a much longer serum half-life. Furthermore, its clearance is neutrophil dependent and is therefore self-regulated. Initial clinical trials have shown that a single subcutaneous dose of the pegylated G-CSF per cycle of chemotherapy is sufficient and as effective as its shorter-acting derivative in reducing the neutropenic period. The safety profile and tolerability of pegylated G-CSF is also similar.

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