Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (rGM-CSF) : A Review of its Pharmacological Properties and Prospective Role in the Management of Myelosuppression.

CONCLUSIONS

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.

UNASSIGNED

Endogenous GM-CSF is produced by T-lymphocytes, macrophages, fibroblasts and endothelial cells, and participates both in the complex regulation of blood cell formation and in activation of mature leucocytes. It is a polypeptide which is variably glycosylated in its native state although the carbohydrate content is not essential for its biological effects, and the 3 available recombinant forms (which differ in extent of glycosylation) are similarly active in vivo. Proliferative activity and priming of mature cells are manifest at similar picomolar concentrations of GM-CSF, and it is the programming of the cell which appears to determine the response to binding of GM-CSF to its cell surface receptor. In concert with other colony-stimulating factors, GM-CSF facilitates lineage commitment and subsequently supports or amplifies the clonogenic activity of lineage-restricted factors, with the strongest effect seen on the granulocyte-macrophage lineage. A biphasic response was seen when rGM-CSF was administered in doses up to 1000 µg/m2/day or 60 µg/kg/day by subcutaneous or intravenous routes in phase I/II trials. Peripheral blood leucocyte counts decreased rapidly and profoundly secondary to sequestration within the lungs. Re-entry of these cells into the circulation restores counts to baseline in 2 to 4 hours and thereafter an increase in the proliferative fraction of haematopoietic cells in bone marrow probably accounts for the progressive rise in the number of neutrophils, eosinophils and monocytes. This effect is dose-proportional. GM-CSF stimulates proliferation of leukaemic progenitors from patients with acute myeloid leukaemia without stimulating differentiation. In contrast, the abnormal clone from myelodysplastic patients can be induced with GM-CSF to differentiate in vitro although karyotype anomalies persist. In vitro studies suggest that stimulation of nonhaematological cancer cells at physiological concentrations of GM-CSF is unlikely. The priming effects of GM-CSF on mature leucocytes which include increased expression of other cytokines, secretion of granule contents, augmentation of antigen presentation, altered chemotaxis, and enhanced phagocytosis, oxidative metabolism and antibody dependent cell-mediated cytotoxicity probably serve to increase the host response to infection. Administration of murine rGM-CSF to mice injected with lethal inocula of, for example, Pseudomonas aeruginosa improved their survival relative to controls. There are several reports of refractory infection in seriously ill neutropenic patients resolving after addition of rGM-CSF to ongoing antimicrobial therapy and subsequent neutrophil recovery; however, the role of rGM-CSF in management of established infection in patients with neutropenia remains to be more thoroughly investigated. The pharmacokinetic properties of rGM-CSF depend on the route of administration. After intravenous administration, serum levels decline rapidly with a half-life of distribution (t1/2α) of 5 to 15 minutes and half-life of elimination (t1/2β) of 1.5 to 2 hours. Maximum serum concentrations are reached 2 hours after subcutaneous injection, then decline with a t1/2β of 3 hours. Serum levels of rGM-CSF increase with dose and a proposed therapeutic target level of 1 µg/L is maintained for 8 to 22 and 16 hours after administration of 15 µg/kg of rGM-CSF by intravenous bolus and subcutaneous injection, respectively.

UNASSIGNED

The correlation between duration and severity of neutropenia and incidence of serious infection is well established. Administration of rGM-CSF to bone marrow transplant recipients is aimed at reducing morbidity in the early post-transplant period by shortening the duration of agranulocytosis. Intravenous administration of rGM-CSF up to 16 µg/kg/day (approximately 640 µg/m2/day) is well tolerated, and when begun within 24 hours of autologous marrow infusion produces the earlier appearance of > 0.5 × 109/L neutrophils in the peripheral circulation as compared with historical controls. Early studies indicate that treated patients have a lower incidence of culture-proven bacteraemia, and recent reports, some preliminary, of placebo-controlled and randomised trials confirm that patients with nonHodgkin's lymphoma or acute lymphocytic leukaemia who receive rGM-CSF 250 µg/m2 by daily 2-hour infusion for 21 days or more post transplantation, have significant reductions in duration of infectious episodes, antibiotic administration and hospitalisation. More limited data support a similar acceleration of neutrophil recovery in allogeneic bone marrow transplant recipients treated with rGM-CSF, with no apparent effect on the incidence or severity of graft-versus-host disease. rGM-CSF is less effective in patients in whom progenitor cell numbers are reduced by chemical purging of the marrow whether administered immediately after marrow infusion or when used as salvage therapy in patients with graft failure. A substantial proportion of patients with failure of autologous or allogeneic bone marrow grafts respond to prompt administration of rGM-CSF after diagnosis of graft failure, with an increase in absolute neutrophil count and bone marrow cellularity. In 1 study of 37 such patients, overall survival was significantly improved compared with historical controls. rGM-CSF increases the number of progenitor cells in peripheral circulation and, either alone or in combination with cyclophosphamide, facilitates the harvest of stem cells by apheresis for subsequent transplantation. Similar to the effect seen after myeloablative therapy and marrow transplantation, rGM-CSF accelerates neutrophil recovery following cytoreductive chemotherapy in patients with nonhaematological malignancies. Less frequent and less severe mucositis was also observed in rGM-CSF-treated versus control patients in several studies. Importantly, adjunctive use of rGM-CSF facilitated delivery of planned cycles of high or escalated doses of antineoplastic drugs although the value of such chemotherapy regimens remains to be proven. There has been no evidence to date that rGM-CSF increases the rate of relapse of patients with haematological malignancies when administered after myeloablative therapy and bone marrow transplantation or, in patients with acute myelogenous leukaemia, after induction therapy. Use of rGM-CSF to recruit quiescent leukaemic blast cells into S phase prior to chemotherapy is under investigation. rGM-CSF has been investigated in various disorders of haematopoiesis. A substantial number of adults and children with refractory aplastic anaemia respond to treatment with increases in bone marrow cellularity and peripheral blood granulocyte count; however, the response is generally not sustained after withdrawal of rGM-CSF. Elevation of neutrophil counts may not occur in patients with long-standing and severe aplasia; however, beneficial stimulation of macrophage function may still occur. Generally, rGM-CSF induces eosinophilia without correcting the neutropenia in patients with congenital neutropenic conditions. In myelodysplasia, rGM-CSF is capable of increasing the neutrophil count in a proportion of patients for the duration of administration. Caution is appropriate in administering this drug to patients with high (> 14% blasts) initial leukaemic burdens or with chronic myelomonocytic leukaemia in view of the potential for rGM-CSF to stimulate the leukaemic clone and precipitate acute leukaemia. Despite this concern, encouraging preliminary results from a trial with rGM-CSF (3 µg/kg/day by subcutaneous injection) and observation-only treatment groups suggest that, after > 6 months, the rate of transformation to acute leukaemia is similar in both groups but that rGM-CSF recipients have a sustained increase in neutrophil counts and an associated reduction in infection rate. rGM-CSF 1 to 5 µg/kg/day by subcutaneous injection ameliorates leucopenia associated with HIV infection and corrects zidovudine (azidothymidine)-induced neutropenia without affecting the disease course as determined by p24 antigen levels, CD4: CD8 ratios and recovery of HIV from mononuclear cells. Similar dosages ameliorate myelosuppression induced by ganciclovir in the treatment of AIDS-associated cytomegalovirus retinitis and by the combination of zidovudine and interferon-α in treating Kaposi's sarcoma. A trilineage response to rGM-CSF has been seen occasionally (e.g. some children with aplastic anaemia and some patients with myelodysplasia). Disease-or drug-induced anaemia or thrombocytopenia is generally not improved; however, both significant increases and decreases in platelet count have been reported, and the effect of rGM-CSF on megakaryocytosis and splenic phagocyte function require clarification. The combination of rGM-CSF with other recombinant colony-stimulating factors to expand the lineages stimulated is an exciting future possibility.

UNASSIGNED

At clinically useful dosages rGM-CSF is generally well tolerated. Limited comparison with placebo suggests that the type and incidence of adverse reactions reported are generally similar in both groups with the possible exception of slightly higher incidences of diarrhoea, asthenia, rash and malaise. However, reports from noncomparative and open-label trials indicate that mild to moderate flu-like symptoms (myalgias, bone pain, fatigue and headache) are common with rGM-CSF. Management of patients in whom this agent is indicated may be complicated by rGM-CSF-induced fever and, rarely, by a capillary leak syndrome causing fluid retention and potentially peripheral oedema, pericardial or pleural effusions which necessitate drug withdrawal. Also reported are rash (particularly at sites of subcutaneous injection), and occasional incidents of central venous catheter thrombosis. The occasional report of respiratory distress has led to the recommendation that respiratory symptoms be monitored and caution exercised in patients with preexisting lung disease.

UNASSIGNED

The approved (USA) dosage of yeast-derived rGM-CSF (sargramostim) for myeloid reconstitution after autologous bone marrow transplantation is 250 µg/m2 by daily 2-hour intravenous infusions, beginning 2 to 4 hours after marrow infusion and continued for 21 days. For management of bone marrow transplantation failure or delayed engraftment, the approved (USA) dosage of yeast-derived rGM-CSF is 250 µg/m2/day by 2-hour intravenous infusion. Treatment should be continued for 14 days and, if clinically indicated, may be repeated after 7 days off therapy. A third 14-day course of rGM-CSF at the increased dosage of 500 µg/m2/day by 2-hour infusion may be administered after a further 7 days off therapy. Further dose escalation in non-responding patients is unlikely to be of benefit. rGM-CSF has also been successfully administered by continuous intravenous infusion and by subcutaneous injection, including self-administration of long term therapy by the subcutaneous route. The optimal route for administration, dose and duration of therapy for indications other than autologous bone marrow transplantation and failure or delay of engraftment have not been established.