Granulocyte–macrophage colony-stimulating factor (GM-CSF)

Uses

The potential clinical applications of GM-CSF have been lengthily reviewed [ ]. It is used:

• to reduce chemotherapy-induced myelosuppression in patients with metastatic sarcoma, breast cancer, or melanoma;

• to facilitate the harvesting of peripheral blood stem cells for autologous bone marrow transplantation;

• in cyclic neutropenia;

• to aid recovery after high doses of ionizing radiation, and less successfully, for severe aplastic anemia.

GM-CSF has also been approved for the alleviation of neutropenia following myeloablative treatment with autologous bone marrow transplantation and ganciclovir-induced neutropenia in patients with AIDS [ ].

General adverse effects and adverse reactions

At the doses of GM-CSF usually recommended, systemic adverse reactions develop in 25–30% of patients, but they are rarely treatment-limiting [ ]. Doses over 250 micrograms/m ² and the intravenous route are associated with more frequent adverse reactions.

Bone pain and flu-like symptoms, with fever, myalgia, chills, and headache, are the most frequent adverse reactions [ ] and occur in 40–60% of all treated patients [ ]. They are probably due to the activation of secondary cytokines (such as TNF-alfa and IL-1) [ ]. Other frequently reported adverse reactions include erythematous eruptions at the injection site, thrombophlebitis, nausea, facial flushing, dyspnea, and gastrointestinal disorders with anorexia and weight loss. Severe fatigue and weakness are rare.

The first dose of GM-CSF can be followed within 3 hours by flushing, hypotension, tachycardia, dyspnea, musculoskeletal pain, and nausea and vomiting [ ]. At very high doses (generally over 16 micrograms/kg/day), erythroderma, weight gain, and edema with pleuropericardial effusions and ascites have been reported [ ]. Renal symptoms have also been described [ , ], as have various biochemical abnormalities, possibly due to secondary hyperaldosteronism [ ].

Fever was observed in up to 50% of patients at doses over 3 micrograms/kg. The fact that the fever peaks at a constant time after GM-CSF injection, the lack of clinical and biological signs of infection, and a prompt response to paracetamol have been proposed as criteria to recognize GM-CSF-induced iatrogenic fever [ ], but this concept is disputed [ ].

Cardiovascular

Mild local phlebitis sometimes occurs at intravenous sites of administration of GM-CSF. Central venous catheter site thrombosis, inferior vena cava thrombosis, and possible pulmonary embolism have sometimes been observed [ , ]. Although chemotherapy for breast cancer is associated with a higher risk of developing vascular thrombosis, iliac artery thrombosis was attributed to GM-CSF in two patients [ ].

Raynaud’s phenomenon has been reported, but confounding factors including the use of high-dose antineoplastic drugs are possible [ ].

A rapidly reversible first-dose syndrome (dyspnea, hypoxia, tachycardia, and hypotension) can occur within the first hour after the first continuous infusion in 15–30% of patients [ ]. A dose-limiting vascular leak syndrome was consistently described in patients receiving GM-CSF 30 micrograms/kg/day or more, but lower doses were also reported to induce a clinically relevant capillary leak syndrome [ , ]. Continuation of GM-CSF treatment at the same dose or lower and careful management was possible in some patients. Endothelial cell damage with an increase in the transcapillary escape rate of albumin and the possible role of IL-1 and TNF production by GM-CSF-activated monocytes were suggested as possible mechanisms. This was consistent with the observation of marked hypoalbuminemia in some instances associated with edema and ascites after GM-CSF in four of nine patients treated for myelodysplastic syndrome or aplastic anemia [ ].

Respiratory

It has been suggested that, as in the case of G-CSF, GM-CSF can increase the pulmonary toxicity of bleomycin and facilitate the development of the adult respiratory distress syndrome (ARDS), but evidence is sparse [ ].

Acute febrile interstitial pneumonitis occurred within less than 48 hours after the second to fourth cycles of chemotherapy (doxorubicin, cyclophosphamide, bleomycin, methotrexate, plus methylprednisolone) in five patients with non-Hodgkin’s lymphoma who were receiving prophylactic G-CSF (n = 3) or GM-CSF (n = 2) [ ]. Lymphocytic alveolitis was confirmed in four of these patients and all three patients tested had an increased number of CD8 + T cells. Even though all the patients received high-dose methylprednisolone, two died as a result of diffuse and extensive interstitial pulmonary fibrosis, demonstrated at postmortem. Although both G-CSF and GM-CSF can cause acute pneumonitis in patients with cancers, it is still unknown to what extent hemopoietic growth factors are involved in this complication.

In one patient, interstitial pulmonary edema with pulmonary failure was supposedly a first-dose reaction [ ]. Reversible eosinophilic pneumonia has also been reported [ ].

One patient had acute bronchospasm after a subcutaneous injection of GM-CSF around a lower limb ulcer [ ].

Nervous system

Very few neurological adverse reactions have been associated with GM-CSF.

• Mania occurred in a 41-year-old woman taking GM-CSF who had previously tolerated G-CSF [ ].

• A 49-year-old woman with chronic hepatitis C received filgrastim (G-CSF) for interferon-alfa-induced leukopenia [ ]. Filgrastim was withdrawn after 3 months, because of leg cramps and back pain. She later received sargramostim (GM-CSF) 500 micrograms twice weekly and she noticed gait unsteadiness and headaches within 2 weeks. During the next 3 months, she developed progressive confusion, forgetfulness, and lethargy, and both interferon alfa and sargramostim were withdrawn. She rapidly deteriorated and died from central hypoventilation 6 days later. Autopsy showed atypical, perivascular, lymphoid infiltrates in the white matter, basal ganglia, hypothalamus, brain stem, cerebellum, and spinal cord. Serum hepatitis C virus DNA sequences were not detected.

This case of fulminant perivascular lymphocytic proliferation suggests that some of the effects of GM-CSF on white blood cell proliferation can sometimes produce unexpected adverse effects.

Endocrine

Three patients with positive thyroid antibodies before GM-CSF treatment developed hypothyroidism or biphasic thyroiditis [ , ], whereas no similar thyroid dysfunction has been observed in patients without pre-existing thyroid antibodies [ ]. Based on these reports, GM-CSF has been thought to exacerbate underlying autoimmune thyroiditis.

Metabolism

Serum cholesterol concentrations have reportedly fallen in patients given GM-CSF [ ].

Electrolyte balance

Severe symptomatic hypokalemia was thought to have resulted from increased intracellular potassium uptake linked to massive leukocytosis after GM-CSF [ ].

Hematologic

Acute exacerbation of autoimmune thrombocytopenia [ ] or hemolytic anemia has been linked to macrophage activation [ ], and it has been suggested that patients with previous autoimmune blood disorders are at increased risk of hematological toxicity from GM-CSF.

A transient, moderate, and reversible rise in leukocyte alkaline phosphatase, lactate dehydrogenase (LDH) and serum uric acid concentrations is usually observed in cancer patients receiving supportive treatment with GM-CSF or G-CSF. Serum LDH increased from 37 to 85% and there was a linear relation between increased leukocyte production and the rise in serum LDH [ ]. Increases in serum LDH activity should therefore not be interpreted as indicative of disease progression, unless LDH activity remains high after growth factor withdrawal.