Clinical Toxicity of Cytokines Used As Haemopoietic Growth Factors

Abstract

A number of cytokines are used as haemopoietic growth factors and this review focuses on toxicities associated with granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-3, IL-4, IL-6 and macrophage colony-stimulating factor (M-CSF). Both GM-CSF and G-CSF, currently approved for clinical use, are generally well tolerated by the majority of patients during short term administration. Constitutional symptoms and bone pain are the most frequently reported adverse effects, but they are rarely treatment-limiting. Reactivation of rheumatoid symptoms, and exacerbation of autoimmune thyroiditis or autoimmune haematological disorders have sometimes been described. Severe cardiovascular complications include the possibility for arterial thromboses and the vascular leak syndrome, which is more specifically observed with GM-CSF. Reports of several cases and small series of patients have suggested that growth factors might increase the pulmonary toxicity of chemotherapy, a possibility that remains debated and requires further attention. Generalised or local cutaneous reactions are frequently noted with GM-CSF. Leukocytoclastic vasculitis was observed with both growth factors, while neutrophilic dermatoses have been mostly described with G-CSF. Exacerbation of psoriasis and isolated anaphylactic reactions have appeared with GM-CSF and G-CSF. The hepatotoxic potential of the growth factors is not clearly established, but the occurrence of coagulation abnormalities has recently been reported. Renal and biological disturbances are usually transient. Long term treatment with GM-CSF and G-CSF also seems to be well tolerated, but the possible occurrence of several adverse events, i.e. bone disorders, leukaemia, unmasking or acceleration of underlying disease, require further investigation in patients receiving prolonged treatment, as in myelodysplasia. Finally, antibodies against growth factors have been reported only with GM-CSF. Other cytokines are still under investigation. Flu-like and constitutional symptoms, sometimes dose-limiting, have been reported with IL-1, IL-3, IL-4 and IL-6, while M-CSF was occasionally associated with such adverse effects. More specific adverse events, also frequently considered as dose-limiting toxicities, include hypotension with IL-1, severe headache or skin rash with IL-3, and nasal congestion and gastroduodenal lesions with IL-4. Severe capillary leak syndrome has been reported only with IL-4. M-CSF toxicity is minimal and limited to reversible but sometimes dose-limiting thrombocytopenia and ophthalmological symptoms with the recombinant product. Again, the safety of long term administration of these cytokines has not yet been determined, and IL-3-induced disease progression in myelodysplastic patients has been suggested.

Analysis of rhG-CSF-effects on platelets by in vitro bleeding test and transcranial Doppler ultrasound examination

“…As we and others have found evidence for an activation of platelets and coagulation factors in patients receiving rhG-CSF, we assessed those parameters in normal donors given rhG-CSF. [9][10][11][12][13][14] In fact, a significant reduction of the closure time in the in vitro bleeding test with rhG-CSF was found, together with increased levels of fibrinogen and factor VIII and reduced activity of protein C and protein S. Although these changes are quite small it seems likely that these changes may lead to a hypercoagulable state especially in donors with other risk factors for thromboembolism. However, these changes did not lead to any evidence of subclinical (or clinical) arterial microembolism as measured by the TCD.…”

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

“…Upon extensive evaluation, we found greater neuroprotective and immune modulating abilities using LBT-3627. Moreover, its use may not be associated with untoward adverse events [23]. Thus, we chose to further assess the neurotherapeutic capacities of LBT-3627 in a preclinically relevant model using bioimaging techniques.…”

Cytokines Induced Skin Adverse Reactions

“…GM-CSF has also been shown to be an important factor in the recruitment and activation of Langerhans' cells in the skin. However, the exact mechanism of cutaneous reaction to GM-CSF remains speculative and may also involve the release of other cytokines or inflammatory mediators [72].…”