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Synopsis: Interleukin-3 is an early- and late-acting haemopoietic growth factor which promotes the proliferation and differentiation of multilineage and single lineage committed progenitor cells. It also has modulatory effects on mature cells, including basophils, monocytes and eosinophils. Interleukin-3 stimulates the proliferation of bone marrow and peripheral blood progenitor cells and increases bone marrow cellularity, causing a shift of haemopoiesis to the left, with a subsequent increase in the proportion of immature haemopoietic cells and in numbers of megakaryocytes and eosinophils. Interleukin-3 also potentiates granulocyte-macrophage colony-stimulating factor- (GM-CSF) and granulocyte colony-stimulating factor- (G-CSF) mediated mobilisation of peripheral blood progenitor cells from the bone marrow to the blood. Pharmacological Properties: Interleukin-3 (multipotential colony-stimulating factor) is a haemopoietic growth factor, secreted predominantly by activated T-helper lymphocytes. It stimulates the proliferation of early haemopoietic progenitor cells in the bone marrow, including colony-forming unit (CFU)-granulocyte-erythroid-macrophage-megakaryocyte (CFU-GEMM), CFU-granulocyte-macrophage (CFU-GM), burst-forming unit-erythroid (BFU-E), CFU-eosinophil (CFU-Eo), CFU-megakaryocyte (CFU-Meg), and CFU-basophil (Bas) cells. It also stimulates the proliferation of peripheral blood progenitor cells in vitro. Clinical Potential: Recombinant human interleukin-3 (referred to as interleukin-3) has shown clinical efficacy in reducing haematological toxicity following standard- and high-dose chemotherapy treatment regimens in small phase I/II clinical trials reported to date. A daily dosage of 5 to 10 μg/kg, administered either subcutaneously or by continuous intravenous infusion, caused a significant increase in neutrophil and platelet counts after chemotherapy and reduced the duration of neutropenia and thrombocytopenia compared to that observed in control chemotherapy cycles in which interleukin-3 was not given. A reduction in the need to postpone further chemotherapy due to prolonged haematological toxicity was observed with interleukin-3 treatment, and the number of patients requiring platelet transfusions was also reduced. Sequential administration of interleukin-3 followed by rGM-CSF or rG-CSF may further reduce myelosuppression. Interleukin-3 also enhanced platelet and neutrophil recovery following autologous bone marrow transplantation, and in patients with bone marrow failure. Tolerability: There are few tolerability data available for interleukin-3. While adverse events have been reported frequently, they have been generally tolerable at dosages ≤ 10 μg/kg/day. Influenza-like symptoms (myalgia, arthralgia, fatigue), headache, and low grade fever have occurred most frequently. Severe headache occurring at dosages > 10 μg/kg/day was often a dose-limiting event. Other adverse events have included nausea, vomiting, skin rash, mild local erythema at the injection site, flushing, oedema, facial erythema, diarrhoea, rigors, malaise and dyspnoea; these were generally mild and resolved at the end of treatment. The tolerability profile of interleukin-3 appeared similar when the drug was administered prior to or following chemotherapy, and during combined sequential treatment with rGM-CSF or rG-CSF. Dosage and Administration: In clinical trials, interleukin-3 has been administered once daily by subcutaneous injection or by continuous intravenous infusion. For the treatment of myelosuppression following chemotherapy, ≥ 5 μg/kg/day for 7 to 14 days appears to be an effective dosage, and 10 μg/kg/day has shown efficacy in patients following autologous bone marrow transplantation. A lower dosage of interleukin-3 2.5 μg/kg/day for 10 days followed by rGM-CSF therapy has also shown efficacy in the bone marrow transplantation setting. Interleukin-3 30 to 500 μg/m2/day for 15 days induced a haematological response in patients with bone marrow failure, and 250 to 500 μg/m2/day for 14 to 15 days induced a response in patients with myelodysplastic syndromes or aplastic anaemia. |
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