Myelodysplastic syndromes: a guide to treatment with epoetin and colony-stimulating factors

Myelodysplastic syndromes (MDS) are clonal disorders of haemopoietic stem cells which are characterised by peripheral cytopenia and, usually, by an increased bone marrow cellularity. Transfusions of red blood cells and platelets comprise the basis of supportive care for anaemia and thrombocytopenia. In patients who progress to acute myeloid leukaemia, cytotoxic chemotherapy is used. In MDS, haemopoietic growth factors can enhance: proliferation and differentiation of normal and myelodysplastic haemopoietic progenitor cells, and prevent premature apoptosisacceleration of haemopoietic recovery after intensive chemotherapy and amelioration of mature cell function; and sensitisation of malignant cells for the cytotoxic action of chemotherapeutic agents. There is widespread clinical experience with the use of epoetin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). A meta-analysis of 17 trials with EPO showed a stimulation of erythropoiesis, resulting in a discontinuation of the need for transfusions or an increase in haemoglobin levels of at least 15 g/L in 16% of 205 patients. Favourable factors for the response were an initial absence of a need for transfusion and a serum EPO level <200 U/L. In clinical phase I/II studies of GM-CSF administration, a dose-dependent increase in the absolute neutrophil count was seen in >80% of patients, as well as a decrease in the infection rate. The effect on survival could not be assessed. Lower platelet counts, with a risk of bleeding, bone pain, local erythema at the subcutaneous injection site and phlebitis during intravenous infusion, were observed. The combined administration of GM-CSF and EPO to a small number of patients resulted in an increase in haemoglobin levels or a decrease in the need for transfusion, with an overall response rate of 46%, but is not a proven treatment. The use of G-CSF increased the absolute neutrophil count in about 90% of patients with MDS, and was accompanied by an improvement of neutrophil function, which is frequently impaired in these patients. However, contradictory data exist on the influence of prophylactic G-CSF treatment on the infection rate. Bone pain and thrombocytopenia were the most important adverse effects of G-CSF treatment. Synergism of G-CSF and EPO has not yet been proven in randomised phase III trials, although selected patients showing no response to EPO alone may achieve normal haemoglobin levels after receiving additional G-CSF. Treatment in vivo with EPO, GM-CSF or G-CSF has not been shown to change the percentage of bone marrow cells carrying cytogenetic aberrations. However, individual patients have shown a reversal from a monoclonal to a polyclonal pattern with GM-CSF therapy.