The use of haemopoietic growth factors in the treatment of myelodysplastic syndromes.

Based on the results of preclinical and in vitro studies demonstrating enhanced granulocytic proliferation and differentiation induced by granulocyte-monocyte and granulocyte-colony stimulating factors (GM-CSF and G-CSF), these recombinant human haemopoietic growth factors have been used to treat cytopenic patients with myelodysplastic syndromes (MDS). Laboratory investigations have shown responsiveness of enriched haemopoietic precursors in vitro to the proliferative and granulocytic differentiative stimuli of G-CSF, generally without increased clonal regeneration. To date, five short-term phase I/II clinical trials using GM-CSF have demonstrated that 38 of 45 treated patients had improvements in neutrophil counts, 14 had increased reticulocyte counts, with three of these patients having decreased red blood cell transfusion requirements, and eight had a transient increase in platelets. In 12 patients an increase in marrow and/or peripheral blood blasts was noted. Seven patients progressed to acute myeloid leukaemia (AML), particularly patients with greater than 15% marrow blasts. In a longer term study, five patients received GM-CSF for two to nine weeks, although only one maintained increased neutrophil counts, one developed antibodies to GM-CSF and one's condition evolved into AML. Eighteen patients have been treated for two months in phase I/II clinical trials with G-CSF, 16 of whom had normalization of neutrophil counts with improved marrow maturation, five had increased reticulocyte counts with three having decreased transfusion requirements, four had transient increases in blasts and no substantial changes in platelet counts were noted. Eleven patients have received maintenance therapy with G-CSF for 6-16 months and 10 had persistent increases in neutrophil counts with enhanced marrow myeloid maturation. Decreased infectious episodes were noted in these patients at times at neutrophil improvements. Four of the 18 patients have subsequently developed AML after 6-16 months. Both CSFs were well tolerated, although the incidence of fever, myalgias and bone pain was more prominent in patients receiving GM-CSF at higher doses. In vitro correlates with these in vivo results were demonstrated as laboratory studies showed that G-CSF had greater myeloid differentiative and less proliferative effects for MDS marrow than did GM-CSF. Marrow cytogenetic studies after treatment generally indicated persistence of the initial normal and/or abnormal clones. These studies have demonstrated that both G-CSF and GM-CSF improve neutrophil counts in a high proportion of patients with MDS and that chronic administration of G-CSF elicits persistent neutrophil responses and may decrease infections. Phase III controlled trials are required to determine whether the natural history of this disorder will be altered by use of colony stimulating factors.