Effects of prolonged treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor

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Abstract
In vitro marrow hemopoietic cultures were utilized to determine the possible efficacy of recombinant human granulocyte colony‐stimulating factor (G‐CSF) for treating the refractory cytopenias present in the myelodysplastic syndromes (MDS). Our studies showed responsiveness of enriched hemopoietic precursors in vitro to the proliferative and granulocytic differentiative stimuli of G‐CSF, generally without increased clonal self‐generation. These in vitro parameters correlated with in vivo hematologic responses in our Phase I and II clinical trials. In this study 18 patients were treated for two months with s.c. administration (0.1–3 m̈g/kg/day) of G‐CSF, escalating doses every two weeks. This study indicated normalization of neutrophil courses in 16 patients and reticulocyte responses with decreased red blood cell (RBC) transfusion requirements in three of 12 transfusion‐dependent patients. Marrow myeloid maturation improved in the responding patients. Extended treatment for additional six‐ to 16‐month periods has indicated persisting neutrophil responses. The relative risk of developing bacterial infections was significantly decreased in patients whose neutrophil level normalized (absolute neutrophil count > 1,500/mm3) during G‐CSF therapy, compared to such episodes in their pretreatment neutropenic period. This therapy was well‐tolerated, without serious toxicity being noted. In vitro neutrophil function (chemotaxis and phagocytosis) remained normal or improved in six of the eight tested patients. Transformation to acute myelogenous leukemia occurred in two patients with refractory anemia with excess blasts in transformation (RAEB‐T) during or within a month of the treatment period. Marrow cytogenetic studies indicate persistence of the initial normal and/or abnormal clones. These data demonstrate hematologic improvement and diminished risk of infections in a substantial proportion of MDS patients and support the need for Phase III controlled trials to determine whether the natural history of these disorders is altered by administration of G‐CSF.

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