Treatment of the anemia of aplastic anemia patients with recombinant human erythropoietin in combination with granulocyte colony ‐ stimulating factor: a multicenter randomized controlled study

Abstract

A multicenter randomized controlled study was undertaken in order to determine whether epoetin beta (EPO) ameliorates the anemia in aplastic anemia (AA) patients treated with granulocyte colony‐stimulating factor (G–CSF). Enrolled patients were randomized into 3 groups: group C receiving G–CSF alone as the control; group L receiving G–CSF and 200 IU/kg of EPO; group H receiving G–CSF and 400 IU/kg of EPO. Throughout the study, the dose and the administration interval of G–CSF were adjusted to maintain neutrophil counts between 1000 and 5000 μl. EPO was administered subcutaneously for 12 wk as the first step in treatment and when favorable effects were observed over this period, treatment was continued for another 12 wk as the second step in treatment. Significant erythroid responses were defined as increases in untransfused hemoglobin values >1.0 g/dl or >50% decreases in RBC transfusion requirements over the treatment period. Of 131 patients enrolled, 88 patients allocated to groups L and H were evaluated for toxicity to EPO and 110 were evaluated for erythroid responses. Four of the 31 patients (12.9%) in group C, 6 of the 41 patients (14.6%) of group L, and 14 of the 38 patients (36.8%) of group H showed erythroid responses in the first step in treatment. The erythroid responses of group H were significantly higher than those of the other 2 groups (p<0.05). The significant effects of EPO were due to erythroid responses in non‐severe AA. Responding patients were significantly different from non‐responders with regard to disease severity, hemoglobin concentration, reticulocyte count, serum endogenous erythropoietin levels and serum transferrin receptors; non‐severe AA patients were more likely to respond to EPO, and responding patients had lower serum EPO and higher hemoglobin concentration, reticulocyte count and serum transferrin receptors than non‐responders. The response rate increased in the second step in treatment, suggesting that long‐term treatment improved the efficacy of EPO. No serious side‐effects were observed. From these results, we conclude that EPO given in combination with G–CSF is a safe and effective alternative for the treatment of anemia of a subset of AA patients.

Erythrocytic Mobilization Enhanced by the Granulocyte Colony-Stimulating Factor Is Associated with Reduced Anthrax-Lethal-Toxin-Induced Mortality in Mice

“…Consequently, the effects of G-CSF on other cell types (e.g., macrophage, lymphocyte, endothelial, dendritic cells, cardiomyocytes, and smooth muscle) may not be completely excluded from the rescue mechanism of G-CSF. Although the mechanism is unclear, combination therapy using G-CSF and EPO has been used to treat myelodysplastic anemia in clinical settings [32]–[36], [48]. This suggests that the medical community has empirically recognized the RBC-enhancing effect of the combination treatment using G-CSF and EPO.…”

“…Both G-CSF and EPO are U.S. FDA-approved drugs. Although the mechanism remains unclear, combined treatments using G-CSF and EPO were shown to ameliorate aplastic anemia in patients with myelodysplastic syndrome [32]–[36]. Given that EPO treatments are beneficial for LT-challenged mice [15], we hypothesized that combining G-CSF and EPO may be useful in treating anthrax.…”

Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis

“…Of them, 19 trials were excluded for various reasons 3,7,[10][11][12]14,15,18,19,[22][23][24][25][26][27][28][29][30][31] (Figure 1). Six trials performed between 1991-2007 and randomizing 414 patients fulfilled inclusion criteria.…”

Different effects of granulocyte colony-stimulating factor and erythropoietin on erythropoiesis

“…In conclusion, although G-CSF combined with EPO has been administered to treat anemia in patients with MDS, aplastic anemia, and HIV for many years [ 38 , 39 , 46 , 47 ], the mechanism through which G-CSF promotes erythropoiesis remains unclear. This study demonstrates that G-CSF promotes erythropoiesis independent of the secretion of EPO and soluble P-selectin.…”