In myelodysplastic syndromes (MDS), anemia responds to recombinant human erythropoietin (rHuEPO) alone and in combination with recombinant human granulocyte-colony-stimulating factor (rHuG-CSF) in 10% to 20% and in 35% to 40% of patients, respectively. We randomly divided 60 patients with low-grade anemic MDS and serum EPO levels lower than 500 IU/L (500 mU/mL) into 2 groups: rHuEPO ؉ rHuG-CSF (arm A) and supportive care (arm B). After 12 weeks, those who had erythroid responses were given rHuEPO alone for 40 additional weeks.They were also given rHuG-CSF if they had relapses. A response was considered major if the hemoglobin (Hb) level was 115 g/L (11.5 g/dL) or higher and minor Hb increase was 15 g/L (1.5 g/dL) or more or if it remained stable without transfusion. Ten of 24 patients responded in arm A, and 0 of 26 responded in arm B (P ‫؍‬ .01). Eight patients in arm A continued rHuEPO therapy alone, and 6 had relapses. Responses were always restored when rHuG-CSF was reintroduced. IntroductionMyelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, peripheral cytopenia, and increased risk for acute myelogenous leukemia (AML). Approximately two thirds of patients with MDS have anemia at diagnosis, and it develops in nearly all the rest as the disease progresses. Many MDS patients require frequent transfusions, leading to secondary hemochromatosis and risk for viral infections. In low-risk MDS, anemia is often the major clinical problem. Anemia significantly affects quality of life and causes significant morbidity in older patients. Cardiovascular diseases are often aggravated. Treatment of anemia with recombinant human erythropoietin (rHuEPO) alone is effective only in a small percentage of MDS patients. A meta-analysis of 205 patients with MDS showed that 16% responded to rHuEPO alone. 1 Patients who responded to treatment had no or limited transfusion requirements. Granulocytecolony-stimulating factor (G-CSF) and granulocyte macrophagecolony-stimulating factor (GM-CSF) increase neutrophil counts, do not increase the risk for leukemia, and have no effect on survival. [2][3][4] When combined with myeloid cytokines, rHuEPO can have synergistic effects on erythropoiesis in vitro. 5,6 Some clinical studies have shown that the combination of rHuG-CSF and rHuEPO has a better response rate (40%-50%) than rHuEPO alone. [7][8][9][10][11][12] However, none of these clinical trials were randomized, and cost analyses and quality-of-life evaluations are lacking. In one randomized study, the response rate was similar with GM-CSF plus EPO and with placebo 4 In these studies, only a small proportion of subjects with baseline serum EPO concentrations exceeding 500 IU/L (500 mU/mL) responded to treatment. 9 Therefore, we designed a multicenter randomized trial comparing treatment with rHuEPO plus rHuG-CSF and supportive care in patients with MDS who had serum EPO concentrations lower than or equal to 500 IU/L (500 mU/mL) to determine the effect of this Patients, materials...

Summary An open‐label, phase II non‐randomised trial was conducted with darbepoetin (DAR), an erythropoiesis‐stimulating factor with prolonged half‐life, at a weekly dose of 300 μg subcutaneously in 62 anaemic patients with myelodysplastic syndrome (MDS) with an endogenous erythropoietin (EPO) level <500 mU/ml. Most of the patients were classified as low or intermediate 1 according to the International Prognostic Scoring System. After 12 weeks, 44 (71%) patients had an erythroid response (34 major and 10 minor), including eight of 13 patients who were previous non‐responders to conventional EPO. Two additional responses (one minor and one major) occurred, in 10 non‐responders, after the addition of granulocyte colony‐stimulating factor (G‐CSF). Thirty‐six of the 46 total responders (31/35 major and 5/11 minor) continued to respond on maintenance DAR after a median of 40 weeks (range 4–84). Median dose of DAR required to maintain response was 300 μg every 14 d. The only prognostic factors of favourable response were low endogenous EPO level and low or absent red blood cell transfusion requirement. Those results suggest that high‐dose DAR alone yields high erythroid response rates in anaemia of lower risk MDS, possibly equivalent to those obtained with conventional EPO + G‐CSF, although this will need to be confirmed in larger and randomised trials.

Nineteen of 36 red blood cell transfusion-dependent patients (53%) showed erythroid response, but only four became transfusionindependent. Among the 23 responders, the median duration of response was 260 d (range 30-650). Responses were sustained in all patients except one, and were observed between week 4 and week 8 in 85% of patients, at doses ranging from 200 to 400 mg. Only two patients responded at 600 mg/d and none at 800 mg/d. No clinical characteristics of responding versus nonresponding patients were identified. The erythroid response rate was identical in all cytogenetic subgroups, including 5q31.1 deletions. Pretreatment vascular endothelial growth factor levels were lower in responders compared with non-responders (P ¼ 0AE004). Microvessel density (MVD) increased and apoptosis decreased in four of six and in all six responders studied respectively whereas MVD and apoptosis were unchanged in three non-responders.