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This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level nonneutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients.