A Phase II intra‐patient dose‐escalation trial of weight‐based darbepoetin alfa with or without granulocyte‐colony stimulating factor in myelodysplastic syndromes

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 non‐neutralizing 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. Am. J. Hematol, 2009. © 2008 Wiley‐Liss, Inc.