A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes

Abstract

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

Figure 1

Study design.

Figure 2

Patient disposition. ^aPrimary analysis sets. ^bSerum EPO⩽500 mU/ml locally but >500 mU/ml centrally, so patient was withdrawn. ^cFor adverse event (n=2), protocol (n=2), administrative (n=1) and other (n=1). ^dFor adverse event (n=2), consent withdrawn (n=1) and protocol (n=1). ^eColon adenocarcinoma (T1aN0M0) treated with polypectomy. ^fPer dosing algorithm (n=9), progression to AML (n=2, both prior darbepoetin alfa). ^gPer investigator (n=2), lack of response (n=2) and unknown (n=3).

Figure 3

Efficacy of darbepoetin alfa. (a) Transfusions assessed from week 5 onward to allow for the effects of darbepoetin alfa to be observed. (b) Erythroid response rates; reasons unevaluable for HI-E in the double-blind period (n=37) included transfusion in prior 28 days (n=33), no hemoglobin measurement within 14 days of first dose (n=3), did not receive darbepoetin alfa (n=1).