A Randomized Study to Determine the Optimal Dose of Darbepoetin Alfa in Patients with Low- or Intermediate-1 Risk Myelodysplastic Syndromes

[Background]

Erythropoiesis stimulating agents (ESAs) are used as standard treatment for anemia in patients with myelodysplastic syndromes (MDS) of low- or intermediate-1 (Int-1) risk according to the International Prognostic Scoring System (IPSS). However, no randomized study has been conducted to determine the optimal dose of ESAs. We conducted a randomized controlled trial of darbepoetin alfa (DA), a long-acting ESA, to find the optimal dose and evaluate efficacy and safety.

[Methods]

This multicenter randomized controlled trial was conducted in 41 sites in Japan and South Korea. Main inclusion criteria were red blood cell (RBC) transfusion-dependent, IPSS low/Int-1-risk MDS patients with hemoglobin (Hb) ≤ 9.0 g/dL and serum erythropoietin (EPO) ≤ 500 mIU/mL. Eligible patients were randomized to receive weekly subcutaneous doses of DA at a fixed dose of 60, 120 or 240 μg for 16 weeks (initial dose evaluation phase). DA was administered for up to 48 weeks, with dose adjustment allowed from week 17 onward. Dosing frequency was allowed either once every week (QW) or once every 2 weeks (Q2W), with the maximum single dose of 240 µg (extended treatment evaluation phase). The primary endpoint was modified IWG 2000 erythroid response defined as the proportion of patients who achieved an erythroid response [major erythroid response (MaR; RBC transfusion-free with an increase in Hb ≥ 1.0 g/dL above baseline) or a minor erythroid response (MiR; a ≥ 50% reduction in RBC transfusion as compared to baseline)] in the initial dose evaluation phase. Mortality and progression to AML were evaluated for one year. Changes in serum drug concentration and pharmacokinetic parameters were also evaluated.

[Results]

A total of 52 subjects were randomized. The subjects’ baseline demographics (mean±SD) included Hb of 7.9±0.9 g/dL, serum EPO concentration of 221.1±134.2 mIU/mL, and total amount of RBC transfusion given within 56 days prior to the first DA treatment of 1459±707.2 mL. Among 50 subjects evaluable for efficacy, the proportion of those who achieved an erythroid response during the initial dose evaluation phase in the 60, 120 and 240 μg group was: 64.7% (11/17 subjects) including 17.6% with MaR; 44.4% (8/18 subjects) including 16.7% with MaR; and 66.7% (10/15 subjects) including 33.3% with MaR, respectively. The proportion of subjects achieving erythroid response was similar across the three groups, but the highest proportion of MaR was noted in the 240 μg group. The mean baseline Hb was similar among the groups (7.7, 8.0, 8.0 g/dL in the 60, 120, 240 μg group, respectively). During the initial dose evaluation phase, the mean Hb level continued to rise over the first 2 weeks of DA treatment and remained between 8.6-9.1 g/dL thereafter in the 240 μg group, whereas the mean Hb was slightly lower in the 60 μg group (7.6-8.1 g/dL) and 120 μg group (8.1-8.4 g/dL). During the extended treatment evaluation phase (week 17-48), an increase in DA dose resulted in an improved response from "no response" to MiR and eventually to MaR in 1 subject in the 60 μg group, and from MiR to MaR in 2 subjects each in the 60 and 120 μg groups. There was no major difference among the groups with respect to time to erythroid response. No clinically significant safety concerns were identified. After 1 year of starting the treatment with DA, the survival rate and the proportion of subjects free from AML estimated by Kaplan-Meier method were 84.5% and 96.0%, respectively. The low baseline serum EPO concentration and low RBC transfusion needs were identified as strong predictors of efficacy.

[Conclusion]

These results demonstrated that treatment with DA is effective and safe in reducing or eliminating transfusion requirements in transfusion-dependent, IPSS low/Int-1-risk MDS patients. Given the highest proportion of subjects achieving MaR in the 240 μg group and the absence of dose-dependent adverse events, the optimal dose was determined to be 240 μg QW. No adverse effects were observed in terms of mortality and proportion of progression to AML.