Darbepoetin for the Treatment of Anemia of Myelodysplastic Syndromes: Efficacy and Improvements in Quality of Life.

Up to 40% of patients with myelodysplastic syndromes (MDS) respond to pharmacological doses of epoetin. Darbepoetin alfa (DPO) has a longer half-life and greater biological activity. Recent data suggest a 60% response rate in patients receiving DPO. We report preliminary results of a Phase II study in 41 patients with low and intermediate-1 risk MDS and Hb < 11 g/dL. The primary endpoint is to evaluate the efficacy of DPO for the treatment of anemia of MDS. Secondary endpoints are the evaluation of the safety of DPO and of the variations in Hb, the number of monthly transfusions and quality of life (QoL) in treated patients. Patients receive DPO 150 mcg s.c weekly to be doubled in non-responders. Treatment target is Hb =12.0 g/dL. Treatment is to be temporarily interrupted for Hb >12 g/dL and re-initiated when Hb <11.0 g/dL at the same dose administered every 3 weeks. Flow cytometry on bone marrow is performed at baseline and after 24 weeks. Single staining with CD34 PE and Annexin V FITC is followed by double staining (FITC/PE) to observe the CD34+/Annexin V+ events. QoL changes are measured using the QOL-E questionnaire.

Results: The 33 patients who received at least 8 weeks of DPO included 19M/14F of median age 74 (range 49–84) years. Morphology was: 31 RA, 1 RARS and 1 CMML. IPSS score was low in 75%, and Int-1 in 25%. Serum epoetin levels were < 200 mU/ml. Meduab Hb level at baseline was 9.5 (range 7.0–10.8) g/dL. Six patients had previously received epoetin alfa or beta without success. Thirteen patients (39%) were transfusion-dependent. At the initial dosage, 6 transfusion-free patients (30%) responded at 4 weeks (3 reached the endpoint of Hb=12.0 g/dL). Total number of cases responding at 8 weeks were 17, including 7 (53%) transfusion-dependent patients. Ten responses were minor (30%) and 7 major (21%). After dosage doubling, there were 56% responders of the 16 patients that have completed the study at 24 weeks: 7 of 12 transfusion-free patients (2 at a dosage of 150 mcg/wk, 2 at 300 mcg/wk and 3 at 300 mcg every 3 weeks) and 2 of 4 transfusion-dependent patients at a dosage of 300 mcg/wk. Five patients reached Hb > 12g/dl during the study period. Finally, 3 of the 6 patients previously unresponsive to epoetin responded to DPO. At univariate ANOVA analysis, response to treatment was associated with increases in QOL-E treatment outcome index (p=0.033), specific (p=0.009), fatigue (p= 0.013), physical (p=0.001), functional (p=0.042), social (0.001), general (p=0.001), and total (p=0.004) scores. There were significant reductions in CD34+ cells (p=0.025) and apoptotic cells (p=0.008) and these were associated with treatment response (p=0.045 and p=0.065, respectively). No adverse events were reported.

Conclusions: DPO is safe and well-tolerated in patients with MDS. A reduction in apoptotic cells is observed during treatment. Therapeutic response is associated with improvements in QoL. Our study suggests that DPO is effective for the treatment of anemia of MDS.