Treatment of Anemia with Darbepoetin Alfa in Patients with Low and Intermediate-1 Risk Myelodysplastic Syndromes. Results from the ARAMYS Study

Anemia is the main symptom in patients (pts) with myelodysplastic syndromes (MDS) which usually makes subjects with this pathology dependent on transfusions, resulting in a very limited quality of life. Darbepoetin alfa (DA) is a highly glycosylated erythropoiesis-stimulating agent (ESA) with a pharmacokinetic profile that includes a longer serum half-life and allows it to be administered less frequently than rHuEPO, thereby increasing patient convenience. This single-arm, open-label, multi-center, phase 2 study evaluated the efficacy and safety of DA in pts with low risk MDS. Eligible pts had low or intermediate-1 risk MDS [International Prognostic Scoring System (IPSS) criteria], anemia [Hemoglobin (Hb) 10 g/dL], FAB (French–American–British) classification of refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or refractory anemia with excess blasts (RAEB) (with marrow blasts ≤ 10%), serum erythropoietin levels < 500 IU/L and transfusion requirements < 2 packed red blood cells cells/month over the preceding 2 months. Pts were evaluated for erythroid response after 8 weeks (wks) and 16 wks of treatment. Major erythroid response (MaR) was defined as an increase in Hb values ³ 2 g/dl on baseline values and/or suppression of transfusion requirements. A minor erythroid response (MiR) was defined as a > 1 g/dL increase in Hb values but < 2 g/dl on baseline values or a reduction in transfusion requirements of at least 50%. DA treatment was initiated at a fixed dose of 300 mcg weekly (QW). For pts achieving a MaR at wk 8, DA could be administered at the same dose every two wks (Q2W). For pts who did not achieve a MaR by 8 weeks, filgrastim 300 mcg QW was added for an additional 8 wks. If at any time during the treatment period Hb values of > 12g/dL were obtained, DA was discontinued until Hb falls to values of < 11 g/dL. At this time, DA treatment was reintroduced with half of the previous dose (150 mcg). A number of 44 evaluable pts were included in the study. Median age 75,8 years (range 41,3-92,4), 53,5% male and 90,7% with ECOG Performance Status (0-1). FAB diagnoses were 30,2% RA, 62,8% RARS and 7% RAEB; divided into IPSS low (76,7%) and intermediate-1 (23,3%). Baseline mean (SD) Hb was 9,2 g/dL (0.8) and serum erythropoietin 122,1 IU/L (124,7).72,7% of the pts were transfusion independent. An erythroid response was achieved by 31 of 44 pts (70,5%) at wk 8 (43,2% MaR, 27,3% MiR, 29,5% no response) and by 30 of 43 pts (69,8%) at week 16 (51,2% MaR, 18,6% MiR, 30,2% no response). A total of 19 pts received filgrastim between wk 8 and 16. Erythroid response at wks 8 and 16 depending on the transfusion dependence were 68,8% (59,1% MaR and 40,9% MiR) and 71.0% (68,2% MaR and 31,8% MiR) in the transfusion independent group and 75.0% (66,7% MaR and 33,7% MiR) and 66,70% (87,5% MaR and 12,5% MiR) in the transfusion dependent group. Baseline serum erythropoietin levels were the only predictive factor of response found in the study population. DA was generally well tolerated. Three mild adverse events were considered related to DA (iron deficiency, flu syndrome and headache), one severe (iron deficiency) and one fatal (thromboembolic event). Results from this study indicate that a fixed dose of 300 mcg DA QW (+/- filgrastim) is an effective and well-tolerated treatment of anemic patients with low- and intermediate-1 risk MDS.