Darbepoetin Efficacy in Myelodysplastic Syndrome.
Authors: Oliva Esther N. , Ronco Francesca , Danova Marco , Rovati Bianca , Dimitrov Borislav D. , Vincelli Iolanda , Alati Caterina , Nobile Francesco 
Published: October 2019

Abstract
Recombinant human epoetin (rHu-EPO) is an effective treatment of anemia in myelodysplastic syndrome (MDS) in up to 40% of patients, mainly in low-risk MDS not yet requiring transfusions. Darbepoetin alpha is an rHuEPO analogue with an approximately 3-fold longer half-life than epoetin alfa, which leads to greater biological activity. We evaluated its effects on anemia in a pilot group of low and intermediate-1 risk MDS patients. The primary objective was to evaluate the efficacy of darbepoetin in terms of response/no response. Secondary objectives were to evaluate: 1) drug safety; 2) variations of Hb and the number of monthly transfusions; 3) changes in quality of life (QoL) of patients; and 4) changes in apoptosis of CD34+ cells. Twelve patients with Hb<11 g/dL were included in the 6-month study to receive an initial weekly dose of darbepoetin 150 mcg s.c. to be increased to 300 mcg in non-responders. Response criteria were defined as follows: complete response if an Hb increase of at least 2 g/dL or Hb = 12.0 g/dL, and no transfusions in transfusion-dependent patients; partial response if an Hb increase of 1 to <2 g/dL, or a 50% or greater (but not complete) reduction of transfusion requirement; no response if variations of Hb levels and of transfusion requirement were not included in the definitions of partial and complete response. At baseline and at 3 months, flow cytometric assays gating the CD34+ cells to observe the CD34+/Annexin V + events were performed on bone marrow aspirates. QOL measures were obtained by the QOL-E© questionnaire. Mean age was 76 (range 63–91) years. Serum erythropoetin levels were median 91 (range 24 – 421) IU/mL. Seven patients required 1 to 4 monthly transfusions and 5 patients were transfusion-free with baseline Hb values ranging from 8.0 to 10.9 g/dL. At the 150 mcg dose, 2 of the 7 transfusion-dependent patients became transfusion-free after 2 months, reaching stable Hb levels of 10.3 and 10.8 g/L, respectively, and 2 patients obtained a partial response. Of these latter 2 patients, one lost the response and one became transfusion-free after 2 months at the same dose. After dosage increase, the remaining 3 non-responders did not obtain a response up to 6 months follow-up. Of the transfusion-free patients, 3 were complete responders after 1 month at a dosage of 150 mcg, 2 of whom had to stop therapy for more than 2 months for Hb>13.0 g/dL (baseline Hb 10.3 and 10.9 g/dL, respectively); 1 became a complete responder after dosage increase. Overall 7 out of 12 patients were complete responders to darbepoetin treatment. At flow cytometric analysis, there was a trend in a reduction in apoptotic cells (p=0.064) associated with treatment response. At univariate ANOVA analysis, response to treatment was associated with increases in QOL-E© functional (p=0.036) and social (p=0.013) scores. Two responsive patients died during study period for unrelated adverse events. No side effects were observed. In conclusion, darbepoetin is safe in patients with MDS. A reduction in apoptotic cells is observed during treatment. Therapeutic response is associated with improvements in QOL. This pilot study suggests that darbepoetin is effective for the treatment of moderate-severe anemia of MDS, though a larger trial is required to evaluate predictive factors for response and QOL scores.