High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM

Abstract

Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500 IU/L received DAR 500 μg once every 2 weeks for 12 weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56 % at 12 and 24 weeks, respectively. Addition of G-CSF rescued 22 % of non-responders. In 48 % of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12 weeks, and its most discriminant cutoff value was 100 IU/L. QoL and VO2max showed improvement over time in responders, compared with non-responders. With a median follow-up of 52 months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70 %, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2 weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents.

Current therapy of myelodysplastic syndromes

“…The doses of ESAs used for MDS-related anemia, which is associated with relative intrinsic resistance to erythropoietin, are higher than those used for renal disease-related anemia which is usually associated with normal BM responsiveness [37–39]. According to the National Comprehensive Cancer Network (NCCN) management guidelines for MDS, the recommended starting doses are 40,000 to 60,000 units given 1 to 3 times a week for the recombinant human erythropoietin alpha (rEPO) and 150–300 mcg/week for the longer acting form darbepoetin, with both agents administered subcutaneously [39].…”

Resuscitating a Dying Marrow: the Role of Hematopoietic Growth Factors

“…The earlier Nordic studies [10,11] reported low response rates to ESAs in RARS patients when compared to RA (despite limited or low transfusion needs and serum EPO <200 U/L), but this was not observed in two large subsequent GFM patient series [18,22]. MDS patients with the del(5q) abnormality are poor responders to ESAs (both epoetin and darbepoetin) used alone or in combination with G-CSF, with responses lasting for a shorter duration compared to those without del(5q) abnormality, probably explained by higher serum EPO levels (>500 U/L) in the former [23].…”

“…Quality-of-life (QOL) benefits with ESAs have been inconsistent. While the Nordic NMDSG03A [17] and GFM study [18] reported improved exercise capacity in EPO responders compared to non-responders, no significant improvement in QOL was observed in the Eastern Cooperative Oncology Group (ECOG) E9116 trial [19] and a French randomized trial [20] in patients treated with growth factors compared to those receiving supportive care. The differences in results could be explained by the use of different QOL scales in these studies, low QOL questionnaire response rates, and the possibility that increase in hemoglobin levels observed was not sufficient enough to impact the QOL considering the relatively small sample size of these studies.…”

Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings

“…Erythropoiesis stimulating agents (ESA) improve quality of life and transfusion dependency in as many as half of lower risk MDS patients. [52, 53] TPO mimetics may decrease platelet transfusion dependency as well as the risk of bleeding. [54] HMAs typically induce cytopenias, particularly in early cycles of treatment, resulting in dose restrictions, treatment delays or discontinuation.…”