A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes

Abstract

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5–24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement–erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

Effects of erythropoiesis-stimulating agents on overall survival of International Prognostic Scoring System Low/Intermediate-1 risk, transfusion-independent myelodysplastic syndrome patients: a cohort study

“…Effects of erythropoiesis-stimulating agents on overall survival of IPSS low/INT-1 risk, transfusion independent myelodysplastic syndrome patients: a cohort study Clinical guidelines recommend the use of erythropoietin stimulating agents (ESAs) in lower risk anaemic myelodisplastic syndrome (MDS) patients [1][2][3][4] and two registration trials for ESAs have just been completed 5,6 . We conducted a retrospective study in MDS patients selected by the characteristics predictive of ESA response 7 , treated in common practice and enrolled in the Italian Network of regional MDS registries (ClinicalTrials.gov Identifier: NCT02808858)…”

Clinical effectiveness and safety of erythropoietin‐stimulating agents for the treatment of low‐ and intermediate‐1−risk myelodysplastic syndrome: a systematic literature review

“…Platzbecker et al () reported that darbepoetin alfa 500 μg every 3 weeks was significantly superior to placebo with regard to the proportion of patients achieving International Working Group (IWG) erythroid response at 24 weeks (14·7% vs. 0% for placebo [ P = 0·016] for IWG 2006 criteria [Tefferi et al , ] and 19% vs. 3% for placebo [ P ‐value not reported] for IWG 2000 criteria [Cheson et al , ]); the minor response rate was also higher for darbepoetin alfa (39% vs. 6% for placebo; P ‐value not reported) (Platzbecker et al , ). After 48‐week open‐label follow‐up treatment with darbepoetin alfa, those who continued to receive treatment exhibited a response rate of 26·4%, and those who had switched from initial placebo treatment had a response rate of 28·9% (IWG 2006 criteria) (Platzbecker et al , ). The response rate for darbepoetin alfa 60–240 μg/week was reportedly higher (58%; IWG 2000 criteria) in a dose‐finding study (no placebo group) after 16 weeks of treatment (Jang et al , ), which had a shorter duration of follow‐up (median, 316 days) than the study reported by Platzbecker et al ().…”

“…After 48‐week open‐label follow‐up treatment with darbepoetin alfa, those who continued to receive treatment exhibited a response rate of 26·4%, and those who had switched from initial placebo treatment had a response rate of 28·9% (IWG 2006 criteria) (Platzbecker et al , ). The response rate for darbepoetin alfa 60–240 μg/week was reportedly higher (58%; IWG 2000 criteria) in a dose‐finding study (no placebo group) after 16 weeks of treatment (Jang et al , ), which had a shorter duration of follow‐up (median, 316 days) than the study reported by Platzbecker et al ().…”

“…Of the 2 publications reporting on RCTs of darbepoetin alfa, only one reported duration of response (mean [SE], 235 [21] days) (Platzbecker et al , ). EPOANE3021 was the only study of the 4 RCTs reporting on short‐acting ESAs that reported duration of response; of those with a response at 24 weeks, duration of response was longer in patients who received epoetin alfa than those who received placebo (median, 192·3 vs. 99 days; P ‐value not reported) (Janssen‐Cilag International N.V., ).…”

“…However, as biases are possible, a rigorous feasibility assessment is needed to ensure that the assumptions of the network are accounted for and that the risks/benefits of indirectly comparing therapies are visible (Cope et al , ). To define the most robust evidence base relevant to the research questions and establish a network related to the ARCADE study, a phase 3, randomized, double‐blind, placebo‐controlled study of darbepoetin alfa in ESA‐naïve patients with low/intermediate‐risk MDS and anaemia (Platzbecker et al , ), additional criteria from those included in the systematic literature search were applied to the studies (Table SII). The clinical and methodological similarities of the studies within the network were assessed by evaluating the differences in potential treatment effect modifiers and risk of bias as defined by Cope et al () and the National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) Technical Support Document 7 (Ades et al , ).…”