Author(s): ,
Uwe Platzbecker
University Hospital Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I,Dresden,Germany
Argiris Symeonidis
Division of Hematology, Department of Internal Medicine,University of Patras Medical School,Patras,Greece
Esther Oliva
Division of Hematology,Azienda Ospedaliera Bianchi-Melacrino-Morelli,Reggio Calabria,Italy
Jeroen S Goede
Division of Hematology,University Hospital and University of Zürich,Zürich,Switzerland
Michel Delforge
University Hospital Leuven,Leuven,Belgium
Jiri Mayer
Department of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
Sejal Badre
Amgen Inc.,Thousand Oaks,United States
Eduard Gasal
Amgen Inc.,Thousand Oaks,United States
Bhakti Mehta
Amgen Inc.,Thousand Oaks,United States
Janet Franklin
Amgen Inc.,Thousand Oaks,United States
EHA Learning Center. Platzbecker U. Jun 10, 2016; 135161
Prof. Dr. Uwe Platzbecker
Prof. Dr. Uwe Platzbecker
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Abstract: S128

Type: Oral Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 11:30 - 11:45

Location: Hall C14

Although erythropoiesis-stimulating agents (ESAs) are recommended in clinical guidelines to treat anemia in patients with lower-risk MDS, ESAs are not widely approved for this indication.

To evaluate the efficacy and safety of darbepoetin alfa (DAR) in IPSS low / intermediate-1 (int-1) risk MDS patients with anemia, in a phase 3, randomized, placebo(PBO)-controlled trial (EudraCT#2009-016522-14, NCT#01362140).

Patients were enrolled from Dec 21, 2011 to Aug 27, 2014 in 9 European countries. Eligible patients had low/int-1 MDS, anemia [hemoglobin (Hgb) ≤10 g/dL], low transfusion burden (<4 transfusion units in each of 2 consecutive 8-week periods prior to randomization), no previous treatment with ESAs or biologic‑response modifiers, and endogenous erythropoietin (EPO) levels ≤500 mU/mL. Patients were randomized 2:1 to receive 24 weeks of subcutaneous DAR 500 µg or PBO every 3 weeks (Q3W), stratified by IPSS status (low or int-1). The dose was reduced if Hgb was >12.0 g/dL or if Hgb increased by >1.5 g/dL in 3 weeks without transfusion. Investigational product (IP) was discontinued and the patient entered follow-up if >3 dose reductions were needed. Key efficacy endpoints included (1) transfusion incidence from weeks 5-24 and (2) erythroid response (HI‑E) per IWG 2006 criteria, ie, ≥1.5 g/dL increase from baseline in Hgb with a mean rise of ≥1.5 g/dL for 8 weeks without transfusions. Results from the 24-week double-blind period are reported here; patients could then receive open-label DAR 500 µg Q3W for 48 weeks and were followed up for survival and progression to AML status for up to 3 years (ongoing).

A total of 147 patients were randomized; 50.7% of patients were IPSS low risk and 49.3% were int‑1 risk, median Hgb levels were 9.3 (Q1:8.8, Q3:9.7) g/dL, median EPO levels were 69 (Q1:36, Q3:158) mU/mL, rates of good / intermediate / poor IPSS karyotype were 91% / 9% / 0%, respectively, and % WHO classifications were RA:15%, RARS:14%, RCMD:44%, del5q:9%, RAEB-1:16%, and MDS‑U/unknown:2%. There were 146 (97 DAR, 49 PBO) patients in the primary analysis set. Baseline demographic and disease characteristics were generally similar between the two arms. Transfusion incidence from weeks 5-24 was significantly reduced with DAR vs. PBO (DAR:36.1% vs. PBO:59.2%, p=0.008). The proportion achieving HI-E was significantly increased with DAR vs. PBO; DAR:14.7% (11 of 75 evaluable) vs. PBO:0% (0 of 35 evaluable), p=0.016. All patients with HI-E (n=11) had a baseline serum EPO level <100 mU/mL. Adverse events (AEs) occurring ≥5% more frequently in the DAR arm than the PBO arm were fatigue, pyrexia, headache, and myalgia. Safety results from this trial were consistent with the previous DAR phase 2 MDS trial (Gabrilove BJH 2008, 142:379-393).
 Placebo (N=48), n (%)Darbepoetin alfa (N=98), n (%)
AEs leading to IP discontinuation2 (4.2)3 (3.1)
Grade ≥3 / grade ≥413 (27.1) / 6 (12.5)15 (15.3) / 5 (5.1)
Fatal AEs (none treatment-related)2 (4.2)1 (1.0)
Serious AEs8 (16.7)11 (11.2)
Treatment-related serious AEs0 (0)1 (1.0)
Venous thromboembolic events0 (0)1 (1.0)
Progression to AML1 (2.2)2 (2.1)

In this phase 3, randomized, double-blind, PBO-controlled trial in low/int-1 MDS patients with anemia, 24 weeks of DAR Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals.

Session topic: Myelodysplastic syndromes - Clinical

Keyword(s): Anemia, Erythropoieisis, Transfusion
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