ARCADE (20090160): A PHASE 3 RANDOMIZED PLACEBO-CONTROLLED DOUBLE-BLIND TRIAL OF DARBEPOETIN ALFA IN THE TREATMENT OF ANEMIA IN PATIENTS WITH LOW OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES (MDS)
Author(s): ,
Uwe Platzbecker
Affiliations:
University Hospital Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik I,Dresden,Germany
,
Argiris Symeonidis
Affiliations:
Division of Hematology, Department of Internal Medicine,University of Patras Medical School,Patras,Greece
,
Esther Oliva
Affiliations:
Division of Hematology,Azienda Ospedaliera Bianchi-Melacrino-Morelli,Reggio Calabria,Italy
,
Jeroen S Goede
Affiliations:
Division of Hematology,University Hospital and University of Zürich,Zürich,Switzerland
,
Michel Delforge
Affiliations:
University Hospital Leuven,Leuven,Belgium
,
Jiri Mayer
Affiliations:
Department of Internal Medicine - Hematology and Oncology,University Hospital Brno and Faculty of Medicine, Masaryk University,Brno,Czech Republic
,
Sejal Badre
Affiliations:
Amgen Inc.,Thousand Oaks,United States
,
Eduard Gasal
Affiliations:
Amgen Inc.,Thousand Oaks,United States
,
Bhakti Mehta
Affiliations:
Amgen Inc.,Thousand Oaks,United States
Janet Franklin
Affiliations:
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
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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

Background
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.

Aims
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).

Methods
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).

Results
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)


Conclusion
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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