TY - JOUR
T1 - Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes
T2 - a phase 2, dose-ranging trial
AU - Komrokji, Rami
AU - Garcia-Manero, Guillermo
AU - Ades, Lionel
AU - Prebet, Thomas
AU - Steensma, David P.
AU - Jurcic, Joseph G.
AU - Sekeres, Mikkael A.
AU - Berdeja, Jesus
AU - Savona, Michael R.
AU - Beyne-Rauzy, Odile
AU - Stamatoullas, Aspasia
AU - DeZern, Amy E.
AU - Delaunay, Jacques
AU - Borthakur, Gautam
AU - Rifkin, Robert
AU - Boyd, Thomas E.
AU - Laadem, Abderrhamane
AU - Vo, Bond
AU - Zhang, Jennie
AU - Puccio-Pick, Marie
AU - Attie, Kenneth M.
AU - Fenaux, Pierre
AU - List, Alan F.
N1 - Funding Information:
RK has received research funding from Celgene Corporation, is a consultant for or has an advisory role at Celgene Corporation and Novartis, has been a member of speakers' bureaus at Novartis, and has received travel, accommodation, and other expenses from Celgene Corporation and Novartis. LA and TP have received research funding from Celgene Corporation. DPS is a consultant for Amgen, Celgene Corporation, Janssen, and Millennium Pharmaceuticals/Takeda Oncology. JGJ has received research funding from Celgene Corporation, Daiichi Sankyo, Astellas, Seattle Genetics, Actinium Pharmaceuticals, Kura Oncology, Syros Pharma, and Forma Therapeutics, is a consultant for Novartis, and has served on advisory boards for Amgen, Bayer, Merck, Seattle Genetics, and Incyte. MAS is a member of the board of directors or advisory committees of Celgene Corporation and Millennium Pharmaceuticals/Takeda Oncology. JB has received research funding from Celgene Corporation, Bristol-Myers Squibb, Amgen, Janssen, Novartis, Takeda, AbbVie, Curis, Pharmacyclics, Vivolux, Teva, Constellation, and Bluebird Bio. MRS has received research funding from Astex, Incyte, Sunesis, Takeda, and TG Therapeutics, is on the steering committee or scientific advisory board of Amgen, Astex, Celgene Corporation, Incyte, Karyopharm, Sunesis, and TG Therapeutics, is on the data safety monitoring boards of Celgene Corporation and Gilead, and is a consultant for and has equity in Karyopharm. OB-R has received research funding from Novartis and has received travel expenses from Celgene Corporation and Novartis. AS has received honoraria from Celgene Corporation. AED has received research funding from Celgene Corporation and Astex. JD is a consultant for and has an advisory role at Novartis. RR is on the advisory board of Celgene Corporation, Amgen, and Takeda. TEB has received research funding from US Oncology. AL, BV, JZ, and MP-P are employed by and have equity in Celgene Corporation. KMA is employed by and has equity in Acceleron Pharma. PF has received research funding from Celgene Corporation, Janssen, Novartis, Astex, and Teva, and honoraria from Celgene Corporation, Novartis, and Teva. AFL has patents with and has received research and clinical trial funding from Celgene Corporation, is a consultant for Celgene Corporation, and has a licensing agreement with Celgene Corporation. GG-M and GB declare no competing interests.
Funding Information:
The authors thank all the patients who participated in this study. Co-investigators included Johnson M Liu, Bruno Quesnel, and Paul R Conkling. Celgene Corporation provided funding for this study. The authors received editorial and writing support from Daniel Gilmartin from Excerpta Medica, funded by Celgene Corporation.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/2
Y1 - 2018/2
N2 - Background: Myelodysplastic syndromes are characterised by ineffective erythropoiesis leading to anaemia. Sotatercept (ACE-011) is a novel activin receptor type IIA fusion protein that acts as a ligand trap to neutralise negative regulators of late-stage erythropoiesis. The aim of the study was to establish a safe and effective dose of sotatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes. Methods: This open-label, multicentre, dose-ranging, phase 2 trial took place at 11 treatment centres in the USA and France. Eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low-risk or intermediate-1-risk myelodysplastic syndromes, had anaemia requiring red blood cell (RBC) transfusions, and were ineligible for, or refractory to, erythropoiesis-stimulating agents (ESAs). Patients were not eligible if they had chromosome 5q deletion myelodysplastic syndromes without documented failure of lenalidomide. Patients were randomly assigned to receive either 0·1 or 0·3 mg/kg sotatercept subcutaneously, using a permuted-block method with stratification for serum erythropoietin concentration and transfusion burden. Patients were assigned to 0·5, 1·0, and 2·0 mg/kg groups in a non-randomised fashion. The primary efficacy endpoint was the proportion of patients who achieved haematological improvement–erythroid (HI-E), according to International Working Group 2006 criteria. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT01736683 and at EU Clinical Trials Register, number 2012–002601–22, and is ongoing. Findings: Between Dec 5, 2012, and July 22, 2015, 74 patients were enrolled into the study (seven to receive 0·1 mg/kg sotatercept, six to 0·3 mg/kg, 21 to 0·5 mg/kg, 35 to 1·0 mg/kg, and five to 2·0 mg/kg). 36 (49%; 95% CI 38–60) of 74 patients achieved HI-E; 29 (47%; 95% CI 35–59) of 62 patients with a high transfusion burden achieved HI-E (RBC-transfusion reduction from baseline of 4 or more units for at least 56 days), and seven (58%; 95% CI 32–81) of 12 patients with a low transfusion burden achieved HI-E (haemoglobin increase of 1·5 g/dL or more sustained for at least 56 days in the absence of transfusions). The most commonly reported adverse events were fatigue in 19 (26%) of 74 patients and peripheral oedema in 18 (24%) of 74 patients. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 25 (34%) of 74 patients; four (5%) patients had grade 3–4 TEAEs that were considered to be treatment related. The most common grade 3–4 TEAEs were lipase increase and anaemia, which each occurred in three (4%) of 74 patients. 17 (23%) of 74 patients had at least one serious TEAE, and one patient died from a treatment-emergent subdural haematoma due to a fall. Interpretation: Sotatercept, a novel activin-receptor fusion protein, was well tolerated and effective for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes in whom previous ESA treatment had failed. Treatment with sotatercept could be beneficial for these patients who have few available treatment options. Funding: Celgene Corporation.
AB - Background: Myelodysplastic syndromes are characterised by ineffective erythropoiesis leading to anaemia. Sotatercept (ACE-011) is a novel activin receptor type IIA fusion protein that acts as a ligand trap to neutralise negative regulators of late-stage erythropoiesis. The aim of the study was to establish a safe and effective dose of sotatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes. Methods: This open-label, multicentre, dose-ranging, phase 2 trial took place at 11 treatment centres in the USA and France. Eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low-risk or intermediate-1-risk myelodysplastic syndromes, had anaemia requiring red blood cell (RBC) transfusions, and were ineligible for, or refractory to, erythropoiesis-stimulating agents (ESAs). Patients were not eligible if they had chromosome 5q deletion myelodysplastic syndromes without documented failure of lenalidomide. Patients were randomly assigned to receive either 0·1 or 0·3 mg/kg sotatercept subcutaneously, using a permuted-block method with stratification for serum erythropoietin concentration and transfusion burden. Patients were assigned to 0·5, 1·0, and 2·0 mg/kg groups in a non-randomised fashion. The primary efficacy endpoint was the proportion of patients who achieved haematological improvement–erythroid (HI-E), according to International Working Group 2006 criteria. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT01736683 and at EU Clinical Trials Register, number 2012–002601–22, and is ongoing. Findings: Between Dec 5, 2012, and July 22, 2015, 74 patients were enrolled into the study (seven to receive 0·1 mg/kg sotatercept, six to 0·3 mg/kg, 21 to 0·5 mg/kg, 35 to 1·0 mg/kg, and five to 2·0 mg/kg). 36 (49%; 95% CI 38–60) of 74 patients achieved HI-E; 29 (47%; 95% CI 35–59) of 62 patients with a high transfusion burden achieved HI-E (RBC-transfusion reduction from baseline of 4 or more units for at least 56 days), and seven (58%; 95% CI 32–81) of 12 patients with a low transfusion burden achieved HI-E (haemoglobin increase of 1·5 g/dL or more sustained for at least 56 days in the absence of transfusions). The most commonly reported adverse events were fatigue in 19 (26%) of 74 patients and peripheral oedema in 18 (24%) of 74 patients. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 25 (34%) of 74 patients; four (5%) patients had grade 3–4 TEAEs that were considered to be treatment related. The most common grade 3–4 TEAEs were lipase increase and anaemia, which each occurred in three (4%) of 74 patients. 17 (23%) of 74 patients had at least one serious TEAE, and one patient died from a treatment-emergent subdural haematoma due to a fall. Interpretation: Sotatercept, a novel activin-receptor fusion protein, was well tolerated and effective for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes in whom previous ESA treatment had failed. Treatment with sotatercept could be beneficial for these patients who have few available treatment options. Funding: Celgene Corporation.
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U2 - 10.1016/S2352-3026(18)30002-4
DO - 10.1016/S2352-3026(18)30002-4
M3 - Article
C2 - 29331635
AN - SCOPUS:85040453479
VL - 5
SP - e63-e72
JO - The Lancet Haematology
JF - The Lancet Haematology
SN - 2352-3026
IS - 2
ER -