BACKGROUND: Myelodysplastic syndromes are characterised by ineffective 
erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks 
transforming growth factor beta (TGF β) superfamily inhibitors of 
erythropoiesis, giving rise to a promising new investigative therapy. We aimed 
to assess the safety and efficacy of luspatercept in patients with anaemia due 
to lower-risk myelodysplastic syndromes.
METHODS: In this phase 2, multicentre, open-label, dose-finding study 
(PACE-MDS), with long-term extension, eligible patients were aged 18 years or 
older, had International Prognostic Scoring System-defined low or intermediate 1 
risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic 
leukaemia (white blood cell count <13 000/μL), and had anaemia with or without 
red blood cell transfusion support. Enrolled patients were classified as having 
low transfusion burden, defined as requiring less than 4 red blood cell units in 
the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high 
transfusion burden, defined as requiring 4 or more red blood cell units in the 8 
weeks before treatment. Patients received luspatercept subcutaneously once every 
21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight 
for five doses (over a maximum of 12 weeks). Patients in the expansion cohort 
were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was 
allowed, and patients could be treated with luspatercept for a maximum of 5 
years. Patients in the base study were assessed for response and safety after 12 
weeks in order to be considered for enrolment into the extension study. The 
primary endpoint was the proportion of patients achieving modified International 
Working Group-defined haematological improvement-erythroid (HI-E), defined as a 
haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 
days or longer in low transfusion burden patients, and a reduction in red blood 
cell transfusion of 4 or more red blood cell units or a 50% or higher reduction 
in red blood cell units over 8 weeks versus pre-treatment transfusion burden in 
high transfusion burden patients. Patient data were subcategorised by: 
luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study 
transfusion burden (high transfusion burden vs low transfusion burden, defined 
as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin 
concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more 
ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were 
carried out on the efficacy evaluable and intention-to-treat populations. This 
trial is currently ongoing. This study is registered with ClinicalTrials.gov, 
numbers NCT01749514 and NCT02268383.
FINDINGS: Between Jan 21, 2013, and Feb 12, 2015, 58 patients with 
myelodysplastic syndromes were enrolled in the 12 week base study at nine 
treatment centres in Germany; 27 patients were enrolled in the dose-escalation 
cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 
mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose 
luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% 
CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three 
treatment-related grade 3 adverse events occurred in one patient each: myalgia 
(one [2%]), increased blast cell count (one [2%]), and general physical health 
deterioration (one [2%]). Two of these treatment-related grade 3 adverse events 
were reversible serious grade 3 adverse events: one patient (2%) had myalgia and 
one patient (2%) had general physical health deterioration.
INTERPRETATION: Luspatercept was well tolerated and effective for the treatment 
of anaemia in lower-risk myelodysplastic syndromes and so could therefore 
provide a novel therapeutic approach for the treatment of anaemia associated 
with lower-risk myelodysplastic syndromes; further studies are ongoing.
FUNDING: Acceleron Pharma.