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Sotatercept TGF-b ligand trap in β-thalassemia
all. The data cutoff date for this analysis was November 27, 2015. Detailed statistical methods are included in the Online Supplementary Data.
Results
Patients
As of November 27, 2015, 46 patients had been enrolled between November 2012 and November 2014 – 16 with TDT and 30 with NTDT (Online Supplementary Figure S1). The patients’ baseline demographic and disease character- istics are shown in Table 1; the data are presented by assigned dose level of sotatercept prior to dose escalation. All patients received two or more doses of sotatercept. The median duration of treatment was 19.6 months (range, 0.6-35.9) for NTDT patients and 13.8 months (range, 1.4-27.7) for TDT patients.
doses of 0.1 to 1.0 mg/kg, 18 (60%) achieved a mean hemoglobin increase of ≥1.0 g/dL, and 11 (37%) had a mean hemoglobin increase of ≥1.5 g/dL sustained for ≥12 weeks (Figure 1A). The highest rate of response was seen with 0.75 mg/kg sotatercept: 86% (6 of 7) of the patients treated with this dose achieved an increase in hemoglobin of ≥1.5 g/dL. Responders receiving sotatercept 0.5 mg/kg experienced the greatest maximum increase in hemoglo- bin levels within 12 weeks versus baseline (3.2±0.2 g/dL) (Figure 1B). No patients receiving sotatercept 0.1 mg/kg achieved a response.
The mean change in hemoglobin levels from baseline in NTDT patients is shown in Figure 2. No significant differ- ences in reticulocyte count or fetal hemoglobin (HbF) lev- els were reported for NTDT patients during the study (data not shown). The starting active dose of sotatercept in patients with NTDT, based on the observed responses, was ≥0.3 mg/kg.
Of four patients with NTDT who were receiving con- comitant hydroxyurea therapy at enrollment, three con- tinued to receive hydroxyurea during the study (dose range 54-84 mg/kg) without interruption or modification;
Erythroid response
Non-transfusion-dependent b-thalassemia patients
Of the 30 patients with NTDT treated with sotatercept
Table 1. Baseline characteristics of patients with non-transfusion-dependent and transfusion-dependent b-thalassemia treated with sotatercept by assigned dose level.
Characteristic
NTDT patients
Age, years Median Range
Sotatercept dose
0.1 mg/kg (n=8)
n=6
39.5 32.0-53.0
0.3 mg/kg (n=9)
n=6
47.0 37.0-55.0
0.5 mg/kg (n=8)
n=6
39.0 34.0-54.0
0.75 mg/kg (n=12)
n=7
43.0 29.0-65.0
1.0 mg/kg (n=9)
n=5
41.0 19.0-52.0
Overall (N=46)
n=30
42.0 19.0-65.0
Female,n(%) 3(50) 3(50) 3(50) 6(86) 1(20) 16(53)
Weight, kg
Median 54.0 Range 48.0-85.0
Hemoglobin, g/dL
Median 8.8 Range 5.9-10.7 Mean±SD 8.6±1.68
Mean corpuscular volume, fL
Mean 76.2 Median 75.8 Range 67.7-83.8
TDT patients n=2
Age, years
Median 41.5 Range 34.0-49.0
58.0 64.2 56.0 53.6-65.0 41.0-75.0 47.6-75.0
8.5 8.5 8.7 6.0-9.5 6.4-9.3 7.1-9.6 8.3±1.26 8.2±1.13 8.5±0.89
75.6 75.5 63.2
75.8 68.4 61.1 61.6-90.5 62.6-103.4 54.6-80.4
n=3 n=2 n=5
34.0 35.0 45.0
62.0 58.9 56.0-67.0 41.0-85.0
7.6 8.4 6.6-9.4 5.9-10.7 7.7±1.04 8.3±1.18
78.6 73.3
80.3 72.1 70.6-89.3 54.6-103.4
n=4 n=16
39.5 35.5
23.0-39.0 34.0-36.0 33.0-51.0
Female,n(%) 1(50) 1(33) 0(0) 2(40) 2(50) 6(38)
27.0-46.0 23.0-51.0
Weight, kg Median Range
49.4
46.9-51.8 2 (100) 0
15, 33
9.5
9.3-9.7
65.7
52.0-71.0 1 (33) 2 (67) 14, 18, 33
8.6
8.5-10.6
70.7 58.0
60.5-80.8 48.5-83.0 2 (100) 3 (60) 0 2 (40)
30, 30 8, 18, 18, 30,
9.8 8.9
9.4-10.1 8.0-10.0
63.0
53.5-85.9 4 (100)
0
18, 18, 18, 24
9.6
8.6-10.9
60.1
46.9-85.9 12 (75) 4 (25) -
9.3
8.0-10.9
b-thalassemia major, n (%)
b-thalassemia intermedia*, n (%)
Transfusion burden, RBC units/24 weeks†
Hemoglobin, g/dL Median
Range
35
NTDT: non-transfusion-dependent b-thalassemia; TDT: transfusion-dependent b-thalassemia; SD: standard deviation; RBC: red blood cell. *Patients with b-thalassemia intermedia gene mutations who met the transfusion burden requirement were classified as having TDT. †Values presented for transfusion burden for individual TDT patients.
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