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Luspatercept for the treatment of anaemia in non-transfusion-dependent β-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial
Taher AT, Cappellini MD, Kattamis A, Voskaridou E, Perrotta S, Piga AG, Filosa A, Porter JB, Coates TD, Forni GL, et al
The Lancet. Haematology. 2022
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Editor's Choice
Abstract
BACKGROUND In patients with non-transfusion-dependent β-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent β-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent β-thalassaemia. METHODS We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of β-thalassaemia or haemoglobin E/β-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent β-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing. FINDINGS Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study. INTERPRETATION Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent β-thalassaemia, for whom effective approved treatment options are scarce. FUNDING Celgene and Acceleron Pharma.
PICO Summary
Population
Patients with non-transfusion-dependent β-thalassaemia enrolled in the BEYOND trial, in Thailand, Lebanon, Greece, Italy, UK, and USA (n= 145).
Intervention
Luspatercept (n= 96).
Comparison
Placebo (n= 49).
Outcome
The primary endpoint was achievement of an increase from baseline of 1.0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1.0 g/dL in haemoglobin concentration (common risk difference 77.1 [95% Confidence Interval: 68.7-85.5]). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs. 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported.
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Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial
Maggio A, Kattamis A, Felisi M, Reggiardo G, El-Beshlawy A, Bejaoui M, Sherief L, Christou S, Cosmi C, Della Pasqua O, et al
Lancet Haematol. 2020;7(6):e469-e478
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Editor's Choice
Abstract
BACKGROUND Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12.5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had beta-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55.2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54.8%] of 146 assigned deferasirox, difference 0.4%; 95% CI -11.9 to 12.6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING EU Seventh Framework Programme.
PICO Summary
Population
Paediatric patients with transfusion-dependent haemoglobinopathies enrolled in the DEEP-2 multicentre randomised trial (n=393).
Intervention
Daily deferiprone (75-100 mg/kg per day) (n=194).
Comparison
Daily deferasirox (20-40 mg/kg per day) (n=199).
Outcome
Non-inferiority of deferiprone versus deferasirox was established (treatment success in 55.2% patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs. 54.8% assigned deferasirox). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Compliance was similar between treatment groups: 95% of patients in the deferiprone group versus 97% of patients in the deferasirox group.
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Population pharmacokinetics and dosing recommendations for the use of deferiprone in children younger than 6 years of age
Bellanti F, Del Vecchio GC, Putti MC, Maggio A, Filosa A, Cosmi C, Mangiarini L, Spino M, Connelly J, Ceci A, et al
British Journal of Clinical Pharmacology. 2016;83((3):):593-602
Abstract
AIMS: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children < 6 years of age. Here we assess the impact of developmental growth on the pharmacokinetics of deferiprone in this population using a population approach. Based on pharmacokinetic bridging concepts, we also evaluate whether the recommended doses yield appropriate systemic exposure in this group of patients. METHODS Data from a study in which 18 paediatric patients were enrolled were available for the purposes of this analysis. Patients were randomised to three deferiprone dose levels (8.3, 16.7 and 33.3 mg/kg). Blood samples were collected according to an optimised sampling scheme in which each patient contributed to a maximum of five samples. A population pharmacokinetic model was developed using NONMEM v.7.2. Model selection criteria were based on graphical and statistical summaries. RESULTS A one-compartment model with first-order absorption and first-order elimination best described the pharmacokinetics of deferiprone. Drug disposition parameters were affected by body weight, with both clearance and volume increasing allometrically with size. Simulation scenarios show that comparable systemic exposure (AUC) is achieved in children and adults after similar dose levels in mg/kg, with median (5-95th quantiles) AUC values respectively of 340.6 (223.2-520.0) and 318.5 (200.4-499.0) micromol/L*h at 75 mg/kg/day and 453.7 (297.3-693.0) and 424.2 (266.9-664.0) at 100 mg/kg/day t.i.d. doses. CONCLUSIONS Based on the current findings, a dosing regimen of 25 mg/kg t.i.d. is recommended in children below 6 years of age, with the possibility of titration up to 33.3 mg/kg t.i.d.
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Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients
Maggio A, Vitrano A, Lucania G, Capra M, Cuccia L, Gagliardotto F, Pitrolo L, Prossomariti L, Filosa A, Caruso V, et al
American Journal of Hematology. 2012;87((7):):732-3.
Abstract
A multicenter randomized open-label long-term sequential deferiprone?deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].
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Iron chelation therapy in thalassemia major: A systematic review with meta-analyses of 1520 patients included on randomized clinical trials
Maggio A, Filosa A, Vitrano A, Aloj G, Kattamis A, Ceci A, Fucharoen S, Cianciulli P, Grady RW, Prossomariti L, et al
Blood Cells, Molecules & Diseases. 2011;47((3):):166-75.
Abstract
The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means+/-SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using chi(2) (Q) and I(2). Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p<0.0001), increases in serum ferritin levels during DFX 5, 10, and 20mg/kg versus DFO-treated groups (p<0.00001, p<0.00001, and p=0.002, respectively), but no statistically significant difference during DFX 30mg/kg versus DFO (p=0.70), no statistically significant variations in heart T2* signal during associated or sequential versus mono-therapy treatment (p=0.46 and p=0.14, respectively), increases in urinary iron excretion during associated or sequential versus monotherapy treatment (p=0.008 and p=0.02, respectively), and improved ejection fraction during associated or sequential versus monotherapy treatment (p=0.01 and p<0.00001, respectively). These findings do not support any specific chelation treatment. The literature shows risks of bias, and additional larger and longer trials are needed. Copyright Copyright 2011 Elsevier Inc. All rights reserved.
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Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassemia major patients
Pantalone GR, Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, Romeo MA, Magnano C, Caruso V, et al
Hemoglobin. 2011;35((3):):206-16.
Abstract
In beta-thalassemia major (beta-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in beta-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some beta-TM patients who may not be able to receive other forms of chelation treatment.
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Chelation treatment in sickle-cell-anaemia: Much ado about nothing?
Lucania G, Vitrano A, Filosa A, Maggio A
British Journal of Haematology. 2011;154((5):):545-555.
Abstract
Blood transfusions may prevent and treat serious complications related to sickle-cell disease (SCD) when performed according to specific guidelines. However, blood transfusion requirements in SCD inevitably lead to increased body iron burden. An adequate chelation treatment may prevent complications and reduce morbidity and mortality. This review evaluates the effectiveness, safety and costs of chelation treatment. The included trials were examined according to the recommendations of the American College of Cardiology (ACC) and the American Heart Association (AHA). Overall, 14 trials and a total of 502 patients with SCD were included in this review. Deferoxamine alone (s.c. or i.v.), deferiprone alone or versus deferoxamine, deferasirox versus deferoxamine and combined treatment with deferoxamine plus deferiprone were included and evaluated in the analysis. Only two randomized clinical trials have been reported. The results of this analysis suggest that use of chelation treatment in SCD to date has been based on little efficacy and safety evidence, although it is widely recommended and practised. The cost/benefit ratio has not been fully explored. Further research with larger randomized clinical trials needs to be performed.
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Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial
Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, Romeo MA, Magnano C, Caruso V, Argento C, et al
British Journal of Haematology. 2009;145((2):):245-54.
Abstract
A multicentre randomized open-label trial was designed to assess the effectiveness of long-term sequential deferiprone-deferoxamine (DFO-DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8-12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5-year follow-up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention-to-treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP-DFO patients compared with DFP-alone patients (P = 0. 005). Kaplan-Meier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P = 0. 3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP-DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs.
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Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies
Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, Magnano C, Rizzo M, Caruso V, Gerardi C, et al
Blood Cells, Molecules & Diseases. 2009;42((3):):247-51.
Abstract
The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48. 3%) females and 137 (51. 7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0. 013). For each increasing year of age, the hazard ratio for males was 1. 03 higher than that for females (p-value<0. 013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.