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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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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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Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial
Calvaruso G, Vitrano A, Di Maggio R, Lai E, Colletta G, Quota A, Gerardi C, Rigoli LC, Sacco M, Pitrolo L, et al
American Journal of Hematology. 2015;90((7)):634-8.
Abstract
In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long-term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value=0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P-value=0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long-term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated. Am. J. Hematol. 90:634-638, 2015. © 2015 Wiley Periodicals, Inc. Copyright © 2015 Wiley Periodicals, Inc.
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Deferiprone versus Deferoxamine in Sickle Cell Disease: Results from a 5-year long-term Italian multi-center randomized clinical trial
Calvaruso G, Vitrano A, Di Maggio R, Ballas S, Steinberg MH, Rigano P, Sacco M, Telfer P, Renda D, Barone R, et al
Blood Cells Molecules & Diseases. 2014;53((4):):265-71.
Abstract
Blood transfusion and iron chelation currently represent a supportive therapy to manage anemia, vasculopathy and vaso-occlusion crises in Sickle-Cell-Disease. Here we describe the first 5-year long-term randomized clinical trial comparing Deferiprone versus Deferoxamine in patients with Sickle-Cell-Disease. The results of this study show that Deferiprone has the same effectiveness as Deferoxamine in decreasing body iron burden, measured as repeated measurements of serum ferritin concentrations on the same patient over 5-years and analyzed according to the linear mixed-effects model (LMM) (p=0.822). Both chelators are able to decrease, significantly, serum ferritin concentrations, during 5-years, without any effect on safety (p=0.005). Moreover, although the basal serum ferritin levels were higher in transfused compared with non-transfused group (p=0.031), the changes over time in serum ferritin levels were not statistically significantly different between transfused and non-transfused cohort of patients (p=0.389). Kaplan-Meier curve, during 5-years of study, suggests that Deferiprone does not alter survival in comparison with Deferoxamine (p=0.38). In conclusion, long-term iron chelation therapy with Deferiprone was associated with efficacy and safety similar to that of Deferoxamine. Therefore, in patients with Sickle-Cell-Disease, Deferiprone may represent an effective long-term treatment option. Copyright 2014. Published by Elsevier Inc.
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Deferiprone versus deferoxamine in thalassemia intermedia: results from 5-Year long-term Italian multi-center randomized clinical trial
Vitrano A, Calvaruso G, Di Maggio R, Sacco M, Quota A, Capra M, Filosa A, D'Ascola DG, Fidone C, Carollo A, et al
Blood. 2014;124((21)): Abstract No. 1354
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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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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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Long-term use of deferiprone enhances significantly the left ventricular ejection function in thalassemia major
Maggio A, Capra M, Cuccia L, Gagliardotto F, Rigano P, Calvaruso G,, et al.,
Blood. 2011;118((21):): Abstract No. 5302.
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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.