-
1.
Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia.
Piga, A, Perrotta, S, Gamberini, MR, Voskaridou, E, Melpignano, A, Filosa, A, Caruso, V, Pietrangelo, A, Longo, F, Tartaglione, I, et al
Blood. 2019;(12):1279-1289
-
-
Free full text
-
Abstract
β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cutoff, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. These findings support a randomized clinical trial to assess efficacy and safety. This study was registered at www.clinicaltrials.gov as #NCT01749540 and #NCT02268409.
-
2.
Brain functional impairment in beta-thalassaemia: the cognitive profile in Italian neurologically asymptomatic adult patients in comparison to the reported literature.
Tartaglione, I, Manara, R, Caiazza, M, Carafa, PA, Caserta, V, Ferrantino, T, Granato, I, Ippolito, N, Maietta, C, Oliveto, T, et al
British journal of haematology. 2019;(4):592-607
-
-
Free full text
-
Abstract
Cognitive involvement in beta-thalassaemia is strikingly controversial and poorly studied in adulthood. This multicentre prospective study investigated 74 adult neurologically-asymptomatic beta-thalassaemia patients (mean-age 34·5 ± 10·3 years; 53 transfusion-dependent [TDT], 21 non-transfusion dependent [NTDT]) and 45 healthy volunteers (mean-age 33·9 ± 10·7 years). Participants underwent testing with Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV), Brief Psychiatric Rating Scale (BPRS) and multiparametric brain 3T-magnetic resonance imaging (MRI) for parenchymal, vascular and iron content evaluation. Patients had lower Full-Scale Intelligence Quotient (FSIQ) than controls (75·5 ± 17·9 vs. 97·4 ± 18·1, P < 0·0001) even after correction for education level. Compared to TDT, NTDT showed a trend of higher FSIQ (P = 0·08) but a similar cognitive profile at WAIS-subtests. FSIQ correlated with total and indirect bilirubin (P < 0·0001 and P = 0·002, respectively); no correlation was found with splenectomy, intracranial MRI/magnetic resonance-angiography findings, brain tissue iron content or other disease-related clinical/laboratory/treatment data. FSIQ did not correlate with BPRS scores, although the latter were higher among patients (28·74 ± 3·1 vs. 27·29 ± 4·8, P = 0·01) mainly because of increased depression and anxiety levels. Occupation rate was higher among controls (84·4% vs. 64·9%, P = 0·004) and correlated with higher FSIQ (P = 0·001) and education level (P = 0·001). In conclusion, Italian adult beta-thalassaemia patients seem to present a characteristic cognitive profile impairment and an increased rate of psychological disorders with possible profound long-term socio-economic consequences.
-
3.
A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major.
Fernandes, JL, Loggetto, SR, Veríssimo, MP, Fertrin, KY, Baldanzi, GR, Fioravante, LA, Tan, DM, Higa, T, Mashima, DA, Piga, A, et al
Blood. 2016;(12):1555-61
-
-
Free full text
-
Abstract
Cardiovascular disease resulting from iron accumulation is still a major cause of death in patients with thalassemia major (TM). Voltage-gated calcium-channel blockade prevents iron entry into cardiomyocytes and may provide an adjuvant treatment to chelation, reducing myocardial iron uptake. We evaluated whether addition of amlodipine to chelation strategies would reduce myocardial iron overload in TM patients compared with placebo. In a multicenter, double-blind, randomized, placebo-controlled trial, 62 patients were allocated to receive oral amlodipine 5 mg/day or placebo in addition to their current chelation regimen. The main outcome was change in myocardial iron concentration (MIC) determined by magnetic resonance imaging at 12 months, with patients stratified into reduction or prevention groups according to their initial T2* below or above the normal human threshold of 35 ms (MIC, 0.59 mg/g dry weight). At 12 months, patients in the reduction group receiving amlodipine (n = 15) had a significant decrease in MIC compared with patients receiving placebo (n = 15) with a median of -0.26 mg/g (95% confidence interval, -1.02 to -0.01) vs 0.01 mg/g (95% confidence interval, -0.13 to 0.23), P = .02. No significant changes were observed in the prevention group (treatment-effect interaction with P = .005). The same findings were observed in the subgroup of patients with T2* <20 ms. Amlodipine treatment did not cause any serious adverse events. Thus, in TM patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone. Because this conclusion is based on subgroup analyses, it needs to be confirmed in ad hoc clinical trials. This trial was registered at www.clinicaltrials.gov identifier as #NCT01395199.
-
4.
A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA).
Pennell, DJ, Porter, JB, Piga, A, Lai, Y, El-Beshlawy, A, Belhoul, KM, Elalfy, M, Yesilipek, A, Kilinç, Y, Lawniczek, T, et al
Blood. 2014;(10):1447-54
-
-
Free full text
-
Abstract
Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.
-
5.
Deferiprone (GPO-L-ONE(®) ) monotherapy reduces iron overload in transfusion-dependent thalassemias: 1-year results from a multicenter prospective, single arm, open label, dose escalating phase III pediatric study (GPO-L-ONE; A001) from Thailand.
Viprakasit, V, Nuchprayoon, I, Chuansumrit, A, Torcharus, K, Pongtanakul, B, Laothamatas, J, Srichairatanakool, S, Pooliam, J, Supajitkasem, S, Suriyaphol, P, et al
American journal of hematology. 2013;(4):251-60
-
-
Free full text
-
Abstract
Accessibility to iron chelators including deferoxamine and deferasirox remains obscured in many developing countries. To provide an alternative, the government pharmaceutical organization of Thailand (GPO) manufactured deferiprone which has similar bioequivalent to the standard product. Seventy-three pediatric patients with severe β thalassemias, age range 3.2-19 years, were recruited to a 1-year multicenter prospective, single arm, open label, dose escalating Phase III study of deferiprone to determine its clinical efficacy and safety. Sixty-four patients (87.6%) completed the study with good compliance (>94%). Average deferiprone dose was 79.1±4.3 mg/kg/day. Overall, mean serum ferritin (SF) levels at 1 year were not significantly changed from baseline. However, 45% of patients (response group) had SF reduced >15% from baseline at 1 year with a median reduction of 1,065 ng ml(-1) . Baseline SF was the major factor that predicts clinical efficacy; patients with baseline SF>3,500 ng ml(-1) had the most significant fall of SF at 1 year. A subgroup analysis by MRI-T2* confirmed that the response group had higher baseline liver iron and deferiprone could significantly reduce liver iron overload and normalize levels of ALT at 1 year. Although, gastrointestinal irritation (20.5%) was the most common drug-related adverse events (AEs) followed by transaminitis (16.4%) and neutropenia (6.8%), all patients were well tolerated. There was no mortality and agranulocytosis found in this trial. Monotherapy of deferiprone with appropriate dose adjustment and monitoring for adverse events appeared to be an effective chelation therapy in some patients with good compliance and acceptable safety profiles.
-
6.
Neridronate improves bone mineral density and reduces back pain in β-thalassaemia patients with osteoporosis: results from a phase 2, randomized, parallel-arm, open-label study.
Forni, GL, Perrotta, S, Giusti, A, Quarta, G, Pitrolo, L, Cappellini, MD, D'Ascola, DG, Borgna Pignatti, C, Rigano, P, Filosa, A, et al
British journal of haematology. 2012;(2):274-282
Abstract
Neridronate is a third generation bisphosphonate with established efficacy in metabolic bone disease. In this randomized, open-label study, 118 adults with β-thalassaemia and bone mineral density (BMD) Z scores ≤-2·0 were randomized 1:1-500 mg calcium with 400 international unis (iu) vitamin D daily or 500 mg calcium with 400 iu vitamin D daily plus neridronate 100 mg intravenously every 90 d. Significant increases in BMD at the lumbar spine and total hip were noted in the neridronate group at 6 and 12 months from baseline (P < 0·001), and values were significantly higher than the control group at both time intervals. Neridronate also significantly decreased serum bone alkaline phosphatase and C-telopeptide of collagen type 1 levels from as early as 3 months (P = 0·04 and P < 0·001, respectively), reaching significantly lower values at 12 months compared with the control group (P < 0·05). Reductions in back pain and analgesic use were also evident, starting 3 months from commencing treatment. Treatment was well tolerated by all patients. In this largest randomized trial in thalassaemia-induced osteoporosis to date, neridronate was safe and effective in reducing bone resorption and increasing BMD. The associated reduction in back pain and improved quality of life will encourage adherence to therapy. (Clinicaltrials.gov identifier NCT01140321.).
-
7.
Achieving treatment goals of reducing or maintaining body iron burden with deferasirox in patients with β-thalassaemia: results from the ESCALATOR study.
Taher, A, Elalfy, MS, Al Zir, K, Daar, S, Al Jefri, A, Habr, D, Kriemler-Krahn, U, Roubert, B, El-Beshlawy, A
European journal of haematology. 2011;(4):349-54
-
-
Free full text
-
Abstract
This analysis evaluated the effects of deferasirox on liver iron concentration in moderate and heavily iron-overloaded patients with β-thalassaemia from the ESCALATOR trial (n = 231). Mean liver iron concentrations (LIC) decreased significantly from 21.1 ± 8.2 to 14.2 ± 12.1 mg Fe/g dry weight (dw) at 2 yr (P < 0.001) in patients with LIC ≥ 7 mg Fe/g dw at baseline; patients with LIC < 7 mg Fe/g dw maintained these levels over the treatment period. The proportion of patients with LIC < 7 mg Fe/g dw increased from 9.4% at core baseline to 39.3% by the end of year 2. The results showed that deferasirox enabled therapeutic goals to be achieved, by maintaining LIC in patients with LIC < 7 mg Fe/g dw at a mean dose of 22.4 ± 5.2 mg/kg/d and significantly reducing LIC in patients with LIC ≥ 7 mg Fe/g dw at a mean dose of 25.7 ± 4.2 mg/kg/d, along with a manageable safety profile.
-
8.
The safety, tolerability, and efficacy of a liquid formulation of deferiprone in young children with transfusional iron overload.
ElAlfy, MS, Sari, TT, Lee, CL, Tricta, F, El-Beshlawy, A
Journal of pediatric hematology/oncology. 2010;(8):601-5
Abstract
Limited data are available on the use of deferiprone in children younger than 10 years of age. This study evaluated the safety and efficacy of a new liquid formulation of deferiprone for the treatment of transfusional iron overload in children 1-10 years old. One hundred children (91 thalassemia major, 8 Hb E-β thalassemia, and 1 sickle cell disease) were enrolled for a 6-month treatment with deferiprone (50 to 100 mg/kg/d). The safety profile was similar to or better than that reported in earlier studies with deferiprone tablets in older children and adults. No unexpected adverse reactions were observed. Gastrointestinal intolerance (GI) was observed in 11% and an increased serum ALT in 12% of the children. Both events were transient. Mild neutropenia, observed in 6% of patients, did not progress to agranulocytosis and resolved despite continuous deferiprone treatment. Two patients experienced agranulocytosis that resolved without complications upon discontinuation of therapy. Deferiprone use was associated with a significant decline in mean serum ferritin level from 2532±1463 μg/L at baseline to 2176±1144 μg/L (P<0.0005). The results of this study show a favorable benefit/risk ratio of deferiprone oral solution for the treatment of young children with transfusional iron overload.
-
9.
Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone.
Cohen, AR, Galanello, R, Piga, A, De Sanctis, V, Tricta, F
Blood. 2003;(5):1583-7
-
-
Free full text
-
Abstract
The identification of a safe, orally active iron chelator is critically important for the prevention of morbidity and early death in patients receiving regular red cell transfusions. Based on our findings in a 1-year multicenter, prospective study of the safety and efficacy of deferiprone in patients with thalassemia major, we have extended the treatment period to 4 years. The mean dose of the chelator was 73 mg/kg per day during 531 patient-years. The rates of agranulocytosis (absolute neutrophil count [ANC] < 500 x 10(9)/L) and milder forms of neutropenia (ANC, 500-1500 x 10(9)/L) were 0.2 and 2.8 per 100 patient-years, respectively. Neutropenia occurred significantly more commonly in patients with intact spleens. Gastrointestinal and joint symptoms decreased significantly after the first year of therapy, and led to discontinuation of deferiprone in only one patient in years 2 to 4. The mean alanine aminotransferase (ALT) value of 71 U/L after 4 years of therapy was significantly higher than the baseline value of 61 U/L. Trend analysis showed no increase in the ALT levels or the percentage of patients with ALT levels greater than twice the upper limit of the reference range. Ferritin levels did not change significantly from the values at the time of change from deferoxamine to deferiprone in either the intention-to-treat analysis or in the 84 patients who completed 4 years of therapy. Because of concerns regarding the effectiveness of the studied dose of deferiprone, 47 patients discontinued therapy, whereas 15 patients interrupted therapy because of concerns regarding low iron levels. The results of this study help to define the safety and effectiveness of long-term therapy with deferiprone.