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Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial.
Magrin, E, Semeraro, M, Hebert, N, Joseph, L, Magnani, A, Chalumeau, A, Gabrion, A, Roudaut, C, Marouene, J, Lefrere, F, et al
Nature medicine. 2022;(1):81-88
Abstract
Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34+ cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling βA-T87Q-globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13-21 years, were treated after busulfan myeloablation 4.6-7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload.
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Population Pharmacokinetics and Exposure-Response Relationship of Luspatercept, an Erythroid Maturation Agent, in Anemic Patients With β-Thalassemia.
Chen, N, Kassir, N, Laadem, A, Giuseppi, AC, Shetty, J, Maxwell, SE, Sriraman, P, Ritland, S, Linde, PG, Budda, B, et al
Journal of clinical pharmacology. 2021;(1):52-63
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Abstract
β-Thalassemia is an inherited blood disorder resulting from defects in hemoglobin production, leading to premature death of red blood cells (RBCs) or their precursors. Patients with transfusion-dependent β-thalassemia often need lifelong regular RBC transfusions to maintain adequate hemoglobin levels. Frequent transfusions may lead to iron overload and organ damage. Thus, there is a large unmet need for alternative therapies. Luspatercept, a first-in-class erythroid maturation agent, is the first approved therapy in the United States for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. The population pharmacokinetics and exposure-response relationship of luspatercept were evaluated in 285 patients with β-thalassemia. Luspatercept displayed linear and time-invariant pharmacokinetics when administered subcutaneously once every 3 weeks. Body weight was the only clinically relevant covariate of luspatercept clearance, favoring weight-based dosing. Magnitude and frequency of hemoglobin increase, if not influenced by RBC transfusions, was positively correlated with luspatercept area under the serum concentration-time curve (AUC), 0.2-1.25 mg/kg, whereas a significant reduction in RBC units transfused was observed in frequently transfused patients. The probability of achieving ≥33% or ≥50% reduction in RBC transfusion burden was similar across the time-averaged AUC (0.6-1.25 mg/kg), with the 1 mg/kg starting dose sufficient for most early responders (71%-80%). Increasing luspatercept AUC (0.2-1.25 mg/kg) did not increase incidence or severity of treatment-emergent adverse events. These results provide a positive benefit-risk profile for the recommended luspatercept doses (1-1.25 mg/kg) in treating adult patients with β-thalassemia who require regular RBC transfusions.
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Erythroferrone, the new iron regulator: evaluation of its levels in Egyptian patients with beta thalassemia.
El-Gamal, RAE, Abdel-Messih, IY, Habashy, DM, Zaiema, SEG, Pessar, SA
Annals of hematology. 2020;(1):31-39
Abstract
Since iron overload is the commonest cause of morbidity and mortality in β thalassemia major (β-TM), it represents one major target in therapeutic management of the disease. The recently discovered erythroid regulator, erythroferrone (ERFE), governed by high levels of erythropoietin, was found to suppress hepcidin expression, thus increasing iron availability for developing erythroid progenitors. We aimed to investigate ERFE levels in Egyptian β-TM patients as an attempt to understand its role in the prediction of iron overload states. Our study included 70 β-TM patients, divided into two subgroups according to the degree of iron overload, and 30 sex and age-matched healthy subjects. ERFE gene expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), and serum hepcidin was measured using enzyme-linked immunosorbent assay (ELISA) technique. Both ERFE gene expression levels and transferrin saturation (TS%) values were able to discriminate among cases with different degrees of iron overload, in contrast to hepcidin. TS% was acknowledged as the best predictor of iron overload (AUC 0.893) in comparison with serum hepcidin and ERFE gene levels (AUC 0.807 and 0.677, respectively), and ERFE gene expression was an independent predictor for the estimated TS%. In conclusion, we suggest that using the ERFE gene expression, combined with serum hepcidin estimation, can substantiate the role of estimated TS% as a promising tool in screening for iron overload in β-TM patients.
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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
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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.
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Assessment of Serum Folic Acid and Homocysteine in Thalassemia Major Patients Before and After Folic Acid Supplement Cessation.
Baghersalimi, A, Hemmati Kolachahi, H, Darbandi, B, Kamran Mavardiani, Z, Alizadeh Alinodehi, M, Dalili, S, Hassanzadeh Rad, A
Journal of pediatric hematology/oncology. 2018;(7):504-507
Abstract
BACKGROUND Thalassemic patients have ineffective erythropoiesis. In recent treatment protocols, there are little data on folic acid supplementation for patients with thalassemia because it is supposed that regular blood transfusions prevent bone marrow hyperfunctioning. OBJECTIVE Investigators aimed to assess serum folic acid and homocysteine (Hcy) in thalassemia major patients before and after folic acid supplement cessation. PATIENTS AND METHODS This study was a before-after controlled clinical trial conducted in 17th Shahrivar Hospital, Rasht, North of Iran, during May to October 2016. The patients enrolled in this study had thalassemia major on regular blood transfusion and older than 2 years of age. They had at least a 6-month history of folic acid supplement consumption before enrollment in the study (1 mg/daily). Complete blood count, serum folic acid, and serum Hcy were measured before discontinuation of folic acid supplement. Then, patients did not receive folic acid for a month and after 1 month of folic acid cessation, the measurements were repeated. All data were entered in SPSS version 20.0 and analyzed. RESULTS Among the 40 patients in this study, 25 (62.5%) were female. The mean age of the participants was 21.39±11.17 years old. The mean of body mass index was 21.38±3.32 kg/m. Most of the participants had used folic acid supplement >5 years (29, 72.5%). The serum Hcy level was significantly increased (5.24±2.35 vs. 5.93±2.56; P=0.008) and serum folic acid level was decreased significantly (14.74±4.20 vs. 8.80±4.16; P<0.0001) from baseline. CONCLUSIONS Cessation of folic acid supplementations in beta thalassemia major patients can lead to a significant decrease in serum folic acid and increase in Hcy levels. According to our findings and efficacy of folic acid in patients with beta thalassemia major, it is recommended to use the supplementation in all patients.
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Inhaled nebulized sodium nitrite decreases pulmonary artery pressure in β-thalassemia patients with pulmonary hypertension.
Yingchoncharoen, T, Rakyhao, T, Chuncharunee, S, Sritara, P, Pienvichit, P, Paiboonsukwong, K, Sathavorasmith, P, Sirirat, K, Sriwantana, T, Srihirun, S, et al
Nitric oxide : biology and chemistry. 2018;:174-178
Abstract
Pulmonary hypertension is a life-threatening complication in β-thalassemia. Inhaled sodium nitrite has vasodilatory effect on pulmonary vasculature. However, its effect on pulmonary artery pressure (PAP) in β-thalassemia subjects with pulmonary hypertension has never been reported. In this study, we investigated the change in PAP during inhalation of sodium nitrite in 5 β-thalassemia patients. We demonstrated that sodium nitrite administered by nebulization rapidly decreased PAP as measured by echocardiography and right heart catheterization. The effect of nitrite was short as PAP returned to baseline at end of inhalation. Our findings support acute pulmonary vasodilation effect of nitrite in β-thalassemia with pulmonary hypertension.
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A randomized, controlled study evaluating effects of amlodipine addition to chelators to reduce iron loading in patients with thalassemia major.
Eghbali, A, Kazemi, H, Taherahmadi, H, Ghandi, Y, Rafiei, M, Bagheri, B
European journal of haematology. 2017;(6):577-581
Abstract
AIM: Cardiomyopathy due to iron overload can be fatal in patients with thalassemia major. Calcium channel blockers seem to be effective to reduce iron loading. Our goal was to study effects of amlodipine addition to chelators on iron loading in patients with thalassemia major. METHODS This randomized, controlled, and single-center trial was performed on 56 patients with thalassemia major. Patients were randomized 1:1 to combined group (iron chelator plus amlodipine) or control group (iron chelator) for 1 year. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. Serum ferritin was also measured. RESULTS After 12 months of treatment, myocardial T2* values had significant improvement in combined group (21.9 ± 8.0 ms to 24.5 ± 7.6 ms; P < .05); Difference between two groups was significant (P = .02). Combined treatment had no effect on hepatic T2* value (9.6 ± 2.8 ms to 9.5 ± 3.6 ms); difference between two groups was not significant (P = .2). In addition, a significant reduction was seen in serum ferritin levels in two groups. Mild gastrointestinal upset was the most common untoward effect. CONCLUSION Addition of amlodipine to iron chelators has beneficial effects for reduction of iron loading in patients with thalassemia major. This combination therapy seems safe.
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Five Years of Deferasirox Therapy for Cardiac Iron in β-Thalassemia Major.
Vlachaki, E, Agapidou, A, Spanos, G, Klonizakis, P, Vetsiou, E, Mavroudi, M, Boura, P
Hemoglobin. 2015;(5):299-304
Abstract
Myocardial siderosis in β-thalassemia major (β-TM) remains the leading cause of death. Deferasirox (DFX), a new iron chelation treatment, has proved to be effective in reducing or preventing cardiac iron burden in thalassemic patients according to clinical trials with maximum duration of up to 3 years except one that was recently published and lasted 5 years. The aim of this study was to evaluate the efficacy of DFX in reducing or preventing cardiac iron burden in 23 patients with β-TM after 5 years of therapy. All patients had a magnetic resonance imaging (MRI) T2* evaluation of their cardiac iron load before starting DFX therapy and after a period of 5 years. Ferritin levels and left ventricular ejection fraction (LVEF) were also evaluated at the same time. Deferasirox was administered in a starting dose of 30 mg/kg/day and never increased to more than 40 mg/kg/day. The MRI T2* cardiac iron load mean values before DFX was 32.82 ± 10.86 ms, and after 32.13 ± 7.74 ms, showing a stability in MRI T2* myocardial value but a significant improvement in two patients with an intermediate iron load (12 vs. 23 ms). The mean LVEF value was 68.43 ± 7.08% before treatment with DFX and 67.95 ± 5.94% after DFX therapy without significant change. Our results confirm previous studies that DFX is considered an effective chelating agent used as monotherapy for at least 5 years and is more efficacious in moderate to severe cardiac iron loaded thalassemic patients.
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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
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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.
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Lactose intolerance is not the cause of gastrointestinal adverse effects in beta thalassemia patients treated with deferasirox.
Pazgal, I, Brown, M, Perets, TT, Niv, Y, Rachmilewitz, E, Stark, P
American journal of hematology. 2014;(9):938-9