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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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β-Thalassemia: evolving treatment options beyond transfusion and iron chelation.
Langer, AL, Esrick, EB
Hematology. American Society of Hematology. Education Program. 2021;(1):600-606
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Abstract
After years of reliance on transfusion alone to address anemia and suppress ineffective erythropoiesis in β-thalassemia, many new therapies are now in development. Luspatercept, a transforming growth factor-β inhibitor, has demonstrated efficacy in reducing ineffective erythropoiesis, improving anemia, and possibly reducing iron loading. However, many patients do not respond to luspatercept, so additional therapeutics are needed. Several medications in development aim to induce hemoglobin F (HbF): sirolimus, benserazide, and IMR-687 (a phosphodiesterase 9 inhibitor). Another group of agents seeks to ameliorate ineffective erythropoiesis and improve anemia by targeting abnormal iron metabolism in thalassemia: apotransferrin, VIT-2763 (a ferroportin inhibitor), PTG-300 (a hepcidin mimetic), and an erythroferrone antibody in early development. Mitapivat, a pyruvate kinase activator, represents a unique mechanism to mitigate ineffective erythropoiesis. Genetically modified autologous hematopoietic stem cell transplantation offers the potential for lifelong transfusion independence. Through a gene addition approach, lentiviral vectors have been used to introduce a β-globin gene into autologous hematopoietic stem cells. One such product, betibeglogene autotemcel (beti-cel), has reached phase 3 trials with promising results. In addition, 2 gene editing techniques (CRISPR-Cas9 and zinc-finger nucleases) are under investigation as a means to silence BCL11A to induce HbF with agents designated CTX001 and ST-400, respectively. Results from the many clinical trials for these agents will yield results in the next few years, which may end the era of relying on transfusion alone as the mainstay of thalassemia therapy.
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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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4.
Hematopoietic stem cell transplantation for people with β-thalassaemia.
Sharma, A, Jagannath, VA, Puri, L
The Cochrane database of systematic reviews. 2021;(4):CD008708
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Abstract
BACKGROUND Thalassaemia is an autosomal recessive blood disorder, caused by mutations in globin genes or their regulatory regions, resulting in a reduced rate of synthesis of one of the globin chains that make up haemoglobin. In β-thalassaemia there is an underproduction of β-globin chains combined with excess of free α-globin chains. The excess free α-globin chains precipitate in red blood cells, leading to their increased destruction (haemolysis) and ineffective erythropoiesis. The conventional treatment is based on the correction of haemoglobin through regular red blood cell transfusions and treating the iron overload that develops subsequently with iron chelation therapy. Although, early detection and initiations of such supportive treatment has improved the quality of life for people with transfusion-dependent thalassaemia, allogeneic hematopoietic stem cell transplantation is the only widely available therapy with a curative potential. Gene therapy for β-thalassaemia has recently received conditional authorisation for marketing in Europe, and may soon become widely available as another alternative therapy with curative potential for people with transfusion-dependent thalassaemia. This is an update of a previously published Cochrane Review. OBJECTIVES To evaluate the effectiveness and safety of different types of hematopoietic stem cell transplantation, in people with transfusion-dependent β-thalassaemia. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. Date of the most recent search: 07 April 2021. SELECTION CRITERIA Randomised controlled trials and quasi-randomised controlled trials comparing hematopoietic stem cell transplantation with each other or with standard therapy (regular transfusion and chelation regimen). DATA COLLECTION AND ANALYSIS Two review authors independently screened trials and had planned to extract data and assess risk of bias using standard Cochrane methodologies and assess the quality using GRADE approach, but no trials were identified for inclusion in the current review. MAIN RESULTS No relevant trials were retrieved after a comprehensive search of the literature. AUTHORS' CONCLUSIONS We were unable to identify any randomised controlled trials or quasi-randomised controlled trials on the effectiveness and safety of different types of hematopoietic stem cell transplantation in people with transfusion-dependent β-thalassaemia. The absence of high-level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately-powered, randomised controlled clinical trials.
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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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Alpha-hemoglobin-stabilizing protein (AHSP): a modulatory factor in β-thalassemia.
Che Yaacob, NS, Islam, MA, Alsaleh, H, Ibrahim, IK, Hassan, R
International journal of hematology. 2020;(3):352-359
Abstract
Hemoglobin (Hb) is an iron-containing metalloprotein that transports oxygen molecules from the lungs to the rest of the human body. Among the different variants of Hb, HbA1 is the most common and is composed of two alpha (αHb) and two beta globin chains (βHb) constructing a heterotetrameric protein complex (α2β2). Due to the higher number of AHSP genes, there is a tendency to produce approximately twice as much of α subunit as β subunit. Therefore, there is a chance of presenting excess α subunit leftover in human blood plasma; excess subunits subsequently bind with each other and aggregates β-thalassemia occurs due to lack of or reduced numbers of βHb subunit. Alpha-hemoglobin-stabilizing protein (AHSP) is a scavenger protein which acts as a molecular chaperon by reversibly binding with free αHb forming a complex (AHSP-αHb) that prevents aggregation and precipitation preventing deleterious effects towards developing serious human diseases including β-thalassemia. Clinical severity worsens if mutations in AHSP gene co-occur in patients with β-thalassemia. Considering the mechanism of action of AHSP and its contribution to ameliorating β-thalassemia severity, it could potentially be used as a modulatory agent in the treatment of β-thalassemia.
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An Evaluation of Bone Health Parameters in Regularly Transfused Beta-Thalassemia Major Patients.
Kothimira, VK, Kumar, A, Richhele, LR, Sood, N, Gulati, A
Journal of pediatric hematology/oncology. 2020;(6):381-385
Abstract
As beta-thalassemia major patients need regular blood transfusions due to the severe hemoglobin deficiency, the occurrence of related bone defects with simultaneous fluctuations in the biochemical and hematologic parameters is seen. The hospital-based cross-sectional observational study was done to determine and correlate the bone mineral density (BMD) with biochemical parameters and hematologic parameters in 50 regularly transfused beta-thalassemia major patients of older than 6 years of age. Descriptive statistics were analyzed with SPSS version 20.0 software. A P<0.05 was considered as statistically significant. The prevalence of suboptimal BMD at lumbar spine was 86% and at femur neck was 74%. A statistically significant correlation of BMD was found with mean pretransfusion hemoglobin values, serum calcium levels, and serum vitamin D levels (P<0.05). It was concluded that continuous monitoring of the BMD, biochemical, and hematologic parameters in regularly transfused beta-thalassemia major patients may help assess the ongoing deficiencies; helping to maintain timely and regular blood transfusions with supplementation of calcium, vitamin D to ensure good bone health.
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Ocular abnormalities in beta thalassemia patients: prevalence, impact, and management strategies.
Heydarian, S, Jafari, R, Dailami, KN, Hashemi, H, Jafarzadehpour, E, Heirani, M, Yekta, A, Mahjoob, M, Khabazkhoob, M
International ophthalmology. 2020;(2):511-527
Abstract
BACKGROUND Beta thalassemia (β-thalassemia) is a hereditary disease caused by defective globin synthesis and can be classified into three categories of minor (β-TMi), intermedia (β-TI), and major (β-TM) thalassemia. The aim of our study is to investigate the effects of β-thalassemia and its treatment methods on different parts of the eye and how early-diagnostic methods of ocular complications in this disorder would prevent further ocular complications in these patients by immediate treatment and diet change. METHODS We developed a search strategy using a combination of the words Beta thalassemia, Ocular abnormalities, Iron overload, chelation therapy to identify all articles from PubMed, Web of Science, Scopus, and Google Scholar up to December 2018. To find more articles and to ensure that databases were thoroughly searched, the reference lists of selected articles were also reviewed. RESULTS Complications such as retinopathy, crystalline lens opacification, color vision deficiency, nyctalopia, depressed visual field, reduced visual acuity, reduced contrast sensitivity, amplitude reduction in a-wave and b-wave in Electroretinography (ERG), and decrease in the Arden ratio in Electrooculography (EOG) have all been reported in β-thalassemia patients undergoing chelation therapy. CONCLUSION Ocular problems due to β-thalassemia may be a result of anemia, iron overload in the body tissue, side effects of iron chelators, and the complications of orbital bone marrow expansion.
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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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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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Pantoprazole reduces serum ferritin in patients with thalassemia major and intermedia: A randomized, controlled study.
Eghbali, A, Khalilpour, A, Taherahmadi, H, Bagheri, B
Therapie. 2019;(5):507-512
Abstract
AIM: Complications due to iron overload exert a problematic situation in patients with thalassemia. Proton pump inhibitors (PPIs) like pantoprazole are effective agents to reduce acid gastric acid secretion and perhaps to interrupt iron absorption in conditions with increased iron absorption. Our purpose was to study effects of pantoprazole addition to chelators on iron levels in patients with thalassemia major and intermedia. METHODS This randomized, controlled, and single center trial was performed on 60 patients with thalassemia major and intermedia in Amir Kabir hospital, Iran. Patients were randomized 1:1 to pantoprazole group (iron chelator plus pantoprazole) or control group (iron chelator) for 6 months. Serum ferritin was measured by ELISA. Iron content was measured by magnetic resonance imaging; heart T2*, and liver T2*. RESULTS After 6 months of treatment, a significant reduction was seen in serum ferritin levels in the pantoprazole group (1444±613μg/mL to 1197±956μg/mL; P<0.001). A further reduction was seen in patients with thalassmeia intermedia. There were no significant changes in myocardial T2* values in pantoprazole group compared to control group (23.6±7.3ms to 24.1±6.4ms). Compared to the control group, pantoprazole therapy had no effect on hepatic T2* value (9.7±2.3ms to 9.8±2.6ms). However, between-group difference was significant (P<0.05). CONCLUSION Pantoprazole therapy for 6 months has benefits for reducing serum ferritin in patients with thalassemia major and intermedia. Pantoprazole addition to iron chelators seems safe.