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1.
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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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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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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Dual-energy X-ray absorptiometry pitfalls in Thalassemia Major.
Pellegrino, F, Zatelli, MC, Bondanelli, M, Carnevale, A, Cittanti, C, Fortini, M, Gamberini, MR, Giganti, M, Ambrosio, MR
Endocrine. 2019;(3):469-482
Abstract
BACKGROUND Low mineral mass and reduced bone strength with increased fracture risk are the main causes of morbidity in Thalassemia Major (TM). The pathogenesis is multifactorial and includes ineffective erythropoiesis with medullary expansion, multiple endocrine dysfunctions, direct iron bone deposition, deferoxamine-induced bone dysplasia, and reduced physical activity associated with disease complications. Dual-energy X-ray absorptiometry (DXA) is the "gold standard" for bone mineral density (BMD) assessment and for bone strength and quality evaluation. This method identifies patients at greater risk of fragility fractures, guiding treatment and monitoring response to therapy. In TM, DXA shows limitations concerning BMD calculation accuracy and fracture risk prediction. One of the main challenges in the assessment of bone health in patients with TM is the accurate interpretation of densitometric results. PURPOSE This review investigates the major pitfalls in DXA implementation and interpretation in TM. METHODS Available literature has been assessed. CONCLUSIONS DXA shows limitations in assessing bone mineral "status" in TM, especially in the paediatric population, due to the peculiar characteristics of bone architecture and deformities associated with the disease. A radiological technique adjustment in this population is mandatory.
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Pathogenesis of Thalassemia Major-associated Osteoporosis: A Review with Insights from Clinical Experience.
Gaudio, A, Morabito, N, Catalano, A, Rapisarda, R, Xourafa, A, Lasco, A
Journal of clinical research in pediatric endocrinology. 2019;(2):110-117
Abstract
Due to increasing life expectancy in thalassemia major (TM), osteoporosis is emerging as a significant problem. Its aetiology is multifactorial, culminating in increased bone resorption and impaired remodelling. Hypogonadism and marrow expansion seem to play an important role, but iron overload, deferoxamine toxicity, a defective growth hormone-insulin-like growth factor-1 axis and multiple endocrinopathies may represent additional causes of bone damage. Many of these patients, though under appropriate treatment programs, do not achieve normal peak bone mass. The receptor activator of nuclear factor kappa-ß (RANK)/RANK ligand/osteoprotegerin and the Wnt/β-catenin systems work as major mediators of imbalanced bone turnover and bone loss. Additional genetic factors, such as collagen type 1 alpha 1 and vitamin D receptor gene polymorphisms, may exert some influence on the enhanced fracture risk observed in TM. To date, in spite of adequate hormone replacement, chelating therapy and acceptable haemoglobin levels, subjects with TM display impaired bone density and imbalanced bone turnover, thus the puzzle of the pathogenesis of TM-induced osteoporosis remains far from being solved.
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Atrial fibrillation in β-thalassemia Major Patients: Diagnosis, Management and Therapeutic Options.
Barbero, U, Fornari, F, Guarguagli, S, Gaglioti, CM, Longo, F, Doronzo, B, Anselmino, M, Piga, A
Hemoglobin. 2018;(3):189-193
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Abstract
The prevalence of atrial fibrillation (AFib) in β-thalassemia major (β-TM) patients has increased in the last few years, reaching up to 33.0%. Several factors may drive this value to even more in the next few years. We summarized the main challenges in the management and therapy of AFib in this very specific group of patients.
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Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia.
Sadaf, A, Hasan, B, Das, JK, Colan, S, Alvi, N
The Cochrane database of systematic reviews. 2018;(7):CD011626
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Abstract
BACKGROUND Beta thalassaemia is a common inherited blood disorder. The need for frequent blood transfusions in this condition poses a difficult problem to healthcare systems. The most common cause of morbidity and mortality is cardiac dysfunction from iron overload. The use of iron chelation therapy has reduced the severity of systemic iron overload but specific, non-toxic treatment is required for removal of iron from the myocardium. OBJECTIVES To assess the effects of calcium channel blockers combined with standard iron chelation therapy in people with transfusion-dependent beta thalassaemia on the amount of iron deposited in the myocardium, on parameters of heart function, and on the incidence of severe heart failure or arrhythmias and related morbidity and mortality. SEARCH METHODS We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials databases, and the reference lists of relevant articles and reviews.Date of last search: 24 February 2018. SELECTION CRITERIA We included randomised controlled trials of calcium channel blockers combined with standard chelation therapy compared with standard chelation therapy alone or combined with placebo in people with transfusion-dependent beta thalassaemia. DATA COLLECTION AND ANALYSIS Two authors independently applied the inclusion criteria for the selection of trials. Two authors assessed the risk of bias of trials and extracted data and a third author verified these assessments. The authors used the GRADE system to assess the quality of the evidence. MAIN RESULTS Two randomised controlled trials (n = 74) were included in the review; there were 35 participants in the amlodipine arms and 39 in the control arms. The mean age of participants was 24.4 years with a standard deviation of 8.5 years. There was comparable participation from both genders. Overall, the risk of bias in included trials was low. The quality of the evidence ranged across outcomes from low to high, but the evidence for most outcomes was judged to be low quality.Cardiac iron assessment, as measured by heart T2*, did not significantly improve in the amlodipine groups compared to the control groups at six or 12 months (low-quality evidence). However, myocardial iron concentration decreased significantly in the amlodipine groups compared to the control groups at both six months, mean difference -0.23 mg/g (95% confidence interval -0.07 to -0.39), and 12 months, mean difference -0.25 mg/g (95% confidence interval -0.44 to -0.05) (low-quality evidence). There were no significant differences between treatment and control groups in serum ferritin (low-quality evidence), liver T2* (low-quality evidence), liver iron content (low-quality evidence) and left ventricular ejection fraction (low-quality evidence). There were no serious adverse events reported in either trial; however, one trial (n = 59) reported mild adverse events, with no statistically significant difference between groups (low-quality evidence). AUTHORS' CONCLUSIONS The available evidence does not clearly suggest that the use of calcium channel blockers is associated with a reduction in myocardial iron in people with transfusion-dependent beta thalassaemia, although a potential for this was seen. There is a need for more long-term, multicentre trials to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should be designed to compare commonly used iron chelation drugs with the addition of calcium channel blockers to investigate the potential interplay of these treatments. In addition, the role of baseline myocardial iron content in affecting the response to calcium channel blockers should be investigated. An analysis of the cost-effectiveness of the treatment is also required.
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Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment.
De Sanctis, V, Soliman, AT, Yassin, MA, Di Maio, S, Daar, S, Elsedfy, H, Soliman, N, Kattamis, C
Acta bio-medica : Atenei Parmensis. 2018;(2-S):6-15
Abstract
Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are frequent and well recognized disturbances among male patients with transfusion dependent (TD) thalassaemia major (β-thal). These problems are attributed mainly to the damage caused by chronic anaemia and the deposition of excess iron in the pituitary gland and testicles. This is a short review of male pubertal disorders in patients with β-thal written by pediatric endocrinologists and haematologists with an interest and active involvement, in the diagnosis and management of these complications in this group of patients. A vigilant clinical evaluation of growth and puberty, as well as an appropriate hormonal evaluation in poly-transfused (TD β-thal) patients is strongly recommended for early detection and treatment of endocrine dysfunction. Of crucial importance also, is the implementation of an efficient chelation regime from early life, to prevent severe iron load and permanent damage to the endocrine glands, particularly those responsible for gonadal function.
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How I manage medical complications of β-thalassemia in adults.
Taher, AT, Cappellini, MD
Blood. 2018;(17):1781-1791
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Abstract
The complex pathophysiology in β-thalassemia can translate to multiple morbidities that affect every organ system. Improved survival due to advances in management means that patients are exposed to the harmful effects of ineffective erythropoiesis, anemia, and iron overload for a longer duration, and we started seeing new or more frequent complications in adult compared with younger patients. In this article, we highlight particular aspects of managing adult patients with β-thalassemia, using our own experience in treating such patients. We cover both transfusion-dependent and nontransfusion-dependent forms of the disease and tackle specific morbidities of highest interest.
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The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major.
Di Maggio, R, Maggio, A
British journal of haematology. 2017;(5):676-688
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Abstract
This review outlines the effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major (TM). For each treatment, the strength of the evidence was documented according to the guidelines of the American College of Cardiology and the American Heart Association. Serum ferritin (SF), liver iron concentration (LIC), heart T2* signal, heart damage and survival were used to assess effectiveness. Five chelation regimens out of 10 showed Level A Evidence in controlling iron overloading, as determined by SF levels and LIC. Three out of 10 chelation regimens were able to control heart iron levels, as determined by T2* signals with Level A Evidence. Two chelation regimens were able to improve/reverse heart damage and four increased of survival with Level B Evidence. These advances mean that the current survival of TM patients is now similar to that of thalassaemia intermedia patients.