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In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent β-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6 years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2 years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging., (© 2024 Wiley Periodicals LLC.)

Background: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs)., Methods: We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent β-thalassemia and a β 0 /β 0 , β 0 /β 0 -like, or non-β 0 /β 0 -like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed., Results: A total of 52 patients with transfusion-dependent β-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred., Conclusions: Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.)., (Copyright © 2024 Massachusetts Medical Society.)

A hypercoagulable state leading to increased risk for thrombotic events represents one of the most common complications observed in transfusion-dependent β-thalassemia (TDT) patients. TDT patients have increased frequencies of circulating activated platelets. However, there is no information so far if platelets from TDT patients can activate T cells. In the present study we showed that T cells treated with platelets from TDT patients showed significant increased surface expression of CD69 compared to the T cells treated with platelets from healthy individuals. Patients with splenectomy showed increased T cell activation compared to patients with intact spleen. No T cell activation was observed following incubation with plasma alone, nor with platelets from healthy subjects. The percentages of regulatory T cells (Tregs) were also examined. TDT patients showed statistically significant increased percentages of Tregs compared to healthy controls. Additionally, we observed a positive statistically significant correlation between the percentages of Tregs and the platelet-induced activated T cells in patients who were not treated with aspirin. TDT patients showed increased levels of sP-selectin, suPAR and GDF-15, molecules implicated in platelet activation. We show that platelets from TDT patients can activate T cells in vitro. This activation correlates with markers of platelet activation and increased numbers of Tregs, perhaps in an effort to eliminate immune dysregulation, conceivably secondary to platelet activation., (Copyright © 2023. Published by Elsevier Inc.)

Patients with transfusion-dependent β-thalassaemia require lifelong, regular red blood cell transfusions for survival; however, frequent blood transfusions are associated with an increased risk of iron overload, transfusion-transmitted disease and alloimmunization, as well as reduced quality of life. Luspatercept, an erythroid maturation agent that promotes late-stage erythroid maturation independently of erythropoietin, has demonstrated efficacy in reducing transfusion burden in patients with transfusion-dependent β-thalassaemia. In this review, we discuss treatment initiation, ongoing evaluation, dose adjustment and management of adverse events in transfusion-dependent patients with β-thalassaemia receiving luspatercept, and we provide guidance on how to determine whether patients are deriving clinical benefit., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Over the past decade, evidence has been mounting on the detrimental clinical sequelae of untreated anemia in patients with non-transfusion-dependent β-thalassemia (NTDT). There are no pharmacologic agents that are specifically approved for the management of anemia in NTDT, and available options such as splenectomy, transfusion therapy, and hydroxyurea each come with their own shortcomings, especially for long-term use. Luspatercept is an erythroid maturation agent that has been evaluated in a Phase 2, randomized trial and showed a significant benefit in raising hemoglobin level by at least 1 g/dL in adults with NTDT and a baseline hemoglobin level ≤10 g/dL. These data led to luspatercept's approval by the European Commission for the treatment of anemia in adults with NTDT and presents the first evidence-based approach for a novel agent that is able to ameliorate anemia in this patient population., Competing Interests: K.M.M. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Agios Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos; and research funding from Agios Pharmaceuticals and Pharmacosmos. A.T.T. reports consultancy fees Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma, Silence Therapeutics and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and Agios Pharmaceuticals. A.K. reports receiving advisory board fees and consulting fees from Agios Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor Pharma; and research support, paid to his institution, from Celgene/Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb, Chiesi Farmaceutici, CRISPR Therapeutics/Vertex, and Novartis; and personal fees from Bristol Myers Squibb. K.H.M.K. reports consultancy fees from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio, Celgene/Bristol Myers Squibb, Forma, Pfizer, Novo Nordisk, Vertex, and Novartis; honoraria from Alexion and Novartis; membership on an advisory committee for Agios Pharmaceuticals and Bioverativ/Sanofi/Sangamo; and research funding from Pfizer. S.S. reports consultancy fees from Agios Pharmaceuticals, Bluebird bio, Bristol Myers Squibb, Forma, and Chiesi; and serving on a clinical trial steering committee for CRISPR/Vertex CTX001 for thalassemia. M.D.C. reports consultancy fees from Novartis, Celgene/Bristol Myers Squibb, Vifor Pharma and Ionis Pharmaceuticals; and research funding from Novartis, Celgene/Bristol Myers Squibb, La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics, and CRISPR Therapeutics. The authors report no other conflicts of interest in this work., (© 2023 Musallam et al.)

Objectives: The non-transfusion-dependent beta-thalassaemia-patient-reported outcome (NTDT-PRO) questionnaire was developed for assessing anaemia-related tiredness/weakness (T/W) and shortness of breath (SoB) among patients with NTDT. Psychometric properties were evaluated using blinded data from the BEYOND trial (NCT03342404)., Design: Analysis of a phase 2, double-blind, randomised, placebo-controlled trial., Setting: USA, Greece, Italy, Lebanon, Thailand and the UK., Participants: Adults (≥18 years) (N=145) with NTDT who had not received a red blood cell transfusion within 8 weeks prior to randomisation, with mean baseline haemoglobin level ≤100 g/L., Measures: NTDT-PRO daily scores from baseline until week 24, and scores at select time points for the 36-Item Short Form Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Patient Global Impression of Severity (PGI-S)., Results: Cronbach's alpha at weeks 13-24 was 0.95 and 0.84 for the T/W and SoB domains, respectively, indicating acceptable internal consistency reliability. Among participants self-reporting no change in thalassaemia symptoms via the PGI-S between baseline and week 1, intraclass correlation coefficients were 0.94 and 0.92 for the T/W and SoB domains, respectively, indicating excellent test-retest reliability. In a known-groups validity analysis, least-squares mean T/W and SoB scores at weeks 13-24 were worse in participants with worse scores for the FACIT-F Fatigue Subscale (FS), SF-36v2 vitality or PGI-S. Indicating responsiveness, changes in T/W and SoB domain scores were moderately correlated with changes in haemoglobin levels, and strongly correlated with changes in SF-36v2 vitality, FACIT-F FS, select FACIT-F items and the PGI-S. Improvements in least-squares mean T/W and SoB scores were higher in participants with greater improvements in scores on other PROs measuring similar constructs., Conclusions: The NTDT-PRO demonstrated adequate psychometric properties to assess anaemia-related symptoms in adults with NTDT and can be used to evaluate treatment efficacy in clinical trials., Competing Interests: Competing interests: ATT—consulting fees from Agios Pharmaceuticals; research funding and consulting fees from Celgene/Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis Pharmaceuticals and Vifor Pharma. KMM—consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Novartis, Pharmacosmos and Vifor Pharma. VV—research funding from Bristol Myers Squibb. AK—advisory board fees and consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, Chiesi Farmaceutici, CRISPR Therapeutics/Vertex Pharmaceuticals, Ionis Pharmaceuticals, Novartis and Vifor Pharma; research support from Celgene/Bristol Myers Squibb and Novartis. JL-B, AY, JKS and LMB—employment by and stock/equity holder of Bristol Myers Squibb. SG—employment by Evidera; consultancy fees from Bristol Myers Squibb, Gilead and Janssen. CP—employment by Evidera. ALS—employment by Adelphi Values. DM—employment by Bristol Myers Squibb. MDC—advisory board fees from Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Ionis Pharmaceuticals, Novartis, Novo Nordisk, Sanofi Genzyme and Vifor Pharma., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Adults with β- thalassemia major (β-TM) develop low BMD and fragility fractures at a higher incidence and at a younger age compared to the general population. The disease itself, including direct effects of anemia and iron overload toxicity on bone turnover, genetic susceptibility, thalassemia-related endocrinopathies and acquittance of suboptimal peak bone mass contribute to low bone mass and increased bone fragility frequently encountered among these patients. Current management of osteoporosis requires long-term treatment that can be provided by agents that reduce the risk of all osteoporotic fractures by modulating bone metabolism with different mechanisms of action. These include inhibitors of bone remodeling (e.g., bisphosphonates, denosumab) and stimulators of bone formation (e.g., PTHR1 agonists and sclerostin antibodies). Considering the unique characteristics of osteoporosis associated with β-TM and the clinical importance of balancing the risk/benefit of treatment in the long-term, appropriate use of these therapeutic approaches is essential for patient care. In this review we outline current literature on the use of anti-osteoporotic drugs in β-TM patients with osteoporosis focusing on data on the efficacy, safety, and duration of treatment. In addition, we propose a long-term management plan for β-TM -associated osteoporosis aiming at the optimal patient care for this special population.

Background: In patients with non-transfusion-dependent β-thalassaemia, haemoglobin concentrations lower than 10 g/dL are associated with a higher risk of morbidity, mortality, and impaired quality of life. No drugs are specifically approved for anaemia management in patients with non-transfusion-dependent β-thalassaemia, other than transfusion therapy administered infrequently in accordance with patients' needs. We assessed the efficacy and safety of luspatercept versus placebo in patients with non-transfusion-dependent β-thalassaemia., Methods: We did a phase 2, randomised, double-blind, multicentre, placebo-controlled trial in 12 centres in six countries (Thailand [n=1], Lebanon [n=1], Greece [n=2], Italy [n=5], the UK [n=1], and the USA [n=2]). Eligible patients were aged 18 years or older, had confirmed diagnosis of β-thalassaemia or haemoglobin E/β-thalassaemia (concomitant α-globin deletion, mutation, or duplication were allowed), and a baseline haemoglobin concentration of 10·0 g/dL or lower. All patients were non-transfusion-dependent. Patients were randomly assigned (2:1) to luspatercept or placebo using an interactive response technology system and stratified by baseline haemoglobin concentration (≥8·5 g/dL vs <8·5 g/dL) and baseline Non-Transfusion-Dependent β-thalassaemia-Patient-Reported Outcome Tiredness/Weakness domain score (≥3 vs <3). All patients, study site staff, and sponsor representatives (who reviewed the data), except for designated individuals, were masked to drug assignment until the time the study was unblinded. Luspatercept or placebo was given once subcutaneously every 3 weeks for 48 weeks in the double-blind treatment period. Luspatercept was started at 1·0 mg/kg with titration up to 1·25 mg/kg, or reduction in the event of toxicity or excessive haemoglobin concentration increase. The primary endpoint was achievement of an increase from baseline of 1·0 g/dL or higher in mean haemoglobin concentration over a continuous 12-week interval during weeks 13-24, in the absence of transfusions. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03342404, and is ongoing., Findings: Between Feb 5, 2018, and Oct 14, 2019, 160 patients were screened for eligiblity, of whom 145 were randomly assigned to luspatercept (n=96) or placebo (n=49). 82 (57%) patients were female and 63 (43%) were male. 44 (30%) patients were Asian, 87 (60%) were White, and 14 (10%) identified as another race. The study met its primary endpoint: 74 (77%) of 96 patients in the luspatercept group and none in the placebo group had an increase of at least 1·0 g/dL in haemoglobin concentration (common risk difference 77·1 [95% CI 68·7-85·5]; p<0·0001). The proportion of patients with serious adverse events was lower in the luspatercept group than in the placebo group (11 [12%] vs 12 [25%]). Treatment-emergent adverse events most commonly reported with luspatercept were bone pain (35 [37%]), headache (29 [30%]), and arthralgia (28 [29%]). No thromboembolic events or deaths were reported during the study., Interpretation: Luspatercept represents a potential treatment for adult patients with non-transfusion-dependent β-thalassaemia, for whom effective approved treatment options are scarce., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests ATT reports receiving consulting fees from Agios Pharmaceuticals; and research funding and consulting fees from Celgene/Bristol Myers Squibb, Ionis Pharmaceuticals, Novartis Pharmaceuticals, and Vifor Pharma. MDC reports receiving advisory board fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Novo Nordisk, Sanofi Genzyme, Silence Therapeutics, and Vifor Pharma. AK reports receiving advisory board fees and consulting fees from Agios Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor Pharma; and research support, paid to his institution, from Celgene/Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb, Chiesi Farmaceutuici, CRISPR Therapeutics/Vertex, and Novartis; and personal fees from Bristol Myers Squibb. SP reports receiving grant support, paid to his institution, from Novartis, and personal fees from bluebird bio and Celgene. AGP reports receiving grant support, paid to his institution, from Acceleron Pharma and Celgene, and advisory board fees from Celgene. AF reports advisory board fees from Celgene and grant support, paid to his institution, from bluebird bio and Novartis. JBP reports receiving advisory board fees from bluebird bio, Bristol Myers Squibb, Silence Therapeutics, and Vifor Pharma. TDC reports receiving consultancy fees from Agios Pharmaceuticals, bluebird bio, Bristol Myers Squibb/Celgene, Chiesi Farmaceutici, and Vifor Pharma. GLF reports receiving consulting fees and grant support, paid to his institution, from Agios Pharmaceuticals, Bristol Myers Squibb, and Novartis; and advisory board fees from Bristol Myers Squibb and Novartis; honoraria for lectures, presentations or speakers’ bureau from Bristol Myers Squibb and Novartis. AA Thompson reports receiving grant support from Baxalta, Biomarin, bluebird bio, Celgene/Bristol Myers Squibb, CRISPR Therapeutics/Vertex, Editas Medicine, and Novartis; and consulting fees from bluebird bio, Celgene/Bristol Myers Squibb, and CRISPR Therapeutics/Vertex; fees for leadership of fiduciary role in a committee or advocacy group from Global Blood Therapeutics; previous employment (last 12 months) at Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; and current employment at Children's Hospital of Philadelphia, Philadelphia, PA, USA. IT reports receiving honoraria from Celgene. KMM reports receiving consulting fees from Agios Pharmaceuticals, Celgene/Bristol Myers Squibb, CRISPR Therapeutics, Novartis, and Vifor Pharma. JTB reports ending employment at Acceleron Pharma in the last 12 months and owning stock in Acceleron Pharma, and Bristol Myers Squibb. OE, W-LK, and DM report being employed by Bristol Myers Squibb. ACG, JL-B, AY, and JKS report being employed by and owning stock in Bristol Myers Squibb. TZ reports ending employment at Bristol Myers Squibb in the last 24 months and owning stock in Bristol Myers Squibb. EV and VV report no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: I have received research funding to my institution from Novartis and Bristol Myers Squib (unrelated to this topic); consulting fees for participation in advisory committees in providing scientific guidance regarding the clinical development of thalassaemia programmes and the phase 3 studies from Agios Pharmaceuticals (related to mitapivat; fees paid to my institution); consulting fees from Bristol Myers Squib, Crispr/Vertex, Ionis Pharmaceuticals, Novartis, and Vifor (related to other treatments for thalassaemia; fees are paid to my institution); honoraria for lectures on the treatment of thalassaemia and sickle cell disease from Bristol Myers Squib, Crispr/Vertex, Chiesi, and Novartis; and travel support for attending meetings from Bristol Myers Squib.

Thalassaemia is a diverse group of genetic disorders with a worldwide distribution affecting globin chain synthesis. The pathogenesis of thalassaemia lies in the unbalanced globin chain production, leading to ineffective erythropoiesis, increased haemolysis, and deranged iron homoeostasis. The clinical phenotype shows heterogeneity, ranging from close to normal without complications to severe requiring lifelong transfusion support. Conservative treatment with transfusion and iron chelation has transformed the natural history of thalassaemia major into a chronic disease with a prolonged life expectancy, albeit with co-morbidities and substantial disease burden. Curative therapy with allogeneic haematopoietic stem cell transplantation is advocated for suitable patients. The understanding of the pathogenesis of the disease is guiding therapeutic advances. Novel agents have shown efficacy in improving anaemia and transfusion burden, and initial results from gene therapy approaches are promising. Despite scientific developments, worldwide inequality in the access of health resources is a major concern, because most patients live in underserved areas., Competing Interests: Declaration of interests AK reports consultation fees from Agios Pharmaceuticals, Amgen, Ionis Pharmaceuticals, and Vifor; consultation fees, research funding, honoraria, and travel support from Bristol Myers Squibb; honoraria from Chiesi; consultancy and honoraria from Crispr Therpeutics and Vertex Pharmaceuticals; and consultation fees, honoraria, and research funding from Novartis, outside of the submitted work. YA reports research funding and consultation fees from Bristol Myers Squibb; research funding and honoraria from Cerus and Novartis; consultation fees from CRISPR Therapeutics and SLN Therapeutics; and research funding from Imara, Ionis Pharmaceuticals, LaJolla, Protagonist, and Resonance Health, outside of the submitted work. JLK reports consultation fees from Agios Pharmaceuticals, Bristol Myers Squibb, and Silence Therapeutics; research funding from Bioverativ, Crispr Therpeutics and Vertex Pharmaceuticals, Editas, Sangamo, and Terumo BCT; and consultation fees and research funding from bluebird bio, Imara, Chiesi, and Forma Therapeutics, outside of the submitted work. JLK also acknowledges grant funding from the National Institutes of Health., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations., Study Design and Method: A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network., Results: Eight  thalassemia care Centers [Bulgaria, Greece, Iran, Italy (4 Centers) and Qatar], following 1.554 with transfusion-dependent thalassemia (TDT), 132 (8.4%) with diabetes and 687 with non-transfusion-dependent thalassemia (NTDT), 27 (3.9%) with diabetes, participated in the retrospective survey. The records of 117 TDT patients and 9 NTDT patients with diabetes treated with GLAs were analyzed. Metformin, a biguanide, was the most frequently used drug (47.6 %), followed by alpha-glucosidase inhibitors (5.5 %), incretins (4.7%) and insulin secretagogues (3.1%).  In 68 (61.2) patients  GLAs was prescribed as monotherapy, while the remaining  49  (38.8%), who had inadequate glucose control with metformin, were treated with combination treatment. Fifty-one patients  of 126 (40.4%) initially treated with oral GLA, for a mean duration of 61.0 ± 35.6 months (range: 12- 120 months), required insulin therapy for better metabolic control., Conclusion: This retrospective study covers an unexplored area of research in patients with thalassemia and GD. Oral GLAs appear to be safe and effective for the treatment of diabetes mellitus in patients with thalassemia, and can achieve adequate glycemic control for a substantial period of time.

Introduction: β-thalassemia is one of the most common inherited monogenic diseases. Many patients are dependent on a lifetime of red blood cell (RBC) transfusions and iron chelation therapy. Although treatments have a significant impact on quality of life (QoL), life expectancy, and long-term health outcomes have improved in recent decades through safer RBC transfusion practices and better iron chelation strategies. Advances in the understanding of the pathology of β-thalassemia have led to the development of new treatment options that have the potential to reduce the RBC transfusion burden in patients with transfusion-dependent (TD) β-thalassemia and improve QoL., Areas Covered: This review provides an overview of currently available treatments for patients with TD β-thalassemia, highlighting QoL issues, and providing an update on current clinical experience plus important practical points for two new treatments available for TD β-thalassemia: betibeglogene autotemcel (beti-cel) gene therapy and the erythroid maturation agent luspatercept, an activin ligand trap., Expert Opinion: Approved therapies, including curative gene therapies and supportive treatments such as luspatercept, have the potential to reduce RBC transfusion burden, and improve clinical outcomes and QoL in patients with TD β-thalassemia. Cost of treatment is, however, likely to be a significant barrier for payors and patients.

Introduction: In β-thalassemia, imbalanced globin synthesis causes reduced red blood cell survival and ineffective erythropoiesis. Suppressed hepcidin levels increase ferroportin-mediated iron transport in enterocytes, causing increased iron absorption and potentially iron overload. Low hepcidin also stimulates ferroportin-mediated iron release from macrophages, increasing transferrin saturation (TSAT), potentially forming non-transferrin-bound iron, which can be toxic. Modulating the hepcidin-ferroportin axis is an attractive strategy to improve ineffective erythropoiesis and limit the potential tissue damage resulting from iron overload. There are no oral β-thalassemia treatments that consistently ameliorate anemia and prevent iron overload., Areas Covered: The preclinical and clinical development of vamifeport (VIT-2763), a novel ferroportin inhibitor, was reviewed. PubMed, EMBASE and ClinicalTrials.gov were searched using the search term 'VIT-2763'., Expert Opinion: Vamifeport is the first oral ferroportin inhibitor in clinical development. In healthy volunteers, vamifeport had comparable safety to placebo, was well tolerated and rapidly decreased iron levels and reduced TSAT, consistent with observations in preclinical models. Data from ongoing/planned Phase II studies are critical to define its potential in β-thalassemia and other conditions associated with iron overabsorption and/or ineffective erythropoiesis. If vamifeport potentially increases hemoglobin and reduces iron-related parameters, it could be a suitable treatment for non-transfusion-dependent and transfusion-dependent β-thalassemia.

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Background: Myocardial iron overload in patients with thalassemia major (TM) is one of the most important complications. The purpose of the study was to identify advanced echocardiography parameters for early identification of myocardial dysfunction during follow-up of patients with TM., Methods: Forty TM patients who were 41 ± 5 years old were included in the study and divided into two groups according to cardiac magnetic resonance T2* results (Group 1: Τ2* > 25 ms, Group 2: Τ2* ≤ 25 ms). Liver T2* parameters were also measured. Conventional and deformational echocardiographic parameters were measured at baseline and approximately 2 years later., Results: Thirty-two patients had Τ2* = 34 ± 4 ms (Group 1), and 8 had Τ2* = 17 ± 9 ms (Group 2). Blood consumption was 185 ± 60 and 199 ± 37 ml/kg/yr (p = 0.64), and liver T2* was 4 ± 5 and 17 ± 21 ms (p = 0.01) in Groups 1 and 2, respectively. At baseline, Group 1 had better left ventricular global longitudinal strain (GLS) (- 22 ± 3 vs. - 18 ± 5, p = 0.01) and similar left ventricular ejection fraction (LVEF) (62 ± 5% vs. 58 ± 10%, p = 0.086) than Group 2. At the 28 ± 11-month follow-up, LVEF, GLS, and T2* values in Group 1 (63 ± 3%, - 21 ± 3%, 34 ± 4 ms) and Group 2 (56 ± 11%, - 17 ± 4%, 17 ± 9 ms) did not change significantly compared to their corresponding baseline values. In 8 patients from Group 1, a worsening (> 15%) in LS (p = 0.001) was detected during follow-up, with a marginal reduction in LVEF., Conclusions: GLS seems to be an efficient echocardiographic parameter for detecting hemochromatosis-related cardiac dysfunction earlier than LVEF. It also seems to be affected by other factors (free radical oxygen, immunogenetic mechanisms or viral infections) in a minority of patients, underscoring the multifactorial etiology of cardiomyopathy.

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.)., (Copyright © 2020 Massachusetts Medical Society.)

Thalassemia major (TM) is a hereditary disease caused by defective globin synthesis. Because of the significant increase in life expectancy, these patients are suffering from various health conditions, including endocrinopathies and low bone mineral density. The aim of the present study was to investigate the correlation between clinical and biochemical parameters as well as to identify possible relations in a genotype to phenotype pattern. Sixty-four patients with TM (32 men and 32 women) participated in a cross-sectional study design. The patients were recruited from "Aghia Sofia" Children's Hospital. Clinical and biochemical parameters were evaluated as well as specific mutations were identified. We have found significant correlations between biochemical parameters and iron chelation, hormone replacement treatment as well as TM genotype and hematocrit and T-score. To conclude, the current study showed that clinical parameters of TM patients correlate significantly with both biochemical factors and genotypical patient parameters. Our present study showed that there is a connection between genotype and phenotype as, for example, the identified relation between hematocrit and T-scores and TM-specific mutations. This connection indicates that there is still much more to learn about the role of mutations not only in the disease itself but also in the underlying comorbidities., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

β-thalassemia major is an inherited hemoglobinopathy that requires lifelong red blood cell transfusions and iron chelation therapy to prevent complications due to iron overload. Traditionally, β-thalassemia has been more common in certain regions of the world such as the Mediterranean, Middle East, and Southeast Asia. However, the prevalence of β-thalassemia is increasing in other regions, including Northern Europe and North America, primarily due to migration. This review summarizes the available data on the changing incidence and prevalence of β-thalassemia as well as factors influencing disease frequency. The data suggest that the epidemiology of β-thalassemia is changing: Migration has increased the prevalence of the disease in regions traditionally believed to have a low prevalence, while, at the same time, prevention and screening programs in endemic regions have reduced the number of affected individuals. Various approaches to prevention and screening have been used. Region-specific prevention and treatment programs, customized to align with local healthcare resources and cultural values, have been effective in identifying patients and carriers and providing information and care. Significant challenges remain in universally implementing these programs., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients., Methods: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies., Results: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo., Conclusions: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)., (Copyright © 2020 Massachusetts Medical Society.)

Streptococcus pnemoniae is a major cause of morbidity and mortality among splenectomised patients with β-thalassemia major. We have previously shown that a 13-valent pneumococcal conjugate vaccine (PCV13) induces robust early immune responses in such patients, while history of repeated immunisations with the 23-valent polysaccharide pneumococcal vaccine (PPSV23) results in attenuation of the response to PCV13. However, the duration of vaccine-induced protection in splenectomised thalassemic patients and the associated need for booster immunisation remains unclear. In the current study, we enumerate antibody persistence 5 years post-PCV13 and investigate any correlation with early immune response and immunisation history. Pneumococcal serotype (PS)-specific antibodies against 5 vaccine antigens were measured 5 years post-PCV13 in 34 asplenic adults with β-thalassemia. PS-specific antibodies against 5 vaccine serotypes had declined significantly at 5 years post-PCV13 (year 5).Year 5 antibody titres remained above baseline for PS9V, 19A and19F, returned to baseline for PS23F, and dropped below baseline for PS3 (p < 0.001).Year 5 antibodies were positively correlated with day 28 antibody titres, while no correlation was found with early memory B cell response. Previous PPSV23 history was correlated with impaired antibody persistence against serotype 19A. Antibody levels dropped significantly but remained at protective levels 5 years post-PCV13.We propose that asplenic patients with β-thalassemia may benefit from measurement of antipneumococcal antibodies after 5 years post-PCV13 as they may eventually be in need for booster pneumococcal vaccination. Clinical Trials Registration ID: www.clinicaltrials.gov NCT01846923.

This study demonstrates the quantitative characteristics of the first patient-reported outcome (PRO) tool developed for patients with nontransfusion-dependent β-thalassemia (NTDT), the NTDT-PRO © . A multicenter validation study was performed over 24 weeks, involving 48 patients from Italy, Lebanon, Greece, and Thailand. Most patients were female (68.8%), with a median age of 34.5 years (range, 18-52); 66.7% were diagnosed with β-thalassemia intermedia, and median time since diagnosis was 22 years (range, 0-43). The NTDT-PRO comprises 6 items across 2 domains (Tiredness/Weakness and Shortness of Breath [SoB]), and was valid and reliable, with good consistency. At baseline, most patients reported symptoms as present via the NTDT-PRO, and were highly compliant, ≥90% completing the NTDT-PRO tool. In a pairwise correlation analysis, all items were positively correlated. Correlations between NTDT-PRO and existing tools-36-Item Short Form Health Survey version 2 (SF-36v2) and Functional Assessment of Cancer Therapy-Anemia (FACT-An)-were assessed at weeks 1, 3, and 12; robust correlations were seen between SoB and SF-36v2-Vitality (r s  = -0.53), and between SoB and Fact-An-Fatigue Experience (r s  = -0.66) at week 1. Internal consistency was high for both Tiredness/Weakness (Cronbach alpha, 0.91) and SoB (Spearman-Brown coefficient, 0.78); intraclass correlation coefficients were high (Tiredness/Weakness, 0.88 and 0.97; SoB, 0.92 and 0.98), demonstrating stability. Further studies are required to fully support the validity of this tool, this study demonstrated the usefulness of the NTDT-PRO in the clinical setting and for longitudinal clinical research, particularly in trials where patient health-related quality of life is expected to change., (© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Background: Thalassemia major (TM) patients eventually face many new health conditions, including endocrinopathies and low bone mineral density, usually observed in the aging general population., Objective: The aim of the current study was to evaluate the biomarkers of bone remodeling in TM patients and to compare them with both osteoporotic and healthy population, in order to investigate the new therapeutic paths., Methods: Sixty-four patients with TM (32 men and 32 women) participated in the study. The patients were evaluated with dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck and with markers of bone remodeling including receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), C-terminal telopeptide (CTX), and sclerostin. Results were compared with those from 12 postmenopausal women with osteoporosis and 12 women with normal bone mineral density., Results: The statistical analysis of the biochemical markers of bone metabolism revealed overall significant differences between the three groups only for RANKL and OPG/RANKL (p=0.049 and p=0.009). RANKL was higher and OPG/RANKL was lower in TM patients compared to osteoporosis group., Conclusion: Patients with TM do not have a higher probability of suffering from osteoporosis from the general population. However, some markers of osteoclast activity differ between patients with TM and osteoporosis, indicating the possible differences in terms of anti-osteoporotic treatment. The lack of significant differences among the three groups in regards to the levels of CTX and sclerostin may indicate the potential efficacy of the current osteoporotic treatment also for TM patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The purpose of this study was to assess the role of various diagnostic tests in early detection of retinal changes in β-thalassemia major patients., Methods: Thirty-eight visually asymptomatic β-thalassemia major patients receiving regular blood transfusions and iron-chelation therapy with deferoxamine (group A, n = 13), deferasirox (group B, n = 11) or deferoxamine with deferiprone (group C, n = 14) and fourteen age- and sex- matched healthy individuals were included in the study. All participants underwent ophthalmoscopy, full-field electroretinography (ERG), visual evoked potentials (VEP), multifocal electroretinography (mfERG), fundus autofluorescence (FAF) imaging and optical coherence tomography (OCT) scans., Results: Retinal pigment epithelium changes were present in two cases. Scotopic ERG demonstrated decreased a-wave amplitude in groups A, B and C (p = 0.03, p = 0.002 and p = 0.002, respectively) and decreased b-wave amplitude in groups B and C (p = 0.002 and p = 0.01, respectively) compared to controls. Photopic ERG showed delayed b-wave latency in groups A and C (p = 0.03 and p = 0.03, respectively) ERG maximal combined response and VEP response did not differ between groups. MfERG showed reduced retinal response density in ring 1 in groups A, B, C (p < 0.001, p < 0.001, p = 0.001, respectively) and ring 2 in group B (p = 0.02) and delayed latency in ring 5 in groups A and B (p = 0.04 and p = 0.04, respectively). Abnormal FAF images appeared in three cases and OCT abnormalities in one case, whereas no changes were observed in controls (p = 0.55 and p = 1.00, respectively)., Conclusions: Full-field ERG and mfERG are more sensitive tools for detecting early retinal changes in β-thalassemia patients compared with ophthalmoscopy, VEP, FAF imaging and OCT scans.

Interferon-based regimens for chronic hepatitis C (CHC) were often deferred in patients with β-thalasaemia major (β-TM) due to poor efficacy and tolerance. Current guidelines recommend direct-acting antivirals (DAAs) for these patients. The aim of this study was to assess the safety and efficacy of DAAs in patients with β-TM and advanced liver disease due to CHC. Patients were recruited from eight liver units in Greece. The stage of liver disease was assessed using transient elastography and/or liver histology. Five regimens were used: sofosbuvir (SOF) + ribavirin (RBV); SOF + simeprevir ± RBV; SOF + daclatasvir ± RBV; ledipasvir/SOF ± RBV and ombitasvir/paritaprevir-ritonavir + dasabuvir ± RBV. Sixty-one patients (median age 43 years) were included. The majority of patients was previously treated for hepatitis C (75%) and had cirrhosis (79%). Viral genotype distribution was: G1a: n = 10 (16%); G1b: n = 22 (36%); G2: n = 2 (3%); G3: n = 14 (23%); G4: n = 13 (22%). The predominant chelation therapy was a combination of deferoxamine and deferiprone (35%). Overall sustained virological response rates were 90%. All treatment regimens were well tolerated and no major adverse events or drug-drug interactions were observed. Approximately half of the patients who received RBV (7/16, 44%) had increased needs for blood transfusion. Treatment of CHC with DAAs in patients with β-TM and advanced liver disease was highly effective and safe., (© 2017 John Wiley & Sons Ltd.)

Background: Patients with non-transfusion-dependent thalassemia (NTDT) present with a spectrum of disease severities. Since there are multiple pathophysiologies in such patients, tailoring treatment remains essential. Therefore, one simple, reliable tool would be beneficial to assess disease severity and tailor therapy, particularly for internal medicine specialists who may treat a variety of NTDT patients with a multitude of complications. This would allow for standardization of assessments leading to timely interventions and prevention of complications., Methods: A working group of NTDT experts was formed to develop a new disease severity scoring system for adult and pediatric patients with NTDT, based on parameters considered to be most pertinent in defining disease severity., Results: 20 parameters were selected for inclusion in the disease severity scoring system. An additional six parameters, largely related to growth and development, were selected specifically for pediatric patients (≤ 16 years of age). Consensus of expert opinion was used to establish the selected methods of assessment for each parameter, based on feasibility and availability of technology, cost containment, and avoidance of patient risk., Conclusion: We propose that this new disease severity scoring system for adult and pediatric NTDT patients could be developed into a practical tool for widespread clinical use., (Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Preimplantation genetic diagnosis (PGD) to select histocompatible siblings to facilitate curative haematopoeitic stem-cell transplantation (HSCT) is now an acceptable option in the absence of an available human leukocyte antigen (HLA) compatible donor. We describe a case where the couple who requested HLA-PGD, were both carriers of two serious haematological diseases, beta-thalassaemia and sideroblastic anaemia. Their daughter, affected with sideroblastic anaemia, was programmed to have HSCT. A multiplex-fluorescent-touchdown-PCR protocol was optimized for the simultaneous amplification of: the two HBB-gene mutated regions (c.118C> T, c.25-26delAA), four short tandem repeats (STRs) in chr11p15.5 linked to the HBB gene, the SLC25A38 gene mutation (c.726C > T), two STRs in chr3p22.1 linked to the SLC25A38 gene, plus eleven informative STRs for HLA-haplotyping (chr6p22.1-21.3). This was followed by real-time nested PCR and high-resolution melting analysis (HRMA) for the detection of HBB and SLC25A38 gene mutations, as well as the analysis of all STRs on an automatic genetic analyzer (sequencer). The couple completed four clinical in vitro fertilization (IVF)/PGD cycles. At least one matched unaffected embryo was identified and transferred in each cycle. A twin pregnancy was established in the fourth PGD cycle and genotyping results at all loci were confirmed by prenatal diagnosis. Two healthy baby girls were delivered at week 38 of pregnancy. The need to exclude two familial disorders for HLA-PGD is rarely encountered. The methodological approach described here is fast, accurate, clinically-validated, and of relatively low cost.

Background: Bone disease is a frequent complication of β-thalassemia major (β-ΤΜ) and its etiology is multifactorial. Marrow expansion, chronic hypoxia, endocrine complications, and iron overload caused chiefly by chronic transfusion treatment are significant factors affecting skeletal health. Bone disease is prevalent even among patients on regular transfusions and adequate iron chelation. The life expectancy of patients with β-thalassemia has increased during the past decade and so, nowadays, patients with thalassemia-associated bone disease (TBD) often require long-term management. There are limited data concerning their pharmacologic treatment. Bisphosphonates represent the most widely studied agents in such patients and there are no published studies about the effects of anabolic treatment. Retreatment with teriparatide has only occasionally been studied in patients with osteoporosis., Case Report: We present a male adult patient with β-ΤΜ with a history of low bone mass and multiple vertebral fractures, who required sequential treatment for his longstanding bone disease. He had exhibited considerable, albeit delayed, response to a course of teriparatide treatment for 18 months but subsequently, and while on alendronate, sustained an insufficiency fracture at the left ischiopubic ramus. A second trial of teriparatide treatment resulted in further remarkable increase in total hip and femoral neck bone mineral density. We present the patient's response to sequential treatment during an 8-year follow-up., Conclusion: Teriparatide could represent an alternative treatment for adults with TBD especially when long-term, sequential treatment is needed. Although there are limited data concerning retreatment, in selected cases, this might be considered., (© 2015 AABB.)

Background: A high incidence of clinically-silent cerebral ischemic events has been reported in splenectomised patients with β-thalassemia intermedia (βTI). These could be due to cerebral large-vessel disease. Based on the example of sickle cell disease, we applied transcranial Doppler sonography (TCD) to evaluate cerebral vessels velocity as a possible indicator of cerebral vasculopathy., Patients and Methods: In our study, we included 17 splenectomised and 13 non-splenectomised (control group) patients with βTI. Non-imaging TCD was performed and the time-averaged mean velocity (TAMV) values of cerebral arteries were measured., Results: There was no statistically significant difference between the two groups concerning age, gender, hemoglobin and hematocrit levels, nor in the TAMV values for all examined vessels (p>0.05). A statistically significant difference was found in platelet count (PLT) (p<0.01) that was higher in splenectomised patients., Conclusion: Our results do not support the presence of large-vessel vasculopathy in splenectomised βTI patients and agree with recent studies reporting that cerebral ischemic events in these patients might be due to microangiopathy or venous thromboembolism., (Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Current guidelines recommend a combined schedule of a 13-valent pneumococcal conjugate vaccine (PCV13) and PPSV23 (23-valent polysaccharide vaccine) for asplenic individuals. We show that PCV13 induces a T-dependent immune response in asplenic individuals with β-thalassemia, but previous PPSV23s affect the memory B-cell response in a dose- and time-dependent manner. Clinical Trials Registration. NCT01846923., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important., Design and Methods: Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3(rd) year, allowing cardiac iron removal to be analyzed over three years., Results: Mean deferasirox dose during year 3 was 33.6 ± 9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ± 39.1% at baseline to 17.1 ms ± 62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43 ± 1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ± 1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥ 20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n = 9, 12.7%)., Conclusions: Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.

Background and Aim:   The primary symptoms of sickle cell disease (SCD) arise from vaso-occlusive crises. The pathogenesis of these crises is complex phenomenon where endothelial activation and damage has a major role. Chronic inflammation also plays an important role in the pathophysiology of SCD. We aimed to investigate endothelial activation in Caucasian Greek patients with SCD by means of measuring adhesion molecules and markers of inflammation., Subjects and Methods: Twenty-eight patients with SCD aged 5-63 years were included in the study. Most of the patients (23/28) were double heterozygotes for sickle cell/beta-thalassaemia, while five patients (5/28) were sickle cell homozygotes. Patients were treated with one/or more of hydroxyurea, therapeutic phlebotomies, blood transfusion or splenectomy. Twenty apparently healthy individuals matched for age and sex formed the control group. Measurements of soluble intercellular adhesion molecule-1, (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), P-selectin, E-selectin, soluble thrombomodulin (sTM) and high-sensitivity C-reactive protein (hs-CRP) levels were performed using immunoassays in both patients and healthy individuals., Results: We found that all endothelial adhesion molecules and hs-CRP were significantly increased (P < 0·001) in patients with SCD compared with controls, while sTM levels did not differ significantly (P > 0·05) and this increase was not influenced by the treatment., Conclusion: Our findings demonstrate the high degree of endothelial activation and damage seen in sickle cell patients even in steady-state condition, as well as the important chronic inflammation underlying the pathophysiology of this widespread disease., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means±SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p<0.0001), increases in serum ferritin levels during DFX 5, 10, and 20 mg/kg versus DFO-treated groups (p<0.00001, p<0.00001, and p=0.002, respectively), but no statistically significant difference during DFX 30 mg/kg versus DFO (p=0.70), no statistically significant variations in heart T2* signal during associated or sequential versus mono-therapy treatment (p=0.46 and p=0.14, respectively), increases in urinary iron excretion during associated or sequential versus monotherapy treatment (p=0.008 and p=0.02, respectively), and improved ejection fraction during associated or sequential versus monotherapy treatment (p=0.01 and p<0.00001, respectively). These findings do not support any specific chelation treatment. The literature shows risks of bias, and additional larger and longer trials are needed., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Purpose: To evaluate whether the introduction of magnetic resonance imaging (MRI) in the management of thalassemia major (TM) patients has affected the risk of cardiac death., Materials and Methods: In all, 804 TM patients from two large reference units were included and the risk of dying of cardiac causes, before and after their first MRI, was assessed by a Cox proportional hazards model with time-dependent covariates., Results: Adding information from MRI reduced the risk of cardiac death from 6.0 deaths/1000 patient-years to 3.9 deaths/1000 patient-years (P = 0.22). The risk of cardiac death before having an MRI study was 82% higher compared to the risk observed after the first MRI., Conclusion: MRI has become a vital component of ongoing management and seems to have a beneficial effect on cardiac mortality in TM., (Copyright © 2011 Wiley-Liss, Inc.)

Background: With transfusions and chelation therapy, the prognosis for transfusion-dependent beta thalassaemia has changed from being fatal in early childhood to a chronic disorder with prolonged survival., Design and Methods:   In this historical prospective study, we present survival, causes of death and mortality ratios compared to the general population in 1044 Greek patients with transfusion-dependent beta thalassaemia., Results:   At the age of 50years, the overall survival was 65.0%, while the cardiac death-free survival was 77%. Birth cohort had a significant effect on survival (P<0.001) with a negative trend towards past decades. The standardised mortality ratio (standardised for sex and ages 20-40years) compared to the general population improved significantly from 28.9 in 1990-1999 to 13.5 in 2000-2008, while the standardised cardiac mortality ratio reduced from 322.9 to 106.6, respectively., Conclusions:  Survival in thalassaemia has dramatically improved over the last twenty years but mortality remains significantly increased, compared to the general population., (© 2011 John Wiley & Sons A/S.)

Background: The efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with β-thalassemia major in the cardiac sub-study of the EPIC trial., Design and Methods: Eligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years., Results: Baseline myocardial T2* was severe (> 5 to < 10 ms) in 39 patients, and moderate-to-mild (10 to < 20 ms) in 62 patients. Mean deferasirox dose was 33.1 ± 3.7 mg/kg/d in the one-year core study increasing to 36.1 ± 7.7 mg/kg/d during the second year of treatment. Geometric mean myocardial T2* increased from a baseline of 11.2 to 14.8 ms at two years (P < 0.001). In patients with moderate-to-mild baseline T2*, an increase was seen from 14.7 to 20.1 ms, with normalization (≥ 20 ms) in 56.7% of patients. In those with severe cardiac iron overload at baseline, 42.9% improved to the moderate-to-mild group. The incidence of drug-related adverse events did not increase during the extension relative to the core study and included (≥ 5%) increased serum creatinine, rash and increased alanine aminotransferase., Conclusions: Continuous treatment with deferasirox for two years with a target dose of 40 mg/kg/d continued to remove iron from the heart in patients with β-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: NCT 00171821).

Abnormal iron regulation in patients with thalassaemia intermedia may lead to iron overload even in the absence of transfusions. There are limited data on iron chelator use in patients with thalassaemia intermedia and no guidelines exist for the management of iron overload. We present data from 11 patients with thalassaemia intermedia treated with deferasirox (Exjade(®) , 10-20 mg/kg/d) for 24 months. Liver iron concentration and serum ferritin levels significantly decreased over the first 12 months (P = 0·005) and continued to decrease over the remainder of the study (P = 0·005). This small-scale study indicated that deferasirox may be suitable for controlling iron levels in patients with thalassaemia intermedia., (© 2010 Blackwell Publishing Ltd.)

Cardiac Magnetic Resonance (CMR) has replaced all other surrogate measurements in the determination of transfusional cardiac iron overload in patients with thalassaemia major. We aimed to determine the diagnostic value of CMR T2* with respect to cardiac dysfunction (CD) as determined by CMR-derived left ventricular ejection fraction (LVEF). Cardiac T2* values and LVEF measured by CMR were recorded in 303 patients with thalassaemia major, at the time of their first CMR. T2* was correlated with LVEF (regression coefficient: 0·57, P<0·001). The prevalence of CD was 32·9% in patients with T2*≤8 ms, 12·5% in patients with T2*>8 ms and ≤14 ms and reduced to 9·1% in patients with T2* between 14-20 ms. As the probability of CD is progressively, and not suddenly, reduced with increasing values of T2*, CMR has a limited diagnostic value for CD (Receiver operating characteristic analysis, area under the curve = 0·68). Patients with cardiac T2*≤8 ms require careful and intensive management. This risk decreases with increasing values of T2* but even in mildly loaded patients the probability of impaired LVEF is not negligible., (© 2010 Blackwell Publishing Ltd.)

Cardiac iron overload causes most deaths in beta-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with beta-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean +/- coefficient of variation) improved from a baseline of 11.2 ms (+/- 40.5%) to 12.9 ms (+/- 49.5%) (+16%; P < .001). LVEF (mean +/- SD) was unchanged: 67.4 (+/- 5.7%) to 67.0 (+/- 6.0%) (-0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (+/- 25.6%) to 32.5 ms (+/- 25.1%) (+2%; P = .57) and LVEF increased from baseline 67.7 (+/- 4.7%) to 69.6 (+/- 4.5%) (+1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.

Deferasirox (Exjade) is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload. This study was conducted to analyze changes in cystatin C concentration, an endogenous marker of glomerular filtration rate (GFR), in patients with thalassemia receiving daily deferasirox therapy over a period of at least 9 months. One hundred and fifty beta-thalassemia patients were treated with deferasirox at doses of 20-40 mg/kg/day for 9 consecutive months. Cystatin C concentrations were measured at regular intervals and GFR was calculated according to the cystatin C-based prediction equation. Plasma concentrations of NGAL protein and NT-proBNP were also monitored as indicators of renal function and LVEF, respectively. Serum ferritin concentration was also measured to assess iron overload. Throughout the 9 months of deferasirox treatment cystatin C concentration remained stable (p>0.850). The baseline cystatin C mean values were 0.97+/-0.27 mg/L and reached a maximum of 1.01+/-0.29 mg/L at 4 months of treatment. No correlation was found between cystatin C and NGAL concentrations (p>0.674). Cystatin C and NT-proBNP concentrations correlated positively with a binomial equation (p<0.004), as also did cystatin C and serum ferritin (p<0.001). These findings suggest that slight changes of cystatin C during deferasirox treatment may not reflect renal injury. However hemodynamic signals such as LVEF alterations and iron mobilization do appear to affect changes in cystatin C concentration., (2010 Elsevier Inc. All rights reserved.)

The term thalassemia intermedia, indicates a clinical condition of intermediate severity between thalassaemia minor, the asymptomatic carrier, and thalassaemia major, the transfusion-dependent, severe form. Thromboembolic events frequently complicate the outcome of thalassemia intermedia patients, reflecting a hypercoagulable state to which endothelial activation is believed to play an important role. The aim of this study was to evaluate the levels of soluble endothelial adhesion molecules that reflect endothelial activation and dysfunction and levels of chronic inflammation markers in the serum of beta-thalassemia intermedia patients. Thirty-five Greek patients with beta-thalassemia intermedia that have received different types of treatment (Hydroxyurea, splenectomy, untreated), aged 8-63 years, were included in the study. Twenty apparently healthy individuals matched for age and sex, formed the control group. Measurements of sVCAM-1, sICAM-1, sTM, P-selectin, E-selectin and CRP levels were performed using immunoassays. We found that all endothelial adhesion molecules and CRP were significantly increased in patients (p<0.001) and not influenced by treatment. A negative correlation was observed between levels of sICAM-1 and sTM and this finding agrees with the results of studies, which propose this correlation as a predictive marker of increased risk for vascular damage. No correlation was observed between endothelial adhesion molecules and inflammation markers. These findings support the hypothesis that a serious degree of endothelial activation and damage along with a state of chronic inflammation underlie the pathophysiology of beta-thalassemia intermedia. Furthermore, these findings are of particular importance in patients who can otherwise be characterized by a subtle clinical phenotype and may have an important role in their clinical care.

Purpose: To investigate the correlation between the degree of hepatic, splenic, pancreatic, vertebral bone marrow (VBM), and myocardial siderosis, as expressed by relaxation rate (R2 = 1/T2) values, in patients with thalassemia., Materials and Methods: R2 relaxation rate values of liver, spleen, VBM, pancreas, and myocardium were estimated in 68 consecutive transfusion-dependent patients with beta-thalassemia major and 10 healthy controls using a respiratory triggered 16-echo Carr-Purcell-Meiboom-Gill (CPMG) spin echo sequence., Results: Hepatic R2 values were significantly increased in all 68 patients; VBM, pancreatic, and myocardial R2 values were increased in 67/68, 35/47, and 47/61 patients, whereas five patients showed decreased pancreatic R2 attributed to fatty degeneration. Of the 39 nonsplenectomized patients, splenic R2 values were decreased in 30 and normal in nine patients. Hepatic R2 values correlated with splenic (r = 0.63, P < 0.001), VBM (r = 0.52, P < 0.001), but not with myocardial and pancreatic R2 values., Conclusion: Despite positive correlations between the degree of hepatic, splenic, and VBM siderosis, as expressed by respective R2 values, there was variability of iron distribution patterns in thalassemic patients. Unpredictable patterns of iron distribution may be seen, such as normal signal of the spleen in the presence of siderotic liver, resembling primary hemochromatosis. Fatty degeneration of the pancreas was not uncommon.

Beta-thalassaemia is a congenital haemolytic anaemia characterized by partial (intermedia, TI) or complete (major, TM) deficiency in the production of beta-globin chains. The primary aim of this study was to determine the prevalence of thromboembolic events in patients with beta-thalassaemia. To achieve this, a multiple choice questionnaire was sent to 56 tertiary referral centres in eight countries (Lebanon, Italy, Israel, Greece, Egypt, Jordan, Saudi Arabia and Iran), requesting specific information on patients who had experienced a thromboembolic event. The study demonstrated that thromboembolic events occurred in a clinically relevant proportion (1.65%) of 8,860 thalassaemia patients (TI - 24.7% or TM - 75.3%) from the Mediterranean and Iran. Thromboembolism occurred 4.38 times more frequently in TI than TM (p < 0.001), with more venous events occurring in TI and more arterial events occurring in TM. Thrombosis in thalassaemia was also more common in females, splenectomized patients and those with profound anaemia (haemoglobin <9 g/dl). Due to the increased risk of thromboembolic events, the rationale for splenectomy should perhaps be re-assessed and the role of transfusion therapy for the prophylaxis of thrombosis, among other complications, be evaluated prospectively.

Hepcidin production is homeostatically regulated by iron stores, anemia and hypoxia. We evaluated the effect of iron overload and of ineffective erythropoeisis on hepcidin expression in patients with thalassemia major. Liver hepcidin mRNA levels correlated with hemoglobin concentration and inversely correlated with serum transferrin receptor, erythropoietin and non-transferrin-bound iron. They did not correlate with indices of iron load. Urinary hepcidin levels were disproportionably suppressed in regards to iron burden. We conclude that hepcidin expression is regulated mainly by increased erythropoietic activity rather than by iron load and that hepcidin plays a central regulatory role in iron circulation and iron toxicity in patients with thalassemia.

Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload.

Purpose: To evaluate the usefulness of a time-efficient MRI method for the quantitative determination of tissue iron in the liver and heart of beta-thalassemic patients using spin-spin relaxation rate, R2, measurements., Materials and Methods: Images were obtained at 1.5 T from aqueous Gd-DTPA solutions (0.106-8 mM) and from the liver and heart of 46 beta-thalassemic patients and 10 controls. The imaging sequence used was a respiratory-triggered 16-echo Carr-Purcell-Meiboom-Gill (CPMG) spin-echo (SE) pulse sequence (TR = 2000 msec, TE(min) = 5 msec, echo spacing (ES) = 5 msec, matrix = 192 x 256, slice thickness = 10 mm). Liver iron concentration (LIC) measurements were obtained for 22 patients through biopsy specimens excised from the relevant liver segment. Biopsy specimens were also evaluated regarding iron grade and fibrosis. Serum ferritin (SF) measurements were obtained in all patients., Results: A statistically significant difference was found between patients and healthy controls in mean liver (P < 0.004) and myocardium (P < 0.004) R2 values. The R2 values correlated well with Gd DTPA concentration (r = 0.996, P < 0.0001) and LIC (r = 0.874, P < 0.0001). A less significant relationship (r = 0.791, P < 0.0001) was found between LIC measurements and SF levels. R2 measurements appear to be significantly affected (P = 0.04) by different degrees of hepatic fibrosis. The patients' liver R2 values did not correlate with myocardial R2 values (r = 0.038, P < 0.21)., Conclusion: Tissue iron deposition in beta-thalassemic patients may be adequately quantified using R2 measurements obtained with a 16-echo MRI sequence with short ES (5 msec), even in patients with a relatively increased iron burden., ((c) 2005 Wiley-Liss, Inc.)