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Patients with transfusion-dependent β-thalassemia were randomly assigned to receive luspatercept (a binder for TGF-β family member ligands) or placebo. During any 12-week period, a greater percentage of patients in the luspatercept group than in the placebo group had a reduction of at least 33% (70.5% vs. 29.5%) or at least 50% (40.2% vs. 6.3%) in the transfusion requirement.

Thalassemias are emerging as a global public health concern. Due to remarkable success in the reduction of childhood mortality by controlling infectious diseases in developing countries, thalassemias are likely to be a major public health concern in the coming decades in South Asia. Despite the fact that Bangladesh lies in the world’s thalassemia belt, the information on different aspects (epidemiology, clinical course, mortality, complications and treatment outcomes) of thalassemias is lacking. In this comprehensive review, the aim is to to depict the epidemiological aspects of thalassemias, mutation profile and current treatment and management practices in the country by sharing the experience of dealing with 1178 cases over 2009–2014 time periods in a specialized thalassemia treatment centre. We have also discussed the preventative strategies of thalassemias from the context of Bangladesh which could be effective for other developing countries.

Non-transfusion-dependent (NTD) thalassaemia is characterised by ineffective erythropoiesis and haemolytic anaemia, leading to long-term complications, poor quality of life, and early mortality. No oral disease-modifying therapies are approved for β-thalassaemia and no agents are approved for α-thalassaemia. The objective of this study was to evaluate the efficacy and safety of mitapivat, an oral activator of pyruvate kinase, in adults with NTD α-thalassaemia or NTD β-thalassaemia. ENERGIZE is a phase 3, double-blind, randomised, placebo-controlled trial followed by an open-label extension conducted at 70 hospitals in 18 countries globally. Participants had to be aged 18 years or older with NTD α-thalassaemia or NTD β-thalassaemia and haemoglobin concentrations of 10 g/dL or lower. Participants were randomly assigned 2:1 to mitapivat or placebo (100 mg orally twice a day for 24 weeks) via a central interactive response technology system using block randomisation, stratified by baseline haemoglobin concentration and thalassaemia genotype. Everyone was masked to the patients' treatment assignment until the study was unblinded for the analysis of the primary endpoint. The primary endpoint was haemoglobin response (≥1·0 g/dL increase from baseline in mean haemoglobin concentration from week 12 through week 24), analysed in all patients who were randomly assigned. Safety was analysed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT04770753, and is active but not recruiting. Between Nov 8, 2021, and March 31, 2023, 235 patients were screened, of whom 194 were enrolled (123 [63%] were female and 71 [37%] were male). 130 patients were randomly assigned to mitapivat and 64 patients to placebo and formed the full analysis set. One patient in each group was randomly assigned but not given treatment and was therefore excluded from the safety analysis set (mitapivat 129 patients and placebo 63 patients). Seven patients in the mitapivat group and one patient in the placebo group discontinued treatment before the end of the 24-week double-blind period. 55 (42%) of 130 patients in the mitapivat group had a haemoglobin response versus one (2%) of 64 in the placebo group (least-squares mean difference 41% [95% CI 32–50], two-sided p<0·0001). Adverse events were reported in 107 (83%) of 129 patients who received mitapivat and 50 (79%) of 63 patients who received placebo. The most commonly reported adverse events with mitapivat were headache (29 [22%] of 129 patients in the mitapivat group vs six [10%] of 63 in the placebo group), initial insomnia (18 [14%] vs three [5%]), nausea (15 [12%] vs five [8%]), and upper respiratory tract infection (14 [11%] vs four [6%]). No deaths were reported. Mitapivat could be a new oral treatment for adults with NTD α-thalassaemia or NTD β-thalassaemia by increasing haemoglobin concentration and improving fatigue. Agios Pharmaceuticals.

Mild to severe anemia is caused by thalassemia, a common genetic disorder affecting over 100 countries worldwide, that results from the abnormality of one or several of the four globin genes. This leads to chronic hemolytic anemia and disrupted synthesis of hemoglobin chains, iron overload, and poor erythropoiesis. Although the diagnosis of thalassemia has improved globally along with the treatment and transfusion support, it is still a major problem in diagnosing in high-prevalence areas like Pakistan. This work aims to assess the performance of numerous combinations of machine learning methods to detect alpha and beta-thalassemia in their minor and major types. These results are obtained from CBC and HPLC analysis. The analyzed models are K-nearest Neighbor (KNN), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost). The study aims to examine the effectiveness of the developed models in discriminating thalassemia variants, especially in the light of Pakistani patients’ data. The study found that XGBoost achieved the highest performance on both the CBC and HPLC datasets, with training accuracies of roughly 99.5% for CBC and 99.3% for HPLC. The test accuracy across both datasets was consistently high and thus the best model for detecting thalassemia in this research study. The imported SVM model, slightly less accurate than XGBoost, still has strong performance, particularly on the HPLC data where the cumulative testing accuracy of the model stood at 99.4%. As can be seen from the results, XGBoost specifically shows a very high accuracy of above 99% in the detection of thalassemia types using CBC and HPLC data for Pakistani patients. To the author’s knowledge, this research is the first to predict alpha and beta-thalassemia in its major and minor forms using these diagnostic reports. These models indicate that they can offer significant support in detecting thalassemia in resource-constrained settings such as Pakistan. If deep learning is incorporated, even greater accuracy could be achieved.

Background Thalassemia, a hereditary hemolytic blood disorder, is characterized by high global allele prevalence and a gradually expanding variant spectrum. In Guangxi, China, routine genetic screening targeting hotspot variants of thalassemia has been implemented for over a decade, significantly reducing the incidence of severe cases. This study assessed the efficacy of the existing thalassemia screening protocol in Guangxi, China, by applying long-read sequencing (LRS) in family trios/quartets analysis for newborns. Methods This study enrolled 1491 families for the family trios/quartets analysis, among which at least one of the parents had undergone routine genetic screening for thalassemia. A total of 1516 newborns from these families were tested using LRS. The efficacy of routine screening was assessed by comparing detection results across generations. Results α-thalassemia demonstrated higher prevalence than β-thalassemia among newborns, with -- SEA and HBB c.52A > T as the predominant variants. Among the 1516 newborns, 1348 (88.92%) exhibited LRS results that were concordant with the predictions from parental screening. Of these 1348 newborns, 28 had parents who had undergone routine prenatal diagnosis. Discordance between the predictions from parental screening and newborn test results occurred in 168 cases (11.08%), with 154 (10.16%) of these attributable to genetic testing of only one of the parents or incomplete testing of both parents, while the remaining 14 (0.92%) were attributed to limitations of routine methods in detecting complex structural variants and rare point mutations. Conclusions Although routine genetic screening targeting hotspot variants is highly effective, its precision is constrained by strategic and methodological limitations. A comprehensive and accurate LRS-based screening method can serve as a valuable supplement to routine screening, enhancing the precision of thalassemia prevention and management.

Severe thalassemia remains a significant public health concern in Southeast Asia. Prenatal screening is an effective strategy for early detection and prevention. This study aimed to determine the prevalence of severe thalassemia and assess the performance of prenatal screening at the Siriraj Thalassemia Center, Siriraj Hospital, Thailand. A retrospective review was conducted using data from January 2018 to December 2023. A total of 18,976 pregnant women underwent initial screening with mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and hemoglobin (Hb) typing. Of these, 12,499 tested positive. Complete screening data from 6,698 male partners identified 18.3% of couples as high-risk. Deoxyribonucleic acid (DNA) analysis and prenatal diagnostic testing were performed for at-risk pregnancies. Among high-risk couples, 75.2% of fetuses were identified by DNA analysis as being at risk for severe thalassemia, and 34.2% were confirmed as affected. The distribution of severe thalassemia types included Hb Bart's Hydrops Fetalis (15.8%), homozygous β-thalassemia (1.6%), and β-thalassemia/Hb E disease (16.8%). The most frequent α-thalassemia genotype in Hb Bart's cases was homozygous α -thalassemia (-- /-- ; 96.3%). The most common β-thalassemia mutation was a 4-base pair deletion at codons 41/42 (-TTCT; 40.2%). DNA testing for α-thalassemia showed 100% specificity and positive predictive value (PPV). For β-thalassemia, the sensitivity, specificity, PPV, and negative predictive value (NPV) were 97.6%, 98.9%, 96.1%, and 99.3%, respectively. The findings underscore the effectiveness of prenatal screening and diagnosis in identifying severe thalassemia, highlighting their importance for informing prevention strategies and guiding public health planning in high-prevalence settings.

PurposeIn clinical practice, the success of preimplantation genetic testing for monogenic diseases (PGT-M) for thalassemia was hindered by the absence of probands, incomplete family members, or failure in detecting embryonic gene mutation sites. This study aimed to address these issues.MethodsThis retrospective study included 342 couples undergoing PGT-M for α- or β-thalassemia at three reproductive medicine centers from 2019 to 2022. Various methods were used to construct parental haplotypes. A total of 1778 embryos were analyzed and selected for transfer based on chromosomal ploidy and PGT-M results. Follow-up involved amniocentesis results and clinical outcomes.ResultsHaplotypes were established using DNA samples from probands or parents, as well as sibling blood samples, single sperm, and affected embryos, achieving an overall success rate was 99.4% (340/342). For α-thalassemia and β-thalassemia, the concordance between embryo single nucleotide polymorphism (SNP) haplotype analysis results and mutation loci detection results was 93.8% (1011/1078) and 98.2% (538/548), respectively. Multiple annealing and looping-based amplification cycles (MALBAC) showed a higher whole genome amplification success rate than multiple displacement amplification (MDA) (98.8% (1031/1044) vs. 96.2% (703/731), p < 0.001). Amniocentesis confirmed PGT-M outcomes in 100% of cases followed up (99/99).ConclusionThis study summarizes feasible solutions to various challenging scenarios encountered in PGT-M for thalassemia, providing valuable insights to enhance success rate of PGT-M in clinical practice.

Purpose: Thalassemia is one of the most common monogenic diseases in southwestern China, especially among the Dai ethnic group. Here, we explore the feasibility of a next-generation sequencing (NGS) screening method specifically for the Dai people. Methods: Blood samples were obtained from Dai people for premarital screening. Double-blind, parallel hemoglobinopathy screening was conducted using both traditional hematological methods (red cell indexes and hemoglobin electrophoresis, then DNA sequencing) and an NGS approach. Results: Among 951 tested individuals, we found a thalassemia carrier rate of 49.5% (471/951) using the NGS screen, in contrast to 22.0% (209/951) found using traditional methods. Almost 74.8% (217/290) of α-thalassemia carriers and 30.5% (25/82) of composite α- and β-thalassemia carriers were missed by traditional screens. The proportion of such α- and β-thalassemia carriers among the Dai people is 8.6% (82/951). For β-thalassemia carriers, the high ratio (66/99) of CD26 mutations may suggest a correlation between CD26 and the environmental adaption of the Dai people. Conclusions: Methodological comparisons demonstrate the superiority of NGS for both sensitivity and specificity, provide a comprehensive assessment of thalassemia screening strategies, and indicate that NGS is a competitive screening method, especially among populations with a high prevalence of disease. Genet Med advance online publication 26 January 2017

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10–20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p  < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p  < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p  < 0.01) and placebo-receivers (102 ± 28ml/kg; p  < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p  < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p  < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn 1 polymorphism of the γ-globin gene.

The blood counts of α thalassemia carriers (α-thal) are similar to those of β thalassemia carriers, except for Hemoglobin A2 (Hb A2), which is not elevated. The objective of this study was to determine whether mathematical formulas are effective for detecting suspected α-thal. The data were obtained from the database of the prevention program for detecting couples at risk for having a child with hemoglobinopathy. Red Blood Cells (RBC) indices were analyzed using mathematical formulas, and the sensitivity and negative predictive value (NPV) were calculated. Among 1334 blood counts suspected of α-thal analyzed, only the Shine and Lal and the Support Vector Machine formulas revealed high sensitivity and NPV. Sensitivity was 85.54 and 99.33%, and NPV was 98.93 and 99.93%, respectively. Molecular defects were found in 291, and 81 had normal α genes. Molecular analysis was not performed in 962 of the samples. Based on these results, mathematical formulas incorporating one of these reliable formulas for detecting suspected α or β thalassemia carriers in the program of the automatic analyzers can flag these results, increase the awareness of the primary physicians about the carrier risk, and send an alert with a recommendation for further testing.