RARE DISEASE
Beta-thalassemia major
Beta-thalassemia major
Beta-thalassemia major
Synonyms: Cooley anemia, Mediterranean anemia
Synonyms: Cooley anemia, Mediterranean anemia
Synonyms: Cooley anemia, Mediterranean anemia
Drug discovery
4
drugs
With orphan designations
Overview
Beta-thalassemia major is a severe inherited hemoglobinopathy caused by mutations in the HBB gene, leading to reduced β-globin production, ineffective erythropoiesis, and transfusion-dependent anemia. Diagnosed in early childhood, it requires lifelong red blood cell transfusions, resulting in iron overload that necessitates chelation therapy. Complications include growth impairment, hepatosplenomegaly, endocrine dysfunction, and cardiovascular complications from iron deposition [1][3][6][16].
Key Clinical Points
Burden
Clinical: Multi-organ damage (heart, liver, endocrine) from iron overload; reduced life expectancy without optimal care [4][6][14].
Economic: Lifetime treatment costs exceed $5 million in high-income countries; lower-income regions face undertreatment due to limited resources [10][15].
Psychosocial: Impaired quality of life, chronic fatigue, and significant caregiver burden [5][9][20].
Therapies
Regular blood transfusions (every 2–4 weeks) and iron chelation therapy (deferasirox, deferiprone) [3][13].
Curative options: Allogeneic hematopoietic stem cell transplant (limited by donor availability) and gene therapy (FDA-approved CASGEVY™/Zynteglo®) [8][16].
Adjuncts: Folic acid supplementation, splenectomy in refractory cases [3][6].
Categories: rare endocrine diseases, rare genetic diseases, rare hematological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
822 drug discovery papers about Beta-thalassemia major, with 4 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
822 drug discovery papers about Beta-thalassemia major, with 4 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-03-19 | Clinical integration of red cell genotyping in children with β-thalassemia major: a prospective observational study.
Blood group serology frequently fails in chronically transfused patients. Discrepancies between phenotype and genotype were reported for 51% of patients with β-thalassemia in 2013; however, red cell genotyping has not become clinical routine in Turkey. We evaluated the current situation by reviewing all patients with β-thalassemia major at the main pediatric hematology outpatient clinic in Ankara for 9 months. A commercial kit was used for red cell genotyping, along with nucleotide sequencing in 51 patients. A total of 1734 antigens were determined by genotyping and were compared with the phenotype on record for 306 antigens of the Rh and Kell systems. We found up to 3 discrepancies in reported phenotype vs the genotype in 25 patients (49%). Notably, the discrepancy rate has remained unchanged over the past 10 years. The 3 patients with alloantibodies received significantly more transfusions than those without (90 ± 9 vs 73 ± 19; P = .015). Patients with discrepancies trended toward hepatic iron overload (84% vs 58%; P = .071). Other clinical parameters, namely transfusion frequency, growth, ferritin levels, and liver and cardiac functions, were comparable between patients with and those without discrepancies. By assessing red cell genotyping for its possible clinical benefit, we immediately improved transfusion practice in half of the children with β-thalassemia major. The implementation of red cell genotyping, a high-throughput method with a rapid turnaround time, will enhance antigen matching. Our real-world data may serve as evidence in the decision processes for the implementation of genotyping in countries in which red cell genotyping is not yet common practice.
2025-07-28 | Unveiling success: determinants of a successful haematopoietic stem cell transplant: a case report
Patients with beta thalassemia major can make an uneventful and miraculous recovery after bone marrow transplantation despite lacking a sibling donor. The once widely accepted belief that only a transplant received from a sibling or mother would lead to a successful outcome has been challenged by the advent of new approaches and drugs. We present the case of a 15-year-old girl who received stem cells from her father and, despite suffering an attack of acute graft versus host disease (aGVHD) and depression, still managed to achieve a 100% success rate. This report highlights the importance of factors other than the source of stem cells in evaluating the patient’s outcome and the lack of awareness about this disease even among the literate population in our country. Keywords: Haematopoietic stem cell transplantation, Beta thalassemia, GVHD.
2025-07-04 | Outcomes of Unrelated Donor Stem Cell Transplantation with Partial T Cell Depletion for Pediatric Patients with Hemoglobinopathies.
Optimal methods of alternative donor allogeneic transplant for pediatric patients with sickle cell disease (SCD) and beta thalassemia major (BTM) lacking matched related donors have remained elusive. Most studies demonstrate unacceptable rates of graft rejection, graft-versus-host disease, and/or organ toxicity in children. Ex vivo partial T cell depletion (pTCD) of unrelated donor peripheral stem cell (URD-PSC) grafts has the potential to facilitate durable engraftment while preventing GVHD. We present a single-center analysis of URD pTCD-PSCT for pediatric patients with SCD and BTM. Sixteen patients underwent URD-SCT with 10/10 or 9/10 HLA-matched donors across 3 clinical trial protocols. Conditioning included hydroxyurea, thymoglobulin, fludarabine, thiotepa, and busulfan. Graft manipulation included CD3+/CD19+ depletion with 1 × 105 CD3+ cells/kg addback in 4 patients, and TCRαβ+ T cell/CD19+ depletion in 12 patients. Median follow-up is 36 months (range 10 to 57). One- and 3-year overall survival is 93.8%, and 3-year graft failure-free survival is 81.3%. One patient with preexisting severe cerebrovasculopathy died from cerebral hemorrhage. All patients demonstrated rapid trilinear engraftment, and notably rapid platelet engraftment. No patients developed Grades III and IV acute GVHD or moderate-to-severe chronic GVHD. All 6 patients with SCD receiving 10/10 matched donor grafts and all patients with BTM (all 5 had 9/10 matched donors) exhibited durable engraftment with median total donor chimerism of 95% (range 88% to 100%) at last follow-up. 3 of 5 patients with SCD receiving 9/10 HLA-matched donor grafts experienced graft failure. Two of these patients had lasting engraftment and resolution of disease phenotype with a second transplant. URD-PSCT with pTCD is associated with excellent engraftment, overall survival, and minimal GVHD in patients with SCD receiving 10/10 URD grafts and patients with BTM with ≥9/10 URD grafts.
2025-02-21 | Prevalence of Alloimmunization Events in Thalassemia Patients With Repeated Transfusions in the Rhesus Blood Group System: A Systematic Review and Meta Analysis.
Alloimmunization presents a significant challenge for patients with β-thalassemia major who depend on regular transfusion therapy. This systematic review and meta-analysis aimed to evaluate the frequency of alloimmunization within the Rhesus blood group system and identify the most prevalent alloantibodies. A comprehensive search across multiple databases was conducted to locate epidemiological studies reporting alloimmunization in thalassemia patients undergoing repeated transfusions, specifically focusing on Rhesus antibodies. Statistical analyses were performed using R software, and heterogeneity was assessed using I2 statistics. This review included 20 studies with a total of 4,650 patients. The overall prevalence of alloimmunization was 5.4% (95% confidence interval (CI): 3.1-9.3%) across all ages, with a prevalence of 9.1% (95% CI: 5.3-15.2%) in children and 25% (95% CI: 12.7-41.2%) in adults. The pooled overall prevalence was 6.6% (95% CI: 4.2-10.2%). Among the 488 alloimmunized patients, 310 developed Rhesus-specific antibodies, with anti-E (34.58%) and anti-D (13.69%) being the most frequent. This study underscores the substantial prevalence of Rhesus antibodies among alloimmunized thalassemia patients. Implementing extended phenotype matching for transfusions could significantly reduce the risk of alloantibody formation in this population. Future analyses should explore factors influencing alloimmunization rates, such as ethnic diversity, matching protocols, and age-related variations, to inform clinical practice better.
2024-02-20 | Treatment of Mixed Chimerism After Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Major
Background: Incomplete donor cell chimerism often occurs in thalassemia transplant due to host cells remain or reappear overtime, which is termed as mixed chimerism (MC). Objective: To compare the immunosuppression withdrawal (ISW) and donor lymphocyte infusion (DLI) in the correction of mixed chimerism (MC) after thalassemia transplantation. Methods: Eighty-seven patients with post-transplant MC admitted in our center from January 2010 to December 2019 were analyzed. Among them donor cells of 90%-95% and 75%-89% were classified as MC1 and MC2 respectively. MC3 donor cells <75%. The incidence and correction rate of MC, the occurrence rate of graft versus host disease (GVHD), timing of DLI were studied. Results: DLI was associated with higher correction rates and higher GVHD than ISW. In MC1 group, higher GVHD occurred in early and intermediate stage (<I>P</I> = 0.024/0.023) than ISW. In MC2 group, DLI in late stages had higher correction rates than ISW (<I>P</I> = 0.001). Conclusion: ISW was the primary strategy for MC1 patients. DLI should be given to the late-stage MC2 patients quickly. The earlier the treatment is provided, regardless of ISW or DLI, the more likely that patients develop GVHD.
proteins
2026-09-01 | Impact of luspatercept in beta-thalassemia major with alloimmunization: A case report
Patients with Beta (β)-thalassemia require regular blood transfusions. The presence of red blood cell (RBC) alloantibodies can complicate transfusion treatment. This can lead to delays in obtaining compatible blood, and in some case temporarily rendering blood transfusion impossible. We present a case demonstrating the successful adjunctive management of a patient with transfusion-dependent β-thalassemia complicated by RBC alloimmunization using a novel therapeutic agent. A 32-year-old Thai female with homozygous β-thalassemia was admitted to the Hospital of Tropical Diseases, Bangkok, with symptoms of anemia. Cross-matching studies revealed the presence of alloantibodies at admission. Treatment with luspatercept, a novel erythroid maturation agent, resulted in an increase in hemoglobin levels and an extension of the transfusion interval. The patient received four doses of luspatercept while awaiting antigen-compatible RBC units. Although luspatercept had no direct effect on RBC alloimmunization or existing alloantibodies, its ability to reduce transfusion requirements may decrease the need for subsequent RBC transfusions, and thereby reduce further antigen exposure. This may be particularly beneficial in patients with complex alloantibody profiles. This case highlights the potential role of luspatercept as adjunctive supportive therapy to delay transfusions requirements in patients with transfusion-dependent β-thalassemia complicated by RBC alloimmunization.
2026-08-11 | A review on the role of Hepicidin hormone in beta thalassemia major disease
Thalassemia is a haemoglobin disorder that is inherited. One or more globin chains of haemoglobin tetramers are produced less frequently or not at all, which causes uncontrollably high RBC destruction and severe anemia. An imbalance in globin chain synthesis causes damage to red blood cells in thalassemia. Hepcidin is severely reduced in thalassemia, and any increase in hepcidin function benefits erythropoiesis and iron metabolism. Clinical trials have been conducted on synthetic hepcidin and hepcidin mimetics. Nevertheless, their efficacy/safety profile has not been satisfactory. When taking hepcidin directly as a medication, it appears to be challenging to prevent iron over-restricted erythropoiesis. Indirect methods are numerous and still evolving, each with pros and cons. Targeting erythroferrone, the primary inhibitor of hepcidin expression, is the best strategy because iron-loading anaemias significantly raise its plasma concentrations. The development of pharmacological agonists and antagonists as well as hepcidin diagnostics should enhance the management of iron diseases.
2026-04-22 | Recent Advances in Thalassemia Management: From Curative Therapies to Artificial Intelligence
Thalassemia is an inherited hemoglobin disorder characterized by chronic hemolytic anemia and substantial long-term healthcare needs. In β-thalassemia major, patients typically require regular red blood cell transfusions with iron chelation to prevent transfusional iron overload. Although supportive care has markedly improved survival, it is associated with a high treatment burden and does not provide a cure. In recent years, curative and disease-modifying therapies have expanded the treatment landscape. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potentially curative option for selected patients, while autologous gene therapy and gene-editing approaches have shown the capacity to achieve transfusion independence in clinical studies. In parallel, pharmacologic advances—including luspatercept, a transforming growth factor-beta (TGF-β) ligand trap—have been shown to enhance erythropoiesis and reduce transfusion requirements, and emerging agents such as fetal hemoglobin inducers (e.g., thalidomide) and the oral pyruvate kinase activator mitapivat have demonstrated clinically meaningful hemoglobin improvements in selected populations. Adjunctive strategies, including antioxidants, are under investigation to mitigate oxidative stress, and applications of artificial intelligence are increasingly used to support screening, diagnosis, and longitudinal monitoring of iron overload. This review synthesizes recent advances in curative therapies, novel pharmacologic agents, supportive strategies, and AI-enabled tools and highlights priorities for future clinical development and implementation.
2025-11-03 | Efficacy of luspatercept in reducing transfusion burden and its impact on liver iron concentration in beta-thalassemia major: A systematic review and meta-analysis
Abstract Introduction Beta thalassemia is an inherited blood disorder caused by mutations in the genes encoding beta globin. In transfusion-dependent patients, transfusions can lead to iron overload, associated with organ damage and increased mortality. Luspatercept has emerged as a promising therapeutic agent to reduce the need for transfusions and to improve iron management in these patients. Objective Evaluate the efficacy of luspatercept versus placebo in reducing transfusion burden and liver iron concentration (LIC) in patients with transfusion-dependent beta-thalassemia. Methods A systematic search was performed in Pubmed, Embase and Cochrane for studies comparing luspatercept versus placebo in patients with transfusion-dependent beta-thalassemia. The main outcomes of interest were reduction of transfusion burden by ≥33% and ≥50% and LIC. Statistical analysis was performed using Review Manager. The I2 test was used to assess heterogeneity, and risk of bias was assessed using ROBINS-I. Results We included 368 patients from two clinical trials. The use of luspatercept was associated with a higher proportion of patients achieving both ≥33% (RR = 2.22; 95%CI 1.70-2.89; p = 0.00001) and ≥50% (RR= 6.22; 95%CI 3.28-11.80; p = 0.00001) reduction in transfusion burden compared to the placebo group. Regarding LIC, no statistically significant difference was observed when comparing both groups (mean difference: 1.33 mg/g; 95% CI -0.79 to 3.45; p = 0.22) Conclusion Luspatercept demonstrated significant efficacy in reducing transfusion requirement in patients with transfusion-dependent beta-thalassemia. Although no clear effect on LIC was demonstrated, the results support its use as a promising alternative. Nevertheless, these findings should be interpreted with caution, as one of the studies did not include a placebo group, which limits the robustness of the comparison. Further confirmation by additional randomized clinical trials is needed to validate these results and to determine in more detail their role in clinical practice.
2024-07-02 | Genetic Correlation of HBB, HFE and HAMP Genes to Endocrinal Complications in Egyptian Beta Thalassemia Major Patients.
Iron loading is regarded as the primary cause of endocrine abnormalities in thalassemia major patients. Thus, the purpose of the current research was to explore the impact of thalassemia genotypes, hepcidin antimicrobial peptide (HAMP) and hereditary hemochromatosis (HFE) gene variants, and hepcidin expression on serum ferritin and endocrinal complications in thalassemia patients. The study comprised fifty beta-thalassemia cases and fifty age- and sex-matched controls. Genotyping of the Beta-globin gene (HBB), HAMP, and exon 2 of the HFE gene was performed using Sanger sequencing. C282Y (c.845G > A) variant of the HFE gene was determined by PCR-RFLP. Hepcidin mRNA expression was assessed by qRT-PCR. Biochemical and hormonal studies were done for all patients. Hypogonadism and short stature were found in 56% and 20% of the investigated cases, respectively. Molecular studies reported a statistically higher frequency of the HAMP variant c.-582A > G in thalassemic patients than controls. Significant downregulation of hepcidin expression was found in cases compared to healthy subjects that was significantly associated with short stature. Considering the thalassemia alleles, the IVSI.1G > A (β0) allele was statistically related to hypogonadism. Our results proposed that thalassemia genotypes and downregulated hepcidin expression were the potential risk factors for endocrinopathies in our cases. We also demonstrated an increased incidence of the HAMP promoter variant c.- 582A > G that might have a role in the pathogenesis of iron overload in thalassemic cases. Significant downregulation of hepcidin expression, that contributes to increased iron burden, could be used as a future therapeutic target in these patients.
small molecules
2026-09-27 | Effect of HFE Gene H63D and S65C Mutations on the Severity of Secondary Iron Overload in Children With β-Thalassemia Major.
Coinheritance of HFE gene mutations in patients with β-thalassemia major (βTM) may further exacerbate systemic iron accumulation, potentially leading to earlier onset of iron-related complications. This study aimed to screen for HFE gene H63D and S65C mutations in children with βTM and evaluate their impact on the severity of secondary iron overload (IO). This cross-sectional study included 76 Sudanese children with βTM who were all receiving regular blood transfusions and iron chelation therapy. Polymerase chain reaction and Sanger DNA sequencing were used to screen for H63D and S65C mutations. IO severity was assessed by measuring serum ferritin (SF) levels using electrochemiluminescence immunoassay. The H63D mutation was identified in 17 (22.4%) of the thalassemic children; 16 (21.1%) were heterozygous, and one (1.3%) was homozygous. The S65C mutation was not present in any of the participants. SF levels were higher among carriers of the H63D variant allele (CG + GG) than among those with the wild-type allele (CC). Still, the difference was not statistically significant (median: 2051.0 vs. 1460.0 μg/L, p = 0.09). Furthermore, no statistically significant association was observed between the H63D mutation and the risk of myocardial iron loading (p = 0.087). The results revealed a statistically significant positive correlation between SF levels and the total number of blood transfusions (Spearman's ρ = 0.496, p < 0.001). A weak, positive, insignificant correlation was observed between SF levels and both the time since the last dose of iron chelation therapy (ρ = 0.257, p = 0.100) and C-reactive protein levels (ρ = 0.129, p = 0.267). The frequency of the HFE gene H63D mutation was relatively high among Sudanese children with βTM, whereas the S65C variant was absent. Although SF levels were higher in the carriers of the H63D variant allele compared to those with the wild-type allele, the difference was not statistically significant. These findings indicate limited clinical utility for routine screening for the HFE H63D and S65C mutations and emphasize the greater importance of optimizing transfusion and iron-chelating therapy practices to manage IO effectively.
2026-09-27 | Successful Management of Severe Hepatic Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in a Child With β-Thalassemia Major: Clinical Lessons From Early Therapeutic Escalation.
Severe hepatic acute graft-versus-host disease can occur early after allogeneic hematopoietic stem cell transplantation without skin involvement, presenting with rapidly progressive cholestatic liver dysfunction. Early recognition and prompt escalation to multimodal immunosuppressive therapy achieve complete biochemical remission and durable hematopoietic recovery, highlighting the crucial role of early, multidisciplinary pediatric management.
2026-07-22 | Endocrine complications of beta-thalassemia major: Primary amenorrhea as a revealing feature of hypogonadotropic hypogonadism
Beta-thalassemia major is a hereditary hemoglobinopathy requiring lifelong blood transfusions, leading to chronic iron overload responsible for multiorgan endocrine complications, of which hypogonadism is the most frequent. We report the case of a 22-year-10-month-old female patient, followed for β-thalassemia major since the age of 3, presenting with primary amenorrhea. Clinical examination revealed late-onset breast development at Tanner stage II and pubic hair at Tanner stageIV. Hormonal workup confirmed isolated hypogonadotropic hypogonadism, with the following results: estradiol<24pg/mL, follicle-stimulating hormone 1.14 uIU/mL (ref: 3.03–8.08), luteinizing hormone 0.2uIU/mL (ref:2.39–6.6), prolactin 9.8ng/ml and serum ferritin at 7288µg/L sixty times above upper limit on deferiprone 500mg, three tablets three times daily. Pituitary MRI demonstrated an age-appropriate gland with T2*-weighted-hypo-intensity consistent with pituitary siderosis, providing objective imaging evidence of iron deposition at the gonadotroph level as the underlying mechanism of central hypogonadism. Bone assessment by bone densitometry revealed osteoporosis at multiple sites. Workup for other iron overload-related endocrinopathies returned within normal limits. The patient was initiated on transdermal-17beta-estradiol at progressively increasing doses starting at0.25mg/day. The pedagogical originality of this case report lies in the association between primary amenorrhea — reflecting gonadotroph damage early enough to prevent pubertal completion — and pituitary siderosis directly visualized on MRI, offering a didactically valuable illustration of the causal link between chronic iron overload and central hypogonadotropic hypogonadism. This case underscores the importance of systematic and early endocrine screening in transfusion-dependent thalassemia patients, and highlights the need for prompt hormone replacement therapy initiation and optimized iron chelation to prevent irreversible endocrine complications.
2026-06-30 | The Adverse Effects of Thalassemia Treatments Including Blood Transfusion and Main Pharmacological Therapies
A B S T R A C T Background: Beta-thalassemia major (β-TM) is a disorder which needs lifelong blood transfusions. Our aim was to examine the treatments side effects in thalassemic patients. Methods: 110 β-TM patients attending two centers were invited to the study. Those who consented were asked to complete a questionnaire. The questionnaire covered demographical information, used medications and their side effects. The data was analyzed using SPSS software version 14. Results: Data was collected between August 2008 and July 2009. Patients' age was 14.0±1.32 years. The duration of treatment was 11.3±7.5 years. Thalassemic patients received blood transfusions, deferoxamine and supportive medications. Number of medications, received by patients was 3.9±1.9. Hemosiderosis in heart (11%) and endocrine system (8%) were main blood transfusion side effects. A few had hepatitis B or C. Conclusion: Because of prevalence of side effects of therapies, reviewing and improving treatment protocol by designing new medicines with lower side effects and establishment of an adverse reactions team seemed necessary.
2026-05-11 | SNH-119014, a novel pyruvate kinase activator, enhances ATP production and reduces oxidative stress in erythroid cells from patients with β-thalassemia major.
Thalassemia is a common disease worldwide. Oxidative stress contributes to ineffective erythropoiesis and hemolysis in β-thalassemia major (β-TM). Increasing cellular adenosine triphosphate (ATP) production by activating the activity of the pyruvate kinase (PK) may counteract oxidative stress. SNH-119014 is a novel allosteric PK activator targeting the same protein as mitapivat (AG-348), a first-in-class agent known to ameliorate anemia in thalassemia. This study aim to evluate the effects of SNH-119014 in erythroid cells from β-TM patients. PK activity was measured in recombinant human PKLR isoforms incubated with a range of concentrations of SNH-119014. Peripheral blood samples were obtained from 30 β-TM patients and 30 healthy controls (HCs), and the isolated red blood cells (RBCs) were assessed for ATP content and analyzed by metabolomics. Bone marrow samples were collected from 14 β-TM patients and four healthy volunteers, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were isolated. HSPCs were differentiated into erythroid precursors. Erythroid precursors were treated with 5 μM SNH-119014, 5 µM AG-348, or vehicle, followed by assessment of ATP content, reactive oxygen species (ROS) levels, the reduced/oxidized glutathione ratio, and metabolomic profiling. SNH-119014 activated PK with an AC50 of 28.90 nM and was characterized by a higher maximal efficacy (Emax = 949.9%) compared to AG-348 (AC50 = 13.71 nM; Emax = 749.4%). Consistently, in RBCs from β-TM patients, SNH-119014 increased ATP by a mean of 129% compared to 131% for AG-348 (p = 0.0928). Based on metabolomics, KEGG pathway analysis revealed that glycolysis/gluconeogenesis and the pentose phosphate pathway were among the top ten most significantly enriched pathways for both SNH-119014 and AG-348. Considering ineffective erythropoiesis is a important factor contributor to thalassemia pathology, we further investigated the effects of SNH-119014 in erythroid precursors. SNH-119014 increased ATP levels, reduced ROS, and improved the GSH/GSSG ratio in erythroid precursors. In conclusion, SNH-119014 activates PK, thereby increasing ATP production and alleviating oxidative stress in erythroid cells from β-TM patients. SNH-119014 exhibits a promising pharmacological profile, supporting its further development as a potential therapy for thalassemia.
gene therapies
2026-09-01 | Analysis of microRNA-451 gene expression and its association with liver function tests in β-thalassemia major.
Introduction: Major β-thalassemia is a severe hereditary anemia caused by defective β-globin production and characterized by a permanent transfusion requirement, which leads to an overload of systemic iron and subsequent liver dysfunction. MicroRNA-451 (miR-451) is an erythroid-specific microRNA that plays a critical role in erythropoiesis, oxidative stress regulation, and iron metabolism. Nevertheless, there is still insufficient research on the connection between β-thalassemia major and liver function. Aim: The study aimed to evaluate the expression of miR-451 in Iraqi patients with β-thalassemia major and correlate it with liver function parameters. Materials and methods: This case-control study involved 50 patients diagnosed with β-thalassemia major and 50 healthy individuals serving as controls. Total RNA was extracted from whole blood samples, and the expression levels of miR-451 were quantified using quantitative real-time PCR (qRT-PCR). U6 small nuclear RNA was utilized as the endogenous control for normalization. Hematological indices and liver function parameters, specifically ALT, AST, and total serum bilirubin, were assessed and analyzed statistically. Results: The expression of miR-451 was upregulated significantly in patients in comparison with the controls (≈260-fold increase). The patients had significantly lower levels of hemoglobin and elevated platelet counts (p≤0.05). The liver enzymes, ALT and AST, and the total serum bilirubin were significantly increased in the patient group (p≤0.01). This study found a positive association between the overexpression of miR-451 and hepatic dysfunction markers. Conclusion: In β-thalassemia major, miR-451 is significantly upregulated, suggesting it could be a biomarker for disease severity and liver function.
2026-06-22 | Diagnostic Utility of High-Performance Liquid Chromatography and Its Correlation With Hematological Indices in the Evaluation of Hemoglobinopathies.
Hemoglobinopathies are common genetic disorders in India and frequently present as microcytic hypochromic anemia, often mimicking iron deficiency anemia. High-performance liquid chromatography (HPLC) enables accurate quantification of hemoglobin fractions and facilitates reliable diagnosis. This cross-sectional study included 150 patients with microcytic hypochromic anemia (mean corpuscular volume (MCV) < 80 fL, mean corpuscular hemoglobin (MCH) < 27 pg) and clinical suspicion of hemoglobinopathy. Complete blood count and HPLC (Bio-Rad D10, Bio-Rad Laboratories, Hercules, CA) were performed. Hemoglobin fractions were quantified, and hematological indices were correlated with HPLC findings. Statistical analysis was performed using independent t-tests and chi-square tests. Abnormal hemoglobin patterns were identified in 100 (66.7%) patients. Beta thalassemia trait was the most common finding, seen in 63 patients (42.0%), and was characterized by elevated HbA2 levels (mean: 5.2% ± 0.8%). These patients showed significantly lower MCV and MCH values and higher red blood cell (RBC) counts compared with those with normal HPLC patterns (P < 0.001). Beta-thalassemia major was identified in 12 (8.0%) with markedly elevated fetal hemoglobin (HbF) (mean: 85.6% ± 8.2%). Structural variants, including HbS trait (7, 4.7%) and homozygous HbE (6, 4.0%), were also detected based on characteristic HPLC patterns. HPLC is a reliable and precise diagnostic tool for hemoglobinopathies, with a strong correlation to hematological indices. Its use enables accurate differentiation of thalassemia carriers from other causes of microcytic anemia, supporting its role in routine diagnostic evaluation.
2026-06-03 | HLA-DQB1 alleles as genetic modifiers in β-thalassemia major: association with clinical heterogeneity.
Clinical expression among children with transfusion-dependent β-thalassemia major varies substantially, and this heterogeneity is not fully explained by HBB mutations alone. We evaluated whether HLA-DQB1 alleles were associated with case status in a pediatric case-control cohort and whether selected alleles correlated with hematologic and hemoglobin fraction profiles among affected children. This single-center case-control study included 45 children with transfusion-dependent β-thalassemia major and 45 age- and sex-matched healthy controls. HLA-DQB1 genotyping was performed using a sequence-specific primer real-time PCR assay. Allele frequencies were compared between groups, and within-patient analyses examined associations with pre-transfusion hemoglobin, reticulocyte counts, and hemoglobin fractions. Multivariable and internal-validation analyses were treated as exploratory because of the modest sample size. DQB1 0601 was more frequent in cases than controls (9.7% vs. 2.2%, p = 0.034), whereas the DQB1 03 family (30.1% vs. 45.6%, p = 0.031) and particularly DQB1 0302 (6.5% vs. 26.7%, p < 0.001) were less frequent among cases. After Bonferroni correction for 15 allele comparisons, only DQB1 0302 remained significant. Within the patient group, DQB1 0502/0504 was associated with higher pre-transfusion hemoglobin (p = 0.036), DQB1 0501 with higher reticulocyte counts (p = 0.021), and DQB1 0601 with lower HbA1 and higher HbF (both p ≈ 0.03); these phenotype associations were exploratory and did not survive strict multiplicity correction. In adjusted exploratory models, the direction of association remained similar. In this Egyptian cohort, HLA-DQB1 alleles were associated with case status and with selected laboratory features among children with transfusion-dependent β-thalassemia major. These findings should be interpreted as association signals rather than evidence of etiologic susceptibility or causation, and they require validation in larger multi-group cohorts that include non-transfusion-dependent thalassemia.
2026-02-02 | Functional correction and genome integrity with duplex base editing of β-thalassemic hematopoietic stem cells
Beta-thalassemia is among the most common monogenic disorders, posing a major global health challenge. Editing of genetic modifiers, such as BCL11A erythroid enhancer and HBG promoters, enhances fetal hemoglobin expression and confers major therapeutic potential. Double-strand-break (DSB)-independent genome editing tools, such as base editors (BE), are potentially safer and better suited for multiplexed application than DSB-dependent CRISPR/Cas technology. However, harmful on- and off-target events remain a concern and must be excluded before clinical application, including chromosomal rearrangements invisible to standard detection technologies. Using primary patient-derived CD34 + cells from three donors, we investigate simplex and duplex BE-based disruption of the BCL11A erythroid enhancer and the BCL11A binding site (-115 bp) on the HBG promoter for DNA-level and functional studies at the RNA, protein, and morphological level. Analyses include direct comparison to DSB-based editing, the current clinically applied standard, and CAST-seq to assess recombination events, allowing wider inferences on relative safety. RNA-seq analyses for clones of primary CD34 + cells across all treatments confirm peak HBG induction for duplex BE and comparable effects on apoptotic and immune response signatures. Overall, duplex BE produces robust γ-globin and fetal hemoglobin induction, improves functional correction over simplex editing and results in low incidence of genomic alterations in both target loci. Duplex BE targeting both BCL11A erythroid enhancer and HBG promoter enables functional correction and genome integrity. Our study highlights the efficacy, safety, and therapeutic potential of the present duplex BE approach.
2025-12-28 | From Transfusions to Transformation: Assessing Gene Therapy against Conventional Treatments for Thalassemia
Thalassemia is an autosomal recessive hemoglobinopathy that results in severe anemia and organ damage, affecting up to 400 million people worldwide.Alpha thalassemia major and beta thalassemia major are the most severe forms of thalassemia.Alpha thalassemia major is fatal before birth, while beta thalassemia major leads to fatality during childhood.Conventional treatments for thalassemia have many drawbacks and can only manage the symptoms without curing the disorder.Gene therapy has recently emerged as a promising treatment for thalassemia, which could serve as a lifelong cure.Some gene therapies aim to cure beta thalassemia by inserting a gene construct for -globin production, and others by gene editing to reactivate fetal hemoglobin (HbF) synthesis.Some of these therapies have even been approved to treat the disorder.This paper evaluates conventional treatments for thalassemia and examines the potential of gene therapy as a new treatment approach.
other
2026-07-02 | Interleukin-1β and Glycolytic Enzyme Alterations in Beta-Thalassemia Major: Insights into Inflammation-Metabolism Crosstalk
Background: Beta-thalassemia major is characterized by chronic hemolytic anemia, ineffective erythropoiesis, and systemic iron overload, leading to metabolic and inflammatory alterations. Objective: This study investigated the relationship between serum interleukin-1β (IL-1β), key glycolytic enzymes (hexokinase [HK], pyruvate kinase [PK], phosphofructokinase [PFK]), and PFKP gene expression in beta-thalassemia major patients. Methods: A case-control study was conducted involving 42 beta-thalassemia major patients and 30 healthy controls. Serum levels of IL-1β, HK, PK, and PFK were measured using ELISA, while PFKP gene expression was assessed by RT-qPCR. Results: Patients exhibited significantly elevated IL-1β (41.34 ± 42.23 vs. 21.43 ± 26.45 pg/mL; p = 0.0276), HK (327.71 ± 282.40 vs. 131.47 ± 158.67 pg/mL; p = 0.0012), and PFK (1.83 ± 1.52 vs. 0.51 ± 0.53 ng/mL; p < 0.0001) compared to controls. Strong positive correlations were observed between IL-1β and glycolytic enzymes (r = 0.637-0.690, p < 0.0001). Conclusion: These findings demonstrate significant inflammation-metabolism crosstalk in beta-thalassemia major, suggesting that targeting inflammatory pathways may ameliorate metabolic disturbances in affected patients.
2026-06-05 | Use of romosozumab for osteoporosis in β-thalassemia major.
Thalassemia bone disease is a common and severe complication of β-thalassemia major (TM), resulting from marrow expansion, hormonal deficiencies, including hypogonadism, iron toxicity, and increased bone turnover. These factors contribute to reduced BMD and increased susceptibility to minimal trauma fracture (MTF). Optimizing transfusions and iron chelation therapy, management of hormonal deficiencies, and antiresorptive therapies are the cornerstone of management. We report the use of romosozumab in 2 patients with TM and severe osteoporosis. This is the first case series describing the efficacy of romosozumab in the treatment of osteoporosis in patients with TM. After completion of 12 mo of monthly romosozumab, DXA scan demonstrated significant improvements in BMD despite previous prolonged exposure to antiresorptive therapy in both subjects. This represents a promising treatment option in patients with TM and osteoporosis.
2025-09-12 | Abatacept improves posttransplant survival and reduces endothelial injury syndromes in β-thalassemia major.
Iron overload in transfusion-dependent β-thalassemia (TDT) generates reactive oxygen species, predisposing to post-hematopoietic stem cell transplant (HSCT) endothelial activation. Abatacept prevents acute graft-versus-host disease (GVHD) by inhibiting CD80/CD86 on T cells, but CD80 is also expressed on neutrophils. Elevated neutrophil extracellular traps (NETs) at day +14 are associated with thrombotic microangiopathy (TMA) after HSCT, mechanistically linking endothelial activation to complement activation. We wanted to compare post-HSCT survival and incidence of endothelial injury syndromes in children with TDT with and without addition of abatacept to standard GVHD prophylaxis. We performed a retrospective review of children with TDT who underwent HSCT at our center. Patients without abatacept served as controls. A total of 64 children underwent HSCT for TDT. Fifty received abatacept and 14 did not. Acute grade 2 to 4 GVHD was lower in the abatacept cohort (0%) compared with the no-abatacept cohort (35%). Incidence of any endothelial injury syndromes (transplant-associated TMA, sinusoidal obstructive syndrome, posterior reversible encephalopathy, and diffuse alveolar hemorrhage) was lower in the abatacept cohort (16%) compared with no abatacept (64%; P = .0009). Day +14 double-stranded DNA (surrogate of NETs) and soluble c5b-9 were lower in the abatacept cohort than the no-abatacept cohort (P = .04 and P < .001, respectively). All patients in the abatacept cohort had full donor myeloid chimerism and remained transfusion independent at a median last follow-up of 1915 days (range, 266-3464) after HSCT. Thalassemia-free survival was 100% in the abatacept cohort and 71% in the no-abatacept cohort. Addition of abatacept to calcineurin inhibitor-based GVHD prophylaxis resulted in excellent thalassemia-free survival and lower endothelial injury syndromes.
2025-08-01 | Risk-Stratified Pretransplant Immunosuppressive Strategy Improves Outcomes of Unrelated Cord Blood Transplantation in Pediatric β-Thalassemia Major.
Unrelated umbilical cord blood transplantation (UD-UCBT) is a curative option for children with β-thalassemia major (β-TM) who lack HLA-matched sibling donors. However, challenges such as low CD34+ cell dose, pre-existing immune activation, and iron overload contribute to poor engraftment and high transplant-related mortality (TRM) in high-risk patients. To evaluate the safety and efficacy of a novel 5-factor risk-stratified pretransplant immunosuppressive strategy, combined with a myeloablative conditioning regimen featuring "early" reduced-dose anti-thymocyte globulin (ATG), in improving transplant outcomes and immune reconstitution in pediatric patients undergoing UD-UCBT for β-TM. In this single-center retrospective study, 30 pediatric patients with β-thalassemia major underwent single-unit unrelated umbilical cord blood transplantation (UD-UCBT) between September 2019 and December 2024. Patients were stratified into low-, intermediate-, and high-risk groups using a novel 5-factor scoring system incorporating age, serum ferritin, liver size, spleen size, and planned CD34+ cell dose. Intermediate- and high-risk patients received one or 2 cycles of pretransplant immunosuppressive therapy (PTIS; fludarabine and dexamethasone), followed by a myeloablative conditioning regimen with upfront low-dose ATG. Outcomes between PTIS and non-PTIS groups were compared using Fisher's exact tests, Mann-Whitney U tests, Kaplan-Meier survival analysis with log-rank tests, and linear mixed-effects models for immune reconstitution. All patients achieved engraftment without primary and secondary graft failure. The 3-yr overall survival (OS) and thalassemia-free survival (TFS) were both 94.4%, with 100% OS in the PTIS group. The cumulative incidence of grade II-IV acute GVHD by d 100 was 31.2%, and grade III-IV acute GVHD was 8.4%. Chronic GVHD occurred in 23.3% of patients, all limited type. Pulmonary infections were significantly lower in the PTIS group (27.8% versus 83.3%, P = .008). PTIS-treated patients demonstrated superior CD3+CD8+ T-cell and CD19+ B-cell recovery at 6 to 12 months post-transplant. This risk-stratified approach combining PTIS with a "early" reduced-dose ATG conditioning was safe, well-tolerated, and associated with excellent survival, engraftment, and immune reconstitution outcomes. It offers a promising strategy to improve the prognosis of high-risk pediatric β-TM patients undergoing UD-UCBT.
2025-07-01 | Is parvovirus a concern in thalassemia?
Background Our study investigated the risk of Parvovirus B19 infection in patients with beta-thalassemia, who regularly receive blood transfusions. Since Parvovirus B19 can remain asymptomatic but have a high viral load, it poses a significant risk of transmission through transfusions, particularly increasing the likelihood of transient aplastic crisis, as the virus targets erythroid progenitor cells. Objectives The study aims to assess the prevalence of the virus in these high-risk patients and explore the relationship between immunoglobulin M (IgM), immunoglobulin G (IgG) antibodies, and viral load as measured by PCR. Patients and methods A case-control study was conducted with 160 participants, including 80 beta-thalassemia major patients receiving regular blood transfusions and 80 matched healthy controls. Medical evaluations and laboratory tests, such as complete blood count, serum ferritin, SGOT, and SGPT, were performed on all subjects. ELISA tested for Parvovirus IgM and IgG antibodies, while conventional PCR was used to detect the Parvovirus B19 viral genome. Results Parvovirus IgM and IgG levels were significantly higher in thalassemia patients, with a prevalence of 56.3% compared to 11.3% in healthy controls. This was confirmed by PCR, which detected the viral genome in 18 patients (22.5%). ELISA results showed 18.8% of patients tested positive for IgM (15/80) and 37.5% for IgG (30/80). Conclusions The study found higher Parvovirus B19 infection rates in thalassemia patients compared with healthy controls, highlighting the need for preventive measures, such as screening donated blood for B19V before transfusions. It also calls for a licensed B19 vaccine to protect thalassemia major patients.
cell therapies
2026-03-19 | Clinical integration of red cell genotyping in children with β-thalassemia major: a prospective observational study.
Blood group serology frequently fails in chronically transfused patients. Discrepancies between phenotype and genotype were reported for 51% of patients with β-thalassemia in 2013; however, red cell genotyping has not become clinical routine in Turkey. We evaluated the current situation by reviewing all patients with β-thalassemia major at the main pediatric hematology outpatient clinic in Ankara for 9 months. A commercial kit was used for red cell genotyping, along with nucleotide sequencing in 51 patients. A total of 1734 antigens were determined by genotyping and were compared with the phenotype on record for 306 antigens of the Rh and Kell systems. We found up to 3 discrepancies in reported phenotype vs the genotype in 25 patients (49%). Notably, the discrepancy rate has remained unchanged over the past 10 years. The 3 patients with alloantibodies received significantly more transfusions than those without (90 ± 9 vs 73 ± 19; P = .015). Patients with discrepancies trended toward hepatic iron overload (84% vs 58%; P = .071). Other clinical parameters, namely transfusion frequency, growth, ferritin levels, and liver and cardiac functions, were comparable between patients with and those without discrepancies. By assessing red cell genotyping for its possible clinical benefit, we immediately improved transfusion practice in half of the children with β-thalassemia major. The implementation of red cell genotyping, a high-throughput method with a rapid turnaround time, will enhance antigen matching. Our real-world data may serve as evidence in the decision processes for the implementation of genotyping in countries in which red cell genotyping is not yet common practice.
2025-07-28 | Unveiling success: determinants of a successful haematopoietic stem cell transplant: a case report
Patients with beta thalassemia major can make an uneventful and miraculous recovery after bone marrow transplantation despite lacking a sibling donor. The once widely accepted belief that only a transplant received from a sibling or mother would lead to a successful outcome has been challenged by the advent of new approaches and drugs. We present the case of a 15-year-old girl who received stem cells from her father and, despite suffering an attack of acute graft versus host disease (aGVHD) and depression, still managed to achieve a 100% success rate. This report highlights the importance of factors other than the source of stem cells in evaluating the patient’s outcome and the lack of awareness about this disease even among the literate population in our country. Keywords: Haematopoietic stem cell transplantation, Beta thalassemia, GVHD.
2025-07-04 | Outcomes of Unrelated Donor Stem Cell Transplantation with Partial T Cell Depletion for Pediatric Patients with Hemoglobinopathies.
Optimal methods of alternative donor allogeneic transplant for pediatric patients with sickle cell disease (SCD) and beta thalassemia major (BTM) lacking matched related donors have remained elusive. Most studies demonstrate unacceptable rates of graft rejection, graft-versus-host disease, and/or organ toxicity in children. Ex vivo partial T cell depletion (pTCD) of unrelated donor peripheral stem cell (URD-PSC) grafts has the potential to facilitate durable engraftment while preventing GVHD. We present a single-center analysis of URD pTCD-PSCT for pediatric patients with SCD and BTM. Sixteen patients underwent URD-SCT with 10/10 or 9/10 HLA-matched donors across 3 clinical trial protocols. Conditioning included hydroxyurea, thymoglobulin, fludarabine, thiotepa, and busulfan. Graft manipulation included CD3+/CD19+ depletion with 1 × 105 CD3+ cells/kg addback in 4 patients, and TCRαβ+ T cell/CD19+ depletion in 12 patients. Median follow-up is 36 months (range 10 to 57). One- and 3-year overall survival is 93.8%, and 3-year graft failure-free survival is 81.3%. One patient with preexisting severe cerebrovasculopathy died from cerebral hemorrhage. All patients demonstrated rapid trilinear engraftment, and notably rapid platelet engraftment. No patients developed Grades III and IV acute GVHD or moderate-to-severe chronic GVHD. All 6 patients with SCD receiving 10/10 matched donor grafts and all patients with BTM (all 5 had 9/10 matched donors) exhibited durable engraftment with median total donor chimerism of 95% (range 88% to 100%) at last follow-up. 3 of 5 patients with SCD receiving 9/10 HLA-matched donor grafts experienced graft failure. Two of these patients had lasting engraftment and resolution of disease phenotype with a second transplant. URD-PSCT with pTCD is associated with excellent engraftment, overall survival, and minimal GVHD in patients with SCD receiving 10/10 URD grafts and patients with BTM with ≥9/10 URD grafts.
2025-02-21 | Prevalence of Alloimmunization Events in Thalassemia Patients With Repeated Transfusions in the Rhesus Blood Group System: A Systematic Review and Meta Analysis.
Alloimmunization presents a significant challenge for patients with β-thalassemia major who depend on regular transfusion therapy. This systematic review and meta-analysis aimed to evaluate the frequency of alloimmunization within the Rhesus blood group system and identify the most prevalent alloantibodies. A comprehensive search across multiple databases was conducted to locate epidemiological studies reporting alloimmunization in thalassemia patients undergoing repeated transfusions, specifically focusing on Rhesus antibodies. Statistical analyses were performed using R software, and heterogeneity was assessed using I2 statistics. This review included 20 studies with a total of 4,650 patients. The overall prevalence of alloimmunization was 5.4% (95% confidence interval (CI): 3.1-9.3%) across all ages, with a prevalence of 9.1% (95% CI: 5.3-15.2%) in children and 25% (95% CI: 12.7-41.2%) in adults. The pooled overall prevalence was 6.6% (95% CI: 4.2-10.2%). Among the 488 alloimmunized patients, 310 developed Rhesus-specific antibodies, with anti-E (34.58%) and anti-D (13.69%) being the most frequent. This study underscores the substantial prevalence of Rhesus antibodies among alloimmunized thalassemia patients. Implementing extended phenotype matching for transfusions could significantly reduce the risk of alloantibody formation in this population. Future analyses should explore factors influencing alloimmunization rates, such as ethnic diversity, matching protocols, and age-related variations, to inform clinical practice better.
2024-02-20 | Treatment of Mixed Chimerism After Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Major
Background: Incomplete donor cell chimerism often occurs in thalassemia transplant due to host cells remain or reappear overtime, which is termed as mixed chimerism (MC). Objective: To compare the immunosuppression withdrawal (ISW) and donor lymphocyte infusion (DLI) in the correction of mixed chimerism (MC) after thalassemia transplantation. Methods: Eighty-seven patients with post-transplant MC admitted in our center from January 2010 to December 2019 were analyzed. Among them donor cells of 90%-95% and 75%-89% were classified as MC1 and MC2 respectively. MC3 donor cells <75%. The incidence and correction rate of MC, the occurrence rate of graft versus host disease (GVHD), timing of DLI were studied. Results: DLI was associated with higher correction rates and higher GVHD than ISW. In MC1 group, higher GVHD occurred in early and intermediate stage (<I>P</I> = 0.024/0.023) than ISW. In MC2 group, DLI in late stages had higher correction rates than ISW (<I>P</I> = 0.001). Conclusion: ISW was the primary strategy for MC1 patients. DLI should be given to the late-stage MC2 patients quickly. The earlier the treatment is provided, regardless of ISW or DLI, the more likely that patients develop GVHD.
proteins
2026-09-01 | Impact of luspatercept in beta-thalassemia major with alloimmunization: A case report
Patients with Beta (β)-thalassemia require regular blood transfusions. The presence of red blood cell (RBC) alloantibodies can complicate transfusion treatment. This can lead to delays in obtaining compatible blood, and in some case temporarily rendering blood transfusion impossible. We present a case demonstrating the successful adjunctive management of a patient with transfusion-dependent β-thalassemia complicated by RBC alloimmunization using a novel therapeutic agent. A 32-year-old Thai female with homozygous β-thalassemia was admitted to the Hospital of Tropical Diseases, Bangkok, with symptoms of anemia. Cross-matching studies revealed the presence of alloantibodies at admission. Treatment with luspatercept, a novel erythroid maturation agent, resulted in an increase in hemoglobin levels and an extension of the transfusion interval. The patient received four doses of luspatercept while awaiting antigen-compatible RBC units. Although luspatercept had no direct effect on RBC alloimmunization or existing alloantibodies, its ability to reduce transfusion requirements may decrease the need for subsequent RBC transfusions, and thereby reduce further antigen exposure. This may be particularly beneficial in patients with complex alloantibody profiles. This case highlights the potential role of luspatercept as adjunctive supportive therapy to delay transfusions requirements in patients with transfusion-dependent β-thalassemia complicated by RBC alloimmunization.
2026-08-11 | A review on the role of Hepicidin hormone in beta thalassemia major disease
Thalassemia is a haemoglobin disorder that is inherited. One or more globin chains of haemoglobin tetramers are produced less frequently or not at all, which causes uncontrollably high RBC destruction and severe anemia. An imbalance in globin chain synthesis causes damage to red blood cells in thalassemia. Hepcidin is severely reduced in thalassemia, and any increase in hepcidin function benefits erythropoiesis and iron metabolism. Clinical trials have been conducted on synthetic hepcidin and hepcidin mimetics. Nevertheless, their efficacy/safety profile has not been satisfactory. When taking hepcidin directly as a medication, it appears to be challenging to prevent iron over-restricted erythropoiesis. Indirect methods are numerous and still evolving, each with pros and cons. Targeting erythroferrone, the primary inhibitor of hepcidin expression, is the best strategy because iron-loading anaemias significantly raise its plasma concentrations. The development of pharmacological agonists and antagonists as well as hepcidin diagnostics should enhance the management of iron diseases.
2026-04-22 | Recent Advances in Thalassemia Management: From Curative Therapies to Artificial Intelligence
Thalassemia is an inherited hemoglobin disorder characterized by chronic hemolytic anemia and substantial long-term healthcare needs. In β-thalassemia major, patients typically require regular red blood cell transfusions with iron chelation to prevent transfusional iron overload. Although supportive care has markedly improved survival, it is associated with a high treatment burden and does not provide a cure. In recent years, curative and disease-modifying therapies have expanded the treatment landscape. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potentially curative option for selected patients, while autologous gene therapy and gene-editing approaches have shown the capacity to achieve transfusion independence in clinical studies. In parallel, pharmacologic advances—including luspatercept, a transforming growth factor-beta (TGF-β) ligand trap—have been shown to enhance erythropoiesis and reduce transfusion requirements, and emerging agents such as fetal hemoglobin inducers (e.g., thalidomide) and the oral pyruvate kinase activator mitapivat have demonstrated clinically meaningful hemoglobin improvements in selected populations. Adjunctive strategies, including antioxidants, are under investigation to mitigate oxidative stress, and applications of artificial intelligence are increasingly used to support screening, diagnosis, and longitudinal monitoring of iron overload. This review synthesizes recent advances in curative therapies, novel pharmacologic agents, supportive strategies, and AI-enabled tools and highlights priorities for future clinical development and implementation.
2025-11-03 | Efficacy of luspatercept in reducing transfusion burden and its impact on liver iron concentration in beta-thalassemia major: A systematic review and meta-analysis
Abstract Introduction Beta thalassemia is an inherited blood disorder caused by mutations in the genes encoding beta globin. In transfusion-dependent patients, transfusions can lead to iron overload, associated with organ damage and increased mortality. Luspatercept has emerged as a promising therapeutic agent to reduce the need for transfusions and to improve iron management in these patients. Objective Evaluate the efficacy of luspatercept versus placebo in reducing transfusion burden and liver iron concentration (LIC) in patients with transfusion-dependent beta-thalassemia. Methods A systematic search was performed in Pubmed, Embase and Cochrane for studies comparing luspatercept versus placebo in patients with transfusion-dependent beta-thalassemia. The main outcomes of interest were reduction of transfusion burden by ≥33% and ≥50% and LIC. Statistical analysis was performed using Review Manager. The I2 test was used to assess heterogeneity, and risk of bias was assessed using ROBINS-I. Results We included 368 patients from two clinical trials. The use of luspatercept was associated with a higher proportion of patients achieving both ≥33% (RR = 2.22; 95%CI 1.70-2.89; p = 0.00001) and ≥50% (RR= 6.22; 95%CI 3.28-11.80; p = 0.00001) reduction in transfusion burden compared to the placebo group. Regarding LIC, no statistically significant difference was observed when comparing both groups (mean difference: 1.33 mg/g; 95% CI -0.79 to 3.45; p = 0.22) Conclusion Luspatercept demonstrated significant efficacy in reducing transfusion requirement in patients with transfusion-dependent beta-thalassemia. Although no clear effect on LIC was demonstrated, the results support its use as a promising alternative. Nevertheless, these findings should be interpreted with caution, as one of the studies did not include a placebo group, which limits the robustness of the comparison. Further confirmation by additional randomized clinical trials is needed to validate these results and to determine in more detail their role in clinical practice.
2024-07-02 | Genetic Correlation of HBB, HFE and HAMP Genes to Endocrinal Complications in Egyptian Beta Thalassemia Major Patients.
Iron loading is regarded as the primary cause of endocrine abnormalities in thalassemia major patients. Thus, the purpose of the current research was to explore the impact of thalassemia genotypes, hepcidin antimicrobial peptide (HAMP) and hereditary hemochromatosis (HFE) gene variants, and hepcidin expression on serum ferritin and endocrinal complications in thalassemia patients. The study comprised fifty beta-thalassemia cases and fifty age- and sex-matched controls. Genotyping of the Beta-globin gene (HBB), HAMP, and exon 2 of the HFE gene was performed using Sanger sequencing. C282Y (c.845G > A) variant of the HFE gene was determined by PCR-RFLP. Hepcidin mRNA expression was assessed by qRT-PCR. Biochemical and hormonal studies were done for all patients. Hypogonadism and short stature were found in 56% and 20% of the investigated cases, respectively. Molecular studies reported a statistically higher frequency of the HAMP variant c.-582A > G in thalassemic patients than controls. Significant downregulation of hepcidin expression was found in cases compared to healthy subjects that was significantly associated with short stature. Considering the thalassemia alleles, the IVSI.1G > A (β0) allele was statistically related to hypogonadism. Our results proposed that thalassemia genotypes and downregulated hepcidin expression were the potential risk factors for endocrinopathies in our cases. We also demonstrated an increased incidence of the HAMP promoter variant c.- 582A > G that might have a role in the pathogenesis of iron overload in thalassemic cases. Significant downregulation of hepcidin expression, that contributes to increased iron burden, could be used as a future therapeutic target in these patients.
small molecules
2026-09-27 | Effect of HFE Gene H63D and S65C Mutations on the Severity of Secondary Iron Overload in Children With β-Thalassemia Major.
Coinheritance of HFE gene mutations in patients with β-thalassemia major (βTM) may further exacerbate systemic iron accumulation, potentially leading to earlier onset of iron-related complications. This study aimed to screen for HFE gene H63D and S65C mutations in children with βTM and evaluate their impact on the severity of secondary iron overload (IO). This cross-sectional study included 76 Sudanese children with βTM who were all receiving regular blood transfusions and iron chelation therapy. Polymerase chain reaction and Sanger DNA sequencing were used to screen for H63D and S65C mutations. IO severity was assessed by measuring serum ferritin (SF) levels using electrochemiluminescence immunoassay. The H63D mutation was identified in 17 (22.4%) of the thalassemic children; 16 (21.1%) were heterozygous, and one (1.3%) was homozygous. The S65C mutation was not present in any of the participants. SF levels were higher among carriers of the H63D variant allele (CG + GG) than among those with the wild-type allele (CC). Still, the difference was not statistically significant (median: 2051.0 vs. 1460.0 μg/L, p = 0.09). Furthermore, no statistically significant association was observed between the H63D mutation and the risk of myocardial iron loading (p = 0.087). The results revealed a statistically significant positive correlation between SF levels and the total number of blood transfusions (Spearman's ρ = 0.496, p < 0.001). A weak, positive, insignificant correlation was observed between SF levels and both the time since the last dose of iron chelation therapy (ρ = 0.257, p = 0.100) and C-reactive protein levels (ρ = 0.129, p = 0.267). The frequency of the HFE gene H63D mutation was relatively high among Sudanese children with βTM, whereas the S65C variant was absent. Although SF levels were higher in the carriers of the H63D variant allele compared to those with the wild-type allele, the difference was not statistically significant. These findings indicate limited clinical utility for routine screening for the HFE H63D and S65C mutations and emphasize the greater importance of optimizing transfusion and iron-chelating therapy practices to manage IO effectively.
2026-09-27 | Successful Management of Severe Hepatic Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in a Child With β-Thalassemia Major: Clinical Lessons From Early Therapeutic Escalation.
Severe hepatic acute graft-versus-host disease can occur early after allogeneic hematopoietic stem cell transplantation without skin involvement, presenting with rapidly progressive cholestatic liver dysfunction. Early recognition and prompt escalation to multimodal immunosuppressive therapy achieve complete biochemical remission and durable hematopoietic recovery, highlighting the crucial role of early, multidisciplinary pediatric management.
2026-07-22 | Endocrine complications of beta-thalassemia major: Primary amenorrhea as a revealing feature of hypogonadotropic hypogonadism
Beta-thalassemia major is a hereditary hemoglobinopathy requiring lifelong blood transfusions, leading to chronic iron overload responsible for multiorgan endocrine complications, of which hypogonadism is the most frequent. We report the case of a 22-year-10-month-old female patient, followed for β-thalassemia major since the age of 3, presenting with primary amenorrhea. Clinical examination revealed late-onset breast development at Tanner stage II and pubic hair at Tanner stageIV. Hormonal workup confirmed isolated hypogonadotropic hypogonadism, with the following results: estradiol<24pg/mL, follicle-stimulating hormone 1.14 uIU/mL (ref: 3.03–8.08), luteinizing hormone 0.2uIU/mL (ref:2.39–6.6), prolactin 9.8ng/ml and serum ferritin at 7288µg/L sixty times above upper limit on deferiprone 500mg, three tablets three times daily. Pituitary MRI demonstrated an age-appropriate gland with T2*-weighted-hypo-intensity consistent with pituitary siderosis, providing objective imaging evidence of iron deposition at the gonadotroph level as the underlying mechanism of central hypogonadism. Bone assessment by bone densitometry revealed osteoporosis at multiple sites. Workup for other iron overload-related endocrinopathies returned within normal limits. The patient was initiated on transdermal-17beta-estradiol at progressively increasing doses starting at0.25mg/day. The pedagogical originality of this case report lies in the association between primary amenorrhea — reflecting gonadotroph damage early enough to prevent pubertal completion — and pituitary siderosis directly visualized on MRI, offering a didactically valuable illustration of the causal link between chronic iron overload and central hypogonadotropic hypogonadism. This case underscores the importance of systematic and early endocrine screening in transfusion-dependent thalassemia patients, and highlights the need for prompt hormone replacement therapy initiation and optimized iron chelation to prevent irreversible endocrine complications.
2026-06-30 | The Adverse Effects of Thalassemia Treatments Including Blood Transfusion and Main Pharmacological Therapies
A B S T R A C T Background: Beta-thalassemia major (β-TM) is a disorder which needs lifelong blood transfusions. Our aim was to examine the treatments side effects in thalassemic patients. Methods: 110 β-TM patients attending two centers were invited to the study. Those who consented were asked to complete a questionnaire. The questionnaire covered demographical information, used medications and their side effects. The data was analyzed using SPSS software version 14. Results: Data was collected between August 2008 and July 2009. Patients' age was 14.0±1.32 years. The duration of treatment was 11.3±7.5 years. Thalassemic patients received blood transfusions, deferoxamine and supportive medications. Number of medications, received by patients was 3.9±1.9. Hemosiderosis in heart (11%) and endocrine system (8%) were main blood transfusion side effects. A few had hepatitis B or C. Conclusion: Because of prevalence of side effects of therapies, reviewing and improving treatment protocol by designing new medicines with lower side effects and establishment of an adverse reactions team seemed necessary.
2026-05-11 | SNH-119014, a novel pyruvate kinase activator, enhances ATP production and reduces oxidative stress in erythroid cells from patients with β-thalassemia major.
Thalassemia is a common disease worldwide. Oxidative stress contributes to ineffective erythropoiesis and hemolysis in β-thalassemia major (β-TM). Increasing cellular adenosine triphosphate (ATP) production by activating the activity of the pyruvate kinase (PK) may counteract oxidative stress. SNH-119014 is a novel allosteric PK activator targeting the same protein as mitapivat (AG-348), a first-in-class agent known to ameliorate anemia in thalassemia. This study aim to evluate the effects of SNH-119014 in erythroid cells from β-TM patients. PK activity was measured in recombinant human PKLR isoforms incubated with a range of concentrations of SNH-119014. Peripheral blood samples were obtained from 30 β-TM patients and 30 healthy controls (HCs), and the isolated red blood cells (RBCs) were assessed for ATP content and analyzed by metabolomics. Bone marrow samples were collected from 14 β-TM patients and four healthy volunteers, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were isolated. HSPCs were differentiated into erythroid precursors. Erythroid precursors were treated with 5 μM SNH-119014, 5 µM AG-348, or vehicle, followed by assessment of ATP content, reactive oxygen species (ROS) levels, the reduced/oxidized glutathione ratio, and metabolomic profiling. SNH-119014 activated PK with an AC50 of 28.90 nM and was characterized by a higher maximal efficacy (Emax = 949.9%) compared to AG-348 (AC50 = 13.71 nM; Emax = 749.4%). Consistently, in RBCs from β-TM patients, SNH-119014 increased ATP by a mean of 129% compared to 131% for AG-348 (p = 0.0928). Based on metabolomics, KEGG pathway analysis revealed that glycolysis/gluconeogenesis and the pentose phosphate pathway were among the top ten most significantly enriched pathways for both SNH-119014 and AG-348. Considering ineffective erythropoiesis is a important factor contributor to thalassemia pathology, we further investigated the effects of SNH-119014 in erythroid precursors. SNH-119014 increased ATP levels, reduced ROS, and improved the GSH/GSSG ratio in erythroid precursors. In conclusion, SNH-119014 activates PK, thereby increasing ATP production and alleviating oxidative stress in erythroid cells from β-TM patients. SNH-119014 exhibits a promising pharmacological profile, supporting its further development as a potential therapy for thalassemia.
gene therapies
2026-09-01 | Analysis of microRNA-451 gene expression and its association with liver function tests in β-thalassemia major.
Introduction: Major β-thalassemia is a severe hereditary anemia caused by defective β-globin production and characterized by a permanent transfusion requirement, which leads to an overload of systemic iron and subsequent liver dysfunction. MicroRNA-451 (miR-451) is an erythroid-specific microRNA that plays a critical role in erythropoiesis, oxidative stress regulation, and iron metabolism. Nevertheless, there is still insufficient research on the connection between β-thalassemia major and liver function. Aim: The study aimed to evaluate the expression of miR-451 in Iraqi patients with β-thalassemia major and correlate it with liver function parameters. Materials and methods: This case-control study involved 50 patients diagnosed with β-thalassemia major and 50 healthy individuals serving as controls. Total RNA was extracted from whole blood samples, and the expression levels of miR-451 were quantified using quantitative real-time PCR (qRT-PCR). U6 small nuclear RNA was utilized as the endogenous control for normalization. Hematological indices and liver function parameters, specifically ALT, AST, and total serum bilirubin, were assessed and analyzed statistically. Results: The expression of miR-451 was upregulated significantly in patients in comparison with the controls (≈260-fold increase). The patients had significantly lower levels of hemoglobin and elevated platelet counts (p≤0.05). The liver enzymes, ALT and AST, and the total serum bilirubin were significantly increased in the patient group (p≤0.01). This study found a positive association between the overexpression of miR-451 and hepatic dysfunction markers. Conclusion: In β-thalassemia major, miR-451 is significantly upregulated, suggesting it could be a biomarker for disease severity and liver function.
2026-06-22 | Diagnostic Utility of High-Performance Liquid Chromatography and Its Correlation With Hematological Indices in the Evaluation of Hemoglobinopathies.
Hemoglobinopathies are common genetic disorders in India and frequently present as microcytic hypochromic anemia, often mimicking iron deficiency anemia. High-performance liquid chromatography (HPLC) enables accurate quantification of hemoglobin fractions and facilitates reliable diagnosis. This cross-sectional study included 150 patients with microcytic hypochromic anemia (mean corpuscular volume (MCV) < 80 fL, mean corpuscular hemoglobin (MCH) < 27 pg) and clinical suspicion of hemoglobinopathy. Complete blood count and HPLC (Bio-Rad D10, Bio-Rad Laboratories, Hercules, CA) were performed. Hemoglobin fractions were quantified, and hematological indices were correlated with HPLC findings. Statistical analysis was performed using independent t-tests and chi-square tests. Abnormal hemoglobin patterns were identified in 100 (66.7%) patients. Beta thalassemia trait was the most common finding, seen in 63 patients (42.0%), and was characterized by elevated HbA2 levels (mean: 5.2% ± 0.8%). These patients showed significantly lower MCV and MCH values and higher red blood cell (RBC) counts compared with those with normal HPLC patterns (P < 0.001). Beta-thalassemia major was identified in 12 (8.0%) with markedly elevated fetal hemoglobin (HbF) (mean: 85.6% ± 8.2%). Structural variants, including HbS trait (7, 4.7%) and homozygous HbE (6, 4.0%), were also detected based on characteristic HPLC patterns. HPLC is a reliable and precise diagnostic tool for hemoglobinopathies, with a strong correlation to hematological indices. Its use enables accurate differentiation of thalassemia carriers from other causes of microcytic anemia, supporting its role in routine diagnostic evaluation.
2026-06-03 | HLA-DQB1 alleles as genetic modifiers in β-thalassemia major: association with clinical heterogeneity.
Clinical expression among children with transfusion-dependent β-thalassemia major varies substantially, and this heterogeneity is not fully explained by HBB mutations alone. We evaluated whether HLA-DQB1 alleles were associated with case status in a pediatric case-control cohort and whether selected alleles correlated with hematologic and hemoglobin fraction profiles among affected children. This single-center case-control study included 45 children with transfusion-dependent β-thalassemia major and 45 age- and sex-matched healthy controls. HLA-DQB1 genotyping was performed using a sequence-specific primer real-time PCR assay. Allele frequencies were compared between groups, and within-patient analyses examined associations with pre-transfusion hemoglobin, reticulocyte counts, and hemoglobin fractions. Multivariable and internal-validation analyses were treated as exploratory because of the modest sample size. DQB1 0601 was more frequent in cases than controls (9.7% vs. 2.2%, p = 0.034), whereas the DQB1 03 family (30.1% vs. 45.6%, p = 0.031) and particularly DQB1 0302 (6.5% vs. 26.7%, p < 0.001) were less frequent among cases. After Bonferroni correction for 15 allele comparisons, only DQB1 0302 remained significant. Within the patient group, DQB1 0502/0504 was associated with higher pre-transfusion hemoglobin (p = 0.036), DQB1 0501 with higher reticulocyte counts (p = 0.021), and DQB1 0601 with lower HbA1 and higher HbF (both p ≈ 0.03); these phenotype associations were exploratory and did not survive strict multiplicity correction. In adjusted exploratory models, the direction of association remained similar. In this Egyptian cohort, HLA-DQB1 alleles were associated with case status and with selected laboratory features among children with transfusion-dependent β-thalassemia major. These findings should be interpreted as association signals rather than evidence of etiologic susceptibility or causation, and they require validation in larger multi-group cohorts that include non-transfusion-dependent thalassemia.
2026-02-02 | Functional correction and genome integrity with duplex base editing of β-thalassemic hematopoietic stem cells
Beta-thalassemia is among the most common monogenic disorders, posing a major global health challenge. Editing of genetic modifiers, such as BCL11A erythroid enhancer and HBG promoters, enhances fetal hemoglobin expression and confers major therapeutic potential. Double-strand-break (DSB)-independent genome editing tools, such as base editors (BE), are potentially safer and better suited for multiplexed application than DSB-dependent CRISPR/Cas technology. However, harmful on- and off-target events remain a concern and must be excluded before clinical application, including chromosomal rearrangements invisible to standard detection technologies. Using primary patient-derived CD34 + cells from three donors, we investigate simplex and duplex BE-based disruption of the BCL11A erythroid enhancer and the BCL11A binding site (-115 bp) on the HBG promoter for DNA-level and functional studies at the RNA, protein, and morphological level. Analyses include direct comparison to DSB-based editing, the current clinically applied standard, and CAST-seq to assess recombination events, allowing wider inferences on relative safety. RNA-seq analyses for clones of primary CD34 + cells across all treatments confirm peak HBG induction for duplex BE and comparable effects on apoptotic and immune response signatures. Overall, duplex BE produces robust γ-globin and fetal hemoglobin induction, improves functional correction over simplex editing and results in low incidence of genomic alterations in both target loci. Duplex BE targeting both BCL11A erythroid enhancer and HBG promoter enables functional correction and genome integrity. Our study highlights the efficacy, safety, and therapeutic potential of the present duplex BE approach.
2025-12-28 | From Transfusions to Transformation: Assessing Gene Therapy against Conventional Treatments for Thalassemia
Thalassemia is an autosomal recessive hemoglobinopathy that results in severe anemia and organ damage, affecting up to 400 million people worldwide.Alpha thalassemia major and beta thalassemia major are the most severe forms of thalassemia.Alpha thalassemia major is fatal before birth, while beta thalassemia major leads to fatality during childhood.Conventional treatments for thalassemia have many drawbacks and can only manage the symptoms without curing the disorder.Gene therapy has recently emerged as a promising treatment for thalassemia, which could serve as a lifelong cure.Some gene therapies aim to cure beta thalassemia by inserting a gene construct for -globin production, and others by gene editing to reactivate fetal hemoglobin (HbF) synthesis.Some of these therapies have even been approved to treat the disorder.This paper evaluates conventional treatments for thalassemia and examines the potential of gene therapy as a new treatment approach.
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2026-07-02 | Interleukin-1β and Glycolytic Enzyme Alterations in Beta-Thalassemia Major: Insights into Inflammation-Metabolism Crosstalk
Background: Beta-thalassemia major is characterized by chronic hemolytic anemia, ineffective erythropoiesis, and systemic iron overload, leading to metabolic and inflammatory alterations. Objective: This study investigated the relationship between serum interleukin-1β (IL-1β), key glycolytic enzymes (hexokinase [HK], pyruvate kinase [PK], phosphofructokinase [PFK]), and PFKP gene expression in beta-thalassemia major patients. Methods: A case-control study was conducted involving 42 beta-thalassemia major patients and 30 healthy controls. Serum levels of IL-1β, HK, PK, and PFK were measured using ELISA, while PFKP gene expression was assessed by RT-qPCR. Results: Patients exhibited significantly elevated IL-1β (41.34 ± 42.23 vs. 21.43 ± 26.45 pg/mL; p = 0.0276), HK (327.71 ± 282.40 vs. 131.47 ± 158.67 pg/mL; p = 0.0012), and PFK (1.83 ± 1.52 vs. 0.51 ± 0.53 ng/mL; p < 0.0001) compared to controls. Strong positive correlations were observed between IL-1β and glycolytic enzymes (r = 0.637-0.690, p < 0.0001). Conclusion: These findings demonstrate significant inflammation-metabolism crosstalk in beta-thalassemia major, suggesting that targeting inflammatory pathways may ameliorate metabolic disturbances in affected patients.
2026-06-05 | Use of romosozumab for osteoporosis in β-thalassemia major.
Thalassemia bone disease is a common and severe complication of β-thalassemia major (TM), resulting from marrow expansion, hormonal deficiencies, including hypogonadism, iron toxicity, and increased bone turnover. These factors contribute to reduced BMD and increased susceptibility to minimal trauma fracture (MTF). Optimizing transfusions and iron chelation therapy, management of hormonal deficiencies, and antiresorptive therapies are the cornerstone of management. We report the use of romosozumab in 2 patients with TM and severe osteoporosis. This is the first case series describing the efficacy of romosozumab in the treatment of osteoporosis in patients with TM. After completion of 12 mo of monthly romosozumab, DXA scan demonstrated significant improvements in BMD despite previous prolonged exposure to antiresorptive therapy in both subjects. This represents a promising treatment option in patients with TM and osteoporosis.
2025-09-12 | Abatacept improves posttransplant survival and reduces endothelial injury syndromes in β-thalassemia major.
Iron overload in transfusion-dependent β-thalassemia (TDT) generates reactive oxygen species, predisposing to post-hematopoietic stem cell transplant (HSCT) endothelial activation. Abatacept prevents acute graft-versus-host disease (GVHD) by inhibiting CD80/CD86 on T cells, but CD80 is also expressed on neutrophils. Elevated neutrophil extracellular traps (NETs) at day +14 are associated with thrombotic microangiopathy (TMA) after HSCT, mechanistically linking endothelial activation to complement activation. We wanted to compare post-HSCT survival and incidence of endothelial injury syndromes in children with TDT with and without addition of abatacept to standard GVHD prophylaxis. We performed a retrospective review of children with TDT who underwent HSCT at our center. Patients without abatacept served as controls. A total of 64 children underwent HSCT for TDT. Fifty received abatacept and 14 did not. Acute grade 2 to 4 GVHD was lower in the abatacept cohort (0%) compared with the no-abatacept cohort (35%). Incidence of any endothelial injury syndromes (transplant-associated TMA, sinusoidal obstructive syndrome, posterior reversible encephalopathy, and diffuse alveolar hemorrhage) was lower in the abatacept cohort (16%) compared with no abatacept (64%; P = .0009). Day +14 double-stranded DNA (surrogate of NETs) and soluble c5b-9 were lower in the abatacept cohort than the no-abatacept cohort (P = .04 and P < .001, respectively). All patients in the abatacept cohort had full donor myeloid chimerism and remained transfusion independent at a median last follow-up of 1915 days (range, 266-3464) after HSCT. Thalassemia-free survival was 100% in the abatacept cohort and 71% in the no-abatacept cohort. Addition of abatacept to calcineurin inhibitor-based GVHD prophylaxis resulted in excellent thalassemia-free survival and lower endothelial injury syndromes.
2025-08-01 | Risk-Stratified Pretransplant Immunosuppressive Strategy Improves Outcomes of Unrelated Cord Blood Transplantation in Pediatric β-Thalassemia Major.
Unrelated umbilical cord blood transplantation (UD-UCBT) is a curative option for children with β-thalassemia major (β-TM) who lack HLA-matched sibling donors. However, challenges such as low CD34+ cell dose, pre-existing immune activation, and iron overload contribute to poor engraftment and high transplant-related mortality (TRM) in high-risk patients. To evaluate the safety and efficacy of a novel 5-factor risk-stratified pretransplant immunosuppressive strategy, combined with a myeloablative conditioning regimen featuring "early" reduced-dose anti-thymocyte globulin (ATG), in improving transplant outcomes and immune reconstitution in pediatric patients undergoing UD-UCBT for β-TM. In this single-center retrospective study, 30 pediatric patients with β-thalassemia major underwent single-unit unrelated umbilical cord blood transplantation (UD-UCBT) between September 2019 and December 2024. Patients were stratified into low-, intermediate-, and high-risk groups using a novel 5-factor scoring system incorporating age, serum ferritin, liver size, spleen size, and planned CD34+ cell dose. Intermediate- and high-risk patients received one or 2 cycles of pretransplant immunosuppressive therapy (PTIS; fludarabine and dexamethasone), followed by a myeloablative conditioning regimen with upfront low-dose ATG. Outcomes between PTIS and non-PTIS groups were compared using Fisher's exact tests, Mann-Whitney U tests, Kaplan-Meier survival analysis with log-rank tests, and linear mixed-effects models for immune reconstitution. All patients achieved engraftment without primary and secondary graft failure. The 3-yr overall survival (OS) and thalassemia-free survival (TFS) were both 94.4%, with 100% OS in the PTIS group. The cumulative incidence of grade II-IV acute GVHD by d 100 was 31.2%, and grade III-IV acute GVHD was 8.4%. Chronic GVHD occurred in 23.3% of patients, all limited type. Pulmonary infections were significantly lower in the PTIS group (27.8% versus 83.3%, P = .008). PTIS-treated patients demonstrated superior CD3+CD8+ T-cell and CD19+ B-cell recovery at 6 to 12 months post-transplant. This risk-stratified approach combining PTIS with a "early" reduced-dose ATG conditioning was safe, well-tolerated, and associated with excellent survival, engraftment, and immune reconstitution outcomes. It offers a promising strategy to improve the prognosis of high-risk pediatric β-TM patients undergoing UD-UCBT.
2025-07-01 | Is parvovirus a concern in thalassemia?
Background Our study investigated the risk of Parvovirus B19 infection in patients with beta-thalassemia, who regularly receive blood transfusions. Since Parvovirus B19 can remain asymptomatic but have a high viral load, it poses a significant risk of transmission through transfusions, particularly increasing the likelihood of transient aplastic crisis, as the virus targets erythroid progenitor cells. Objectives The study aims to assess the prevalence of the virus in these high-risk patients and explore the relationship between immunoglobulin M (IgM), immunoglobulin G (IgG) antibodies, and viral load as measured by PCR. Patients and methods A case-control study was conducted with 160 participants, including 80 beta-thalassemia major patients receiving regular blood transfusions and 80 matched healthy controls. Medical evaluations and laboratory tests, such as complete blood count, serum ferritin, SGOT, and SGPT, were performed on all subjects. ELISA tested for Parvovirus IgM and IgG antibodies, while conventional PCR was used to detect the Parvovirus B19 viral genome. Results Parvovirus IgM and IgG levels were significantly higher in thalassemia patients, with a prevalence of 56.3% compared to 11.3% in healthy controls. This was confirmed by PCR, which detected the viral genome in 18 patients (22.5%). ELISA results showed 18.8% of patients tested positive for IgM (15/80) and 37.5% for IgG (30/80). Conclusions The study found higher Parvovirus B19 infection rates in thalassemia patients compared with healthy controls, highlighting the need for preventive measures, such as screening donated blood for B19V before transfusions. It also calls for a licensed B19 vaccine to protect thalassemia major patients.
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Drug Discovery Landscape
4 orphan drug designations for Beta-thalassemia major.
4 orphan drug designations for Beta-thalassemia major.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Human apotransferrin | proteins | EMA | Sanquin Plasma Products B.V. | |
Autologous CD34+ cells transduced with lentiviral vector encoding the human beta globin gene | gene therapies | EMA | Fondazione Telethon Ets | |
2,2-dimethylbutyric acid, sodium salt | small molecules | EMA | Isabelle Ramirez | |
deferoxamine starch conjugate | small molecules | FDA | — | Biomedical Frontiers, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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