Exploring the bone marrow micro environment in thalassemia patients: potential therapeutic alternatives.

Genetic mutations in the ß-globin gene lead to a decrease or removal of the ß-globin chain, causing the build-up of unstable alpha-hemoglobin. This condition is referred to as beta-thalassemia (BT). The present treatment strategies primarily target the correction of defective erythropoiesis, with a particular emphasis on gene therapy and hematopoietic stem cell transplantation. However, the presence of inefficient erythropoiesis in BT bone marrow (BM) is likely to disturb the previously functioning BM microenvironment. This includes accumulation of various macromolecules, damage to hematopoietic function, destruction of bone cell production and damage to osteoblast(OBs), and so on. In addition, the changes of BT BM microenvironment may have a certain correlation with the occurrence of hematological malignancies. Correction of the microenvironment can be achieved through treatments such as iron chelation, antioxidants, hypoglycemia, and biologics. Hence, This review describes damage in the BT BM microenvironment and some potential remedies.

Alterations in trace elements and cation profiles in transfusion-dependent thalassemia patients.

BACKGROUND: Transfusion-dependent thalassemia (TDT) is a severe form of beta-thalassemia, characterized by defective-globin production, resulting in a buildup of unpaired alpha globin chains. Patients with TDT can only survive if they receive safe blood transfusions regularly, which causes iron overload in their blood, which causes a variety of disorders. Cations and trace elements in TDT patients as a drug target deserve more studies. OBJECTIVES: In the present study, the cations and some trace elements were studied in TDT patients as a tool to adjust their level in the case of any disturbances. METHODS: Serum calcium, magnesium, zinc, copper, and iron were measured spectrophotometrically while manganese and cobalt were measured by flameless atomic absorption spectroscopy in 100 TDT patients and compared with 35 healthy control children. RESULTS: Patients with TDT exhibit a notable elevation in blood levels of iron, copper, copper/zinc ratio, and manganese, with a substantial reduction in serum levels of zinc, magnesium, calcium, and cobalt, as compared to the control group. These minerals have diverse associations with clinical data and transfusion frequencies. The receiver operating characteristic (ROC) analysis revealed that the elevated levels of iron, manganese, and calcium exhibit the greatest diagnostic capability, with a sensitivity and specificity of over 80 %, and a Youdin's J value of more than 0.6. CONCLUSION: The levels of cations and trace elements are disturbed in TDT patients. Hence, the monitoring and adjustment of the level of these minerals are important to prevent further consequences.

Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders.

ABSTRACT: In this last decade, a deeper understanding of the pathophysiology of hereditary red cell disorders and the development of novel classes of pharmacologic agents have provided novel therapeutic approaches to thalassemias, sickle cell disease (SCD), and other red cell disorders. Here, we analyze and discuss the novel therapeutic options according to their targets, taking into consideration the complex process of erythroid differentiation, maturation, and survival of erythrocytes in the peripheral circulation. We focus on active clinical exploratory and confirmatory trials on thalassemias, SCD, and other red cell disorders. Beside ß-thalassemia and SCD, we found that the development of new therapeutic strategies has allowed for the design of clinic studies for hereditary red cell disorders still lacking valuable therapeutic alternative such as α-thalassemias, congenital dyserythropoietic anemia, or Diamond-Blackfan anemia. In addition, reduction of heme synthesis, which can be achieved by the repurposed antipsychotic drug bitopertin, might affect not only hematological disorders but multiorgan diseases such as erythropoietic protoporphyria. Finally, our review highlights the current state of therapeutic scenarios, in which multiple indications targeting different red cell disorders are being considered for a single agent. This is a welcome change that will hopefully expand therapeutic option for patients affected by thalassemias, SCD, and other red cell disorders.

Obesity, liver steatosis and metabolic syndrome: The hidden enemies in transfusion-dependent thalassaemia.

In their paper, the authors quantified liver iron concentration (LIC) and hepatic steatosis (HS) using MRI-T2* technology in transfusion-dependent thalassaemia (TDT) patients and healthy controls and found that the prevalence of HS among patients with TDT was 36.4%. In comparison with healthy controls, the hepatic fat fraction (FF) was significantly higher in the TDT population (p = 0.013). Active hepatitis C virus infection, body mass index (BMI) and LIC were independent predictors of HS. An inverse correlation between hepatic FF and high-density lipoprotein cholesterol (p = 0.042) and a significant association of high glycaemia level (p = 0.037) with higher hepatic FF and a significant relationship (p = 0.026) between HS and higher BMI (though in a 'lean' group of patients) in TDT patients indicated that 'metabolic syndrome' was present in this subset with TDT. The impact of metabolic syndrome on TDT, including cardiac disease unrelated to iron overload, needs further study. Commentary on: Ricchi et al. Liver steatosis in patients with transfusion-dependent thalassaemia. Br J Haematol 2024;204:2458-2467.

Haemoglobinopathies and other rare anemias in Spain: ten years of a nationwide registry (REHem-AR).

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments.

Guideline for the management of conception and pregnancy in thalassaemia syndromes: A British Society for Haematology Guideline.

This comprehensive guideline, developed by a representative group of UK-based medical experts specialising in haemoglobinopathies, addresses the management of conception and pregnancy in patients with thalassaemia. A systematic search of PubMed and EMBASE using specific keywords, formed the basis of the literature review. Key terms included "thalassaemia," "pregnancy," "Cooley's anaemia," "Mediterranean anaemia," and others, covering aspects such as fertility, iron burden and ultrasonography. The guideline underwent rigorous review by prominent organisations, including the Endocrine Society, the Royal College of Obstetricians and Gynaecologists (RCOG), the United Kingdom Thalassaemia Society and the British Society of Haematology (BSH) guideline writing group. Additional feedback was solicited from a sounding board of UK haematologists, ensuring a thorough and collaborative approach. The objective of the guideline is to equip healthcare professionals with precise recommendations for managing conception and pregnancy in patients with thalassaemia.

Iron burden and endocrine complications in transfusion-dependent thalassemia patients In Sarawak, Malaysia: a retrospective study.

INTRODUCTION: Thalassaemia is one of the major health problems in Malaysia. With safe blood transfusion regime, the lifespan of patients with transfusion-dependent thalassaemia (TDT) has improved but at the cost of a higher risk of developing endocrine disorders. It is crucial for us to monitor the iron overload to prevent end organ damage. This study aims to evaluate the iron burden and prevalence of endocrinopathies in patients with TDT in Sarawak. MATERIALS AND METHODS: This retrospective cohort study was conducted between January 2020 to June 2020 in six government hospitals in Sarawak. A total of 89 patients with TDT, aged 10 years and above, were recruited. RESULTS: Out of the 89 patients, there were 54 males (60.7%) and 35 females (39.3%) with a median age of 21 years (range 10.0-65.0). Sixty-seven (75.3%) patients had betathalassaemia major and 15 (16.9%) patients had haemoglobin E beta-thalassaemia (HbE beta-thalassaemia), remaining seven patients had other genotypes. Thirty-one (34.8%) patients had mean serum ferritin 2500ng/ml and above, and 44 (66.6%) had liver iron concentration (LIC) ≥7mg/g. The prevalence of endocrine disorders in our cohort was 69.7%. The most common endocrinopathies were short stature (n=46, 51.7%), followed by hypogonadism (n=24, 26.9%), delayed puberty (n=23, 25.8%), hypothyroidism (n=10, 11.2%), diabetes mellitus (n=9, 10.1%), impaired glucose tolerance (n=6, 6.7%) and hypoparathyroidism (n=3, 3.3%). Endocrinopathies were significantly associated with age (p=0.01), age at initiating regular blood transfusion (p<0.01) and duration of regular blood transfusion (p<0.01). CONCLUSION: Our data shows that the development of endocrinopathies in TDT can be time dependent. Early detection of endocrine-related complications and prompt treatment with iron chelation therapy are important to improve morbidity and mortality. A multidisciplinary approach with good patient-doctor collaboration is the key to improving patient care in our settings.

Quality of Life in Transfusion-Dependent Thalassemia Patients in Greece Before and During the COVID-19 Pandemic.

OBJECTIVES: The peak of the COVID-19 pandemic was a challenging situation for transfusion-dependent thalassemia (TDT) patients. The objectives of this study were to measure the quality of life (QoL) in TDT patients during the COVID-19 lockdown restriction measures, compare the results with the pre-COVID-19 era, and evaluate the influence of sociodemographic and clinical factors on QoL. METHODS: This was a cross-sectional study of 110 consecutively selected adult TDT patients, during the stringent lockdown restriction measures implemented in Greece. All participants completed a combination of 2 QoL questionnaires, the generic Short-Form Health Survey 36 version 2 and the disease-specific Transfusion-Quality of life (TranQol). We used the "1/2 SD method," a distribution-based approach to calculate minimal clinically important differences and clinically compare the QoL scores between the pre-COVID-19 and post-COVID-19 era. A backward stepwise linear regression was selected to explore the influence of potential predictors on TranQol scores. RESULTS: The Short-Form Health Survey 36 version 2 and TranQol scores remained low but not clinically different compared with the pre-COVID-19 era. Older, married, and higher educated TDT patients exhibited significantly lower TranQol summary scores. The patients who reported a negative effect of the COVID-19 pandemic had significantly lower TranQol scores in summary and all subdomains except for school and career. CONCLUSIONS: During the COVID-19 pandemic, the overall QoL of TDT patients was clinically similar to the status of the pre-COVID-19 era. Nevertheless, most of the significant QoL subdomains were negatively affected, and distinct groups of TDT patients were more vulnerable.

Proportion of Hypogonadism in Transfusion-Dependent Thalassemia Patients and Its Contributing Factors.

BACKGROUND: Beta thalassemia is a lifelong disease involving malformed red blood cells (RBC). One of the disease's complications is hypogonadism, in which adults tend to exhibit regression in sexual characteristics, experience sexual dysfunction, and therefore have a lower quality of life. Around 3-10% of the Indonesian population carries the beta-thalassemia gene. This study aimed to see the proportions of hypogonadism in transfusion-dependent thalassemia patients and its contributing factors. METHODS: This is a cross-sectional study involving 60 male patients admitted to three Indonesian general hospitals from July 2022 to July 2023. All patients were diagnosed with beta-thalassemia via chromatography hemoglobin analysis. We performed a single-time physical examination and laboratory examinations to determine FSH, LH, and free testosterone levels. The correlation between Hb and sexual hormone levels was analyzed using Spearman's rank correlation coefficient. ROC curve analysis was conducted afterward. All statistical analysis was done in SPSS version 29. RESULTS: 31 out of 60 thalassemia patients had hypogonadism. Pre-transfusion Hb count was found to be linearly correlated with FSH (r = 0.388, p = 0.049), LH (r = 0.338, p = 0.008), and free testosterone (r = 0.255, p = 0.049). ROC analysis indicated that pre-transfusion Hb was viable as a predictor for hypogonadism (AUC = 0.655, 65.5% sensitivity, 67.7% specificity). CONCLUSION: We confirmed the role of pre-transfusion Hb count as a potential predictor for hypogonadism due to the tissue hypoxia mechanism and transfusion-related iron overload in TDT patients. Decreased Hb is linearly correlated with FSH, LH, and testosterone levels. Decreased Hb also downregulates these factors.

Significant Inverse Correlation of Serum Levels of Osteoprotegerin (OPG) and Transferrin Saturation in Thalassemia Dependent Transfusion (TDT) Patients.

BACKGROUND: Osteoporosis is a major problem in transfusion-dependent thalassemia patients (TDT) patients. Osteoprotegerin (OPG) is one of several bone markers that are closely associated with osteoporosis in TDT patients. OPG is a glycoprotein that functions as a feedback receptor for the Receptor Activator of Nuclear Factor kappa B Ligand (RANKL), which is an alpha tumor necrosis factor receptor. One of the causes of decreased bone mass density is iron toxicity, which can be identified by showing elevated transferrin saturation. Bone mass dual X-ray absorptiometry (DEXA) is a gold standard for the diagnosis of osteoporosis, these procedures are not commonly available in Indonesia. This study was conducted to analyze the correlation between serum levels of OPG and transferrin saturation in TDT patients. METHODS: A correlational study with a cross-sectional approach analyzed data from TDT patients at Hemato-Oncology Medic Outpatient Clinic, Hasan Sadikin General Hospital, Bandung, Indonesia. Primary data were obtained through blood sampling and anthropometry measurement while secondary data were obtained from the patient's medical records. OPG and transferrin saturation levels were assessed using the ELISA method. Research data were analyzed using the rank Spearman correlation test. RESULTS: Data were collected from 51 research subjects (30 women dan 21 men). The median OPG level was 380 (170-1230) pg/mL and the median transferrin saturation level was 89.4 (66.7 - 96.2)%. Analysis of correlation showed a significant correlation between and transferrin saturation level with a coefficient value of r -0.539 and p-value <0.001. CONCLUSION: There was a significant inverse correlation between OPG with transferrin saturation in TDT patients.

[Analysis of Plasma Metabolic Profile in Children with Transfusion-Dependent Thalassemia].

OBJECTIVE: To explore the plasma metabolomic characteristics of children with transfusion-dependent thalassemia (TDT), and reveal the changes of metabolic pattern in children with TDT. METHODS: 23 children with TDT who received regular blood transfusion in Ganzhou Women and Children's Health Care Hospital in 2021 were selected, and 11 healthy children who underwent physical examination during the same period were selected as the control group. The routine indexes between children with TDT and the control group were compared, and then the metabolic composition of plasma samples from children with TDT and the control group was detected by liquid chromatography-mass spectrometry. An OPLS-DA model was established to perform differential analysis on the detected metabolites, and the differential metabolic pathways between the two groups were analyzed based on the differential metabolites. RESULTS: The results of routine testing showed that the indexes of ferritin, bilirubin, total bile acid, glucose and triglycerides in children with TDT were significantly higher than those in healthy controls, while hemoglobin and total cholesterol were significantly lower (all P <0.05). However there was no significant difference in lactate dehydrogenase between the two groups (P >0.05). Compared with the control group, 190 differential metabolites (VIP>1) were identified in TDT children. Among them, 168 compounds such as arginine, proline and glycocholic acid were significantly increased, while the other 22 compounds such as myristic acid, eleostearic acid, palmitic acid and linoleic acid were significantly decreased. The metabolic pathway analysis showed that the metabolic impact of TDT on children mainly focused on the upregulation of amino acid metabolism and downregulation of lipid metabolism. CONCLUSION: The amino acid and lipid metabolism in children with TDT were significantly changed compared with the healthy control group. This finding is helpful to optimize the treatment choice for children with TDT, and provides a new idea for clinical treatment.

Good engraftment after reduced intensity targeted busulfan-based conditioning and matched related donor hematopoietic cell transplantation in hemoglobinopathies.

BACKGROUND: Hematopoietic cell transplantation (HCT) is an established curative therapy for transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD). The latest American Society of Hematology guidelines recommend myeloablative preparative regimen in patients under 18 years of age. PROCEDURE: The objective was to demonstrate safety and efficacy of a reduced intensity conditioning (RIC) regimen including high-dose fludarabine, anti-thymocyte globulin, and targeted busulfan as a single alkylator to sub-myeloablative exposures. RESULTS: Between 2012 and 2021, 11 patients with SCD and five patients with TDT and matched related donor (MRD) HCT were included. The median age at transplantation was 8.3 years (range: 3.7-18.8 years). The median administered busulfan AUC was 67.4 mg/L×h (range: 60.7-80 mg/L×h). Overall survival was 93.8% and event-free survival 87.5% with one engrafted SCD patient with pre-existing moyamoya disease succumbing after drainage of a subdural hematoma. One SCD patient developed a secondary graft failure and was treated with a second HCT. Myeloid chimerism was full in all other patients with a median follow-up time of 4.1 years (range: 2.0-11.1 years), whereas T-cell donor chimerism was frequently mixed. CONCLUSION: This RIC conditioning followed by MRD HCT is sufficiently myeloablative to cure pediatric patients with hemoglobinopathies without the need for additional total body irradiation or thiotepa.

Impact of SCOPE Program on Health-Related Quality of Life and Health Status of Children With Thalassemia: A Quasi-Experimental Study.

Background: Iron chelation, blood transfusions, and complication management are typical hospital requirements for children with beta-thalassemia major. This affects their health-related quality of life (HRQoL). The purpose of this study was to evaluate how the Supportive and Coping strategies, Ongoing Assessment, Prevention of Complications, and Empowerment (SCOPE) Program impacted the HRQoL and overall health of children with thalassemia. Method: The study employed a quasi-experimental pretest-posttest control group with a sequential follow-up design. A nonprobability purposive sampling technique was used to include 80 children with beta-thalassemia major in the sample, ranging in age from 6 to 18. Data were gathered using a Demographic Profile, PedsQLTM Version 4.0, and a Clinical Profile. The children in the intervention group received the SCOPE Program over the course of 6 months. The data collection included a pretest and a posttest with four follow-up evaluations. Results: During the pretest, children with thalassemia had a very low HRQoL. However, the final assessment after the intervention showed a significant difference in the mean scores between the two groups in the areas of physical functioning (p = .001), emotional functioning (p = .0001), social functioning (p = .001), and school functioning (p = .001). Growth indicators also demonstrated a notable improvement in the intervention group of children. Discussion: The SCOPE Program may be a thorough and efficient intervention for enhancing the general health of children with thalassemia. It can be used as a cooperative, well-organized, family-focused care strategy. Further study with a larger sample size is suggested.

Liver steatosis in patients with transfusion-dependent thalassaemia.

We evaluated the prevalence and the clinical associations of liver steatosis (LS) in patients with transfusion-dependent thalassaemia (TDT). We considered 301 TDT patients (177 females, median age = 40.61 years) enrolled in the Extension-Myocardial Iron Overload in Thalassaemia Network, and 25 healthy subjects. Magnetic resonance imaging was used to quantify iron overload and hepatic fat fraction (FF) by T2* technique and cardiac function by cine images. The glucose metabolism was assessed by the oral glucose tolerance test (OGTT). Hepatic FF was significantly higher in TDT patients than in healthy subjects (median value: 1.48% vs. 0.55%; p = 0.013). In TDT, hepatic FF was not associated with age, gender, serum ferritin levels or liver function parameters, but showed a weak inverse correlation with high-density lipoprotein cholesterol. The 36.4% of TDT patients showed LS (FF >3.7%). Active hepatitis C virus (HCV) infection, increased body mass index and hepatic iron were independent determinants of LS. A hepatic FF >3.53% predicted the presence of an abnormal OGTT. Hepatic FF was not correlated with cardiac iron, biventricular volumes or ejection fractions, but was correlated with left ventricular mass index. In TDT, LS is a frequent finding, associated with iron overload, increased weight and HCV, and conveying an increased risk for the alterations of glucose metabolism.

Addressing Thalassaemia Management from Patients' Perspectives: An International Collaborative Assessment.

Background and Objectives: The effective management of chronic diseases, particularly hereditary and rare diseases and thalassaemia, is an important indicator of the quality of healthcare systems. We aimed to assess healthcare services in different countries for thalassaemia patients by using publicly available health indicators and by surveying thalassaemia patients and their caregivers. Materials and Methods: We reviewed official worldwide databases from the WHO, World Bank, and scientific resources, and we used a structured patient-tailored self-completed questionnaire to survey thalassaemia patients and their caregivers in 2023. Results: A total of 2082 participants were surveyed (mean age, 27 years; males, 42%). About 1 in 4 respondents did not complete high-school education, while 24% had a bachelor's degree. About a third of respondents were married and were in either full- or part-time employment. The vast majority (~80%) had initiated transfusion therapy between 1 and 4 years of age. Only 42% reported no delays in receiving blood transfusion, while 47% reported occasional delays and 8% serious delays. About half of patients reported being very satisfied (11%) or satisfied (38%) with the quality of services provided, while 1 in 3 patients reported being unsatisfied or very unsatisfied, and that their access to treatment was difficult or very difficult due to traveling expenses and the high cost of treatment. Conclusions: Important improvements in the care of thalassaemia patients have been documented during the past few decades. Nevertheless, additional focus is required through national healthcare systems to effectively address the many unmet needs revealed by our recent survey, as well as to achieve satisfactory patient outcomes.

Factors Related to the Quality of Life in Children with Transfusion-Dependent Thalassemia.

Objective: Increased survival rate of patients with Transfusion-dependent Thalassemia (TDT) should be in line with their good quality of life (QoL). The study aimed to analyze the relationship between sociodemographic factors and clinical characteristics with the QoL of children with TDT. Methods: A cross-sectional study was conducted at Hasan Sadikin General Hospital from December 2022 to February 2023. A total of 158 eligible subjects aged 5-18 years with TDT were included in the analysis. QoL assessment was performed using child self-report and parent-proxy report questionnaires, along with physical examination findings. Bivariate and multivariate analyses were conducted to analyze the data. Results: A total of 158 subjects who met the research criteria were included in the analysis. Of 58.9% of children with TDT had a low adherence rate to iron chelating therapy (ICT). School function had the lowest score in QoL based on child-self report and parent proxy. Gender (p<0,05) and adherence to ICT (p<0,05) were significantly associated with lower quality of life. Conclusion: Female and adherence to ICT were predictors of children with TDT's QoL.