Pharmacogenomics of Drugs Used in ß-Thalassemia and Sickle-Cell Disease: From Basic Research to Clinical Applications.

In this short review we have presented and discussed studies on pharmacogenomics (also termed pharmacogenetics) of the drugs employed in the treatment of ß-thalassemia or Sickle-cell disease (SCD). This field of investigation is relevant, since it is expected to help clinicians select the appropriate drug and the correct dosage for each patient. We first discussed the search for DNA polymorphisms associated with a high expression of γ-globin genes and identified this using GWAS studies and CRISPR-based gene editing approaches. We then presented validated DNA polymorphisms associated with a high HbF production (including, but not limited to the HBG2 XmnI polymorphism and those related to the BCL11A, MYB, KLF-1, and LYAR genes). The expression of microRNAs involved in the regulation of γ-globin genes was also presented in the context of pharmacomiRNomics. Then, the pharmacogenomics of validated fetal hemoglobin inducers (hydroxyurea, butyrate and butyrate analogues, thalidomide, and sirolimus), of iron chelators, and of analgesics in the pain management of SCD patients were considered. Finally, we discuss current clinical trials, as well as international research networks focusing on clinical issues related to pharmacogenomics in hematological diseases.

Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent ß-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial.

INTRODUCTION: Despite the improvement in medical management, many patients with transfusion-dependent ß-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent ß-thalassaemia with very high iron overload. METHODS AND ANALYSIS: This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent ß-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures. ETHICS AND DISSEMINATION: Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals. TRIAL REGISTRATION NUMBER: The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).

Cost-effectiveness analysis of Manuka honey-Omega-3 combination treatments in treating oxidative stress of pediatric ß-thalassemia major.

OBJECTIVE: Oxidative stress represents a ruthless complication of ß-thalassemia that worsens the severity of that medical condition. There is no conclusive evidence on the best antioxidant used for that issue. Our earlier clinical study concluded that omega-3 and Manuka honey add-on to the conventional therapy had a potential therapeutic impact on reducing oxidative stress. However, there is no research evaluating their cost-effectiveness. This paper compares the cost-effectiveness of Omega-3 and Manuka honey supplementation to conventional therapy in treating oxidative stress among children with ß-thalassemia major. SUBJECTS AND METHODS: Cost-effectiveness evaluation of daily supplementation of Omega-3-Manuka honey and Manuka honey alone to the conventional therapy was performed. The economic evaluation was performed on data from a prospective 10-month randomized clinical trial. Fifty patients were recruited into the Omega-3-Manuka honey plus conventional therapy group, 50 patients were included in the Manuka honey alone plus conventional therapy group, and 50 patients receiving the conventional therapy alone served as a control group. Effectiveness measures from the randomized clinical trial were used to determine incremental effectiveness. Cost estimates were calculated from the healthcare payer's perspective. The analysis considered the improvement in oxidative stress biomarkers presented here as a percent change from baseline to determine the incremental effectiveness and cost for the treatment by both interventions. RESULTS: Adding Omega-3 or Manuka honey to conventional therapy was a more cost-effective add-on than conventional treatment alone. Omega-3-Manuka honey was more cost-effective than Manuka honey alone in treating oxidative stress in that condition. Oxidative stress biomarkers were significantly reduced with both experimental medications compared to the conventional therapy alone. CONCLUSIONS: The present study showed that using Manuka honey and Omega-3 as add-on treatments for oxidative stress in pediatric ß-thalassemia disease could have significant cost-saving and clinical improvement.

Lactate administration improves laboratory parameters in murine models of iron overload.

ABSTRACT: Current iron overload therapeutics have inherent drawbacks including perpetuated low hepcidin. Here, we unveiled that lactate, a potent hepcidin agonist, effectively reduced serum and hepatic iron levels in mouse models of iron overload with an improved erythropoiesis in ß-thalassemic mice.

Suppression of Growth Differentiation Factor 15 Gene Expression by Curcumin in Patients with Beta-Thalassemia Intermedia.

BACKGROUND: ß-thalassemia is an inherited disorder caused by defects in the synthesis of the beta-globin chain. One of the significant clinical complications in ß-thalassemia intermedia is iron overload toxicity, which may be attributed to reduced levels of hepcidin. This reduction in hepcidin leads to increased absorption of iron in the intestines, ultimately resulting in iron overload. The objective of this study was to assess the impact of curcumin on the expression of growth differentiating factor-15 (GDF-15) and hepcidin genes in patients with beta-thalassemia intermedia. METHODS: This study was designed as a randomized controlled double-blind clinical trial. Prior to and after the intervention period with curcumin, a blood sample of 5 mL was collected from both the placebo and curcumin-treated groups for the assessment of hepcidin and growth differentiating factor-15 gene expression. RESULTS: This study revealed a significant reduction in the expression of growth differentiating factor-15 in the curcumin group compared to the placebo group during the 3-month treatment period. Furthermore, curcumin supplementation led to a remarkable 10.1-fold increase in the levels of hepcidin in the curcumin group compared to the placebo group. CONCLUSIONS: The results of this study show that curcumin administration increases the mRNA levels of hepcidin in whole blood of thalassemia intermedia patients and supports the idea that curcumin could be a potential treatment to reduce suppression of hepcidin in thalassemias and other iron-loading anemias. CONCLUSIONS: The results of this study show that curcumin administration increases the mRNA levels of hepcidin in whole blood of thalassemia intermedia patients and supports the idea that curcumin could be a potential treatment to reduce suppression of hepcidin in thalassemias and other iron-loading anemias.

Two risk factors for hypozincemia in diabetic ß-thalassemia patients: Hepatitis C and deferasirox.

BACKGROUND AND AIM: Hypozincemia is a prevalent adverse consequence in diabetes mellitus (DM) and ß-Thalassemia patients. We aimed to evaluate the level of serum zinc in ß-thalassemia patients with DM and a risk assessment for hypozincemia. METHODS: The study population included transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) with overt DM (fasting plasma glucose (FPG) ≥126 mg/dL, and/or 2-h plasma glucose≥200 mg/dL). Serum zinc concentration was measured by the colorimetric method, and the values below 70 µg/dL were defined as hypozincemia. Myocardial and liver T2*-weighted magnetic resonance imaging (MRI T2*, millisecond [ms]) were valued by a free contrast MRI. The demographic, clinical, paraclinical, and laboratory data were also recorded. The data belonged to the period from December 2018 until December 2020. RESULTS: Of 64 diabetic ß-thalassemia patients, 41 cases had zinc data in their medical files (aged 38 ± 9 years, 48.8% female). 78.05% of patients (n = 32) were TDT, and 21.95% were NTDT (n = 9). The mean ± standard deviation of zinc level was 110.2 ± 127.6 µg/dL. The prevalence of hypozincemia was 9.76%, 95% confidence interval [CI] 0.27 to 19.24 (four cases). After controlling age, the odds of hypozincemia for using deferasirox (DFX) was 8.77, 95% CI 0.60 to 127.1. In ß-thalassemia patients, the age-adjusted risk of hypozincemia was calculated at 15.85, 95% CI 0.47 to 529.3 for hepatitis C. The adjusted risk of hypozincemia based on age for antacid use was 6.34, 95% CI 0.39 to 102.7. CONCLUSION: In light of this study, as well as hepatitis C, using DFX and antacids is associated with a high risk of hypozincemia amid diabetic ß-thalassemia cases. However, upward bias should be taken into consideration.

Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.

BACKGROUND: In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months. MATERIALS AND METHODS: We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique. RESULTS: At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups. DISCUSSION: In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.

Effects on hearing after long-term use of iron chelators in beta-thalassemia: Over twenty years of longitudinal follow-up.

OBJECTIVE: The role of iron chelation in causing hearing loss (HL) is still unclear. The present study assessed the prevalence of HL among transfusion-dependent thalassemia (TDT) patients who underwent audiological follow-up over a 20-year period. METHODS: We retrospectively analyzed clinical records and audiological tests from January 1990 (T0) to December 2022 (T22) of a group of TDT patients who received iron chelation therapy with deferoxamine (DFO), deferiprone (DFP) or deferasirox (DFX), in monotherapy or as part of combination therapy. RESULTS: A total of 42 adult TDT patients (18 male, 24 female; age range: 41-55 years; mean age: 49.2 ± 3.7 years) were included in the study. At the T22 assessment, the overall prevalence of sensorineural HL was 23.8 % (10/42). When patients were stratified into two groups, with and without ototoxicity, no differences were observed for sex, age, BMI, creatinine level, pre-transfusional hemoglobin, start of transfusions, cardiac or hepatic T2 MRI; only ferritin serum values and duration of chelation were significantly higher (p = 0.02 and p = 0.01, respectively) in patients with hearing impairment in comparison to those with normal hearing. CONCLUSION: This study with long-term follow-up suggests that iron chelation therapy might induce ototoxicity; therefore, a long and accurate audiological follow-up should be performed in TDT patients.

Management of transfusion-dependent ß-thalassemia (TDT): Expert insights and practical overview from the Middle East.

ß-Thalassemia is one of the most common monogenetic diseases worldwide, with a particularly high prevalence in the Middle East region. As such, we have developed long-standing experience with disease management and devising solutions to address challenges attributed to resource limitations. The region has also participated in the majority of clinical trials and development programs of iron chelators and more novel ineffective erythropoiesis-targeted therapy. In this review, we provide a practical overview of management for patients with transfusion-dependent ß-thalassemia, primarily driven by such experiences, with the aim of transferring knowledge to colleagues in other regions facing similar challenges.

Reduction of extramedullary erythropoiesis and amelioration of anemia in a ß-thalassemia patient treated with thalidomide.

ß-thalassemia patient treated with thalidomide: dimensional reduction of EMH foci (MRI evaluation) and reduction of hematological responce at follow-up.

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs.

The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.

Adherence to Iron Chelation Therapy Among Children with Beta Thalassemia Major: A Multicenter Cross-Sectional Study.

BACKGROUND: Adherence to iron chelation therapy (ICT) remains an issue among thalassemia patients. This study aimed to determine the prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia and the factors associated with it. METHODS: This was a cross-sectional study conducted between November 2019 and November 2021 at seven tertiary hospitals in Malaysia. Participants registered with Malaysian Thalassemia Registry were recruited by convenience sampling. Adherence was measured via pill count and self-reported adherence. Knowledge about thalassemia and ICT was measured using a questionnaire from Modul Thalassemia by Ministry of Health of Malaysia. A decision tree was used to identify predictors of non-adherence. RESULTS: A total of 135 patients were recruited. The prevalence of non-adherence to ICT in those who took subcutaneous ± oral medications was 47.5% (95% CI: 31.5%, 63.9%) and the prevalence of non-adherence to ICT in those who took oral medications only was 21.1% (95% CI: 13.4%, 30.6%). The median knowledge score was 67.5% (IQR 15%). A decision tree has identified two factors associated with non-adherence. They were ICT's route of administration and knowledge score. Out of 100 patients who were on oral medications only, 79 were expected to adhere. Out of 100 patients who were on subcutaneous ± oral medications and scored less than 56.25% in knowledge questionnaire, 86 were expected to non-adhere. Based on the logistic regression, the odds of non-adherence in patients who took oral medications only was 71% lower than the odds of non-adherence in patients who took subcutaneous ± oral medications (OR = 0.29; 95% CI = 0.13, 0.65; p = .002). CONCLUSION: The prevalence of non-adherence to ICT among children with beta thalassemia major in Malaysia was 20/95 (21.1%) in those who took oral medications only and the prevalence of non-adherence was 19/40 (47.5%) in those who took subcutaneous ± oral medications. The factors associated with non-adherence were ICT's route of administration and knowledge score.

Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia.

BACKGROUND: Beta-thalassaemia is an inherited blood disorder that reduces the production of haemoglobin. The most severe form requires recurrent blood transfusions, which can lead to iron overload. Cardiovascular dysfunction caused by iron overload is the leading cause of morbidity and mortality in people with transfusion-dependent beta-thalassaemia. Iron chelation therapy has reduced the severity of systemic iron overload, but removal of iron from the myocardium requires a very proactive preventive strategy. There is evidence that calcium channel blockers may reduce myocardial iron deposition. This is an update of a Cochrane Review first published in 2018. OBJECTIVES: To assess the effects of calcium channel blockers plus standard iron chelation therapy, compared with standard iron chelation therapy (alone or with a placebo), on cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia. SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books, to 13 January 2022. We also searched ongoing trials databases and the reference lists of relevant articles and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of calcium channel blockers combined with standard chelation therapy versus standard chelation therapy alone or combined with placebo in people with transfusion-dependent beta thalassaemia. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included six RCTs (five parallel-group trials and one cross-over trial) with 253 participants; there were 126 participants in the amlodipine arms and 127 in the control arms. The certainty of the evidence was low for most outcomes at 12 months; the evidence for liver iron concentration was of moderate certainty, and the evidence for adverse events was of very low certainty. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may have little or no effect on cardiac T2* values at 12 months (mean difference (MD) 1.30 ms, 95% confidence interval (CI) -0.53 to 3.14; 4 trials, 191 participants; low-certainty evidence) and left ventricular ejection fraction (LVEF) at 12 months (MD 0.81%, 95% CI -0.92% to 2.54%; 3 trials, 136 participants; low-certainty evidence). Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may reduce myocardial iron concentration (MIC) after 12 months (MD -0.27 mg/g, 95% CI -0.46 to -0.08; 3 trials, 138 participants; low-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on heart T2*, MIC, or LVEF after six months, but the evidence is very uncertain. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may increase liver T2* values after 12 months (MD 1.48 ms, 95% CI 0.27 to 2.69; 3 trials, 127 participants; low-certainty evidence), but may have little or no effect on serum ferritin at 12 months (MD 0.07 µg/mL, 95% CI -0.20 to 0.35; 4 trials, 187 participants; low-certainty evidence), and probably has little or no effect on liver iron concentration (LIC) after 12 months (MD -0.86 mg/g, 95% CI -4.39 to 2.66; 2 trials, 123 participants; moderate-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on serum ferritin, liver T2* values, or LIC after six months, but the evidence is very uncertain. The included trials did not report any serious adverse events at six or 12 months of intervention. The studies did report mild adverse effects such as oedema, dizziness, mild cutaneous allergy, joint swelling, and mild gastrointestinal symptoms. Amlodipine may be associated with a higher risk of oedema (risk ratio (RR) 5.54, 95% CI 1.24 to 24.76; 4 trials, 167 participants; very low-certainty evidence). We found no difference between the groups in the occurrence of other adverse events, but the evidence was very uncertain. No trials reported mortality, cardiac function assessments other than echocardiographic estimation of LVEF, electrocardiographic abnormalities, quality of life, compliance with treatment, or cost of interventions. AUTHORS' CONCLUSIONS: The available evidence suggests that calcium channel blockers may reduce MIC and may increase liver T2* values in people with transfusion-dependent beta thalassaemia. Longer-term multicentre RCTs are needed to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should also investigate the role of baseline MIC in the response to calcium channel blockers, and include a cost-effectiveness analysis.

In Silico Molecular Docking and Dynamics Simulation Analysis of Potential Histone Lysine Methyl Transferase Inhibitors for Managing ß-Thalassemia.

A decreased hemoglobin synthesis is contemplated as a pathological indication of ß-thalassemia. Recent studies show that EPZ035544 from Epizyme could induce fetal hemoglobin (HbF) levels due to its proven capability to inhibit euchromatin histone lysine methyl transferase (EHMT2). Therefore, the development of EHMT2 inhibitors is considered promising in managing ß-thalassemia. Our strategy to find novel compounds that are EHMT2 inhibitors relies on the virtual screening of ligands that have a structural similarity to N2-[4-methoxy-3-(2,3,4,7-tetrahydro-1H-azepin-5-yl) phenyl]-N4,6-dimethyl-pyrimidine-2,4-diamine (F80) using the PubChem database. In silico docking studies using Autodock Vina were employed to screen a library of 985 compounds and evaluate their binding ability with EHMT2. The selection of hit compounds was based on the docking score and mode of interaction with the protein. The top two ranked compounds were selected for further investigations, including pharmacokinetic properties analysis and molecular dynamics simulations (MDS). Based on the obtained docking score and interaction analysis, N-(4-methoxy-3-methylphenyl)-4,6-diphenylpyrimidin-2-amine (TP1) and 2-N-[4-methoxy-3-(5-methoxy-3H-indol-2-yl)phenyl]-4-N,6-dimethylpyrimidine-2,4-diamine (TP2) were found to be promising candidates, and TP1 exhibited better stability in the MDS study compared to TP2. In summary, our approach helps identify potential EHMT2 inhibitors, and further validation using in vitro and in vivo experiments could certainly enable this molecule to be used as a therapeutic drug in managing ß-thalassemia disease.

Deferasirox causing duodenal ulcer leading to upper gastrointestinal bleed and hemorrhagic shock in a child with beta-thalassemia major.

Iron chelators have significantly reduced the morbidity associated with iron overload and improved the quality of life in children with beta-thalassemia major. A 5-year-old female child with beta-thalassemia major on recurrent transfusions and oral chelation with deferasirox was brought with repeated episodes of frank hematemesis and progressive lethargy. Her evaluation revealed anemia, leukocytosis, and deranged liver function with coagulopathy. She was given red blood cell and plasma transfusions with liver supportive medication and proton-pump inhibitor (PPI) infusion. Her upper gastrointestinal endoscopy revealed multiple ulcers in all three parts of the duodenum, which in the absence of any other likely etiology were attributed to prolonged use of oral deferasirox. The child improved with the above-mentioned measures. Chelation therapy was withheld for 2 weeks and restarted at a lower dose using enteric-coated preparation while PPIs were given for 8 weeks. She showed sustained improvement and remained well on follow-up.

Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from ß-Thalassemia Patients Treated with Sirolimus.

The ß-thalassemias are hereditary monogenic diseases characterized by a low or absent production of adult hemoglobin and excess in the content of α-globin. This excess is cytotoxic for the erythroid cells and responsible for the ß-thalassemia-associated ineffective erythropoiesis. Therefore, the decrease in excess α-globin is a relevant clinical effect for these patients and can be realized through the induction of fetal hemoglobin, autophagy, or both. The in vivo effects of sirolimus (rapamycin) and analogs on the induction of fetal hemoglobin (HbF) are of key importance for therapeutic protocols in a variety of hemoglobinopathies, including ß-thalassemias. In this research communication, we report data showing that a decrease in autophagy-associated p62 protein, increased expression of ULK-1, and reduction in excess α-globin are occurring in erythroid precursors (ErPCs) stimulated in vitro with low dosages of sirolimus. In addition, increased ULK-1 mRNA content and a decrease in α-globin content were found in ErPCs isolated from ß-thalassemia patients recruited for the NCT03877809 clinical trial and treated with 0.5-2 mg/day sirolimus. Our data support the concept that autophagy, ULK1 expression, and α-globin chain reduction should be considered important endpoints in sirolimus-based clinical trials for ß-thalassemias.

Successful chelation in beta-thalassemia major in the 21st century.

This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209 patients, independent of the chelation regimen, ferritin, cardiac T2* and liver iron concentration changes were evaluated. We defined chelation success (ChS) as no iron load in the heart and acceptable levels in the liver. Over 3 early magnetic resonance imagings, the same parameters were assessed in 2 subgroups, the only 2 that had sufficient patients continuing on 1 regimen and for a significant period of time, 1 on deferrioxamine (low iron load patients n = 41, Group A) and 1 on deferoxamine-deferiprone (iron overloaded n = 60, Group B). Finally, 28 deaths and causes were compared to those of an earlier period. The 209 patients significantly optimized those indices, while the number of patients with chelation success, increased from 6% to 51% (P < .0001). In group A, ChS after about 8 years increased from 21 to 46% (P = .006), while in Group B, from 0% to 60% (P < .001) after about 7 years. Deaths over the 2 periods showed significant reduction. Combined clearance of cardiac and liver iron (ChS) is feasible and should become the new target for all patients. This requires, serial magnetic resonance imagings and often prolonged intensified chelation for patients.

Grape seed extract in combination with deferasirox ameliorates iron overload, oxidative stress, inflammation, and liver dysfunction in beta thalassemia children.

BACKGROUND AND PURPOSE: Iron overload in the body is associated with serious and irreversible tissue damage. This study aimed to investigate the iron-chelating, antioxidant, anti-inflammatory, and hepatoprotective activities of grape seed extract (GSE) supplement as well as its safety in ß-thalassemia major (ß-TM) pediatric patients receiving deferasirox as a standard iron-chelation therapy. MATERIALS AND METHODS: The children were randomly allocated to either GSE group (n = 30) or control group (n = 30) to receive GSE (100 mg/day) or placebo capsules, respectively, for 4 weeks. The serum levels of iron, ferritin, total iron-binding capacity (TIBC), alanine transaminase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and glutathione (GSH) as well as superoxide dismutase (SOD) activity and hemoglobin (Hb) concentration were measured pre-and post-intervention. RESULTS: GSE supplement significantly attenuated the serum levels of iron (p = 0.030), ferritin (p = 0.017), ALT (p = 0.000), AST (p = 0.000), TNF-α (p = 0.000), and hs-CRP (p = 0.001). The TIBC level (p = 0.020) significantly enhanced in the GSE group compared with the placebo group. Moreover, GSE supplement remarkably improved the oxidative stress markers, MDA (p = 0.000) and GSH (p = 0.001). The changes in the SOD activity (p = 0.590) and Hb concentration (p = 0.670) were not statistically different between the groups. CONCLUSION: GSE supplement possesses several health beneficial influences on children with ß-TM by alleviating iron burden, oxidative stress, inflammation, and liver dysfunction.