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Objective: Iron overload (IO) in transfusion‐dependent anemia persists after hematopoietic stem cell transplantation (HSCT) and can cause long‐term organ damage. In many studies, the diagnosis of IO before and after HSCT is based on serum ferritin (SF) levels rather than on assessment of liver iron concentration (LIC) by MRI or SQUID. Method: In a retrospective multicenter study, we analyzed the concordance for indication of iron depletion therapy and correlation between LIC and SF of 36 thalassemia patients after HSCT. LIC was determined either by MRI‐R2 (FerriScan®) or SQUID. Results: The concordance between LIC and SF varies over time after transplant (P = 0.011). The correlation between SF and LIC was strong in the first year (Spearman's rho 0.75; P < 0.001). In agreement, the concordance between SF and LIC concerning indication for treatment was close to 1 with an overall error rate ca. of 10%. In particular in the first year after HSCT, SF underestimates the degree of iron overload. However, in the longitudinal analysis since the second year post‐HSCT onward no association was found between LIC and SF (P = 0.217). Furthermore, in the second year after HSCT, the overall error rate was 35%, whereas in the 3rd, 4th, and >4th year, it was 58%, 60%, and 25%, respectively. Conclusions: Our data suggest serum ferritin is not a reliable predictor to determine iron overload in thalassemia patients after HSCT. [ABSTRACT FROM AUTHOR]

Background Vitamin C, as antioxidant, increases the efficacy of deferoxamine (DFO). Aim To investigate the effects of vitamin C as an adjuvant therapy to the three used iron chelators in moderately iron-overloaded young vitamin C-deficient patients with β-thalassemia major (β-TM) in relation to tissue iron overload. Methods This randomized prospective trial that included 180 β-TM vitamin C-deficient patients were equally divided into three groups ( n = 60) and received DFO, deferiprone (DFP), and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin C supplementation (100 mg daily) or not ( n = 30). All patients received vitamin C (group A) or no vitamin C (group B) were followed up for 1 yr with assessment of transfusion index, hemoglobin, iron profile, liver iron concentration (LIC) and cardiac magnetic resonance imaging (MRI) T2*. Results Baseline vitamin C was negatively correlated with transfusion index, serum ferritin (SF), and LIC. After vitamin C therapy, transfusion index, serum iron, SF, transferrin saturation (Tsat), and LIC were significantly decreased in group A patients, while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin C. The same improvement was found among DFO-treated patients post-vitamin C compared with baseline data. DFO-treated patients had the highest hemoglobin with the lowest iron, SF, and Tsat compared with DFP or DFX subgroups. Conclusions Vitamin C as an adjuvant therapy possibly potentiates the efficacy of DFO more than DFP and DFX in reducing iron burden in the moderately iron-overloaded vitamin C-deficient patients with β-TM, with no adverse events. [ABSTRACT FROM AUTHOR]

Objectives: Plasma markers in addition to serum ferritin (SF) may be useful for the assessment of iron overload; however, predictive utility may differ depending on underlying, transfusion-dependent, anemias. Methods: Data were collected before and after 1 year of deferasirox treatment (end of study; EOS) from the large, 1-year EPIC (Evaluation of Patients' Iron Chelation with Exjade®) study. Trends were evaluated between liver iron concentration (LIC), transferrin saturation (TfSat), predose labile plasma iron (LPI) and their relationship to SF categories in 1530 patients: thalassemia major (TM; n = 1114), myelodysplastic syndromes (MDS, n = 336), and sickle-cell disease (SCD, n = 80). Results: Baseline and EOS SF values showed a clear and similar relationship to LIC for all disease groups. TfSat also showed a relationship to SF, most clearly in patients with SCD, where TfSat was lowest in the lowest relative SF category. Unlike SF or LIC, TfSat did not decrease at EOS in any disease group. Baseline LPI was raised in TM and MDS, but not in patients with SCD, decreasing at EOS in both patient groups. After 1 year of chelation therapy, there was a significant trend for greater LPI reduction in patients with TM achieving LIC <7 mg Fe/g dw (P = 0.0137). Conclusions: Despite limitations, SF showed the clearest relationship, of the plasma markers evaluated, to LIC before and after 1 year of deferasirox in patients with TM, MDS, and SCD. In patients with TM, changes in LPI with chelation show a significant relationship to EOS LIC and may provide an additional indicator of chelation response (clinicaltrials.gov identifier: NCT00171821). [ABSTRACT FROM AUTHOR]

Objective Minimal data are available on the combined two oral iron chelators in β-thalassemia major ( β- TM). Comparison of safety, efficacy, compliance, treatment satisfaction, and quality of life (QoL) of two regimens: deferiprone ( DFP) and deferoxamine ( DFO) versus DFP and deferasirox ( DFX) were studied. Methods A prospective randomized trial ( NCT01511848) was conducted on 96 young β- TM patients with severe iron overload. Patients were randomized to receive either DFP with DFO (arm 1) or DFP and DFX (arm 2). Efficacy endpoints were the difference between two groups in the change of serum ferritin ( SF), liver iron concentration ( LIC), cardiac MRI, and quality of life (QoL). Results In both arms, SF and LIC at 12 months were significantly lower, and geometric mean cardiac T2* was higher compared to baseline. On regression analysis of change in each studied variable against time, significant difference between slopes of the two groups regarding cardiac T2* ( P = 0.001 with more improvement in DFP/ DFX patients) was found with no significant difference in the slopes of SF and LIC ( P = 0.218 and 0.340). Conclusion Both iron chelation combination regimens were equally effective in reducing iron overload and improving QoL. DFP/ DFX combination proved superior in improving cardiac T2*, treatment compliance, and patients satisfaction with no greater adverse events. [ABSTRACT FROM AUTHOR]

Endocrinopathies are common complications of transfusional hemosiderosis among patients with β thalassemia major ( TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36 yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI- R2 since 2008 and average 10-yr serum ferritin ( SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus ( DM) (41%), and these were independently associated with myocardial T2* <20 ms ( P < 0.001 and P = 0.008, respectively) and increased age ( P = 0.002 and P = 0.016, respectively). DM and hypogonadism were independently associated with average SF >1250 μg/L ( P = 0.003) and >2000 μg/L ( P = 0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30 yr vs. 24 yr, P = 0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM. [ABSTRACT FROM AUTHOR]

Objectives: An observational study was conducted to explore postmarketing safety and efficacy of Deferasirox (DFX) in comparison with conventional Desferrioxamine (DFO) in chelation-naïve children with transfusional iron overload. Methods: Transfusion-dependent children (aged ≤5 yr) who had serum ferritin above 1000 μg/L and had been prescribed either first-line DFX or DFO for at least 12 months to maintain serum ferritin between 500 and 1000 μg/L were included. Initial DFX dose was 20 mg/kg/d for 7 d a week, and DFO dose was 25-35 mg/kg/d subcutaneously, given for 5 d a week. Dose adjustments were based on serum ferritin changes and safety markers. The primary efficacy endpoint was change in serum ferritin from baseline. The effect of transfusional iron loading rate (ILR) and different doses of chelators on serum ferritin was also assessed. Results: A total of 111 patients were observed for a median of 2.29 yr on DFX ( n = 71) and 2.75 yr on DFO ( n = 40). Absolute change in serum ferritin from baseline to the last available observation was not significant with DFX (91 μg/L, P = 0.5) but significantly higher with DFO (385 μg/L, P < 0.005). ILR and DFX doses had a major impact on serum ferritin changes in DFX cohort. The height- and weight-standard deviation scores did not differ significantly in both cohorts during the study. Fluctuations in liver enzymes and non-progressive increase in serum creatinine were the most common adverse events (DFX; 9.8%, 18.0% and DFO; 5.0%, 7.5%, respectively). Conclusion: DFX is well tolerable and at least as effective as DFO to maintain safe serum ferritin levels and normal growth progression in chelation-naïve children. [ABSTRACT FROM AUTHOR]

Background: Cardiac failure remains the major cause of death in beta-thalassemia major (TM). Reduced heart rate variability (HRV) is associated with a higher risk of arrhythmias after myocardial infarction and heart failure. We evaluated HRV in TM patients and its relationship with hemodynamics and echocardiographic parameters during a 6-month follow-up. Methods: Thirty-four TM patients (19 ± 10 yr) and 20 healthy subjects (17 ± 6 yr) were evaluated. Hematologic, biochemical, echocardiographic and HRV parameters were determined at entry and at 6-month follow-up. Time and frequency domain HRV parameters were analyzed from 24-h recorded electrocardiograms. All TM patients received blood transfusion and chelation therapy. Results: Both time and frequency domain HRV parameters were markedly reduced in TM patients, compared to the control. The significantly improved HRV was seen in correlation with higher hemoglobin (Hb) level when compared within TM group at different time point. No correlation was seen between HRV and serum ferritin, reactive oxygen species (ROS) and non-transferrin bound iron (NTBI). Conclusion: HRV is depressed in TM patients. HRV was significantly correlated with Hb level, suggesting that anemia greatly influences the cardiac autonomic balance. [ABSTRACT FROM AUTHOR]

Objectives: Aim of this study was to evaluate prevalence and characteristics of cholelithiasis in a large population of patients with thalassemia major (TM). Methods: Data from 858 consecutive patients with transfusion-dependent thalassemia at five major Italian centers were analyzed. In these centers, a complete abdomen ultrasonography is performed yearly after the beginning of the transfusion regimen. The role of co-inheriting Gilbert’s syndrome genotype was investigated studying the promoter region of the UGT1-A1 gene by automated sequencing. Results: Thirty percent of TM patients had gallstones. The Gilbert’s genotype [homozygosity for (TA)7 motif at UGT1A promoter gene], influenced both the prevalence of cholelithiasis and the age at which it developed. Conclusions: Cholelithiasis has a remarkable frequency and precocity in patients with TM and especially in those with (TA)7/(TA)7 UGT1-A1 genotype. An early biliary ultrasonography is recommended from childhood and a closer follow-up in patients with thalassemia and associated Gilbert’s syndrome may be indicated. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: In patients with thalassemia major (TM) who are non-compliant with long-term deferoxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional siderosis. It was recently shown in a small group of TM patients with established cardiac damage that continuous 24-h DFO infusion via an indwelling intravenous (i.v.) catheter is effective in reversing cardiac toxicity. The aim of the present study was to evaluate the results with intermittent daily (8–10 h) i.v. DFO. Patients: Eight TM patients with cardiac complications treated with intensive intermittent DFO were retrospectively evaluated by the mean annual serum ferritin, radionucleated ventriculography and 24-h electrocardiography recordings. Results: The median age at diagnosis of cardiac disease was 17.5 yr (range 14–21), and the median follow-up time was 84 months (range, 36–120). In the majority of patients (seven of eight) high-dose DFO (mean 95 ± 18.3 mg/kg/d) was administered via a central venous line. During follow-up, there was a significant decrease in the mean ferritin levels (5828 ± 2016 ng/mL to 1585 ± 1849 ng/mL, P < 0.001). Both cardiac failure (mean ejection fraction 32 ± 5) and cardiac arrhythmias were resolved in four of five patients. One non-compliant patient died during the follow-up. Following discontinuation of the i.v. therapy, compliance with conventional DFO therapy improved. The complications of this regimen, mainly catheter-related infections and catheter-related thrombosis, were similar to those described earlier. Conclusions: These results with the longest follow-up period in the literature suggest that i.v. high-dose DFO for 8–10 h daily may be as effective as continuous 24-h infusion for the reversal of established cardiac disease in TM. [ABSTRACT FROM AUTHOR]

We studied 36 patients (17 males and 19 females) with thalassemia major by performing pulmonary function testing (PFT), arterial blood gas analysis (ABG), as well as determining the serum ferritin level. In addition, 19 of these patients were transfused with two units of packed cells, and a repeat ABG and PFT were performed. Twenty‐three patients had normal PFTs, eleven patients (30.6%) showed a restrictive pattern (significant decrease in both TLC and DLCO), and only two patients (5.6%) showed an obstructive pattern. A significant negative correlation was found between serum ferritin and restrictive parameters, DLCO and TLC (p =0.01 and p =0.03, respectively). This correlation was even stronger after transfusion. Controlling for age, ferritin was still negatively correlated with DLCO (p =0.04), but no longer with TLC. There was no correlation between age and DLCO or age and TLC; however, there was a statistically significant negative correlation between age and FVC (p =0.003). Analysis of patients who were transfused revealed a significant decrease in forced vital capacity (89±4% vs. 74±5% of predicted; p ‐value<0.001) and in maximum midexpiratory flow rate (79±4% vs. 67±5% of predicted; p ‐value=0.004). For patients older than 15 yr of age, there was a statistically significant decrease in FEV1/FVC (84±2 vs. 83±2%; p ‐value=0.04). The ABGs showed no significant change post‐ transfusion. In this study, PFT findings in thalassemia major were restrictive and correlated with serum ferritin level. Transfusion had an acute effect on the obstructive parameters of PFT. [ABSTRACT FROM AUTHOR]

In general, in women with transfusion-dependent thalassemia, during pregnancy, iron chelation therapy is ceased. We report a splenectomized patient, who was an excellent complier with chelation therapy, who before embarking on a pregnancy showed no evidence of iron overload, with normal cardiac, thyroid function and glucose metabolism. Laboratory findings showed ferritin 67 μg/L, myocardial T2* of 34 ms and liver magnetic resonance imaging (MRI) liver iron concentration of 1 mg/g dry weight. She became pregnant by in vitro fertilization in October 2006, delivery occurred in June 2007. She breast fed for 2 months. After 12 months without iron chelation, ferritin was 1583 μg/L. Quantitative MRI showed myocardial T2* of 27 ms, that the liver iron concentration had increased to 11.3 mg/g dry weight, indicative of moderate to heavy iron load. This case demonstrates that iron overload can develop rapidly and that physicians caring for patients with transfusion-dependent thalassemia should be particularly alert to any discontinuation of chelation therapy over time. [ABSTRACT FROM AUTHOR]