Combined chelation therapy in thalassemia major with deferiprone and desferrioxamine: a retrospective study

Objectives: The benefits of combined chelation therapy with daily deferiprone (DFP) and subcutaneous desferrioxamine (DFO) have been widely reported in literature. We retrospectively evaluated the efficacy of different schedules of combined chelation therapy and the incidence of adverse events. Methods: We evaluated 36 patients affected by thalassemia major treated with combined chelation therapy. Patients were subdivided into four treatment arms according to severity of iron overload and previous onset of adverse events to DFP therapy: Group 1 (13 pts) DFP 75 mg/kg per d plus DFO (25–35 mg/kg per d for 5 d); Group 2 (6 pts) DFP 50 mg/kg per d plus DFO (25–35 mg/kg for 5 d), Group 3 (10 pts) DFP 75 mg/kg per d plus DFO (25–35 mg/kg for 3 d), and Group 4 (7 pts) DFP 50 mg/kg per d plus DFO (25–35 mg/kg for 3 d). Change in serum ferritin level was evaluated in all patients. Results: Overall, ferritin decreased from 2592 ± 1701 to 899 ± 833 ng/mL (P < 0.001). All treatments were able to reduce ferritin levels, but in patients of group 1 and group 2 the highest mean decrease in serum ferritin level and the greatest improvement in liver iron concentration (LIC) and in T2* values were observed. Conclusions: This study showed that the administration of DFO for 5 d a wk in combination with daily administration of DFP at 75 mg/Kg seemed to be the most efficacy and rapid method for reducing iron overload at liver and heart level. Furthermore, the use of different schedules of combined DFO and DFP administration was not associated with different incidence of adverse effects between the groups.     

Comparison of effects of different long-term iron-chelation regimens on myocardial and hepatic iron concentrations assessed with T2* magnetic resonance imaging in patients with β-thalassemia major

The aim of this study was to compare the effect of different long-term chelation regimens on heart and liver iron stores with the use of T2* magnetic resonance imaging (MRI) in patients with transfusion-dependent β-thalassemia major. Sixty-four patients (28 men, 36 women; mean age, 26.49 ± 5.8 years) were enrolled in the study. The 3 groups were based on the chelation therapy received. The first group (19 patients) received deferiprone (DFP) (75 mg/kg per day orally), the second group (23 patients) received deferoxamine (DFO) (30–50 mg/kg per day subcutaneously at least 5 times/week), and the third group (22 patients) received a combination of DFO (30–50 mg/kg per day, 2–3 days/week) and DFP (75 mg/kg per day, 7 days/week). MRI scans were acquired with an imager equipped with a 1.5 T magnet, and the data included myocardial and hepatic iron measurements obtained by means of T2*, and ventricular volumes and ejection fractions obtained with standard cardiovascular MRI techniques. The results revealed that the DFP and the combined groups had significantly less myocardial iron than the DFO group (mean myocardial T2*, 35.77 ± 18.3 milliseconds and 38.05 ± 15.3 milliseconds versus 23.77 ± 13 milliseconds [P =.02, andP =.001], respectively). On the contrary, the DFP group had a significantly higher hepatic iron content than the DFO and combined groups (mean hepatic T2*, 3.29 ± 2.5 milliseconds versus 8.16 ± 8.4 milliseconds and 11.3 ±10.9 milliseconds [P =.014, andP =.003], respectively). No correlation was observed between myocardial T2* and hepatic T2* values (r =-0.043;P =.37). Myocardial T2* values were inversely correlated with age (r =-0.249;P =.024) and positively correlated with both left and right ventricular ejection fractions (r = 0.33 [P =.004], andr = 0.279 [P =.014], respectively). Finally, liver T2* was strongly and inversely correlated with serum ferritin concentration (r =-0.465;P =.001). In conclusion, combined chelation therapy seems to sum the beneficial effects of DFO and DFP with respect to hepatic and myocardial iron. Because myocardial iron is not related to measurements of serum ferritin or hepatic T2*, important decisions on clinical management relating to cardiac risk should not rely on these conventional parameters. Thus, the use of MRI for assessing myocardial iron should be adopted in the routine clinical management of patients with β-thalassemia major.     

Correlation of Iron Overload and Glomerular Filtration Rate Estimated by Cystatin C in Patients with β-Thalassemia Major

Historically, renal involvement has not been a commonly recognized complication in patients with β-thalassemia major (β-TM). Herein, we studied the impact of iron overload on glomerular filtration rate (GFR) estimated by cystatin C based GFR (Cyst C eGFR). We enrolled 149 patients with β-TM in a cross sectional study in a single center in Oman. We investigated the correlation between measurement of serum ferritin and Cyst C eGFR. We used univariable linear regression to study the impact of serum ferritin on Cyst C eGFR and backwards stepwise regression to adjust for potential confounders. We included 78 males and 71 females with a mean age of 17.3?±?9 years (range 2.5–38.5). Seventeen patients had diabetes mellitus. Patients were taking deferiprone (DFP) and deferoxamine (DFO) (26 patients), DFP (58 patients), deferasirox (DFX) (62 patients) and one patient was taking only DFO. There was a very weak negative linear relationship between serum ferritin and Cyst C eGFR (correlation coefficient ?0.25). In the univariable analyses, serum ferritin (p?=?0.004), diabetes status (p?p?p?=?0.033), chelation with DFX (p?=?0.05) and diabetes status (p?相似文献   

Iron chelation treatment with combined therapy with deferiprone and deferioxamine: a 12-month trial

The simultaneous use of deferioxamine (DFO) and deferiprone (DFP) has an additive effect in iron excretion in transfusion-dependent thalassemic patients. In a prospective study, we evaluated the safety and effectiveness of combined therapy with these two chelators. Fifty patients with beta-thalassemia were uniformly treated with DFP for 4 days per week and combined therapy with DFP and DFO for 3 days of the week. Efficacy was evaluated by ferritin and cardiac shortening fraction (SF). Hepatic hemosiderosis was also assessed by estimation of the T2 relaxation time by magnetic resonance in a subgroup of patients. Forty-three patients completed 1 year of therapy. Mean ferritin decreased from 3363.7 +/- 2144.5 microg/L to 2323.2 +/- 1740.8 microg/L (P < 0.0001). The reduction was significant even in the group of patients with ferritin <2500 microg/L. Significant improvement in T2 relaxation and SF was observed. The most common adverse events were gastrointestinal symptoms (20%) and transaminasemia (18%). The rate of agranulocytosis was 4.2 cases per 100 patient-years. Prolonged use of combined therapy with DFP and DFO is effective in decreasing iron load and improving cardiac function. Its possible association with higher incidence of agranulocytosis emphasizes the need for close monitoring.     

Hb G-CHINESE: A G → C SUBSTITUTION AT CODON 30 OF THE α2-GLOBIN GENE CREATES A PstI CUTTING SITE

We used magnetic resonance imaging (MRI) to compare the effect of iron chelation on liver, spleen and bone marrow. We examined 21 β-thalassemic patients undergoing deferoxamine (DFO) (9/21) or combined therapy [DFO and deferiprone (L1), 12/21] with two abdominal MRI studies using T1-w/Pd-w/T2*-wGRE and T1-wTSE sequences. Changes in serum ferritin (DF%), and liver, spleen and marrow to paraspinous muscles signal intensity ratios (SI) in T1-wTSE sequence were calculated as D%=[(2^ndvalue-1^st value)/1^st value] ×100%. Negative DF% and positive D(SI)% indicated reduction of iron. Although 17/21 (80.9%) patients demonstrated reduction in ferritin, only 8/21 (38%), 7/21 (33.3%) and 7/21 (33.3%) patients had decreased liver, spleen and marrow iron. Patients undergoing combined therapy showed significantly greater reduction (Student's t-test, p < 0.05) or less increase (t-test, p <0.05) in iron stores. Combined therapy is more effective than DFO for removing and preventing liver, spleen and bone marrow iron accumulation in β-thalassemic patients. Magnetic resonance imaging is valuable for organ-specific monitoring of chelation therapy.     

Deferiprone or Deferoxamine vs. Combination Therapyin Patients with β-Thalassemia Major: A Case Studyin Taiwan

Deferiprone (L1) has been recommended as an effective oral chelation therapy for patients with β-thalassemia major (TM). From 1999 to 2004, 114 patients with TM from five treatment centers were enrolled in this program: iron (Fe) was chelated with L1 in 57 patients, deferoxamine (DFO) in 26, and combined L1/DFO therapy in 31. We found that serum ferritin (SF) was significantly lower in nine patients receiving L1 for more than 5 years (p = 0.04), 22 patients receiving L1 for 1–2 years (p < 0.01) and 31 receiving the combined therapy (p = 0.01), yet significantly higher in those receiving DFO only (p < 0.01). One patient showed transient neutropenia; arthropathy in one patient and gastrointestinal upset in two were noted, with no significant change in alanine aminotransferase (ALT) level. Of 17 patients who were submitted to a liver biopsy, 15 showed no significant change in hepatic fibrosis scores after therapy with L1. None of the 88 patients, including 31 who received the combined therapy, have abandoned oral L1 treatment due to adverse effects. Results of this study proved that L1 or combined therapy with L1 and DFO is effective in reducing SF; incidence of adverse events was low in patients with TM.     

Prevalence of abnormal iron studies in heterozygotes for hereditary hemochromatosis: An analysis of 255 heterozygotes

Iron studies were compared in 434 patients from 80 hemochromatosis families classified as putative homozygotes, heterozygotes, and normal by HLA typing. There were 28 of 255 (11%) heterozygotes with an elevated serum ferritin and 22 of 255 (8.6%) with an elevated transferrin saturation. Serum ferritin (140 ± 10.2 μg/liter; mean ± standard error) was greater in heterozygotes than in normal subjects (87 ± 8.5 μg/liter; P < .05, Mann Whitney test). Transferrin saturation was greater in heterozygotes (38% ± 0.88%) than in normal patients (29% ± 1.1%; P < .0001). Mean hepatic iron concentration was 54 ± 6 μmol/g (n = 17), and the hepatic iron index was <2 in these patients. Most heterozygotes for hemochromatosis have a normal serum ferritin and transferrin saturation. Heterorygotes with minor elevations in serum ferritin or transferrin saturation do not have significant iron overload as assessed by hepatic iron concentration. © 1994 Wiley-Liss, Inc.     

Pulmonary hypertension in non-transfusion-dependent thalassemia: Correlation with clinical parameters,liver iron concentration,and non-transferrin-bound iron

Abstract

Background

Pulmonary hypertension is a major cardiac complication in non-transfusion-dependent thalassemia (NTDT). Several clinical and laboratory parameters, including iron overload, have been shown to have a positive correlation with the incidence of pulmonary hypertension. Non-transferrin-bound iron (NTBI) is a form of free-plasma iron that is a good indicator of iron overload.

Objectives

The aim of this study was to determine the prevalence of pulmonary hypertension in patients with NTDT and to investigate its correlation with the clinical parameters, liver iron concentration (LIC) and NTBI.

Methods

Patients with NTDT were evaluated using echocardiography, and magnetic resonance imaging for cardiac T2* and LIC. Pulmonary hypertension was de?ned as peak tricuspid regurgitation velocity ≥2.9 m/s measured using trans-thoracic echocardiography. Clinical parameters and the status of iron overload as determined by LIC, serum ferritin, and NTBI level were evaluated for their association with pulmonary hypertension.

Results

Of 76 NTDT patients, mean age 23.7 ± 8.5 years, seven patients (9.2%) had pulmonary hypertension. Previous splenectomy (71.4 vs. 24.6%, P-value 0.019), higher cumulative red blood cell (RBC) transfusions (received ≥10 RBC transfusions 85.7 vs. 33.3%, P-value 0.011), higher nucleated RBCs (353 ± 287 vs. 63 ± 160/100 white blood cells, P-value <0.001), and a high NTBI level (5.7 ± 3.0 vs. 3.3 ± 2.8 µmol/l, P-value 0.034) were associated with pulmonary hypertension. There was no significant correlation between LIC or serum ferritin and pulmonary hypertension.

Conclusion

Pulmonary hypertension in NTDT is common, and is associated with splenectomy and its related factors. NTBI level shows a significant correlation with pulmonary hypertension.     

A Systematic Review and Meta-Analysis of Deferiprone Monotherapy and in Combination with Deferoxamine for Reduction of Iron Overload in Chronically Transfused Patients with β-Thalassemia

β-Thalassemia major (β-TM) patients require life-long blood transfusions, resulting in iron overload with multi-organ morbidity and mortality. Evidence from small randomized controlled trials (RCTs) published to date for deferiprone (DFP) monotherapy or in combination with deferoxamine (DFO) is unclear. We summarized evidence on the efficacy of DFP monotherapy compared to DFO, and DFP-DFO combination therapy compared to DFP or DFO monotherapy in chronically transfused β-TM. We searched four electronic databases and examined the grey literature. Two authors independently assessed trial quality and extracted data. We calculated the relative risk for dichotomous outcomes and mean difference (MD) for continuous outcomes. We identified 15 RCTs (1003 participants) that met the inclusion criteria. Deferiprone was more efficacious than DFO in improving cardiac ejection fraction [MD 2.88, 95% CI (95% confidence interval) 1.12 to 4.64, p?=?0.001) and endocrine dysfunction (MD 0.09, 95% CI 0.08 to 0.10, p?p?=?0.008). There was no significant difference in all other outcomes examined. Meta-analysis on changes in myocardial iron content was not possible due to differences in data presentation. The quality of evidence for all outcomes was low. There is currently insufficient evidence to show that DFP is superior to DFO in the treatment of iron overload. The use of DFP must be weighed against the potential side-effects, patient compliance and preference. Large RCTs with clinically relevant outcomes are required.     

Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience

Patients with thalassemia major requiring regular blood transfusions accumulate iron that is toxic to the heart, liver, and endocrine systems. The following prospective, randomized trial was carried out to determine the effectiveness, in children and young adults, of combined deferiprone (DFP) and deferoxamine (DFO) in reducing transfusional iron overload compared to either drug alone and to assess the safety and tolerability of DFP. Sixty-six patients were randomized into three treatment arms: daily DFP combined with DFO twice weekly; daily DFP only; and DFO only 5 days/week. Fifty-six patients completed the 54 weeks and were assessed by different indices. A significant reduction of liver iron concentration and serum ferritin was observed in all three arms while significant reduction of liver iron score was observed in patients on combination therapy only. Cardiac function did not significantly change in any arm. Compliance improved in patients who received combined therapy. Toxicity of DFP was mild to moderate and acceptable; most commonly, transient arthropathy and nausea/vomiting were observed. Thus, combination therapy has shown to be effective in reducing iron overload in thalassemia patients.     

Efficacy,Compliance And Toxicity Factors Are Affecting The Rate Of Normalization Of Body Iron Stores In Thalassemia Patients Using The Deferiprone And Deferoxamine Combination Therapy

The international committee on chelation (ICOC) of deferiprone (L1) and deferoxamine (DFO) combination therapy was the first protocol reported to have achieved normal range body iron store levels (NRBISL) in β-thalassemia major (β-TM) patients. A follow-up study in eight β-TM patients has been designed to investigate the factors affecting the rate of iron removal leading to NRBISL. The patients had variable serum ferritin [mean ± SE (standard error) =1692 ± 366, range 539–3845 μg/L)] and magnetic resonance imaging (MRI) T2* relaxation times cardiac (mean ± SE =11.1 ± 2.5, range 4.5–24.2 ms) and liver (mean ± SE = 4.3 ± 1.8, range 1.4–14 ms). Organ function, blood and other biochemical parameters were regularly monitored for toxicity. The ICOC L1 (80–100 mg/kg/day) and DFO (40–60 mg/kg, at least 3 days per week) combination therapy caused an increase in cardiac (mean ± SE =30.2 ± 2.3, range 22–41 ms) and liver (mean ± SE =27.6 ± 2.8, range 9.1–35 ms) T2* and reduction in serum ferritin (mean ± SE = 158 ± 49, range 40–421 μg/L) to within the NRBISL. The rate of normalization was variable and in one case was achieved within 9 months, whereas the longest was about 3 years. The initial iron load, the rate of transfusions, the combination dose protocol and the level of compliance were the major factors affecting the rate of normalization of the iron stores. No serious toxicity was observed during the study period, which lasted a total of 24.7 patient years.     

Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion‐dependent thalassemia: A randomized controlled trial

Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion‐dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ≤6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to “early start deferiprone” (.ES‐DFP) at a low dose (50 mg/kg/day) or to “delay chelation” (DC), and remained in the study until their serum ferritin (SF) level reached ≥1000 μg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 µg/L and TSAT > 70% compared with none in the ES‐DFP group. LPI level > 0.6 µM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 µg/L was delayed by 6 months in the ES‐DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES‐DFP group.     

Labile plasma iron,more practical and more sensitive to iron overload in myelodysplastic syndromes

Objectives: In order to gain an insight into labile plasma iron (LPI) in iron metabolism microenvironment in MDS.

Methods: We performed ELISA, quantitative real-time polymerase chain reaction, flow cytometry, MRI T2* assays to test LPI, iron biochemical parameters, and liver iron concentration (LIC) among 22 MDS patients.

Results: LPI has a statistical difference (P?P?=?0.086 by ANOVA). After DFO treatment, serum hepcidin expression increased from 301.26?±?59.78 to 340.33?±?49.78?µg/l (P?=?0.032), while hepcidin/ASF was upregulated gradually from 0.16?±?0.08 to 0.22?±?0.03 (P?=?0.045). APAF-1 expression (P?=?0.047) and erythroid apoptosis rate (P?=?0.009) decreased significantly, respectively. No statistical difference was found in EPO (P?=?0.247) and GDF15 expression (P?=?0.172). LIC dropped from 9.83?±?4.84 to 6.28?±?4.01?mg/g dry weight (P?P?=?0.594). LPI has a closer connection to LIC than ASF (r?=?0.739, P?r?=?0.321, P?=?0.034).

Discussion: LPI seems to be a real-time indicator which reflects body iron loading status instantaneously. Despite the limited knowledge available on LPI speciation in different types and degrees of IO, LPI measurements can be and are in fact used for identifying systemic IO and for initiating/adjusting chelation regimens.     

Individuals Homozygous for the H63D Mutation Have Significantly Elevated Iron Indexes

Our objective was to assess the iron indexes of patients with one or more mutations of the HFE gene with a specific interest in studying the effect of the H63D/H63D genotype. Eight hundred twenty subjects who underwent HFE mutational testing for C282Y and H63D mutations were retrospectively identified. Data collected included age, gender, HFE genotype, and values for serum ferritin, iron saturation, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Compared to the Wild/Wild genotype (0.34 ± 0.17), genotypes H63D/C282Y (0.44 ± 0.14 P < 0.01), H63D/H63D (0.51 ± 0.21 P < 0.01), and C282Y/C282Y (0.64 ± 0.20 P < 0.01) had significantly higher transferrin saturation levels and were independent predictors of higher iron saturation in multivariate regression analysis. Compared to the Wild/Wild genotype, no abnormal HFE genotypes had significantly higher ferritin levels, although the genotype H63D/H63D was an independent predictor of higher serum ferritin (P = 0.02) in regression analysis. There was no significant difference in the proportion of patients with abnormally elevated AST (P = 0.64) or ALT (P = 0.80) between groups. H63D homozygotes have elevated transferrin saturation compared to the Wild genotype, comparable to that of C282Y homozygotes and compound heterozygotes. The clinical significance of this finding is unclear but warrants further study.     

Sustained improvements in myocardial T2* over 2 years in severely iron‐overloaded patients with beta thalassemia major treated with deferasirox or deferoxamine

Long‐term controlled studies are needed to inform on the clinical benefit of chelation therapy for myocardial iron removal in transfusion‐dependent beta thalassemia patients. In a 1‐year nonrandomized extension to the CORDELIA study, data collected from patients with myocardial siderosis provided additional information on deferasirox or deferoxamine (DFO) efficacy and safety. Myocardial (m)T2* increased from baseline 11.6 to 15.9 ms in patients receiving deferasirox for 24 months (n = 74; geometric mean [G_mean] ratio of month 24/baseline 1.38 [95% confidence interval 1.28, 1.49]) and from 10.8 to 14.2 ms in those receiving DFO (n = 29; G_mean ratio 1.33 [1.13, 1.55]; P = 0.93 between groups). Improved mT2* with deferasirox was evident across all subgroups evaluated irrespective of baseline myocardial (mT2* < 10 vs. ≥ 10 ms) or liver (LIC <15 vs. ≥15 mg Fe/g dw) iron burden. Mean LVEF was stable and remained within normal limits with deferasirox or DFO. Liver iron concentration decreased from high baseline values of 30.6 ± 18.0 to 14.4 ± 16.6 mg Fe/g dw at month 24 in deferasirox patients and from 36.8 ± 15.6 to 11.0 ± 12.1 mg Fe/g dw in DFO patients. The long‐term safety profile of deferasirox or DFO was consistent with previous reports; serious drug‐related AEs were reported in 6.8% of deferasirox and 6.9% of DFO patients. Continued treatment of severely iron‐overloaded beta thalassemia patients with deferasirox or DFO led to sustained improvements in myocardial iron irrespective of high or low baseline myocardial or liver iron burden, in parallel with substantial improvements in liver iron ( Clinicaltrials.gov identifier: NCT00600938). Am. J. Hematol. 90:91–96, 2015. © 2014 Wiley Periodicals, Inc.     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

Abstract

Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20?pg/ml versus 61 ± 8?pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36?pg/ml versus 413 ± 49?pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258?pg/ml; HGF, 1500 ± 295?pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94?pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43?pg/ml; HGF, 1294 ± 224?pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients.     

Observational study comparing long-term safety and efficacy of Deferasirox with Desferrioxamine therapy in chelation-naïve children with transfusional iron overload

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.     

Neurocognitive dysfunction in children with β thalassemia major: psychometric,neurophysiologic and radiologic evaluation

Objective: To evaluate the impact of iron chelating drugs and serum ferritin on the neurocognitive functions of patients with β thalassemia major (β-TM), using psychometric, neurophysiologic and radiologic tests.

Methods: Eighty children with β-TM were enrolled into the study and were compared to 40 healthy controls. All participants were evaluated by measuring serum ferritin, neurocognitive assessment by Benton Visual Retention Test, Wechsler Intelligence Scale for Children, Wisconsin Card Sort Test, P300 and magnetic resonance spectroscopy (MRS).

Results: WISC in our study showed that 40% of cases were borderline mental function as regards total IQ. Neurophysiologic tests were significantly impaired in patients compared to control group, with significant impairment in those receiving desferrioxamine (DFO). P300 amplitude was significantly lower in cases compared to controls (2.24 and 4.66?uv, respectively), recording the shortest amplitude in patients receiving DFO. Altered metabolic markers in the brain were detected by MRS in the form of reduced N-acetylaspartate to creatine ratio in 78.3% of our cases. There were significant correlations between psychometric tests and both neurophysiologic (P300) and radiologic (MRS) tests.

Conclusion: β-TM is associated with neurocognitive impairment that can be assessed by psychometric, neurophysiologic and radiologic tests. The role of hemosiderosis and iron chelation therapy on cognitive functioning still need more research.

Abbreviations: β-TM: beta thalassemia major; DFO: Dysferal; DFP: Deferiprone; DFX: Deferasirox; WISC: Wechsler Intelligence Scale for Children; VIQ: verbal IQ; PIQ: performance IQ; TIQ: total IQ; BVRT: Benton Visual Retention Test; WCST: Wisconsin Card Sort Test; MRS: Magnetic resonant spectroscopy; NAA/Cr ratio: N-acetylaspartate to creatine ratio     

Low prevalence of cardiac siderosis in heavily iron loaded Egyptian thalassemia major patients

Myocardial siderosis in thalassemia major remains the leading cause of death in developing countries. Once heart failure develops, the outlook is usually poor with precipitous deterioration and death. Cardiovascular magnetic resonance (CMR) can measure cardiac iron deposition directly using the magnetic relaxation time T2*. This allows earlier diagnosis and treatment and helps to reduce mortality from this cardiac affection. This study aims to determine the prevalence of cardiac siderosis in Egyptian patients who are heavily iron loaded and its relation to liver iron concentration, serum ferritin, and left ventricular ejection fraction. Eighty-nine β-thalassemia patients receiving chelation therapy (mean age of 20.8?±?6.4 years) were recruited in this study. Tissue iron levels were determined by CMR with cardiac T2* and liver R2*. The mean ± standard deviation (range) of cardiac T2* was 28.5?±?11.7 ms (4.3 to 53.8 ms), the left ventricular ejection fraction (LVEF) was 67.7?±?4.7 % (55 to 78 %), and the liver iron concentration (LIC) was 26.1?±?13.4 mg Fe/g dry weight (dw) (1.5 to 56 mg Fe/g dw). The mean serum ferritin was 4,510?±?2,847 ng/ml (533 to 22,360 ng/ml), and in 83.2 %, the serum ferritin was >2,500 ng/ml. The prevalence of myocardial siderosis (T2* of <20 ms) was 24.7 % (mean age 20.9?±?7.5 years), with mean T2* of 12.7?±?4.4 ms, mean LVEF of 68.6 ±5.8 %, mean LIC of 30.9?±?13 mg Fe/g dw, and median serum ferritin of 4,996 ng/ml. There was no correlation between T2* and age, LVEF, LIC, and serum ferritin (P?=?0.65, P?=?0.085, P?=?0.99, and P?=?0.63, respectively). Severe cardiac siderosis (T2* of <10 ms) was present in 7.9 %, with a mean age of 18.4?±?4.4 years. Although these patients had a mean T2* of 7.8?±?1.7 ms, the LVEF was 65.1?±?6.2 %, and only one patient had heart failure (T2* of 4.3 ms and LVEF of 55 %). LIC and serum ferritin results were 29.8?±?17.0 mg/g and 7,200?±?6,950 ng/ml, respectively. In this group of severe cardiac siderosis, T2* was also not correlated to age (P?=?0.5), LVEF (P?=?0.14), LIC (P?=?0.97), or serum ferritin (P?=?0.82). There was a low prevalence of myocardial siderosis in the Egyptian thalassemia patients in spite of very high serum ferritin and high LIC. T2* is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy. The possibility of a genetic component for the resistance to cardiac iron loading in our population should be considered.     

Long Term Comparative Studies in Thalassemia Patients Treated with Deferoxamine or a Deferoxamine/Deferiprone Combination. Identification of Effective Chelation Therapy Protocols

For the past 2–6 years, two groups of thalassemia patients, one of 16 patients on deferoxamine (DFO) monotherapy (35–80 mg/kg, 2–5 days/week) and the other group comprising 19 patients on a deferiprone (L1) and DFO combination therapy (L1 75–100 mg/kg/day and DFO 30–60 mg/kg, 1–5 days/week), have been studied and compared before and after the introduction of the combination therapy. The patients on the combination therapy were mainly those not complying or experiencing toxicity with DFO. The effects of chelation therapy on iron load was monitored using regular serum ferritin measurements and also magnetic resonance imaging (MRI) T2* relaxation time measurements at the end of the study. In both groups, cardiac MRI T2* levels were within the normal range (>19 ms) in more than 75% of the patients. There was a substantial improvement in serum ferritin levels and normalization of the MRI T2* levels of the liver in many cases treated with the combination therapy at effective doses by comparison to the DFO group, where the serum ferritin and MRI T2* levels were largely unchanged. It would appear that the major overall determining factor in the rapid clearance of excess iron in thalassemia patients and the maintenance of normal iron stores is the selection and implementation of effective chelation dose protocols. The International Committee on Chelation (ICOC) combination protocol L1 (80–110 mg/kg/day)/DFO (40–60 mg/kg at least 3 days per week) and to a lesser extent, DFO monotherapy at about 50 mg/kg/day, 5 days/week, appears to achieve this goal.