Efficacy and safety of early-start deferiprone in infants and young children with transfusion-dependent beta thalassemia: Evidence for iron shuttling to transferrin in a randomized, double-blind, placebo-controlled, clinical trial (START).

Children with transfusion-dependent thalassemia (TDT) require regular blood transfusions that, without iron-chelation therapy, lead to iron-overload toxicities. Current practice delays chelation therapy (late-start) until reaching iron overload (serum ferritin ≥1000 µg/L) to minimize risks of iron-depletion. Deferiprone's distinct pharmacological properties, including iron-shuttling to transferrin, may reduce risks of iron depletion during mild-to-moderate iron loads and iron overload/toxicity in children with TDT. The early-start deferiprone (START) study evaluated the efficacy/safety of early-start deferiprone in infants/young children with TDT. Sixty-four infants/children recently diagnosed with beta-thalassemia and serum ferritin (SF) between 200 and 600 µg/L were randomly assigned 1:1 to receive deferiprone or placebo for 12 months or until reaching SF-threshold (≥1000 µg/L at two consecutive visits). Deferiprone was initiated at 25 mg/kg/day and increased to 50 mg/kg/day; some recipients' dosages increased to 75 mg/kg/day based on iron levels. The primary endpoint was the proportion of patients ≥SF-threshold by month 12. Monthly transferrin saturation (TSAT) assessment evaluated iron-shuttling. At baseline, there was no significant difference in mean age (deferiprone: 3.03 years, placebo: 2.63 years), SF (deferiprone: 513.8 µg/L, placebo: 451.7 µg/L), or TSAT (deferiprone: 47.98%, placebo: 43.43%) between groups. At month 12, there was no significant difference in growth or adverse event (AE) rates between groups. No deferiprone-treated patients were iron-depleted. At month 12, 66% of patients receiving deferiprone remained below SF threshold versus 39% of placebo (p = .045). Deferiprone-treated patients showed higher TSAT levels and reached ≥60% TSAT threshold faster. Early-start deferiprone was well-tolerated, not associated with iron depletion, and efficacious in reducing iron overload in infants/children with TDT. TSAT results provide the first clinical evidence of deferiprone shuttling iron to transferrin.

Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study.

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload that requires chelation therapy. The iron chelator deferiprone is frequently used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range, 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was -4.04 (0.48) mg/g dry weight for deferiprone vs -4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, -0.76 to 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia. This trial study was registered at www://clinicaltrials.gov as #NCT02041299.

Role of vitamin C as an adjuvant therapy to different iron chelators in young ß-thalassemia major patients: efficacy and safety in relation to tissue iron overload.

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 ß-thalassemia major (ß-TM) in relation to tissue iron overload. METHODS: This randomized prospective trial that included 180 ß-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 ß-TM, with no adverse events.

Pattern of milk feeding and family size as risk factors for iron deficiency anemia among poor Egyptian infants 6 to 24 months old.

Infants between 6 and 24 months of age are at the highest risk of development of iron deficiency anemia (IDA) in developing countries. Consuming unmodified cow's milk, delayed introduction of solid foods after 6 months, and high birth order could be predictors of the presence of IDA. Three hundred infants between the ages of 6 and 24 months (mean, 13.94 ± 6.17 months) from Ain Shams University Children's Hospital were enrolled in the study. Data collected included demographic information and dietary assessment including the type of milk feeding, introduction of solid foods, and daily iron intake. The infants were examined, and anthropometric measurements were recorded. Anemic infants (hemoglobin level <11 g/dL) were further evaluated by complete blood count, hemoglobin electrophoresis, and iron profile. Anemia was diagnosed among 198 infants (66%), of whom 129 (43%) had IDA. Red cell distribution width at a cutoff value of 15.8% was 86% sensitive and 74% specific in predicting IDA. The main risk factors for IDA included being between 6 and 18 months of age, of the male sex, birth order above the second order, consuming cow's milk, predominant breast-feeding beyond 6 months of age, and low daily iron intake. We conclude that IDA is the most common cause of anemia among Egyptian infants 6 to 24 months old of low socioeconomic standard. Independent clinical predictors were consuming cow's milk during the first 6 months, delayed introduction of solid foods after 6 months, and birth order beyond the second order.

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with ß-thalassemia major.

BACKGROUND: Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important. DESIGN AND METHODS: Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3(rd) year, allowing cardiac iron removal to be analyzed over three years. RESULTS: Mean deferasirox dose during year 3 was 33.6 ± 9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ± 39.1% at baseline to 17.1 ms ± 62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43 ± 1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ± 1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥ 20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n = 9, 12.7%). CONCLUSIONS: Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.

A new tool for the assessment of satisfaction with iron chelation therapy (ICT-Sat) for patients with ß-thalassemia major.

BACKGROUND: High satisfaction with iron chelation is a major determinant for adherence to ICT in beta-thalassaemia major (ß-TM) patients. In this study, a new tool to assess different domains of satisfaction for available forms of ICT was developed and validated. The impact of patients' satisfaction with ICT has been tested. METHODS: Items were generated via focus groups and a preliminary version with 24 items (ICT-Sat) with an additional item for treatment preference and a knowledge questionnaire (KQ) was developed. 170 ß-TM patients from three Thalassaemia centers in Egypt, aged 2-32 years received three questionnaires to fill in; the new ICT-Sat, a KQ, and a previously validated tool for satisfaction with ICT (SICT) and retested 4-6 weeks later to ensure re-test reliability. Type of chelation, drug related adverse events, compliance with ICT, and serum ferritin level (SF) during the year prior to the study as well as available cardiac T2*data were recorded. RESULTS: One hundred and fifty two ß-TM patients completed all questionnaires; median age was 12 years. The final 15 remaining ICT-Sat items, yielding to four domain scores, explained 70.6% of the total variance. The "perceived effectiveness" and "fear and worries" domains of the ICT-Sat correlated significantly with the domains "perceived effectiveness" and "acceptance" of the SICT. Patients treated with oral ICT were more satisfied with perceived effectiveness, and their side effects. CONCLUSIONS: A new clinically based ICT-Sat tool was developed and revealed good psychometric characteristics. Adherence to ICT was better correlated with "perceived effectiveness" and SF level.