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 for transfusional iron overload in sickle cell disease and other anemias: open-label study of up to 3 years.

Long-term safety and efficacy data on the iron chelator deferiprone in sickle cell disease (SCD) and other anemias are limited. FIRST-EXT was a 2-year extension study of FIRST (Ferriprox in Patients With Iron Overload in Sickle Cell Disease Trial), a 1-year, randomized noninferiority study of deferiprone vs deferoxamine in these populations. Patients who entered FIRST-EXT continued to receive, or were switched to, deferiprone. Altogether, 134 patients were enrolled in FIRST-EXT (mean age: 16.2 years), with mean (SD) exposure to deferiprone of 2.1 (0.8) years over the 2 studies. The primary end point was safety. Secondary end points were change in liver iron concentration (LIC), cardiac T2∗, serum ferritin (SF), and the proportion of responders (≥20% improvement in efficacy measure). The most common adverse events considered at least possibly related to deferiprone were neutropenia (9.0%) and abdominal pain (7.5%). LIC (mg/g dry weight) decreased over time, with mean (SD) changes from baseline at each time point (year 1, -2.64 [4.64]; year 2, -3.91 [6.38]; year 3, -6.64 [7.72], all P < .0001). Mean SF levels (µg/L) decreased significantly after year 2 (-771, P = .0008) and year 3 (-1016, P = .0420). Responder rates for LIC and SF increased each year (LIC: year 1, 46.5%; year 2, 57.1%; year 3, 66.1%; SF: year 1, 35.2%; year 2, 55.2%; year 3, 70.9%). Cardiac T2∗ remained normal in all patients. In conclusion, long-term therapy with deferiprone was not associated with new safety concerns and led to continued and progressive reduction in iron load in individuals with SCD or other anemias. The trial was registered at www.clinicaltrials.gov as #NCT02443545.

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.

Study of the diagnostic criteria for hemophagocytic lymphohistiocytosis in neonatal and pediatric patients with severe sepsis or septic shock.

Septic shock is a major public health concern. However, the clinical and laboratory criteria for sepsis overlap with those for hemophagocytic lymphohistiocytosis (HLH), and their differentiation can be challenging. The aim of this study was to compare HLH criteria among patients diagnosed with neonatal sepsis and childhood sepsis and to study the outcomes in patients fulfilling the diagnostic criteria for HLH. A cross-sectional study included 50 neonates and children with severe sepsis and/or septic shock. Clinical and laboratory data and HLH diagnostic criteria were studied in relation to patients outcome. Of all patients, 18% fulfilled three of the eight HLH diagnostic criteria, 2% fulfilled four criteria, and 4% fulfilled five criteria. All patients who fulfilled three or more of the criteria died. Mortality was higher in the presence of more positive HLH criteria and in pediatric age groups. However, the distributions of the HLH criteria were comparable for pediatric and neonatal patients with severe sepsis/septic shock, and their mortality rates were not significantly different when based on the criteria.

Body Composition in Egyptian Children With Transfusion-dependent Thalassemia: The Impact of Nutrition and Metabolic Profile.

BACKGROUND: Growth failure is a common complication in children with beta-thalassemia major (ß-TM) that has persisted despite major treatment advances. It could stem from malnutrition, especially in those who live in poor countries and who have inadequate nutrient intake. AIM: The aim of this study was to assess the influence of nutrition on growth, total body composition, and metabolic profile in Egyptian children with ß-TM. SUBJECTS AND METHODS: This cross-sectional study included 200 children with ß-TM and 50 age-matched and sex-matched healthy children. All subjects underwent full clinical assessment, which included assessment of growth and total body composition using anthropometric measurements (weight, height, mid-arm circumference, skinfold thickness, and body mass index) and bioelectric impedance analysis device (TANITA SC330). Nutritional assessment was performed using 24-hour dietary recall. Fasting serum insulin, C-peptide, and fasting serum lipid profile (high-density lipoprotein, low-density lipoprotein, cholesterol, and triglyceride) were measured. RESULTS: Children with ß-TM had a significantly lower mean value of the daily consumption of the studied nutrient elements including kilocalories, protein, carbohydrate, calcium, and phosphorus (P<0.001). ß-TM had a negative impact on anthropometric measures; the mean of all measurements recorded in children with ß-TM was significantly lower than that in the control group (P<0.001). Children with ß-TM had a significant abnormality in lipid profile, with higher triglyceride levels and lower cholesterol, low-density lipoprotein, and high-density lipoprotein than controls. They had significantly lower serum insulin and C-peptide. Age, sex, serum ferritin, and caloric intake have a significant impact on body composition in children with ß-TM. CONCLUSION: Regular assessment of nutrition is crucial for the health of children with ß-TM.

Left Ventricular Structural and Functional Changes in Children With ß-Thalassemia and Sickle Cell Disease: Relationship to Sleep-disordered Breathing.

Cardiovascular complications are well recognized in ß-thalassemia and sickle cell disease (SCD). The objective of this study was to evaluate left ventricular (LV) structural and functional changes and their relationship to sleep-disordered breathing (SDB) in children with ß-thalassemia and SCD. One hundred patients recruited from the hematology clinic were subjected to Pittsburgh Sleep Quality Index score; 26 patients had positive score (Pittsburgh Sleep Quality Index ≥5) (15 ß-thalassemia major and 11 SCD) and were compared with 25 age-matched and sex-matched controls. All underwent polysomnography and tissue Doppler echocardiography. SDB was detected in 73% of thalassemia patients (all had increased LV mass index [LVMI], diastolic dysfunction [increased E/Em], and 53% had pulmonary hypertension [tricuspid valve resurgence (TR) velocity ≥2.5 m/s]) and in 46% of SCD patients ( all had increased LVMI, 81.8% had pulmonary hypertension, and 76% had diastolic dysfunction). Sleep O2 saturation of ß-thalassemia patients negatively correlated with TR velocity and LVMI (P=0.027, 0.015), and lower asleep O2 saturation was associated with increased E/Em. In SCD patients, sleep and awake O2 saturation negatively correlated with TR velocity and E/Em (P=0.024 and 0.041), and lower sleep O2 saturation was associated with increased LV diameter (P=0.021). SDB is common and associated with LV structural and functional changes in ß-thalassemia and SCD.

Klf10 Gene, a Secondary Modifier and a Pharmacogenomic Biomarker of Hydroxyurea Treatment Among Patients With Hemoglobinopathies.

BACKGROUND: The klf10 gene could indirectly modify γ-globin chain production and hence the level of fetal hemoglobin (HbF) ameliorating the phenotype of ß-hemoglobinopathies and the response to hydroxycarbamide (hydroxyurea [HU]) therapy. In this study, we aimed to evaluate the frequency of different genotypes for the klf10 gene in ß-thalassemia major (B-TM), ß-thalassemia intermedia (B-TI), and sickle cell disease (SCD) patients by polymerase chain reaction and to assess its relation to disease phenotypes and HU response. METHODS: This cross-sectional study included 75 patients: 50 B-TM, 12 SCD, and 13 B-TI patients (on stable HU dose). The relation of the klf10 gene polymorphism (TIEG, TIEG1, EGRα) (rs3191333: c*0.141C>T) to phenotype was studied through baseline mean corpuscular volume, HbF, and transfusion history, whereas evaluation of response to HU therapy was carried out clinically and laboratory. RESULTS: The frequency of the mutant klf10 genotype (TT) and that of the mutant allele (T) was significantly higher among B-TM patients compared with those with B-TI and SCD patients. Only homozygous SCD patients for the wild-type allele within the klf10 gene had a significantly lower transfusion frequency. The percentage of HU responders and nonresponders between different klf10 polymorphic genotypes among B-TI or SCD patients was comparable. CONCLUSIONS: Although the klf10 gene does not play a standalone role as an HbF modifier, our data support its importance in ameliorating phenotype among ß-hemoglobinopathies.

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.

Efficacy and safety of a novel combination of two oral chelators deferasirox/deferiprone over deferoxamine/deferiprone in severely iron overloaded young beta thalassemia major patients.

OBJECTIVE: Minimal data are available on the combined two oral iron chelators in ß-thalassemia major (ß-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 ß-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.

Effect of antioxidant therapy on hepatic fibrosis and liver iron concentrations in ß-thalassemia major patients.

To assess the effects of combined vitamin therapy on oxidant-antioxidant hepatic status and hemoglobin (Hb) derivatives on ß-thalassemia major (ß-TM), a prospective study of 60 ß-TM patients aged 4 to 17 years, was conducted. Thirty-nine patients with initial low serum vitamins E, C and A, were treated with oral combined vitamins for 1 year compared to 21 patients with normal vitamin levels. Serum transaminases, serum ferritin, hepatic fibroscan elastography (TE) and magnetic resonance imaging R2* (MRI R2*) for liver iron concentration (LIC), were assessed before and after 6 and 12 months of therapy. Antioxidant capacity was assessed by levels of reduced glutathione (GSH), malondialdehyde (MDA), catalase, superoxide dismutase and GSH enzymes. The studied vitamins, reduced GSH and Hb levels were significantly elevated and paralleled by progressive decline in MDA and ferritin during therapy (p <0.001). Serum transaminase and superoxide dismutase were significantly decreased, while GSH reductase was significantly elevated during therapy (p <0.001). Improvement of hepatic fibrosis as 23.0% had TE (>12 kPa) at baseline compared to 20.5% after therapy (p >0.05), although LIC values were significantly decreased (p <0.001). Combined vitamin therapy improves the antioxidant/oxidant balance, LIC and hepatic fibrosis in young ß-TM patients.

Liver fibrosis in young Egyptian beta-thalassemia major patients: relation to hepatitis C virus and compliance with chelation.

BACKGROUND: The main causes of liver fibrosis in transfusion-dependent thalassemia major are hepatitis C virus (HCV) infection and hepatic iron overload. The study aimed to assess liver fibrosis in Egyptian adolescents and young adult poly-transfused beta thalassemia patients infected with HCV using liver FibroScan in relation to iron overload and Liver iron concentration (LIC). MATERIAL AND METHODS: Fifty-one regularly transfused beta thalassemia patients above 12 years old were subjected to measurement of serum alanine transaminase (ALT), serum ferritin (SF), HCV (antibody and RNA), LIC assessed by hepatic R2* and transient elastography (TE) (FibroScan). FibroTest and liver biopsy were done to 25 patients. RESULTS: Eighty two% of studied thalassemia patients were HCV antibody positive; 21(49%) of them were viremic (HCV RNA positive); median LIC was 12 mg/gm dry weight. There were strong positive correlation between the degree of liver stiffness and Ishak fibrosis score assessed in liver biopsy specimens (P = 0.002) and between FibroScan and FibroTest results (P < 0.001). Patients with HCV viremia showed significantly higher ALT, γ-glutamyl transpeptidase (GGT), SF, LIC and increased liver stiffness compared to patients with no viremia (P = 0.0001, 0.001, 0.012, 0.006 and 0.001) respectively. Liver cirrhosis (TE values > 12.5kPa) was encountered in 23.5% and variable degrees of liver fibrosis (TE values > 6-12.5 kPa) in 35% of studied thalassemic patients. CONCLUSION: Young beta thalassemia patients with active hepatitis C infection may have hepatic cirrhosis or fibrosis at young age when accompanied with hepatic siderosis. Non invasive Liver FibroScan and Fibro-Test were reliable methods to assess liver fibrosis in young thalassemic-patients.

Risk of bleeding and inhibitor development after circumcision of previously untreated or minimally treated severe hemophilia A children.

BACKGROUND: Surgery and intensive factor VIII (FVIII) replacement may be risk factors for development of inhibitors. OBJECTIVE: To evaluate time and rate of inhibitor development postcircumcision over 12-month period, and to assess bleeding of children with severe hemophilia A after low-dose FVIII replacement and local hemostasis. PATIENTS AND METHODS: Sixty-one previously untreated patients (PUPs) or minimally treated patients (MTPs) with severe hemophilia A less than 36 months were enrolled; 25 underwent circumcision during the 18-month enrollment period, and 36 matched patients were not circumcised. All patients were treated on demand with plasma-derived FVIII, and all were inhibitor negative at the time of enrollment. Intron 22 inversion was analyzed. A potent hemostatic agent (gelatin sponge) was applied on the site of surgery, and then dressed with gauze. Two doses of FVIII concentrate (25 U/kg) were given, 1 hour before circumcision and 1 hour before removal of dressing. The inhibitor was determined every 8 exposure days (EDs). RESULTS: None of the patients had bleeding or infection, except one who had minimal transient bleeding 8 days after surgery, and was treated easily by a single dose of FVIII (50 U/kg). After a median of 16 EDs, high-titer inhibitors developed in seven patients: three patients in the circumcised group (12%) in contrast to four patients (11.1%) in the noncircumcised group. CONCLUSION: Two doses factor concentrate and gelatin sponge application were generally enough to prevent bleeding after circumcision of severe hemophilia A. Circumcision and low-dose FVIII protocol were not an additional risk for development of high-titer inhibitor.

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.

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.

Achieving treatment goals of reducing or maintaining body iron burden with deferasirox in patients with ß-thalassaemia: results from the ESCALATOR study.

This analysis evaluated the effects of deferasirox on liver iron concentration in moderate and heavily iron-overloaded patients with ß-thalassaemia from the ESCALATOR trial (n = 231). Mean liver iron concentrations (LIC) decreased significantly from 21.1 ± 8.2 to 14.2 ± 12.1 mg Fe/g dry weight (dw) at 2 yr (P < 0.001) in patients with LIC ≥ 7 mg Fe/g dw at baseline; patients with LIC < 7 mg Fe/g dw maintained these levels over the treatment period. The proportion of patients with LIC < 7 mg Fe/g dw increased from 9.4% at core baseline to 39.3% by the end of year 2. The results showed that deferasirox enabled therapeutic goals to be achieved, by maintaining LIC in patients with LIC < 7 mg Fe/g dw at a mean dose of 22.4 ± 5.2 mg/kg/d and significantly reducing LIC in patients with LIC ≥ 7 mg Fe/g dw at a mean dose of 25.7 ± 4.2 mg/kg/d, along with a manageable safety profile.

Cardiac events and cardiac T2* in Egyptian children and young adults with beta-thalassemia major taking deferoxamine.

BACKGROUND AND OBJECTIVES: Cardiac events and death are not uncommon in adults with beta-thalassemia (b-TM) taking deferoxamine (DFO) monotherapy because of poor compliance and possibly the less effectiveness of DFO in controlling cardiac iron overload. We sought to assess compliance with DFO, the percentage of shift to other iron chelators, and the occurrence of cardiac siderosis, and cardiac events and death in b-TM patients on DFO monotherapy. DESIGN AND SETTING: Prospective, observational, 10-year follow-up of patients attending Ain Shams Thalassemia Unit, Cairo, Egypt. METHODS: For all b-TM patients aged 2-18 years attending the unit during January 1998 and taking DFO, we recorded all cardiac events (whether fatal or not) during January 2008. All patients still on DFO monotherapy and with a normal EKG and not showing symptoms or signs suggestive of heart failure (HF) were evaluated for cardiac siderosis by T2*. RESULTS: Of 412 patients, only 126 (31%) were still taking DFO monotherapy (only 43% of those were compliant), 136 were taking combined DFO and deferiprone (DFP), 72 were taking DFP and 32 were taking deferasirox (DFX). Twenty-one were lost to follow-up and 25 died (10 cardiac). Eight of ten cardiac deaths and 12 of 15 non-cardiac deaths were in the DFO monotherapy group. Those taking DFO monotherapy with no HF and left ventricular ejection fraction (LVEF) by T2* >56% had a median age of 19 years and 56% were males; cardiac T2* was less than 20 ms in 30 (22%), 10-20 ms in 20 (14.7%) and less than 10 ms in 10 (7.3%). LVEF ranged from 58%-76% (median 64%). Forty percent of T2* patients less than 10 ms were compliant with DFO. CONCLUSION: Fifty-eight percent of patients on DFO monotherapy were noncompliant, but even compliance did not prevent severe cardiac siderosis and most cardiac events (whether fatal or not) that occurred in the DFO monotherapy group.

Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia: the ESCALATOR study.

OBJECTIVE: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20-30 mg/kg/d reduces iron burden, depending on transfusional iron intake. METHODS: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients > or =2 yr with beta-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of > or =3 mg Fe/g dry weight (dw) if baseline LIC was > or =10 mg Fe/g dw, or final LIC of 1-7 mg Fe/g dw for patients with baseline LIC of 2 to <10 mg Fe/g dw. RESULTS: Overall, 233/237 enrolled patients completed 1 yr's treatment. Mean baseline LIC was 18.0 +/- 9.1 mg Fe/g dw, while median serum ferritin was 3356 ng/mL. After 1 yr's deferasirox treatment, the intent-to-treat population experienced a significant treatment success rate of 57.0% (P = 0.016) and a mean reduction in LIC of 3.4 mg Fe/g dw. Changes in serum ferritin appeared to parallel dose increases at around 24 wk. Most patients (78.1%) underwent dose increases above 20 mg/kg/d, primarily to 30 mg/kg/d. Drug-related adverse events were mostly mild to moderate and resolved without discontinuing treatment. CONCLUSIONS: The results of the ESCALATOR study in primarily heavily iron-overloaded patients confirm previous observations in patients with beta-thalassaemia, highlighting the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure patients achieve their therapeutic goal of maintenance or reduction in iron burden.