Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration.

PURPOSE: Magnetic resonance imaging (MRI)-based techniques for assessing liver iron concentration (LIC) have been limited by single scanner calibration against biopsy. Here, the calibration of spin-density projection-assisted (SDPA) R2-MRI (FerriScan®) in iron-overloaded ß-thalassemia patients treated with the iron chelator, deferasirox, for 12 months is validated. METHODS: SDPA R2-MRI measurements and percutaneous needle liver biopsy samples were obtained from a subgroup of patients (n = 233) from the ESCALATOR trial. Five different makes and models of scanner were used in the study. RESULTS: LIC, derived from mean of MRI- and biopsy-derived values, ranged from 0.7 to 50.1 mg Fe/g dry weight. Mean fractional differences between SDPA R2-MRI- and biopsy-measured LIC were not significantly different from zero. They were also not significantly different from zero when categorized for each of the Ishak stages of fibrosis and grades of necroinflammation, for subjects aged 3 to <8 versus ≥8 years, or for each scanner model. Upper and lower 95% limits of agreement between SDPA R2-MRI and biopsy LIC measurements were 74 and -71%. CONCLUSION: The calibration curve appears independent of scanner type, patient age, stage of liver fibrosis, grade of necroinflammation, and use of deferasirox chelation therapy, confirming the clinical usefulness of SDPA R2-MRI for monitoring iron overload.

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.

Importance of optimal dosing ≥ 30 mg/kg/d during deferasirox treatment: 2.7-yr follow-up from the ESCALATOR study in patients with ß-thalassaemia.

Following 1-yr deferasirox therapy in the ESCALATOR study, 57% of previously chelated patients with ß-thalassaemia achieved treatment success (maintenance of or reduction in liver iron concentration (LIC) vs. baseline LIC). Seventy-eight per cent had dose increases at median of 26 wk, suggesting that 1-yr results may not have reflected full deferasirox efficacy. Extension data are presented here. Deferasirox starting dose was 20 mg/kg/d (increases to 30/40 mg/kg/d permitted in the core/extension, respectively). Efficacy was primarily assessed by absolute change in LIC and serum ferritin. Overall, 231 patients received deferasirox in the extension; 67.4% (P < 0.0001) achieved treatment success. By the end of the extension, 66.2% of patients were receiving doses ≥ 30 mg/kg/d. By the end of the 1-yr extension, mean LIC had decreased by 6.6 ± 9.4 mg Fe/g dw (baseline 19.6 ± 9.2; P < 0.001) and median serum ferritin by 929 ng/mL (baseline 3356; P < 0.0001). There was a concomitant improvement in liver function markers (P < 0.0001). Fewer drug-related adverse events were reported in extension than core study (23.8% vs. 44.3%). Doses ≥ 30 mg/kg/d were generally required because of high transfusional iron intake and high baseline serum ferritin levels, highlighting the importance of administering an adequate dose to achieve net negative iron balance.

Improved treatment satisfaction and convenience with deferasirox in iron-overloaded patients with beta-Thalassemia: Results from the ESCALATOR Trial.

Patient-reported outcomes of once-daily oral deferasirox (Exjade) in iron-overloaded patients with beta-thalassemia not achieving successful chelation with prior deferoxamine and/or deferiprone were investigated in a prospective, open-label, 1-year, multicenter study in the Middle East (ESCALATOR). The initial dose of deferasirox was 20 mg/kg/day, with subsequent dose adjustments. At baseline and the end of study (EOS), patients (n = 237) completed a 5-point rating scale for treatment satisfaction and convenience, and recorded time lost to treatment. At EOS, 90.7% of patients were 'satisfied'/'very satisfied' with their iron chelation therapy (ICT) versus 23.2% at baseline. 92.8% (EOS) versus 21.5% (baseline) of patients considered their therapy to be 'convenient'/'very convenient'. Time lost to therapy for daily activities was substantially reduced (3.2 +/- 8.6 [mean +/- SD; EOS] vs. 30.1 +/- 44.2 [baseline] h/month). Patients reported greater satisfaction and convenience, and lower impact on daily activities, with deferasirox than with previous ICT. This may help improve adherence to lifelong ICT in iron-overloaded beta-thalassemia patients.

Prevention of hemoglobinopathies in Syria.

Hemoglobin disorders are highly prevalent in Syria resulting in a significant strain to national resources. To ensure survival and good quality of life of existing patients who are currently almost 8,000 and increasing by almost 800 each year, it is necessary to introduce a national prevention program. This brief report explains the measures that are under discussion currently and proposed for inclusion in a comprehensive control program.

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.