Inadequate Long-Term Control Of Transfusion Iron Overload In Children With Sickle Cell Disease Chelated With Deferasirox

Evidence-based indications for regular transfusions in children with SCD are increasing, and there is now a large population of children on long-term transfusion who require effective control of iron stores to prevent toxicity from transfusion iron overload. The oral iron chelating agent deferasirox (DFX) has been evaluated extensively in thalassemia major, but long-term data on efficacy and safety in children with SCD is relatively sparse. A Phase II trial by Vichinsky et al (2006) compared DFX with deferrioxamine (DFO) in 185 patients (50% paediatric) over one year. The extension study up to 5 years indicated a gradual improvement in serum ferritin associated with increased dose reaching a mean of 25 mg/kg/day. Responses were noted to be poorer in children. The extension study included only 33.5% of the original cohort and is not representative of the full population of children with SCD requiring long-term chelation. Furthermore, the study did not include sequential monitoring of liver iron concentration (LIC), which is considered a better measure of body iron and of chelation efficacy in SCD. In this study, we have evaluated the long-term efficacy and safety of DFX in a clinical care setting and addressed some of the deficiencies of the above study.

This was a multicentre retrospective, observational study of regularly transfused children in the East London and Essex Clinical Haemoglobinopathy Network. A standard protocol for dosing and monitoring was initiated after licensing of DFX in the EU in 2006. Initial dose was 20mg/kg, and increased in increments of 5mg/kg up to 35 mg/kg/day. Dose was interrupted for creatinine above the normal range for age, or for ALT elevations over 2 times the upper limit of normal when other aetiologies had been excluded. Monitoring of body iron was with monthly serum ferritin (SF) and annual R2 MRI-estimated LIC (in children aged >8 years). Adherence was assessed at monthly transfusion episodes. Support and encouragement with adherence to therapy was provided by dedicated nurse specialists in the hospital and community and a clinical psychologist. Adherence and acceptability were assessed by a questionnaire adapted from Alvarez et al (2009). For this study, data was censored at 36 months from treatment initiation.

Sixty-two patients were included, the mean age at initiation of DFX was 9.2 years and mean chelation duration 2.5 ±1.4 years. There were 120.7 years of patient exposure up to 36 months of treatment. The initial mean (± SD) daily dose was 19.8 ± 3.1 mg/kg and at 36 months was 24.6 ± 9.7 mg/kg. Mean SF increased significantly from 2542 ± 964ng/ml at baseline to 4691 ± 2255ng/ml at 36 months; the mean change was 1548ng/ml (95% confidence intervals; -26, 3122ng/ml, p=0.053). There was no significant change in LIC from first to second MRI scan (mean 10.3 mg/g dw on initial and 11.4 mg/g dw on second scan, p=0.35). We observed a statistically significant correlation (R² =0.66, p <0.001) between the relative change in LIC and in SF. Serum creatinine and estimated Glomerular Filtration Rate (Schwartz formula) remained stable and within normal range. Fifty-two episodes of ALT elevation were recorded in 33 patients, with 14 having recurrent episodes (mean number of episodes per year 2.1± 0.8). In the questionnaire responses, adherence for at least 80% of doses was reported by 75% of respondents. However, more than 50% indicated problems when taking DFX, the most frequent complaint being unpleasant taste.

Our experience in a large cohort of children with SCD indicate that iron stores, assessed by combined modalities of SF and LIC, are not adequately controlled with current recommended dosing regimes for DFX. This may be due to inadequate adherence, less favorable pharmacokinetics in children compared to adults, frequent elevations of ALT necessitating interruptions of dosing, or insufficient efficacy of DFX in this population. Changes in SF appear to have a useful role in assessing efficacy and show a reasonable correlation with changes in LIC. Alternative dosing regimes, combinations with other chelators, and more use of exchange transfusion in children may be needed to optimize iron stores in chronically transfused children with SCD. Studies that include a larger number of children and longer follow up periods are required in order to further validate these observations, and explore the role of alternative management strategies.

No relevant conflicts of interest to declare.