Iron Chelation Therapy: A Review of the Literature on the Issues and Importance of Adherence to Treatment in Iron Overload
Authors: Huang Vicky , Luini Cecilia , El-Ali Ali , Kessabi Sophia 
Published: October 2019

Abstract
Background: Iron chelation therapy (ICT) is important for chronic conditions where blood transfusions are an essential therapy (eg transfusion-dependent thalassemia [TDT], sickle-cell disease and myelodysplastic syndromes), to avoid serious long-term clinical consequences of iron overload. There are currently three iron chelators licensed to treat iron overload: deferoxamine (DFO; Desferal®), given subcutaneously over 8-12 hours, 5-7 days/week; deferiprone (Ferriprox®), a three-times daily oral chelator; and deferasirox (Exjade®) a once-daily oral chelator, available as a dispersible or film-coated tablet (JadenuTM; FDA approved Mar 2015). Ensuring adherence is challenging - ICT is part of a lifelong treatment regimen and the benefits are not always readily apparent to the patient - but necessary to prevent morbidity and mortality associated with iron overload. Here, we present key findings from a review of the literature assessing adherence to ICT in clinical trial and real-life settings, including the underlying factors and long-term consequences of suboptimal adherence.
Methods: A systematic search of OVID Medline over the past 10 years was conducted using predefined criteria associated with iron overload, ICTs, transfusion-dependent anemias, adherence, compliance, persistence, health-related quality of life (HR-QoL) and economic burden. In total, 156 articles were identified. Of these, 26 were retained (fulfilling all inclusion criteria) and eight additional articles were sourced manually, providing important supportive evidence.
Results: Despite variations in the measurements of adherence to ICT in controlled clinical trials, in general, data indicate relatively high adherence rates, (59-98%), with a preference towards oral therapies.1-5 Of patients switching to deferasirox following treatment with DFO, nearly all patients (96.9%) preferred to continue with deferasirox.6 In a real-life setting however, although the likelihood of treatment discontinuation with DFO was 1.30-fold higher than for deferasirox,7 discontinuation rates were high in both groups; 95% for DFO and 80% for deferasirox.
A number of factors were identified to be commonly associated with non-adherence to ICT.8 Regimen/practical aspects of drug administration were particularly notable. For example, subcutaneous infusions with DFO are time-consuming and can be painful; shown to negatively impact on satisfaction with ICT.9 Oral formulations offer a more practical route of administration. Deferiprone requires three-times daily administration. Once-daily deferasirox, as a dispersible tablet, must be dissolved in water or juice and taken on an empty stomach, thus requiring some preparation and planning. The taste and texture may also contribute to suboptimal adherence, especially in young children.10,11 Side effects related to both DFO and deferasirox were found to be negatively related to adherence in adult and adolescent TDT patients.2 On the contrary, older age (maturity) and higher HR-QoL on the physical component were associated with increased adherence to deferasirox.2
Ensuring adherence to ICT is essential in order to prevent the consequences of iron overload. Evidence from long-term epidemiologic studies has demonstrated a link between sub-optimal adherence and increased mortality and morbidity (eg cardiac disease, diabetes, hypogonadism, hypothyroidism; Table), as well as increased markers of iron overload (eg myocardial T2*, serum ferritin12,13). As such, these consequences of poor-adherence translate into increased treatment costs for iron overload-related complications.1
Discussion: The benefits of optimal adherence are clear from both a patient and healthcare cost perspective. Clinical studies have demonstrated high adherence rates to ICT with oral chelators such as deferasirox, as a result of improved convenience and HR-QoL compared with DFO. However, since adherence remains a challenge in real-life settings where adherence appears lower, there remains scope for improvements towards more patient-friendly formulations to prevent long-term health consequences associated with iron overload. Further investigation of a film-coated deferasirox tablet (JadenuTM) is ongoing, offering improved palatability and convenience, with minimal food effect (ClinicalTrials.gov Identifier: NCT02125877).

Disclosures
Huang: Novartis: Employment. Luini:Novartis: Consultancy. El-Ali:Novartis: Employment. Kessabi:Novartis: Consultancy.