SPECIAL ARTICLE Comparison of Deferiprone to Deferasirox and Deferoxamine to Cardiac and Hepatic T2* MRI in Thalassemia Patients: Evidence-based Case Report Pustika A. Wahidiyat, Mikhael Yosia, Teny T. Sari Department of Child Health, Faculty of Medicine Universitas Indonesia – Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Corresponding Author: Pustika Amalia Wahidiyat, MD., PhD. Division of Pediatric Haematology - Oncology, Department of Child Health, Faculty of Medicine Universitas Indonesia – Cipto Mangunkusumo Hospital. Jl. Pangeran Diponegoro no. 71, Jakarta 10430, Indonesia. email: [email protected]. ABSTRAK Latar belakang: saat ini terdapat tiga jenis kelasi besi yang tersedia untuk pasien di Indonesia: deferiprone/ DFP (dengan merk dagang Ferriprox), deferasirox/DFX (dengan merk dagang Exjade) and deferoxamine/DFO (dengan merk dagang Desferal). Tujuan dari studi ini adalah untuk melihat kelasi besi mana yang paling efisien dalam menurunkan kelebihan besi pada miokard dan hepar yang dilihat dari hasil T2* MRI. Metode: pencarian jurnal dengan terminologi MeSH dilakukan di PubMed dan Scopus. Studi pada pasien thalassemia mayor di semua umur yang menggunakan monoterapi kelasi besi dan melihat efeknya pada T2* MRI liver atau miokard diikutkan ke dalam analisis. Penilaian dari studi yang digunakan dilakukan dengan metoda penilaian studi dari Oxford’s CEBM dan Joana Brigs Institute. Hasil: total 11 studi dengan jumlah total 611 sampel diikutkan dalam analisa studi ini. Nilai rerata T2* MRI dan (jika tersedia) nilai rerata perubahan T2* MRI setelah penggunaan satu jenis kelasi besi dianalisa dari semua studi yang diikutkan. Studi komparasi maupun studi individu menemukan kontrol dan peningkatan miokardiak T2* MRI pada sampel menggunakan DFP, sedangkan penggunaan DFO yang taat lebih baik dalam mengontrol dan meningkatkan liver T2* MRI. Kesimpulan: DFP lebih superior dalam mengontrol dan menurunkan beban besi miokard (dibuktikan oleh miokardial T2* MRI) sedangkan DFO memiliki kemampuan lebih baik dalam mengontrol dan menurunkan beban besi pada hepar (dibuktikan oleh liver T2* MRI). Studi dengan waktu observasi lebih lama dan sampel yang lebih besar dibutuhkan untuk melihat efek signifikan DFX terhadap T2* MRI. Kata kunci: besi, talasemia, T2* MRI. ABSTRACT Background: there are currently three iron chelator readily available for patients Indonesia; deferiprone/ DFP (branded as Ferriprox), deferasirox/DFX (branded as Exjade) and deferoxamine/DFO (branded as Desferal). This study aims to determine which iron chelator is the most efficient in reducing cardiac and hepatic iron overload (measured by means of T2* MRI). Methods: journal search with determined MeSH term was done in PubMed and Scopus. Studies that looked upon thalassemia major patient in all ages with usage of monotherapy iron chelation and its effect on myocardial T2* MRI and/or liver T2* MRI was included. Appraisal of studies was done using Oxford’s CEBM appraisal tools and Joanna Brigs Institute critical appraisal tools. Results: total of 11 studies with grand total of 611 samples were included. Mean T2* MRI value or (when available) mean changes in T2* MRI value after usage of specific iron chelator was gained from all the studies included. Comparison study and individual studies shows better control and increase of myocardial T2* MRI in those 168 Acta Med Indones - Indones J Intern Med • Vol 50 • Number 2 • April 2018 Vol 50 • Number 2 • April 2018 Comparison of deferiprone to deferasirox and deferoxamine to cardiac with DFP, and of liver T2* in those with good adherence to DFO chelation. Conclusion: DFP is superior in controlling or reducing myocardial iron load (as proven by mT2* MRI) and DFO had better capabilities in controlling or reducing hepatic iron load (as proven by liver T2* MRI). Studies with longer observation and larger samples is needed to see a significant changes of T2* MRI in DFX. Keywords: iron chelation, thalassemia, T2* MRI. INTRODUCTION the benefits of all different iron chelator; 1 2 Iron overload (hemochromatosis) is a Luangasanatip et al and Pepe et al both uses condition of excess iron accumulation in the Quality Adjusted Life Years (QALY) assessment body from any cause, one of them being repeated to see economic benefits of each drugs, Xia 3 blood transfusions.1 In patients who needs et al look upon serum ferritin (SF), liver iron frequent and/or continuous blood transfusion concentration (LIC), myocardial iron content (e.g. Sickle cell anaemia, thalassemia, aplastic (MIC), left ventricular ejection fraction (LVEF) anaemia, leukaemia, etc), excess iron from donor and adverse events (AEs) as means of assessing blood accumulate and in time manifest itself effectiveness of each different iron chelator. Yet into transfusional hemosiderosis in which iron the question still remains, which iron chelator is accumulates in the liver, heart and endocrine the most efficient in regards to reducing cardiac organs causing clinical syndromes such as and hepatic iron overload through assessment cardiomyopathy, diabetes and hepatic cirrhosis. via T2* MRI. In order to prevent manifestation of excess iron into diseases, iron chelator had long CLINICAL QUESTION been used. There are currently three different 11-year-old boy with beta-thalassemia major, types of iron chelator readily available for had been receiving continuous blood transfusion. patients Indonesia; deferiprone/DFP (branded as His recent T2* MRI result shows a moderate Ferriprox), deferasirox/DFX (branded as Exjade) hepatic and myocardial iron load. Previous and deferoxamine/DFO (branded as Desferal). doctor prescribed DFO for the last 3 years, but Each of the three chelator offers different benefits compliance level had been very low due to the and challenges to the patients; DFP comes in hassle of sc administration. Current attending tablet (500 mg/tab) or syrup (100mg/mL) which doctor decided to prescribed oral DFP with hopes makes it easier for children to consume, DFX are that compliance level may increase and his body also available in 250 and 500 mg/tablet form, iron load can be controlled. The patient parents DFO is the first iron chelator available for use become concern with the change of iron chelator in RSCM but it can only be administered via and T2* MRI results, they asked whether the oral subcutaneous (sc) or intravenous (iv) injection drug given is more effective compared to the sc thus explaining its unpopularity and low ones their child had been using. compliance.2 From the case illustration, a clinical question There are different means of assessing iron arises: “Which of the three iron chelator (DFP, overload in patients; simple blood examination DFX, DFO) is the most effective in reducing (total iron binding capacity/TIBC, serum iron/ cardiac and hepatic iron load proven by means SI, transferrin saturation/TS and serum ferritin/ of T2* MRI?” SF) and radiology (T2* MRI). As a more reliable mean to predict iron overload in organ (especially METHODS heart and liver), T2* MRI had been meticulously This review will consider all in vivo studies used to assess hemosiderosis and whether dose in human subjects of any age who suffers from adjustment or combination iron chelation therapy thalassemia. Intervention includes usage of DFP is needed.2 and/or DFX and/or DFO monotherapy in any There are studies available that assess dose. Those on combination iron chelator aren’t 169 Pustika A. Wahidiyat Acta Med Indones-Indones J Intern Med going to be included. Outcome measure wanted to meet the inclusion criteria, based on their title, are T2* MRI that assess both/either hepatic or abstract and subject descriptors, will be critically cardiac iron load. All Randomized Control Trial appraised. (RCT), prospective study, retrospective study, cross-sectional study with full text available in RESULTS English or Indonesian since 20 years ago will Summary of the literature search process be included. and result can be seen in Figure 1. This study Search Strategy included 6 prospective studies, 1 randomized The initial search terms will be ‘iron control trial, 1 prospective-comparative studies, chelator’, ‘MRI T2*’, ‘thalassemia’, followed 2 cross-sectional studies and 1 retrospective by proper MeSH search (Table 1). Articles studies. In total, 11 studies are included with a published in the following databases will be total of 611 patients using different monotherapy searched: PubMed and Scopus. Full copies of of either DFP, DFO or DFX. All the studies articles identified by the search, and considered used adhere to the criteria that is set by the Table 1. Search strategy and MeSH term used Selected Database Search terms Hits article (“iron”[MeSH terms] OR “iron”[All Fields]) AND (“chelating agents” [Pharmacological Action] OR “chelating agents” [MeSH Terms] OR (“chelating” [All Fields] AND “agents” [All Fields]) OR “chelating agents” [All Fields] OR “chelator” [All Fields]) AND (“thalassemia” [All Fields] OR “thalassemia” [MESH PubMed/Scopus 140 10 Terms] OR “thalassemia” [All Fields]) AND (“magnetic resonance imaging” [MeSH Terms] OR (“magnetic” [All Fields] AND “resonance” [All Fields] AND “imaging” [All Fields]) OR “magnetic resonance imaging” [All Fields] OR “mri” [All Fields]) and t2 [All Fields Figure 1. Flowchart of search result 170 Vol 50 • Number 2 • April 2018 Comparison of deferiprone to deferasirox and deferoxamine to cardiac Joanna Briggs Institute (JBI) critical appraisal can be seen in Table 4. tools (for randomized control trial, cohort and cross-sectional studies