An overview of the efficacy and safety of deferiprone in paediatric patients with congenital haemoglobinopathies and chronic iron overload

References

• Weatherall DJ. Hemoglobinopathies worldwide: present and future. Curr Mol Med. 2008 Nov;8(7):592–599.
   PubMed Web of Science ®Google Scholar
• Bonifazi F, Conte R, Baiardi P, et al.; HTA-THAL Multiregional Registry. Pattern of complications and burden of disease in patients affected by beta thalassaemia major. Curr Med Res Opin. 2017 Aug;33(8):1525–1533.
   PubMed Web of Science ®Google Scholar
• Cappellini MD, Cohen A, Porter J, et al. Guidelines for the management of transfusion dependent thalassaemia (TDT), 3rd Rev 2014. Publishers Thalassaemia International Federation (TIF) Publication N. 20. Available from: https://www.resonancehealth.com/images/files/clinician-information/patient-management-guidelines/TIF%20Guidelines%20for%20the%20Management%20of%20Transfusion%20Dependent%20Thalassaemia.pdf Last access: 20.03.2019
   Google Scholar
• Aydinok Y. Iron chelation therapy as a modality of management. Hematol Oncol Clin. 2018;32(2):261–275.
   PubMed Web of Science ®Google Scholar
• Aydinok Y, Kattamis A, Viprakasit V. Current approach to iron chelation in children. Br J Haematol. 2014 Jun;165(6):745–755.
   PubMed Web of Science ®Google Scholar
• Casale M, Meloni A, Filosa A, et al. Multiparametric cardiac magnetic resonance survey in children with thalassaemia major: a multicenter study. Circ Cardiovasc Imaging. 2015 8;Aug(8):e003230.
   Google Scholar
• Maggio A, Filosa A, Vitrano A, et al. Iron chelation therapy in thalassaemia major: A systematic review with meta-analyses of 1520 patients included on randomised clinical trials. Blood Cells Mol Dis. 2011 Oct 15; 47 (3): 166–75.
   Google Scholar
• Agenzia Italiana del farmaco. Riassunto delle caratteristiche di prodotto desferal. 2016 Jun 10. [cited 2018 Dec 15]. Available from: https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_000114_020417_RCP.pdf&retry=0&sys=m0b1l3
   Google Scholar
• European Medicines Agency (EMA). Annex 1. summary of product characteristics ferriprox. [ cited 2018 Nov 23]. Available from: https://www.ema.europa.eu/en/documents/product-information/ferriprox-epar-product-information_en.pdf
   Google Scholar
• European Medicine Agency (EMA). Annex 1 summary of product characteristics exjade. [ cited 2018 Dec 20]. Available from: https://www.ema.europa.eu/en/documents/product-information/exjade-epar-product-information_en.pdf
   Google Scholar
• Maggio A, D‘Amico G, Morabito A, et al. Deferiprone versus deferoxamine in patients with thalassaemia major: a randomized clinical trial. Blood Cells Mol Dis. 2002 Mar,Apr;28(2):196–198.
   PubMed Web of Science ®Google Scholar
• Galanello R, Kattamis A, Piga A, et al. A prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassaemia. Haematologica. 2006 Sep;91(9):1241–1243.
   PubMed Web of Science ®Google Scholar
• Pennell DJ, Carpenter JP, Roughton M, et al. On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure. J Cardiovasc Magn Reson. 2011;13(1):45.
   PubMedGoogle Scholar
• Maggio A, Vitrano A, Calvaruso G, et al. Serial echocardiographic left ventricular ejection fraction measurements: a tool for detecting thalassemia major patients at risk of cardiac death. Blood Cells Mol Dis. 2013 Apr;50(4):241–246.
   PubMed Web of Science ®Google Scholar
• Kuo HM, Mrkobrada M. A systematic review and meta-analysis of deferiprone monotherapy and in combination with deferoxamine for reduction of iron overload in chronically transfused patients with b-thalassaemia. Hemoglobin. 2014;38(6):409–421.
   PubMed Web of Science ®Google Scholar
• Hider RC, Hoffbrand AV. The role of deferiprone in iron chelation. N Engl J Med. 2018;379:2140–2150.
   PubMed Web of Science ®Google Scholar
• Al-Refaie FN, Sheppard LN, Nortey P, et al. Pharmacokinetics of the oral iron chelator deferiprone (L1) in patients with iron overload. Br J Haematol. 1995;89:403–408.
   PubMed Web of Science ®Google Scholar
• Ceci A, Baiardi P, Felisi M, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol. 2002 Jul;118(1):330–336.
   PubMed Web of Science ®Google Scholar
• Botzenhardt S, Sing CW, Wong IC, et al. Safety profile of oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. Curr Drug Saf. 2016;11(2):137–144.
   PubMed Web of Science ®Google Scholar
• Kwiatkowski JL, Tricta F, Anna Rozova A. Safety of deferiprone in individuals with sickle cell disease. Blood. 2017;130:2249.
   Web of Science ®Google Scholar
• Tricta F, Uetrecht J, Galanello R, et al. Deferiprone-induced agranulocytosis: 20 years of clinical observations. Am J Hematol. 2016 Oct;91(10):1026–1031.
   PubMed Web of Science ®Google Scholar
• Regulation (EC) no 1901/2006 of the European parliament and of the council of 12 December 2006 on medicinal products for paediatric use and amending regulation (EEC) no. 1768/92, Directive No. 2001/20/EC, Directive No. 2001/83/EC and Regulation (EC) No. 726/2004.
   Google Scholar
• DEferiprone Evaluation in Paediatrics (DEEP). Project ID: 261483 Funded under: FP7-HEALTH. [ cited 2018 Nov 24]. Available from: https://cordis.europa.eu/project/rcn/97667_en.html
   Google Scholar
• European Medicines Agency (EMA). Ferriprox. scientific discussion. [ cited 2018 Nov 25]. Available from: https://www.ema.europa.eu/en/documents/scientific-discussion/ferriprox-epar-scientific-discussion_en.pdf
   Google Scholar
• European Medicines Agency Committee for Medicinal Products for Human use (CHMP). Assessment report of ferriprox (EMA/591403/2015) 28 April 2016. [cited: 2018 Nov 15]. Available from: https://www.ema.europa.eu/documents/variation-report/ferriprox-h-c-236-ii-0103-epar-assessment-report-variation_en.pdf
   Google Scholar
• Addis A, Loebstein R, Koren G, et al. Meta-analytic review of the clinical effectiveness of oral deferiprone (L1). Eur J Clin Pharmacol. 1999 Mar;55(1):1–6.
   PubMed Web of Science ®Google Scholar
• Voskaridou E, Douskou M, Terpos E, et al. Deferiprone as an oral iron chelator in sickle cell disease. Ann Hematol. 2005 Jul;84(7):434–440.
   PubMed Web of Science ®Google Scholar
• Cohen AR, Galanello R, Piga A, et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood. 2003 Sep 1;102(5):1583–1587.
   PubMed Web of Science ®Google Scholar
• Al-Refaie FN, De Silva CE, Wonke B, et al. Changes in transferrin saturation after treatment with the oral iron chelator deferiprone in patients with iron overload. J Clin Pathol. 1995 Feb;48(2):110–114.
   PubMed Web of Science ®Google Scholar
• Al-Refaie FN, Hershko C, Hoffbrand AV, et al. Results of long-term deferiprone (L1) therapy: a report by the international study group on oral iron chelators. Br J Haematol. 1995 Sep;91(1):224–229.
   PubMed Web of Science ®Google Scholar
• Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with oral deferiprone in patients with thalassaemia major. N Engl J Med. 1995 Apr;332(14):918–922.
   PubMed Web of Science ®Google Scholar
• Pubmed.gov, US national library of medicine national institutes of health. [ cited 2018 Dec 20]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/
   Google Scholar
• Clinicaltrials.gov, US national library of medicine. [ cited 2018 Dec 20]. Available from: https://clinicaltrials.gov/
   Google Scholar
• EU Clinical Trial Register (EUDRACT). [ cited 2018 Dec 20]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract
   Google Scholar
• The European union electronic register of post-authorisation studies (EU PAS register -ENCEEP). [ cited 2018 Dec 20]. Available from: http://www.encepp.eu/encepp/studySearch.htm
   Google Scholar
• Maggio A, Vitrano A, Capra M, et al. Long-term sequential deferiprone–deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial. Br J Haematol. 2009 Apr;145(2):245–254.
   PubMed Web of Science ®Google Scholar
• Zareifar S, Jabbari A, Cohan N, et al. Efficacy of combined desferrioxamine and deferiprone versus single desferrioxamine therapy in patients with major thalassaemia. Arch Iran Med. 2009 Sep;12(5):488–491.
   PubMed Web of Science ®Google Scholar
• Mirbehbahani N, Jahazi A, Rahim Abad HH. The effect of combined therapy with deferoxamine and deferiprone on serum ferritin level of beta-thalassemic patients. Hematology. 2012 May;17(3):183–186.
   PubMed Web of Science ®Google Scholar
• Shahvazian N, Hashemi A, Farahzadi MH, et al. Combined therapy with deferiprone and desferrioxamine as compared to desferasirox on ventricular function in thalassaemia major patients. Iran J Ped Hematol Oncol. 2012;2(3):103–108.
   Google Scholar
• Ha SY, Chik KW, Ling SC, et al. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassaemia major patients from Hong Kong. Hemoglobin. 2006;30(2):263–274.
   PubMed Web of Science ®Google Scholar
• Balveer K, Pyar K, Wonke B. Combined oral and parenteral iron chelation in beta thalassaemia major. Med J Malaysia. 2000 Dec;55(4):493–497.
   PubMedGoogle Scholar
• Kattamis A, Ladis V, Berdousi H, et al. Iron chelation treatment with combined therapy with deferiprone and deferioxamine: a 12-month trial. Blood Cells Mol Dis. 2006 Jan,Feb;36(1):21–25.
   PubMed Web of Science ®Google Scholar
• Keikhaei B. Combined and alternative iron chelator drugs in treatment of thalassaemia major. Pak J Med Sci. 2011 April;27(3):630–633.
   Web of Science ®Google Scholar
• Aydinok Y, Ulger Z, Nart D, et al. A randomized controlled 1-year study of daily deferiprone plus twice weekly desferrioxamine compared with daily deferiprone monotherapy in patients with thalassaemia major. Haematologica. 2007 Dec;92(12):1599–1606.
   PubMed Web of Science ®Google Scholar
• Aydinok Y, Evans P, Manz CY, et al. Timed non-transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response. Haematologica. 2012 Jun;97(6):835–841.
   PubMed Web of Science ®Google Scholar
• El-Beshlawy A, Manz C, Naja M, et al. Iron chelation in thalassaemia: combined or monotherapy? The Egyptian experience. Ann Hematol. 2008 Jul;87(7):545–550.
   PubMed Web of Science ®Google Scholar
• Athanassiou-Metaxa M, Kousi A, Hatzipantelis ES, et al. Combined chelation therapy with deferiprone and desferrioxamine in iron overloaded beta-thalassaemia patients. Haematologica. 2004 Apr;89(4):ELT07.
   PubMedGoogle Scholar
• Tamaddoni A, Ramezani MS. Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassaemia patients. Iran Red Crescent Med J. 2010 Nov;12(6):655–659.
   Web of Science ®Google Scholar
• Mourad FH, Hoffbrand AV, Sheikh-Taha M, et al. Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Br J Haematol. 2003 Apr;121(1):187–189.
   PubMed Web of Science ®Google Scholar
• Berdoukas V, Carson S, Nord A, et al. Combining two orally active iron chelators for thalassaemia. Ann Hematol. 2010 Nov;89(11):1177–1178.
   PubMed Web of Science ®Google Scholar
• Origa R, Bina P, Agus A, et al. Combined therapy with deferiprone and desferrioxamine in thalassaemia major. Haematologica. 2005 Oct;90(10):1309–1314.
   PubMedGoogle Scholar
• Christoforidis A, Kazantzidou E, Tsatra I, et al. Normal lumbar bone mineral density in optimally treated children and young adolescents with beta-thalassaemia major. Hormones (Athens). 2007 Oct,Dec;6(4):334–340.
   PubMedGoogle Scholar
• Al Hawsawi ZM, Sairafy H, A Tarawah AM, et al. Experience with combination therapy of deferiprone and desferrioxamine in β-thalassaemia major patients with iron overload at maternity and children hospital, Al Madinah Al Munawarah, Saudi Arabia. J Taibah Univ Med Sci. 2010;5(1):27–35.
   Google Scholar
• Farmaki K, Angelopoulos N, Anagnostopoulos G, et al. Effect of enhanced iron chelation therapy on glucose metabolism in patients with beta-thalassaemia major. Br J Haematol. 2006 Aug;134(4):438–444.
   PubMed Web of Science ®Google Scholar
• Totadri S, Bansal D, Bhatia P, et al. The deferiprone and deferasirox combination is efficacious in iron overloaded patients with β-thalassaemia major: A prospective, single center, open-label study. Pediatr Blood Cancer. 2015 Sep;62(9):1592–1596.
   PubMed Web of Science ®Google Scholar
• Daar S, Pathare AV. Combined therapy with desferrioxamine and deferiprone in beta thalassaemia major patients with transfusional iron overload. Ann Hematol. 2006 May;85(5):315–319.
   PubMed Web of Science ®Google Scholar
• Farmaki K, Tzoumari I, Pappa C, et al. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol. 2010 Feb;148(3):466–475.
   PubMed Web of Science ®Google Scholar
• Peng CT, Wu KH, Wu SF, et al. Deferiprone or deferoxamine vs. combination therapy in patients with beta-thalassaemia major: a case study in Taiwan. Hemoglobin. 2006;30(1):125–130.
   PubMed Web of Science ®Google Scholar
• Economou M, Printza N, Teli A, et al. Renal dysfunction in patients with beta-thalassaemia major receiving iron chelation therapy either with deferoxamine and deferiprone or with deferasirox. Acta Haematol. 2010;123(3):148–152.
   PubMed Web of Science ®Google Scholar
• Ricchi P, Ammirabile M, Spasiano A, et al. Combined chelation therapy in thalassaemia major with deferiprone and desferrioxamine: a retrospective study. Eur J Haematol. 2010 Jul;85(1):36–42.
   PubMed Web of Science ®Google Scholar
• Ha SY, Mok AS, Chu WC, et al. Intermediate-term evaluation of a practical chelation protocol based on stratification of thalassemic patients by serum ferritin and magnetic resonance imaging cardiac t2*. Hemoglobin. 2011;35(3):323–331.
   PubMed Web of Science ®Google Scholar
• Ha SY, Mok AS, Chu WC, et al. A practical chelation protocol based on stratification of thalassemic patients by serum ferritin and magnetic resonance imaging cardiac T2*. Hemoglobin. 2009;33(5):323–331.
   PubMed Web of Science ®Google Scholar
• Christoforidis A, Zevgaridou E, Tsatra I, et al. Urinary iron excretion in young thalassemic patients receiving combined chelation treatment with deferoxamine and deferiprone. J Pediatr Hematol Oncol. 2007 Sep;29(9):598–601.
   PubMed Web of Science ®Google Scholar
• Tanphaichitr A, Kusuwan T, Limviriyakul S, et al. Incidence of ototoxicity in pediatric patients with transfusion-dependent thalassaemia who are less well-chelated by mono- and combined therapy of iron chelating agents. Hemoglobin. 2014;38(5):345–350.
   PubMed Web of Science ®Google Scholar
• Abdelrazik N. Pattern of iron chelation therapy in Egyptian beta thalassemic patients: mansoura university children‘s hospital experience. Hematology. 2007;Dec;12(6):577–585.
   PubMed Web of Science ®Google Scholar
• Calvaruso G, Vitrano A, Di Maggio R, et al. Deferiprone versus deferoxamine in sickle cell disease: results from a 5 year long-term Italian multi-center randomized clinical trial. Blood Cells Mol Dis. 2014 Dec;53(4):265–271.
   PubMed Web of Science ®Google Scholar
• Dadheech S, Rao AV, Shaheen U, et al. Three most common nonsynonymous UGT1A6*2 polymorphisms (Thr181Ala, Arg184Ser and Ser7Ala) and therapeutic response to deferiprone in β-thalassaemia major patients. Gene. 2013 Dec 1;531(2):301–305.
   PubMed Web of Science ®Google Scholar
• El-Alfy M, Wali YA, Qari M, et al. Deviating from safety guidelines during deferiprone therapy in clinical practice may not be associated with higher risk of agranulocytosis. Pediatr Blood Cancer. 2014 May;61(5):879–884.
   PubMed Web of Science ®Google Scholar
• Goel H, Girisha KM, Phadke SR. Long-term efficacy of oral deferiprone in management of iron overload in beta thalassaemia major. Hematology. 2008 Apr;13(2):77–82.
   PubMed Web of Science ®Google Scholar
• Hanneman K, Raju VM, Moshonov H, et al. Heterogeneity of myocardial iron distribution in response to chelation therapy in patients with transfusion-dependent anemias. Int J Cardiovasc Imaging. 2013 Oct;29(7):1517–1526.
   PubMed Web of Science ®Google Scholar
• Jamuar SS, Lai AH, Tan AM, et al. Use of deferiprone for iron chelation in patients with transfusion-dependent thalassaemia. J Paediatr Child Health. 2011 Nov;47(11):812–817.
   PubMed Web of Science ®Google Scholar
• Karakukcu C, Karakukcu M, Unal E, et al. Coenzyme Q10 levels in β-thalassaemia and its association with ferritin levels and chelation therapy. Hemoglobin. 2012;36(3):219–229.
   PubMed Web of Science ®Google Scholar
• Kattamis A, Kassou C, Berdousi H, et al. Combined therapy with desferrioxamine and deferiprone in thalassemic patients: effect on urinary iron excretion. Haematologica. 2003 Dec;88(12):1423–1425.
   PubMed Web of Science ®Google Scholar
• Ladis V, Chouliaras G, Berdoukas V, et al. Relation of chelation regimes to cardiac mortality and morbidity in patients with thalassaemia major: an observational study from a large Greek Unit. Eur J Haematol. 2010 Oct;85(4):335–344.
   PubMed Web of Science ®Google Scholar
• Panigrahi I, Marwaha RK, Das RR. Long-term response to deferiprone therapy in Asian Indians. Ann Hematol. 2010 Feb;89(2):135–140.
   PubMed Web of Science ®Google Scholar
• Pantalone GR, Maggio A, Vitrano A, et al. Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassaemia major patients. Hemoglobin. 2011;35(3):206–216.
   PubMed Web of Science ®Google Scholar
• Sajid R, Ghani F, Adil S, et al. Oral iron chelation therapy with deferiprone in patients with thalassaemia major. J Pak Med Assoc. 2009 Jun;59(6):388–390.
   PubMedGoogle Scholar
• Tourkantoni N, Athanassiou-Metaxa M, Zafiriou D, et al. Immune and neural status of thalassemic patients receiving deferiprone or combined deferiprone and deferoxamine chelation treatment. Hemoglobin. 2008;32(1–2):35–40.
   PubMed Web of Science ®Google Scholar
• Peng CT, Chow KC, Chen JH, et al. Safety monitoring of cardiac and hepatic systems in beta-thalassaemia patients with chelating treatment in Taiwan. Eur J Haematol. 2003 Jun;70(6):392–397.
   PubMed Web of Science ®Google Scholar
• Taher A, Chamoun FM, Koussa S, et al. Efficacy and side effects of deferiprone (L1) in thalassaemia patients not compliant with desferrioxamine. Acta Haematol. 1999;101(4):173–177.
   PubMed Web of Science ®Google Scholar
• Borgna-Pignatti C, Cappellini MD, De Stefano P, et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassaemia major. Blood. 2006 May 1;107(9):3733–3737.
   PubMed Web of Science ®Google Scholar
• Piga A, Gaglioti C, Fogliacco E, et al. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassaemia major: a retrospective analysis. Haematologica. 2003 May;88(5):489–496.
   PubMed Web of Science ®Google Scholar
• Wanless IR, Sweeney G, Dhillon AP, et al. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassaemia. Blood. 2002 Sep 1;100(5):1566–1569.
   PubMed Web of Science ®Google Scholar
• Annayev A, Karakaş Z, Karaman S, et al. Glomerular and tubular functions in children and adults withtransfusion-dependent thalassaemia. Turk J Haematol. 2018 Mar 1;35(1):66–70.
   PubMed Web of Science ®Google Scholar
• Uygun V, Kurtoglu E. Iron-chelation therapy with oral chelators in patients with thalassaemia major. Hematology. 2013 Jan;18(1):50–55.
   PubMed Web of Science ®Google Scholar
• Erdoğan E, Canatan D, Ormeci AR, et al. The effects of chelators on zinc levels in patients with thalassaemia major. J Trace Elem Med Biol. 2013 Apr;27(2):109–111.
   PubMed Web of Science ®Google Scholar
• Pepe A, Meloni A, Capra M, et al. Deferasirox, deferiprone and desferrioxamine treatment in thalassaemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica. 2011 Jan;96(1):41–47.
   PubMed Web of Science ®Google Scholar
• Hazirolan T, Eldem G, Unal S, et al. Dual-echo TFE MRI for the assessment of myocardial iron overload in beta-thalassaemia major patients. Diagn Interv Radiol. 2010 Mar;16(1):59–62.
   PubMed Web of Science ®Google Scholar
• Perifanis V, Christoforidis A, Vlachaki E, et al. Comparison of effects of different long-term iron-chelation regimens on myocardial and hepatic iron concentrations assessed with T2* magnetic resonance imaging in patients with beta-thalassaemia major. Int J Hematol. 2007 Dec;86(5):385–389.
   PubMed Web of Science ®Google Scholar
• Wang CH, Wu KH, Tsai FJ, et al. Comparison of oral and subcutaneous iron chelation therapies in the prevention of major endocrinopathies in beta-thalassaemia major patients. Hemoglobin. 2006;30(2):257–262.
   PubMed Web of Science ®Google Scholar
• Wu KH, Chang JG, Ho YJ, et al. Glutathione S-transferase M1 gene polymorphisms are associated with cardiac iron deposition in patients with beta-thalassaemia major. Hemoglobin. 2006;30(2):251–256.
   PubMed Web of Science ®Google Scholar
• Chen AC, Peng CT, Wu SF, et al. Effect of deferiprone on liver iron overload and fibrosis in hepatitis-C-virus-infected thalassaemia. Hemoglobin. 2006;30(2):209–214.
   PubMed Web of Science ®Google Scholar
• Taher A, Sheikh-Taha M, Sharara A, et al. Safety and effectiveness of 100 mg/kg/day deferiprone in patients with thalassaemia major: a two-year study. Acta Haematol. 2005;114(3):146–149.
   PubMed Web of Science ®Google Scholar
• Payne KA, Rofail D, Baladi JF, et al. Iron chelation therapy: clinical effectiveness, economic burden and quality of life in patients with iron overload. Adv Ther. 2008 Aug;25(8):725–742.
   PubMed Web of Science ®Google Scholar
• Ayyub M, Ali W, Anwar M, et al. Efficacy and adverse effects of oral iron chelator deferiprone (l1, 1,2-dimethyl-3-hydroxypyrid-4-one) in patients with beta thalassaemia major in Pakistan. J Ayub Med Coll Abbottabad. 2005 Oct,Dec;17(4):12–15.
   PubMedGoogle Scholar
• Athanassiou-Metaxa M, Tzimouli V, Economou M, et al. Immune status of thalassemic patients receiving deferiprone or combined deferiprone and desferrioxamine chelation treatment. Acta Haematol. 2003;110(4):224–226.
   PubMed Web of Science ®Google Scholar
• Food and Drug administration (FDA). Retrospective assessment of heart failure and survival during iron chelation with deferiprone or deferoxamine in subjects with transfusion dependent ß-thalassaemia LA 12-9907. Center for drug evaluation and research. application number: 021825Orig1s000 medical review(s). [ cited 2018 Nov 03]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/021825Orig1s000MedR.pdf
   Google Scholar
• Food and Drug administration (FDA). Analysis of data from clinical studies of ferriprox to evaluate its efficacy in patients with iron overload for whom previous chelation therapy has been inadequate LA36-0310. center for drug evaluation and research. application number: 021825Orig1s000 medical review(s). [ cited 2018 Nov 03]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/021825Orig1s000MedR.pdf
   Google Scholar
• Karakas Z, Yilmaz Y2, Bayramoglu Z, et al. Magnetic resonance imaging during management of patients with transfusion-dependent thalassaemia: a single-center experience. Radiol Med. 2018 Aug;123(8):572–576.
   PubMed Web of Science ®Google Scholar
• EU Clinical Trials Register. Clinical trials for deferiprone evaluation in paediatrics (DEEP-2) eudract 2012-000353-31. consorzio per valutazioni biologiche e farmacologiche. [ cited 2018 Nov 24]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-000353-31/IT
   Google Scholar
• El-Alfy MS, Sari TT, Lee CL, et al. The safety, tolerability, and efficacy of a liquid formulation of deferiprone in young children with transfusional iron overload. J Pediatr Hematol Oncol. 2010 Nov;32(8):601–605.
   PubMed Web of Science ®Google Scholar
• El-Alfy MS, Adly AM, Wali Y, et al. Efficacy and safety of a novel combination of two oral chelators deferasirox/deferiprone over deferoxamine/deferiprone in severely iron overloaded young beta thalassaemia major patients. Eur J Haematol. 2015 Nov;95(5):411–420.
   PubMed Web of Science ®Google Scholar
• Songdej D, Sirachainan N, Wongwerawattanakoon P, et al. Combined chelation therapy with daily oral deferiprone and twice-weekly subcutaneous infusion of desferrioxamine in children with β-thalassaemia: 3 year experience. Acta Haematol. 2015;133(2):226–236.
   PubMed Web of Science ®Google Scholar
• Aydinok Y, Nisli G, Kavakli K, et al. Sequential use of deferiprone and desferrioxamine in primary school children with thalassaemia major in Turkey. Acta Haematol. 1999;102(1):17–21.
   PubMed Web of Science ®Google Scholar
• Chuansumrit A, Songdej D, Sirachainan N, et al. Safety profile of a liquid formulation of deferiprone in young children with transfusion-induced iron overload: a 1 year experience. Paediatr Int Child Health. 2016 Aug;36(3):209–213.
   PubMed Web of Science ®Google Scholar
• Viprakasit V, Nuchprayoon I, Chuansumrit A, et al. Deferiprone (GPO-L-ONE (®)) monotherapy reduces iron overload in transfusion-dependent thalassaemias: 1 year results from a multicenter prospective, single arm, open label, dose escalating phase III pediatric study (GPO-L-ONE; A001) from Thailand. Am J Hematol. 2013 Apr;88(4):251–260.
   PubMed Web of Science ®Google Scholar
• Naithani R, Chandra J, Sharma S. Safety of oral iron chelator deferiprone in young thalassaemics. Eur J Haematol. 2005 Mar;74(3):217–220.
   PubMed Web of Science ®Google Scholar
• Zachariah M, Tony S, Bashir W, et al. Comparative assessment of deferiprone and deferasirox in thalassaemia major patients in the first two decades-single centre experience. Pediatr Hematol Oncol. 2013 Mar;30(2):104–112.
   PubMed Web of Science ®Google Scholar
• Gomber S, Saxena R, Madan N. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. Indian Pediatr. 2004 Jan;41(1):21–27.
   PubMedGoogle Scholar
• Lucas GN, Perera BJ, Fonseka EA, et al. Experience with the oral iron chelator deferiprone in transfusion-dependent children. Ceylon Med J. 2002 Dec;47(4):119–121.
   PubMedGoogle Scholar
• Waheed N, Ali S, Butt MA. Comparison of deferiprone and deferrioxamine for the treatment of transfusional iron overload in children with beta thalassaemia major. J Ayub Med Coll Abbottabad. 2014 Jul,Sep;26(3):297–300.
   PubMedGoogle Scholar
• Parakh N, Chandra J, Sharma S, et al. Efficacy and safety of combined oral chelation with deferiprone and deferasirox in children with β-thalassaemia major: an experience from North India. J Pediatr Hematol Oncol. 2017 Apr;39(3):209–213.
   PubMed Web of Science ®Google Scholar
• Gomber S, Jain P, Sharma S, et al. Comparative efficacy and safety of oral iron chelators and their novel combination in children with thalassaemia. Indian Pediatr. 2016 Mar;53(3):207–210.
   PubMed Web of Science ®Google Scholar
• Hagag AA, Hamam MA, Taha OA, et al. Therapeutic efficacy of different iron chelators in Egyptian children with beta thalassaemia with iron overload. Infect Disord Drug Targets. 2015;15(2):189–195.
   PubMedGoogle Scholar
• Belen BF, Polat M, Özsevik SN, et al. Frequency of neutropenia among Turkish and Syrian pediatric thalassaemia patients under deferiprone monotherapy. Pediatr Hematol Oncol. 2016 Feb;33(1):51–58.
   PubMed Web of Science ®Google Scholar
• Sharma R, Anand R, Chandra J, et al. Distal ulnar changes in children with thalassaemia and deferiprone related arthropathy. Pediatr Blood Cancer. 2013 Dec;60(12):1957–1962.
   PubMed Web of Science ®Google Scholar
• Taneja R, Malik P, Sharma M, et al. Multiple transfused thalassaemia major: ocular manifestations in a hospital-based population. Indian J Ophthalmol. 2010 Mar,Apr;58(2):125–130.
   PubMed Web of Science ®Google Scholar
• Hagag AA, Elfaragy MS, Elrifaey SM, et al. Therapeutic value of combined therapy with deferiprone and silymarin as iron chelators in Egyptian children with beta thalassaemia major. Infect Disord Drug Targets. 2015;15(3):189–195.
   PubMedGoogle Scholar
• Kellenberger CJ, Schmugge M, Saurenmann T, et al. Radiographic and MRI features of deferiprone-related arthropathy of the knees in patients with beta-thalassaemia. AJR Am J Roentgenol. 2004 Oct;183(4):989–994.
   PubMed Web of Science ®Google Scholar
• D‘Angelo E, Mirra N, Rocca A, et al. Combined therapy with desferrioxamine and deferiprone: a new protocol for iron chelation in thalassaemia. J Pediatr Hematol Oncol. 2004 Jul;26(7):451–453.
   PubMed Web of Science ®Google Scholar
• Choudhry VP, Pati HP, Saxena A, et al. Deferiprone, efficacy and safety. Indian J Pediatr. 2004 Mar;71(3):213–216.
   PubMedGoogle Scholar
• Botzenhardt S, Felisi M, Bonifazi D, et al. Long-term safety of deferiprone treatment in children from the Mediterranean region with beta-thalassaemia major: the DEEP-3 multi-center observational safety study. Haematologica. 2017 Jan;103(1):e1–e4.
   PubMed Web of Science ®Google Scholar
• Ceci A. Evidenze di efficacia e sicurezza dell’uso del Deferiprone in età pediatrica. Personal communication. Miot network - MCO International Group Srl, Miot network: una rete in crescita per il paziente con emoglobinopatia. 15-16 November 2018. Napoli, Hotel Royal Continental.
   Google Scholar
• Bellanti F, Danhof M, Della Pasqua O. Population pharmacokinetics of deferiprone in healthy subjects. Br J Clin Pharmacol. 2014 Dec;78(6):1397–1406.
   PubMed Web of Science ®Google Scholar
• EU Clinical Trials Register. DEferiprone evaluation in paediatrics (DEEP-1) EudraCT 2012-000658-67. consorzio per valutazioni biologiche e farmacologiche. [ cited 2018 Nov 27]. Available from: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-000658-67
   Google Scholar
• Guideline for good clinical practice E6(R2). 1 december 2016 EMA/CHMP/ICH/135/1995 committee for human medicinal products. [ cited 2018 Dec. 15]. Available from: https://www.ema.europa.eu/documents/scientific-guideline/ich-e-6-r1-guideline-good-clinical-practice-step-5_en.pdf
   Google Scholar
• Botzenhardt S, Li N, Chan EW, et al. Safety profiles of iron chelators in young patients with Haemoglobinopathies. Eur J Haematol. 2017 Mar;98(3):198–217.
   PubMed Web of Science ®Google Scholar
• US Food and Drug Administration. FDA briefing document, pediatric advisory committee meeting, march 6, 2017: update on safety issues associated with exjade (deferasirox) use in young children who have fever. [ cited 2018 Dec 15]. Available from: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisory%20Committee/UCM543659.pdf
   Google Scholar
• Bird ST, Swain RS, Tian F, et al. Effects of deferasirox dose and decreasing serum ferritin concentrations on kidney function in paediatric patients: an analysis of clinical laboratory data from pooled clinical studies. Lancet Child Adolesc Health. 2019 Jan;3(1):15–22.
   PubMedGoogle Scholar
• European Medicines Agency (EMA). Opinion/decision on a paediatric investigation plan (PIP): deferiprone. PIP number: EMEA-001126-PIP01-10-M02. Decision date: 21/ Dec/2016, last updated 2017 Feb 03 Consorzio per Valutazioni Biologiche e Farmacologiche. Available from: https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001126-pip01-10-m02.
   Google Scholar
• Ceci A, Baiardi P, Catapano M, et al. Risk factors for death in patients with beta-thalassaemia major: results of a case-control study. Haematologica. 2006 Jan;91(10):1420–1421.
   PubMed Web of Science ®Google Scholar
• Reggiardo G. Deep-2 study: preliminary results. Personal communication. Consorzio per Valutazioni Biologiche e Farmacologiche. DEEP final meeting: preliminary results. 2018 Feb 28 - 2018 Mar 01. Milano, Hilton Hotel.
   Google Scholar
• Kattamis AA, Felisi MG, Reggiardo G, et al. Multicentre, randomized, non-inferiority trial comparing the efficacy of deferiprone versus deferasirox in pediatric patients affected by transfusion-dependent Hemoglobinopathies (DEEP-2 trial). Submitted abstract Amsterdam: 24th Congress of the European Hematology Association (EHA). 13–16 June 2019.
   Google Scholar
• E-MIOT (Extension-Myocardial Iron Overload in Thalassemia). Studio multicentrico, sperimentale, controllato, quinquennale, “no profit” Protocollo di studio n° 709 approvato dal comitato etico area vasta nord-ovest (CEAVNO) in data 8 ottobre 2015. unità operativa complessa risonanza magnetica – pisa - fondazione G. monasterio CNR-regione toscana. [ cited 2019 Apr 05]. Available from: https://emiot.ftgm.it
   Google Scholar