DEFERASIROX: OVER A DECADE OF EXPERIENCE IN THALASSEMIA
Main Article Content
Keywords
iron overload, iron chelation therapy, transfusion dependent thalassemia, non-transfusion dependent thalassemia, serum ferritin, liver iron concentration, deferasirox
Abstract
Thalassemia incorporates a broad clinical spectrum characterized by decreased or absent production of normal hemoglobin leading to decreased red blood cell survival and ineffective erythropoiesis. Chronic iron overload remains an inevitable complication resulting from regular blood transfusions (transfusion-dependent) and/or increased iron absorption (mainly non-transfusion-dependent thalassemia), requiring adequate treatment to prevent the significant associated morbidity and mortality. Iron chelation therapy has become a cornerstone in the management of thalassemia patients, leading to improvements in their outcome and quality of life. Deferasirox, an oral iron chelating agent is approved for use in transfusion dependent and non-transfusion-dependent thalassemia and has shown excellent efficacy in this setting. We herein present an updated review of the role of deferasirox in thalassemia, exploring over a decade of experience, which has documented its effectiveness and convenience; in addition to its manageable safety profile.
Keywords: iron overload, iron chelation therapy, transfusion-dependent thalassemia, non-transfusion dependent thalassemia, serum ferritin, liver iron concentration, deferasirox
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References
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2. Giardina P, Forget B. Thalassemia syndromes. In: Hoffman R, Benz E, Shattil S, et al, eds. Hematology: Basic Principles and Practice (5th ed). Philadelphia, PA: Churchill Livingstone; 2008:535-563.
3. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010; 115 (22):4331-4336.
4. Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major. Haematologica. 2006; 91(10): 1343-1351.
5. Borgna-Pignatti C, Rugolotto S, De Stefano P, Piga A, Di Gregorio F, Gamberini MR, Sabato V, Melevendi C, Cappellini MD, Verlato G. Survival and disease complications in thalassemia major. Ann N Y Acad Sci 1998; 850:227–31.
6. Taher AT, Saliba AN. Iron overload in thalassemia: different organs at different rates. Hematology Am Soc Hematol Educ Program 2017; 2017(1):265-71.
7. Saliba A, Taher A. Iron overload in transfusion-dependent thalassemia. Hematology (Amsterdam, Netherlands). 2015;20(5):311-2.
8. In: rd, Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V, editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). Nicosia (CY): Thalassaemia International Federation (c) 2014 Thalassaemia International Federation.; 2014.
9. Taher AT, Musallam KM, Wood JC, Cappellini MD. Magnetic resonance evaluation of hepatic and myocardial iron deposition in transfusion-independent thalassemia intermedia compared to regularly transfused thalassemia major patients. American journal of hematology. 2010;85(4):288-90.
10. Pootrakul P, Kitcharoen K, Yansukon P, Wasi P, Fucharoen S, Charoenlarp P, et al. The effect of erythroid hyperplasia on iron balance. Blood. 1988;71(4):1124-9.
11. Tanno T, Miller JL. Iron Loading and Overloading due to Ineffective Erythropoiesis. Adv Hematol. 2010;2010:358283.
12. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(11):7811-9.
13. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425-33.
14. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090-3.
15. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110(7):1037-44.
16. Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007;92(5):583-8.
17. Camaschella C, Nai A. Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. Br J Haematol. 2016;172(4):512-23.
18. Musallam KM, Taher AT, Duca L, Cesaretti C, Halawi R, Cappellini MD. Levels of growth differentiation factor-15 are high and correlate with clinical severity in transfusion-independent patients with beta thalassemia intermedia. Blood Cells Mol Dis. 2011;47(4):232-4.
19. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096-101.
20. Tanno T, Porayette P, Sripichai O, Noh SJ, Byrnes C, Bhupatiraju A, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114(1):181-6.
21. Taher A, El Rassi F, Isma’eel H, et al. Correlation of liver iron concentration determined by R2 magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia. Haematologica. 2008;93(10):1584–1586.
22. Pakbaz Z, Fischer R, Fung E, et al. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr Blood Cancer. 2007;49(3):329–332).
23. Cheng HL, Holowka S, Moineddin R, et al. Liver iron overload assessment by t *2 magnetic resonance imaging in pediatric patients: an accuracy and reproducibility study. Am J Hematol. 2012;87(4):435–437.
24. Kirk P, Roughton M, Porter JB, et al. Cardiac t2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation. 2009;120(20):1961–1968.
25. Aubart M, ou P, Elie C et al. Longitudinal MRI and Ferritin Monitoring of Iron Overload in Chronically Transfused and Chelated Children With Sickle Cell Anemia and Thalassemia Major. J Pediatr Hematol Oncol 2016; 38: 497-502.
26. Porter J, Elalfy M, taher A et al. Limitations of serum ferritin to predict liver iron concentration responses to deferasirox therapy in patients with transfusion-dependent thalassaemia. Eur J Hematol 2016; 98: 280-288.
27. Saliba A, El Rassi F, Taher A. Clinical monitoring and management of complications related to chelation therapy in patients with ?-thalassemia. Expert Review of Hematology, 9:2, 151-168.
28. Cappellini MD, Taher A. Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload. Expert Opin Pharmacother. 2008; 9(13): 2391-2402.
29. Nick H. Deferasirox (Exjade®, ICL670) Preclinical overview. Semin Hematol .2007; 44: S12-15.
30. Daar S, Pathare A, Nick H, et al. Reduction in labile plasma iron during treatment with deferasirox, a once-daily oral iron chelator, in heavily iron-overloaded patients with beta-thalassaemia. Eur J Haematol. 2009; 82(6): 454-457.
31. Waldmeier F, Bruin GJ, Glaenzel U, et al. Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos. 2010; 38(5): 808-816.
32. Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem. 2003; 10(12):1065-1076.
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