Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease

Hematology/Oncology Clinics of North America

Volumn 28, Issue 4, 2014, Pages 703-727

  Marsella, Maria ^a   Borgna Pignatti, Caterina ^a  

^a UNIVERSITY OF FERRARA   (Italy)

Author keywords

Deferasirox; Deferiprone; Deferoxamine; Iron chelation; Iron overload; Sickle cell disease; Thalassemia major

Indexed keywords

DEFERASIROX; DEFERIPRONE; DEFEROXAMINE; FERRITIN; HEMOGLOBIN S; IRON CHELATING AGENT;

BLOOD TRANSFUSION; ENDOCRINE DISEASE; ERYTHROCYTE TRANSFUSION; ERYTHROPOIESIS; EXCHANGE BLOOD TRANSFUSION; HEART ARRHYTHMIA; HEART FAILURE; HEMOGLOBIN DETERMINATION; HEPATITIS C; HUMAN; IRON ABSORPTION; IRON CHELATION; IRON OVERLOAD; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FAILURE; LIVER FIBROSIS; MEDICATION COMPLIANCE; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RETICULOENDOTHELIAL SYSTEM; REVIEW; SICKLE CELL ANEMIA; THALASSEMIA MAJOR; ADVERSE EFFECTS; ANEMIA, SICKLE CELL; BETA-THALASSEMIA; BONE MARROW TRANSPLANTATION; COMPLICATION;

ANEMIA, SICKLE CELL; BETA-THALASSEMIA; BLOOD TRANSFUSION; BONE MARROW TRANSPLANTATION; HUMANS; IRON CHELATING AGENTS; IRON OVERLOAD;

EID: 84904735205     PISSN: 08898588     EISSN: 15581977     Source Type: Journal    
DOI: 10.1016/j.hoc.2014.04.004     Document Type: Review

References (134)

1. Quinn C.T., Rogers Z.R., Buchanan G.R. Survival of children with sickle cell disease. Blood 2004, 103(11):4023-4027. 10.1182/blood-2003-11-3758.
2. Quinn C.T., Rogers Z.R., McCavit T.L., et al. Improved survival of children and adolescents with sickle cell disease. Blood 2010, 115(17):3447-3452. 10.1182/blood-2009-07-233700.
3. Lee A., Thomas P., Cupidore L., et al. Improved survival in homozygous sickle cell disease: lessons from a cohort study. BMJ 1995, 311(7020):1600-1602. Available at:, Accessed July 11, 2012. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2551498%26tool=pmcentrez%26rendertype=abstract.
4. Serjeant G.R., Serjeant B.E., Mason K.P., et al. The changing face of homozygous sickle cell disease: 102 patients over 60 years. Int J Lab Hematol 2009, 31(6):585-596. 10.1111/j.1751-553X.2008.01089.x.
5. Vichinsky E.P. Current issues with blood transfusions in sickle cell disease. Semin Hematol 2001, 38(1 Suppl 1):14-22. Available at:, Accessed September 22, 2013. http://www.ncbi.nlm.nih.gov/pubmed/11206956.
6. Wahl S., Quirolo K.C. Current issues in blood transfusion for sickle cell disease. Curr Opin Pediatr 2009, 21(1):15-21. 10.1097/MOP.0b013e328321882e.
7. Uchida K., Rackoff W.R., Ohene-Frempong K., et al. Effect of erythrocytapheresis on arterial oxygen saturation and hemoglobin oxygen affinity in patients with sickle cell disease. Am J Hematol 1998, 59(1):5-8. Available at:, Accessed July 12, 2012. http://www.ncbi.nlm.nih.gov/pubmed/9723569.
8. Switzer J.A., Hess D.C., Nichols F.T., et al. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol 2006, 5(6):501-512. 10.1016/S1474-4422(06)70469-0.
9. Dunbar L.N., Coleman Brown L., Rivera D.R., et al. Transfusion practices in the management of sickle cell disease: a survey of Florida hematologists/oncologists. ISRN Hematol 2012, 2012:524513. 10.5402/2012/524513.
10. Hirst C., Williamson L. Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev 2012, (1). [review], CD003149.
11. Vichinsky E.P., Haberkern C.M., Neumayr L., et al. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med 1995, 333(4):206-213. 10.1056/NEJM199507273330402.
12. Brousse V., Elie C., Benkerrou M., et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol 2012, 156(5):643-648. 10.1111/j.1365-2141.2011.08999.x.
13. Al-Salem A.H. Splenic complications of sickle cell anemia and the role of splenectomy. ISRN Hematol 2011, 2011:864257. 10.5402/2011/864257.
14. Booth C., Inusa B., Obaro S.K. Infection in sickle cell disease: a review. Int J Infect Dis 2010, 14(1):e2-e12. 10.1016/j.ijid.2009.03.010.
15. Laurie G.A. Acute chest syndrome in sickle cell disease. Intern Med J 2010, 40(5):372-376. 10.1111/j.1445-5994.2010.02129.x.
16. Miller A.C., Gladwin M.T. Pulmonary complications of sickle cell disease. Am J Respir Crit Care Med 2012, 185(11):1154-1165. 10.1164/rccm.201111-2082CI.
17. Islam M.S., Anoop P. Current concepts in the management of stroke in children with sickle cell disease. Childs Nerv Syst 2011, 27(7):1037-1043. 10.1007/s00381-011-1394-0.
18. Webb J., Kwiatkowski J.L. Stroke in patients with sickle cell disease. Expert Rev Hematol 2013, 6(3):301-316. 10.1586/ehm.13.25.
19. Hiran S. Multiorgan dysfunction syndrome in sickle cell disease. J Assoc Physicians India 2005, 53:19-22. Available at:, Accessed September 26, 2013. http://www.ncbi.nlm.nih.gov/pubmed/15857006.
20. Adams R., McKie V., Hsu L., et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998, 339:5-11. Available at:, Accessed July 10, 2012. http://www.nejm.org/doi/full/10.1056/NEJM199807023390102.
21. Adams R.J., Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005, 353(26):2769-2778. 10.1056/NEJMoa050460.
22. Miller S.T., Wright E., Abboud M., et al. Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia. J Pediatr 2001, 139(6):785-789. 10.1067/mpd.2001.119593.
23. Kalff A., Dowsing C., Grigg A. The impact of a regular erythrocytapheresis programme on the acute and chronic complications of sickle cell disease in adults. Br J Haematol 2010, 149(5):768-774. 10.1111/j.1365-2141.2010.08150.x.
24. Hankins J., Jeng M., Harris S., et al. Chronic transfusion therapy for children with sickle cell disease and recurrent acute chest syndrome. J Pediatr Hematol Oncol 2005, 27(3):158-161. Available at:, Accessed September 28, 2013. http://www.ncbi.nlm.nih.gov/pubmed/15750449.
25. Cho G., Ir H. Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. Cochrane Database Syst Rev 2011, (9). [review], CD008360.
26. Singer S.T., Quirolo K., Nishi K., et al. Erythrocytapheresis for chronically transfused children with sickle cell disease: an effective method for maintaining a low hemoglobin S level and reducing iron overload. J Clin Apheresis 1999, 14(3):122-125. Available at:, Accessed December 7, 2013. http://www.ncbi.nlm.nih.gov/pubmed/10540366.
27. Cappellini M.D., Cohen A.R., Eleftheriou A. Guidelines for the clinical management of thalassemia 2008, Thalassaemia International Federation, Nicosia (Cyprus). 2nd edition.
28. Bracey A.W., Klein H.G., Chambers S., et al. Ex vivo selective isolation of young red blood cells using the IBM-2991 cell washer. Blood 1983, 61(6):1068-1071. Available at:, Accessed December 17, 2013. http://www.ncbi.nlm.nih.gov/pubmed/6839016.
29. Esposito B.P., Breuer W., Sirankapracha P., et al. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood 2003, 102(7):2670-2677. 10.1182/blood-2003-03-0807.
30. Cartwright G.E., Edwards C.Q., Kravitz K., et al. Hereditary hemochromatosis. Phenotypic expression of the disease. N Engl J Med 1979, 301(4):175-179. 10.1056/NEJM197907263010402.
31. King L., Reid M., Forrester T.E. Iron deficiency anaemia in Jamaican children, aged 1-5 years, with sickle cell disease. West Indian Med J 2005, 54(5):292-296. Available at:, Accessed July 14, 2012. http://www.ncbi.nlm.nih.gov/pubmed/16459510.
32. Walter P.B., Harmatz P., Vichinsky E. Iron metabolism and iron chelation in sickle cell disease. Acta Haematol 2009, 122(2-3):174-183. 10.1159/000243802.
33. Walter P.B., Fung E.B., Killilea D.W., et al. Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol 2006, 135(2):254-263. 10.1111/j.1365-2141.2006.06277.x.
34. Vichinsky E., Butensky E., Fung E. Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia. Am J Hematol 2005, 80:70-74. Available at:, Accessed July 10, 2012. http://onlinelibrary.wiley.com/doi/10.1002/ajh.20402/abstract.
35. Marsella M., Borgna-Pignatti C., Meloni A., et al. Cardiac iron and cardiac disease in males and females with transfusion-dependent thalassemia major: a T2* magnetic resonance imaging study. Haematologica 2011, 96(4):515-520. 10.3324/haematol.2010.025510.
36. Borgna-Pignatti C., Rugolotto S., De Stefano P., et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004, 89(10):1187-1193.
37. Telfer P., Coen P.G., Christou S., et al. Survival of medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Haematologica 2006, 91(9):1187-1192.
38. Mokhtar G.M., Gadallah M., El Sherif N.H., et al. Morbidities and mortality in transfusion-dependent beta-thalassemia patients (single-center experience). Pediatr Hematol Oncol 2013, 30(2):93-103. 10.3109/08880018.2012.752054.
39. Au W.Y., Lee V., Lau C.W., et al. A synopsis of current care of thalassaemia major patients in Hong Kong. Hong Kong Med J 2011, 17(4):261-266. Available at:, Accessed April 10, 2014. http://www.ncbi.nlm.nih.gov/pubmed/21813892.
40. Pennell D.J., Udelson J.E., Arai A.E., et al. Cardiovascular function and treatment in β-thalassemia major: a consensus statement from the American Heart Association. Circulation 2013, 128(3):281-308. 10.1161/CIR.0b013e31829b2be6.
41. Inati A., Musallam K.M., Wood J.C., et al. Absence of cardiac siderosis by MRI T2* despite transfusion burden, hepatic and serum iron overload in Lebanese patients with sickle cell disease. Eur J Haematol 2009, 83(6):565-571. 10.1111/j.1600-0609.2009.01345.x.
42. Voskaridou E., Douskou M., Terpos E., et al. Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease. Br J Haematol 2004, 126(5):736-742. 10.1111/j.1365-2141.2004.05104.x.
43. Wood J.C., Tyszka J.M., Carson S., et al. Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease. Blood 2004, 103(5):1934-1936. 10.1182/blood-2003-06-1919.
44. Angelucci E., Muretto P., Nicolucci A., et al. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood 2002, 100(1):17-21.
45. Borgna-Pignatti C., Cappellini M.D., De Stefano P., et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood 2006, 107(9):3733-3737. 10.1182/blood-2005-07-2933.
46. Perifanis V., Tziomalos K., Tsatra I., et al. Prevalence and severity of liver disease in patients with b thalassemia major. A single-institution fifteen-year experience. Haematologica 2005, 90(8):1136-1138. Available at:, Accessed December 10, 2013. http://www.ncbi.nlm.nih.gov/pubmed/16079116.
47. Anderson L.J., Holden S., Davis B., et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001, 22(23):2171-2179.
48. Hankins J., Smeltzer M. Patterns of liver iron accumulation in patients with sickle cell disease and thalassemia with iron overload. Eur J 2010, 85(1):51-57. 10.1111/j.1600-0609.2010.01449.x.Patterns.
49. Hassan M., Hasan S., Giday S., et al. Hepatitis C virus in sickle cell disease. J Natl Med Assoc 2003, 95(10):939-942. Available at:, Accessed November 26, 2013. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2594496%26tool=pmcentrez%26rendertype=abstract.
50. Namasopo S., Ndugwa C., Tumwine J. Hepatitis C and blood transfusion among children attending the Sickle Cell Clinic at Mulago Hospital, Uganda. Afr Health Sci 2013, 13(2):255-260. 10.4314/ahs.v13i2.8.
51. Ejiofor O.S., Ibe B.C., Emodi I.J., et al. The role of blood transfusion on the prevalence of hepatitis C virus antibodies in children with sickle cell anaemia in Enugu, South East Nigeria. Niger J Clin Pract 2009, 12(4):355-358. Available at:, Accessed November 26, 2013. http://www.ncbi.nlm.nih.gov/pubmed/20329670.
52. Fung E.B., Harmatz P.R., Lee P.D., et al. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol 2006, 135(4):574-582. 10.1111/j.1365-2141.2006.06332.x.
53. Cohen A.R., Glimm E., Porter J.B. Effect of transfusional iron intake on response to chelation therapy in beta-thalassemia major. Blood 2008, 111(2):583-587. 10.1182/blood-2007-08-109306.
54. Desferal summary of product characteristics. 3-12. Available at: http://www.pharma.us.novartis.com/product/pi/pdf/desferal.pdf.
55. Ferriprox summary of product characteristics. 1-56. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000236/WC500022050.pdf.
56. Exjade summary of product characteristics. 1-73. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000670/WC500033925.pdf.
57. Olivieri N.F., Koren G., Harris J., et al. Growth failure and bony changes induced by deferoxamine. Am J Pediatr Hematol Oncol 1992, 14(1):48-56.
58. De Virgiliis S., Congia M., Frau F., et al. Deferoxamine-induced growth retardation in patients with thalassemia major. J Pediatr 1988, 113(4):661-669.
59. Cianciulli P., Sorrentino F., Maffei L., et al. Continuous low-dose subcutaneous desferrioxamine (DFO) to prevent allergic manifestations in patients with iron overload. Ann Hematol 1996, 73(6):279-281.
60. Bousquet J., Navarro M., Robert G., et al. Rapid desensitisation for desferrioxamine anaphylactoid reaction. Lancet 1983, 2(8354):859-860.
61. Olivieri N.F., Buncic J.R., Chew E., et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 1986, 314(14):869-873. 10.1056/NEJM198604033141402.
62. Gallant T., Boyden M.H., Gallant L.A., et al. Serial studies of auditory neurotoxicity in patients receiving deferoxamine therapy. Am J Med 1987, 83(6):1085-1090.
63. Davies S., Hungerford J.L., Arden G.B., et al. Ocular toxicity of high-dose intravenous desferrioxamine. Lancet 1983, 322(8343):181-184. 10.1016/S0140-6736(83)90170-8.
64. Borgna-Pignatti C., De Stefano P., Broglia A.M. Visual loss in patient on high-dose subcutaneous desferrioxamine. Lancet 1984, 1(8378):681.
65. Koren G., Bentur Y., Strong D., et al. Acute changes in renal function associated with deferoxamine therapy. Am J Dis Child 1989, 143(9):1077-1080.
66. Koren G., Kochavi-Atiya Y., Bentur Y., et al. The effects of subcutaneous deferoxamine administration on renal function in thalassemia major. Int J Hematol 1991, 54(5):371-375.
67. Robins-Browne R.M., Prpic J.K., Stuart S.J. Yersiniae and iron. A study in host-parasite relationships. Contrib Microbiol Immunol 1987, 9:254-258.
68. Chan G.C., Chan S., Ho P.L., et al. Effects of chelators (deferoxamine, deferiprone and deferasirox) on the growth of Klebsiella pneumoniae and Aeromonas hydrophila isolated from transfusion-dependent thalassemia patients. Hemoglobin 2009, 33(5):352-360. 10.3109/03630260903211888.
69. Cohen A.R., Galanello R., Piga A., et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003, 102(5):1583-1587. 10.1182/blood-2002-10-3280.
70. al-Refaie F.N., Hershko C., Hoffbrand A.V., et al. Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. Br J Haematol 1995, 91(1):224-229. Available at:, Accessed November 28, 2013. http://www.ncbi.nlm.nih.gov/pubmed/7577638.
71. al-Refaie F.N., Wonke B., Wickens D.G., et al. Zinc concentration in patients with iron overload receiving oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one or desferrioxamine. J Clin Pathol 1994, 47(7):657-660.
72. Berkovitch M., Laxer R.M., Inman R., et al. Arthropathy in thalassaemia patients receiving deferiprone. Lancet 1994, 343(8911):1471-1472. Available at:, Accessed November 28, 2013. http://www.ncbi.nlm.nih.gov/pubmed/7911181.
73. Chand G., Chowdhury V., Manchanda A., et al. Deferiprone-induced arthropathy in thalassemia: MRI findings in a case. Indian J Radiol Imaging 2009, 19(2):155-157. 10.4103/0971-3026.50839.
74. Cappellini M.D., Bejaoui M., Agaoglu L., et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up. Blood 2011, 118(4):884-893. 10.1182/blood-2010-11-316646.
75. Vichinsky E., Onyekwere O., Porter J., et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007, 136(3):501-508. 10.1111/j.1365-2141.2006.06455.x.
76. Rafat C., Fakhouri F., Ribeil J.A., et al. Fanconi syndrome due to deferasirox. Am J Kidney Dis 2009, 54(5):931-934. 10.1053/j.ajkd.2009.03.013.
77. Rheault M.N., Bechtel H., Neglia J.P., et al. Reversible Fanconi syndrome in a pediatric patient on deferasirox. Pediatr Blood Cancer 2011, 56(4):674-676. 10.1002/pbc.22711.
78. Wei H.Y., Yang C.P., Cheng C.H., et al. Fanconi syndrome in a patient with β-thalassemia major after using deferasirox for 27 months. Transfusion 2011, 51(5):949-954. 10.1111/j.1537-2995.2010.02939.x.
79. Cappellini M.D. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 2006, 107(9):3455-3462. 10.1182/blood-2005-08-3430.
80. Grandvuillemin A., Audia S., Leguy-Seguin V., et al. Severe thrombocytopenia and mild leucopenia associated with deferasirox therapy. Therapie 2009, 64(6):405-407. [in French].
81. Breuer W., Ronson A., Slotki I.N., et al. The assessment of serum nontransferrin-bound iron in chelation therapy and iron supplementation. Blood 2000, 95(9):2975-2982.
82. Kalpatthi R., Peters B., Kane I., et al. Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease. Pediatr Blood Cancer 2010, 55(7):1338-1342. 10.1002/pbc.22660.
83. Anderson L.J., Westwood M.A., Holden S., et al. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol 2004, 127(3):348-355. 10.1111/j.1365-2141.2004.05202.x.
84. Borgna-Pignatti C., Cohen A. Evaluation of a new method of administration of the iron chelating agent deferoxamine. J Pediatr 1997, 130(1):86-88.
85. Borgna-Pignatti C., Franchini M., Gandini G., et al. Subcutaneous bolus injection of deferoxamine in adult patients affected by onco-hematologic diseases and iron overload. Haematologica 1998, 83(9):788-790.
86. Franchini M., Gandini G., de Gironcoli M., et al. Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood 2000, 95(9):2776-2779.
87. Hoffbrand A.V. Oral iron chelation. Semin Hematol 1996, 33(1):1-8.
88. Lucania G., Vitrano A., Filosa A., et al. Chelation treatment in sickle-cell-anaemia: much ado about nothing?. Br J Haematol 2011, 154(5):545-555. 10.1111/j.1365-2141.2011.08769.x.
89. Gomber S., Saxena R., Madan N. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. Indian Pediatr 2004, 41(1):21-27. Available at:, Accessed December 10, 2013. http://www.ncbi.nlm.nih.gov/pubmed/14767084.
90. ElAlfy M.S., El Alfy M., Sari T.T., 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, 32(8):601-605. 10.1097/MPH.0b013e3181ec0f13.
91. Makis A., Chaliasos N., Alfantaki S., et al. Chelation therapy with oral solution of deferiprone in transfusional iron-overloaded children with hemoglobinopathies. Anemia 2013, 2013:121762. 10.1155/2013/121762.
92. Viprakasit V., Nuchprayoon I., Chuansumrit A., et al. Deferiprone (GPO-L-ONE(®)) monotherapy reduces iron overload in transfusion-dependent thalassemias: 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, 88(4):251-260. 10.1002/ajh.23386.
93. Efficacy/Safety Study of Deferiprone Compared to Deferasirox in Paediatric Patients - Full Text View. Available at: http://clinicaltrial.gov/ct2/show/NCT01825512?term=deferiprone%26rank=16.
94. Voskaridou E., Douskou M., Terpos E., et al. Deferiprone as an oral iron chelator in sickle cell disease. Ann Hematol 2005, 84(7):434-440. 10.1007/s00277-005-1015-7.
95. McLeod C., Fleeman N., Kirkham J., et al. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation. Health Technol Assess 2009, 13(1):iii-iiv. ix-xi, 1-121. 10.3310/hta13010.
96. Piga A., Gaglioti C., Fogliacco E., et al. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica 2003, 88(5):489-496.
97. Ladis V., Chouliaras G., Berdoukas V., et al. Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population. Eur J Haematol 2011, 86(4):332-338. 10.1111/j.1600-0609.2011.01582.x.
98. Pennell D.J., Berdoukas V., Karagiorga M., et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 2006, 107(9):3738-3744. 10.1182/blood-2005-07-2948.
99. Pepe A., Meloni A., Capra M., et al. Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging. Haematologica 2011, 96(1):41-47. 10.3324/haematol.2009.019042.
100. Pennell D.J., Porter J.B., Cappellini M.D., et al. Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with beta-thalassemia major. Haematologica 2012, 97(6):842-848. 10.3324/haematol.2011.049957.
101. Cappellini M.D., Porter J., El-Beshlawy A., et al. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica 2010, 95(4):557-566. 10.3324/haematol.2009.014696.
102. Vichinsky E., Bernaudin F., Forni G.L., et al. Long-term safety and efficacy of deferasirox (Exjade®) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease. Br J Haematol 2011, 154(3):387-397. 10.1111/j.1365-2141.2011.08720.x.
103. Galanello R., Campus S., Origa R. Deferasirox: pharmacokinetics and clinical experience. Expert Opin Drug Metab Toxicol 2012, 8(1):123-134. 10.1517/17425255.2012.640674.
104. Angelucci E., Barosi G., Camaschella C., et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008, 93(5):741-752. 10.3324/haematol.12413.
105. Wood J.C., Origa R., Agus A., et al. Onset of cardiac iron loading in pediatric patients with thalassemia major. Haematologica 2008, 93(6):917-920. 10.3324/haematol.12513.
106. Fernandes J.L., Fabron A., Verissimo M. Early cardiac iron overload in children with transfusion-dependent anemias. Haematologica 2009, 94(12):1776-1777. 10.3324/haematol.2009.013193.
107. Borgna-Pignatti C., Meloni A., Guerrini G., et al. Myocardial iron overload in thalassaemia major. How early to check?. Br J Haematol 2013, 10.1111/bjh.12643.
108. Berdoukas V., Nord A., Carson S., et al. Tissue iron evaluation in chronically transfused children shows significant levels of iron loading at a very young age. Am J Hematol 2013, 88(11):E283-E285. 10.1002/ajh.23543.
109. Neufeld E.J., Galanello R., Viprakasit V., et al. A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload. Blood 2012, 119(14):3263-3268. 10.1182/blood-2011-10-386268.
110. Link G., Konijn A.M., Breuer W., et al. Exploring the "iron shuttle" hypothesis in chelation therapy: effects of combined deferoxamine and deferiprone treatment in hypertransfused rats with labeled iron stores and in iron-loaded rat heart cells in culture. J Lab Clin Med 2001, 138(2):130-138. 10.1067/mlc.2001.116487.
111. Alpendurada F., Smith G.C., Carpenter J.-P., et al. Effects of combined deferiprone with deferoxamine on right ventricular function in thalassaemia major. J Cardiovasc Magn Reson 2012, 14:8. 10.1186/1532-429X-14-8.
112. Tanner M.A., Galanello R., Dessi C., et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation 2007, 115(14):1876-1884. 10.1161/CIRCULATIONAHA.106.648790.
113. Daar S., Pathare A.V. Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload. Ann Hematol 2006, 85(5):315-319. 10.1007/s00277-005-0075-z.
114. 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, 148(3):466-475. 10.1111/j.1365-2141.2009.07970.x.
115. Maggio A., Vitrano A., Capra M., et al. Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies. Blood Cells Mol Dis 2009, 42(3):247-251. 10.1016/j.bcmd.2009.01.002.
116. Lai M.E., Grady R.W., Vacquer S., et al. Increased survival and reversion of iron-induced cardiac disease in patients with thalassemia major receiving intensive combined chelation therapy as compared to desferoxamine alone. Blood Cells Mol Dis 2010, 45(2):136-139. 10.1016/j.bcmd.2010.05.005.
117. Telfer P.T., Warburton F., Christou S., et al. Improved survival in thalassemia major patients on switching from desferrioxamine to combined chelation therapy with desferrioxamine and deferiprone. Haematologica 2009, 94(12):1777-1778. 10.3324/haematol.2009.009118.
118. Grady R.W., Galanello R., Randolph R.E., et al. Toward optimizing the use of deferasirox: potential benefits of combined use with deferoxamine. Haematologica 2013, 98(1):129-135. 10.3324/haematol.2012.070607.
119. Voskaridou E., Komninaka V., Karavas A., et al. Combination therapy of deferasirox and deferoxamine shows significant improvements in markers of iron overload in a patient with β-thalassemia major and severe iron burden. Transfusion 2013, 10.1111/trf.12335.
120. Voskaridou E., Christoulas D., Terpos E. Successful chelation therapy with the combination of deferasirox and deferiprone in a patient with thalassaemia major and persisting severe iron overload after single-agent chelation therapies. Br J Haematol 2011, 154(5):654-656. 10.1111/j.1365-2141.2011.08626.x.
121. Berdoukas V., Carson S., Nord A., et al. Combining two orally active iron chelators for thalassemia. Ann Hematol 2010, 89(11):1177-1178. 10.1007/s00277-010-0933-1.
122. 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.
123. 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 thalassemia. Haematologica 2006, 91(9):1241-1243.
124. Pantalone G.R., 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 -thalassemia major patients. Hemoglobin 2011, 35(3):206-216. 10.3109/03630269.2011.570674.
125. Balocco M., Carrara P., Pinto V., et al. Daily alternating deferasirox and deferiprone therapy for "hard-to-chelate" beta-thalassemia major patients. Am J Hematol 2010, 85(6):460-461. 10.1002/ajh.21711.
126. Delea T.E., Edelsberg J., Sofrygin O., et al. Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review. Transfusion 2007, 47(10):1919-1929. 10.1111/j.1537-2995.2007.01416.x.
127. Alvarez O., Rodriguez-Cortes H., Robinson N., et al. Adherence to deferasirox in children and adolescents with sickle cell disease during 1-year of therapy. J Pediatr Hematol Oncol 2009, 31(10):739-744. 10.1097/MPH.0b013e3181b53363.
128. Yesilipek M.A., Karasu G., Kazik M., et al. Posttransplant oral iron-chelating therapy in patients with beta-thalassemia major. Pediatr Hematol Oncol 2010, 27(5):374-379. 10.3109/08880011003739463.
129. Li C.K., Lai D.H., Shing M.M., et al. Early iron reduction programme for thalassaemia patients after bone marrow transplantation. Bone Marrow Transplant 2000, 25(6):653-656. 10.1038/sj.bmt.1702212.
130. Giardini C., Galimberti M., Lucarelli G., et al. Desferrioxamine therapy accelerates clearance of iron deposits after bone marrow transplantation for thalassaemia. Br J Haematol 1995, 89(4):868-873. Available at:, Accessed December 7, 2013. http://www.ncbi.nlm.nih.gov/pubmed/7772524.
131. Mariotti E., Angelucci E., Agostini A., et al. Evaluation of cardiac status in iron-loaded thalassaemia patients following bone marrow transplantation: improvement in cardiac function during reduction in body iron burden. Br J Haematol 1998, 103(4):916-921. Available at:, Accessed December 7, 2013. http://www.ncbi.nlm.nih.gov/pubmed/9886301.
132. Karnon J., Tolley K., Vieira J., et al. Lifetime cost-utility analyses of deferasirox in beta-thalassaemia patients with chronic iron overload: a UK perspective. Clin Drug Investig 2012, 32(12):805-815. 10.1007/s40261-012-0008-2.
133. Bentley A., Gillard S., Spino M., et al. Cost-utility analysis of deferiprone for the treatment of β-thalassaemia patients with chronic iron overload: a UK perspective. Pharmacoeconomics 2013, 10.1007/s40273-013-0101-2.
134. Modell B., Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008, 86(6):480-487. Available at:, Accessed December 7, 2013. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid52647473&tool5pmcentrez&rendertype5abstract.