Oral Iron Chelators

Pediatric Clinics of North America

Volumn 55, Issue 2, 2008, Pages 461-482

  Kwiatkowski, Janet L ^a,b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DEFERASIROX; DEFERIPRONE; DEFERITRIN; DEFEROXAMINE; IRON; IRON CHELATE;

ABDOMINAL PAIN; AGRANULOCYTOSIS; ALLERGIC REACTION; ARTHRALGIA; BONE DISEASE; BRAIN DISEASE; CHELATION THERAPY; CONTINUOUS INFUSION; CREATININE BLOOD LEVEL; DRUG EFFICACY; DRUG HALF LIFE; DRUG WITHDRAWAL; EAR DISEASE; EYE DISEASE; GASTROINTESTINAL SYMPTOM; HEMOCHROMATOSIS; HUMAN; IRON OVERLOAD; LUNG DISEASE; MONOTHERAPY; NAUSEA; NEUTROPENIA; NONHUMAN; NORTH AMERICA; PATIENT CARE; PROTEINURIA; RASH; REVIEW; SIDE EFFECT; THALASSEMIA; VOMITING;

ADMINISTRATION, ORAL; BENZOIC ACIDS; CHELATING AGENTS; CHILD; DEFEROXAMINE; ERYTHROCYTE TRANSFUSION; HUMANS; IRON OVERLOAD; PYRIDONES; SIDEROPHORES; TRIAZOLES;

EID: 41349117246     PISSN: 00313955     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pcl.2008.01.005     Document Type: Review

References (97)

1. Adams R.J., McKie V.C., 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 339 (1998) 5-11
2. Lieu P.T., Heiskala M., Peterson P.A., et al. The roles of iron in health and disease. Mol Aspects Med 22 1-2 (2001) 1-87
3. Hugman A. Hepcidin: an important new regulator of iron homeostasis. Clin Lab Haematol 28 2 (2006) 75-83
4. Bridle K.R., Frazer D.M., Wilkins S.J., et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361 9358 (2003) 669-673
5. Wallace D.F., and Subramaniam V.N. Non-HFE haemochromatosis. World J Gastroenterol 13 35 (2007) 4690-4698
6. Breuer W., Hershko C., and Cabantchik Z.I. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci 23 (2000) 185-192
7. Kushner J.P., Porter J.P., and Olivieri N.F. Secondary iron overload. Hematology Am Soc Hematol Educ Program (2001) 47-61
8. 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 135 4 (2006) 574-582
9. Wood J.C., Tyszka M., Carson S., et al. Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease. Blood 103 5 (2004) 1934-1936
10. Zurlo M.G., De Stefano P., Borgna-Pignatti C., et al. Survival and causes of death in thalassaemia major. Lancet 2 (1989) 27-30
11. Jean G., Terzoli S., Mauri R., et al. Cirrhosis associated with multiple transfusions in thalassaemia. Arch Dis Child 59 1 (1984) 67-70
12. Borgna-Pignatti C., De Stefano P., Zonta L., et al. Growth and sexual maturation in thalassemia major. J Pediatr 106 (1985) 150-155
13. Cunningham M.J., Macklin E.A., Neufeld E.J., et al. Complications of beta-thalassemia major in North America. Blood 104 1 (2004) 34-39
14. Brittenham G.M., Cohen A.R., McLaren C.E., et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 42 (1993) 81-85
15. Cappellini M.D., Cohen A., Piga A., et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 107 9 (2006) 3455-3462
16. 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 136 3 (2007) 501-508
17. Olivieri N.F., Nathan D.G., MacMillan J.H., et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med 331 9 (1994) 574-578
18. Telfer P.T., Prestcott E., Holden S., et al. Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol 110 4 (2000) 971-977
19. Files B., Brambilla D., Kutlar A., et al. Longitudinal changes in ferritin during chronic transfusion: a report from the Stroke Prevention Trial in Sickle Cell Anemia (STOP). J Pediatr Hematol Oncol 24 4 (2002) 284-290
20. 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 49 3 (2007) 329-332
21. Angelucci E., Brittenham G.M., McLaren C.E., et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 343 5 (2000) 327-331
22. Olivieri N.F., and Brittenham G.M. Iron-chelating therapy and the treatment of thalassemia. Blood 89 3 (1997) 739-761
23. Olivieri N.F. The beta-thalassemias. N Engl J Med 341 2 (1999) 99-109
24. Villeneuve J.P., Bilodeau M., Lepage R., et al. Variability in hepatic iron concentration measurement from needle-biopsy specimens. J Hepatol 25 2 (1996) 172-177
25. *) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 22 23 (2001) 2171-2179
26. * cardiovascular magnetic resonance. Br J Haematol 127 3 (2004) 348-355
27. Brittenham G.M., Farrell D.E., Harris J.W., et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med 307 27 (1982) 1671-1675
28. Galanello R., Piga A., Forni G.L., et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major. Haematologica 91 10 (2006) 1343-1351
29. Piga A., Galanello R., Forni G.L., et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 91 7 (2006) 873-880
30. Olivieri N.F., Brittenham G.M., Matsui D., et al. Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med 332 14 (1995) 918-922
31. Brittenham G.M., and Badman D.G. Noninvasive measurement of iron: report of an NIDDK workshop. Blood 101 1 (2003) 15-19
32. St. Pierre T.G., Clark P.R., Chua-Anusorn W., et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 105 2 (2005) 855-861
33. * cardiovascular magnetic resonance for early detection of myocardial iron overload in thalassemia major. J Magn Reson Imaging 22 2 (2005) 229-233
34. Wood J.C. Magnetic resonance imaging measurement of iron overload. Curr Opin Hematol 14 3 (2007) 183-190
35. Clark P.R., Chua-Anusorn W., and St. Pierre T.G. Proton transverse relaxation rate (R2) images of iron-loaded liver tissue; mapping local tissue iron concentrations with MRI. Magnet Reson Med 49 (2003) 572-575
36. * mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood 106 4 (2005) 1460-1465
37. Brittenham G.M., Griffith P.M., Nienhuis A.W., et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 331 9 (1994) 567-573
38. Lee P., Mohammed N., Marshall L., et al. Intravenous infusion pharmacokinetics of desferrioxamine in thalassaemic patients. Drug Metab Disp 21 (1993) 640-644
39. Pippard M.J., Letsky E.A., Callender S.T., et al. Prevention of iron loading in transfusion-dependent thalassaemia. Lancet 1 8075 (1978) 1178-1181
40. Barry M., Flynn D.M., Letsky E.A., et al. Long-term chelation therapy in thalassaemia major: effect on liver iron concentration, liver histology, and clinical progress. Br Med J 2 (1974) 16-20
41. Wolfe L., Oliveri N., Sallan D., et al. Prevention of cardiac disease by sucutaneous deferoxamine in patients with thalassemia major. N Engl J Med 312 25 (1985) 1600-1603
42. Davis B.A., and Porter J.B. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia. Blood 95 4 (2000) 1229-1236
43. Olivieri N.F., Buncic J.R., Chew E., et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 314 14 (1986) 869-873
44. De Sanctis V., Pinamonti A., DiPalma A., et al. Growth and development in thalassemia major patients with severe bone lesions due to desferrioxamine. Eur J Pediatr 155 (1996) 368-372
45. Porter J.B., Jaswon M.S., Huehns E.R., et al. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol 73 73 (1989) 403-409
46. Freedman M.H., Grisaru D., Oliveri N., et al. Pulmonary syndrome in patients with thalassemia major receiving intravenous deferoxamine infusions. Am J Dis Child 144 (1990) 565-569
47. Borgna-Pignatti C., Rugolotto S., DeStefano P., et al. Survival and disease complications in thalassemia major. Ann N Y Acad Sci 850 (1998) 227-231
48. Ceci A., Baiardi P., Catapano M., et al. Risk factors for death in patients with beta-thalassemia major: results of a case-control study. Haematologica 91 10 (2006) 1420-1421
49. Al-Refaie F.N., Sheppard L.N., Nortey P., et al. Pharmacokinetics of the oral iron chelator deferiprone (L1) in patients with iron overload. Br J Haematol 89 2 (1995) 403-408
50. Matsui D., Klein J., and Hermann C. Relationship between the pharmacokinetics and iron excretion of the new oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-1 in patients with thalassemia. Clin Pharmacol Ther 50 (1991) 294-298
51. Al-Refaie F.N., Wonke B., Hoffbrand A.V., et al. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major. Blood 80 3 (1992) 593-599
52. Collins A.F., Fassos F.F., Stobie S., et al. Iron-balance and dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease. Blood 83 8 (1994) 2329-2333
53. Olivieri N.F., Koren G., Hermann C., et al. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. Lancet 336 8726 (1990) 1275-1279
54. Agarwal M.B., Gupte S.S., Viswanathan C., et al. Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion dependent thalassaemia: Indian trial. Br J Haematol 82 2 (1992) 460-466
55. Wonke B., Wright C., and Hoffbrand A.V. Combined therapy with deferiprone and desferrioxamine. Br J Haematol 103 4 (1998) 361-364
56. Kersten M.J., Lange R., Smeets M.E., et al. Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial. Ann Hematol 73 5 (1996) 247-252
57. Maggio A., D'Amico G., Morabito A., et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis 28 2 (2002) 196-208
58. Voskaridou E., Douskou M., Terpos E., et al. Deferiprone as an oral iron chelator in sickle cell disease. Ann Hematol 84 7 (2005) 434-440
59. Cohen A.R., Galanello R., Piga A., et al. Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 108 2 (2000) 305-312
60. 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 Haematol 91 1 (1995) 224-229
61. 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 118 1 (2002) 330-336
62. Hoffbrand A.V., Al-Refaie F., Davis B., et al. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood 91 1 (1998) 295-300
63. Cohen A.R., Galanello R., Piga A., et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 102 5 (2003) 1583-1587
64. Mazza P., Amurri B., Lazzari G., et al. Oral iron chelating therapy. A single center interim report on deferiprone (L1) in thalassemia. Haematologica 83 6 (1998) 496-501
65. Olivieri N.F., Brittenham G.M., McLaren C.E., et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 339 7 (1998) 417-423
66. 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 107 9 (2006) 3738-3744
67. Gomber S., Saxena R., and Madan N. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. Indian Pediatr 41 1 (2004) 21-27
68. Taher A., Sheikh-Taha M., Sharara A., et al. Safety and effectiveness of 100 mg/kg/day deferiprone in patients with thalassemia major: a two-year study. Acta Haematol 114 3 (2005) 146-149
69. Anderson L.J., Wonke B., Prescott E., et al. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassaemia. Lancet 360 9332 (2002) 516-520
70. 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 107 9 (2006) 3733-3737
71. 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 88 5 (2003) 489-496
72. Galia M., Midiri M., Bartolotta V., et al. Potential myocardial iron content evaluation by magnetic resonance imaging in thalassemia major patients treated with Deferoxamine or Deferiprone during a randomized multicenter prospective clinical study. Hemoglobin 27 2 (2003) 63-76
73. Peng C.T., Chow K.C., Chen J.H., et al. Safety monitoring of cardiac and hepatic systems in beta-thalassemia patients with chelating treatment in Taiwan. Eur J Haematol 70 6 (2003) 392-397
74. Al-Refaie F.N., Wonke B., and Hoffbrand A.V. Deferiprone-associated myelotoxicity. Eur J Haematol 53 5 (1994) 298-301
75. Henter J.I., and Karlen J. Fatal agranulocytosis after deferiprone therapy in a child with Diamond-Blackfan anemia. Blood 109 12 (2007) 5157-5159
76. Hoffbrand A.V., Bartlett A.N., Veys P.A., et al. Agranulocytosis and thrombocytopenia in patient with Blackfan-Diamond anaemia during oral chelator trial. Lancet 2 8660 (1989) 457
77. Tondury P., Zimmerman A., Nielsen P., et al. Liver iron and fibrosis during long-term treatment with deferiprone in Swiss thalassaemic patients. Br J Haematol 101 3 (1998) 413-415
78. Wanless I.R., Sweeney G., Dhillon A.P., et al. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood 100 5 (2002) 1566-1569
79. Origa R., Bina P., Agus A., et al. Combined therapy with deferiprone and desferrioxamine in thalassemia major. Haematologica 90 10 (2005) 1309-1314
80. 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 36 1 (2006) 21-25
81. Breuer W., Ermers M.J.J., Pootrakul P., et al. Desferrioxamine-chelatable iron, a component of serum non-transferrin-bound iron, used for assessing chelation therapy. Blood 97 3 (2001) 792-798
82. 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 138 2 (2001) 130-138
83. 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 115 14 (2007) 1876-1884
84. Galanello R., Piga A., Alberti D., et al. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol 43 6 (2003) 565-572
85. Nisbet-Brown E., Olivieri N.F., Giardina P.J., et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 361 9369 (2003) 1597-1602
86. Porter J., Galanello R., Saglio G., et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-year prospective study. Eur J Haematol 80 2 (2008) 168-176
87. Cohen A.R., Glimm E., and Porter J.B. Effect of transfusional iron intake on response to chelation therapy in beta-thalassemia major. Blood 111 2 (2008) 583-587
88. Glickstein H., El R.B., Link G., et al. Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences. Blood 108 9 (2006) 3195-3203
89. Wood J.C., Otto-Duessel M., Gonzalez I., et al. Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil. Transl Res 148 5 (2006) 272-280
90. * in transfusion dependent anemias receiving ICL670 (deferasirox). Blood 106 11 (2005) 1003a
91. Cappellini M.D., Bejaoui M., Agaoglu L., et al. Prospective evaluation of patient-reported outcomes during treatment with deferasirox or deferoxamine for iron overload in patients with beta-thalassemia. Clin Ther 29 5 (2007) 909-917
92. Barton J.C. Drug evaluation: Deferitrin for iron overload disorders. IDrugs 10 7 (2007) 480-490
93. Donovan J.M., Yardumian A., Gunawardena K.A., et al. The safety and pharmacokinetics of deferitrin, a novel orally available iron chelator. Blood 104 11 (2004) 146a
94. Link G., Ponka P., Konijn A.M., et al. Effects of combined chelation treatment with pyridoxal isonicotinoyl hydrazone analogs and deferoxamine in hypertransfused rats and in iron-loaded rat heart cells. Blood 101 10 (2003) 4172-4179
95. Brittenham G.M. Pyridoxal isonicotinoyl hydrazone: an effective iron-chelator after oral administration. Semin Hematol 27 2 (1990) 112-116
96. Cohen A.R., Galanello R., Pennell D.J., et al. Thalassemia. Hematology Am Soc Hematol Educ Program (2004) 14-34
97. Vichinsky E. Consensus document for transfusion-related iron overload. Semin Hematol 38 Suppl 1 (2001) 2-4