Prevention of Iron Overload and Long Term Maintenance of Normal Iron Stores in Thalassaemia Major Patients using Deferiprone or Deferiprone Deferoxamine Combination

Abstract

Background

Decrease in mortality and morbidity is observed in thalassaemia major patients with reduced iron load in comparison to heavy iron loaded patients. Effective and complete treatment of transfusional iron overload can be achieved by chelation protocols that can eliminate excess iron and maintain normal iron stores (NIS).

Methods

The maintenance of NIS, i. e., serum ferritin (350 μg/L >), MRI T2* cardiac (>20 ms) and liver (>6.3 ms) relaxation time levels was monitored in 16 thalassaemia major patients (32–53 years, 12 splenectomized, 10 male, erythrocyte transfusions 120–323 ml/kg/year) for about 90 patient years. The patients were treated with individualised tailor-made deferiprone or deferiprone/deferoxamine combination protocols.

Results

In 8 patients deferiprone (50–100 mg/kg/day) was sufficient for maintaining NIS and withdrawal of deferiprone for 28 months in total was necessary in 4 patients for preventing iron deficiency. In 3 other patients intermittent deferoxamine (50–75 mg/kg/8–30 h, 1–4 days/week) in combination with deferiprone (75–100 mg/kg/day) was sufficient for maintaining NIS. In the remaining 5 patients deferiprone (75–100 mg/kg/day) and deferoxamine (50–60 mg/kg/8–15 h, 1–7 days/week) combination was used for maintaining NIS, as a result of increased transfusions which were caused mainly by splenomegaly and infections. No toxic side effects were detected during the study. Lower chelation doses were used for the maintenance of NIS in comparison to iron loaded categories of patients.

Conclusion

The safe maintenance of NIS using deferiprone and deferiprone/deferoxamine combinations should be considered as an optimum therapy for the complete treatment of iron overload in the majority of thalassaemia patients.

Key words

thalassaemia major - iron overload - normalization of iron stores - prevention of iron overload - deferoxamine - deferiprone - combination therapy

• References

• 1 Olivieri NF, Koren G, Matsui D. et al. Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia. Blood 1992; 79: 2741-2748
• 2 Kolnagou A, Kleanthous M, Kontoghiorghes GJ. Reduction of body iron stores to normal range levels in thalassaemia by using a deferiprone/deferoxamine combination and their maintenance thereafter by deferiprone monotherapy. Eur J Haematol 2010; 85: 430-438
• 3 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: 466-475
• 4 Tanner MA, 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: 1876-1884
• 5 Kolnagou A, Kleanthous M, Kontoghiorghes GJ. Efficacy, compliance and toxicity factors are affecting the rate of normalization of body iron stores in thalassemia patients using the deferiprone and deferoxamine combination therapy. Hemoglobin 2011; 35: 186-198
• 6 Kolnagou A, Kontoghiorghes GJ. Effective combination therapy of deferiprone and deferoxamine for the rapid clearance of excess cardiac iron and the prevention of heart disease in thalassemia. The protocol of the International Committee on Oral Chelators. Hemoglobin 2006; 30: 239-249
• 7 Tanner MA, Galanello R, Dessi C. et al. Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. J Cardiovasc Magn Reson 2008; 10: 12
• 8 Maggio A, Vitrano A, Lucania G. et al. Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients. Am J Hematol 2012; 87: 732-733
• 9 Anderson LJ, 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 2002; 360: 516-520
• 10 Kolnagou A, Michaelides Y, Kontos C. et al. Myocyte damage and loss of myofibers is the potential mechanism of iron overload toxicity in congestive cardiac failure in thalassemia. Complete reversal of the cardiomyopathy and normalization of iron load by deferiprone. Hemoglobin 2008; 32: 17-28
• 11 Aessopos A, Farmakis D, Hatziliami A. et al. Cardiac status in well-treated patients with thalassaemia major. Eur J Haematol 2004; 73: 359-366
• 12 Telfer P, Coen PG, Christou S. et al. Survival of medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Haematologica 2006; 91: 1187-1192
• 13 Au WY, Lee V, Lau CW. et al. A synopsis of current care of thalassaemia major patients in Hong Kong. Hong Kong Med J 2011; 17: 261-266
• 14 Borgna-Pignatti C, Cappellini MD, De Stefano P. et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood 2006; 107: 3733-3737
• 15 Modell B, Khan M, Darlison M. et al. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2008; 10: 42
• 16 Voskaridou E, Ladis V, Kattamis A. et al. (2012) A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births. Ann Hematol 2012; 91: 1451-1458
• 17 Wu KH, Chang JS, Tsai CH. et al. Combined therapy with deferiprone and desferrioxamine successfully regresses severe heart failure in patients with beta-thalassemia major. Ann Hematol 2004; 83: 471-473
• 18 Cohen AR, Galanello R, Piga A. et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003; 102: 1583-1587
• 19 Kolnagou A, Kontoghiorghe CN, Kontoghiorghes GJ. Transition of thalassaemia and Friedreich ataxia from fatal to chronic diseases. World J Methodol 2014; 4: 197-218
• 20 Kontoghiorghes GJ, Kolnagou A, Peng CT. et al. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases. Expert Opin Drug Saf 2010; 9: 201-206
• 21 Aessopos A, Kati M, Farmaki D. et al. Intensive chelation therapy in b-thalassemia and possible adverse cardiac effects of desferrioxamine. Int J Haematol 2007; 86: 212-215
• 22 Anonymous Fatal adverse drug events. ISMP Medication Safety Alert 2010; 15: 1-3
• 23 Rajapurkar MM, Hegde U, Bhattacharya A. et al. Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease. Toxicol Mech Methods 2013; 23: 5-10
• 24 Pandolfo M, Arpa J, Delatycki MB. et al. Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann Neurol 2014; 76: 509-521
• 25 Devos D, Moreau C, Devedjian JC. et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid Redox Signal 2014; 21: 195-210
• 26 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: E283-285
• 27 Kontoghiorghes GJ, Bartlett AN, Sheppard L. et al. Oral iron chelation therapy with deferiprone. Monitoring of biochemical, drug and iron excretion changes. Drug Res/Arzneimittelforschung 1995; 45: 65-69