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Meta-Analysis
. 2013 Aug 21;2013(8):CD004839.
doi: 10.1002/14651858.CD004839.pub3.

Oral deferiprone for iron chelation in people with thalassaemia

Sheila A Fisher  1 , Susan J Brunskill, Carolyn Doree, Onima Chowdhury, Sarah Gooding, David J Roberts
Affiliations
Meta-Analysis

Oral deferiprone for iron chelation in people with thalassaemia

Sheila A Fisher et al. Cochrane Database Syst Rev. .

Abstract

Background: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine.

Objectives: To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone with desferrioxamine for thalassaemia.

Search methods: We searched the Cochrane Cystic fibrosis and Genetic Disorders Group's Haemoglobinopathies trials Register and MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus registers of ongoing trials and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). We also contacted the manufacturers of deferiprone and desferrioxamine.All searches were updated to 05 March 2013.

Selection criteria: Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules or doses of deferiprone, in people with transfusion-dependent thalassaemia.

Data collection and analysis: Two authors independently assessed trials for risk of bias and extracted data. Missing data were requested from the original investigators.

Main results: A total of 17 trials involving 1061 participants (range 13 to 213 participants per trial) were included. Of these, 16 trials compared either deferiprone alone with desferrioxamine alone, or a combined therapy of deferiprone and desferrioxamine with either deferiprone alone or desferrioxamine alone; one compared different schedules of deferiprone. There was little consistency between outcomes and limited information to fully assess the risk of bias of most of the included trials.Four trials reported mortality; each reported the death of one individual receiving deferiprone with or without desferrioxamine. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage.Earlier trials measuring the cardiac iron load indirectly by magnetic resonance imaging (MRI) T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, a meta-analysis of two trials suggested that left ventricular ejection fraction was significantly reduced in patients who received desferrioxamine alone compared with combination therapy. One trial, which planned five years of follow up, was stopped early due to the beneficial effects of combined treatment compared with deferiprone alone in terms of serum ferritin levels reduction.The results of this and three other trials suggest an advantage of combined therapy over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no conclusive or consistent evidence for the improved efficacy of combined deferiprone and desferrioxamine therapy over monotherapy from direct or indirect measures of liver iron. Both deferiprone and desferrioxamine produce a significant reduction in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised controlled trials to suggest that either has a greater reduction of clinically significant end organ damage.Evidence of adverse events were observed in all treatment groups. Occurrence of any adverse event was significantly more likely with deferiprone than desferrioxamine in one trial, RR 2.24 (95% CI 1.19 to 4.23). Meta-analysis of a further two trials showed a significant increased risk of adverse events associated with combined deferiprone and desferrioxamine compared with desferrioxamine alone, RR 3.04 (95% CI 1.18 to 7.83). The most commonly reported adverse event was joint pain, which occurred significantly more frequently in patients receiving deferiprone than desferrioxamine, RR 2.64 (95% CI 1.21 to 5.77). Other common adverse events included gastrointestinal disturbances as well as neutropenia or leucopenia, or both.

Authors' conclusions: In the absence of data from randomised controlled trials, there is no evidence to suggest the need for a change in current treatment recommendations; namely that deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. Intensified desferrioxamine treatment (by either subcutaneous or intravenous route) or use of other oral iron chelators, or both, remains the established treatment to reverse cardiac dysfunction due to iron overload. Indeed, the US Food and Drug Administration (FDA) recently only gave support for deferiprone to be used as a last resort for treating iron overload in thalassaemia, myelodysplasia and sickle cell disease. However, there is evidence that adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.

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Conflict of interest statement

None known.

Figures

1
1
PRISMA study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Deferiprone alone versus DFO alone, outcome: 1.14 Adverse events.
4
4
Forest plot of comparison: 3 Deferiprone and DFO in combination versus DFO alone, outcome: 3.11 Adverse events.
1.1
1.1. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 1 Left ventricular ejection fraction: mean change from baseline (%).
1.2
1.2. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 2 Right ventricular ejection fraction: mean at endpoint (%).
1.3
1.3. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 3 Liver fibrosis Ishak score: mean at endpoint.
1.4
1.4. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 4 Serum ferritin concentration: mean change from baseline (ng/ml).
1.5
1.5. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 5 Urinary iron excretion: mean at endpoint (mg/24h).
1.6
1.6. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 6 Urinary iron excretion: mean over study (%).
1.7
1.7. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 7 Urinary iron excretion: mean change from baseline (mg/24h).
1.8
1.8. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 8 Liver iron concentration: ratio of geometric means at endpoint (mg/g dry weight).
1.9
1.9. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 9 Liver iron concentration: mean change from baseline (mg/g dry weight).
1.10
1.10. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 10 Myocardial T2*: ratio of geometric means of change from baseline.
1.11
1.11. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 11 Chelation efficiency (%).
1.12
1.12. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 12 Plasma NTBI: mean change from baseline (mM).
1.13
1.13. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 13 Total iron excretion: mean at endpoint (mg/kg/day).
1.14
1.14. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 14 Adverse events.
1.15
1.15. Analysis
Comparison 1 Deferiprone alone versus DFO alone, Outcome 15 Participant compliance (%).
2.1
2.1. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 1 Left ventricular ejection fraction: mean at endpoint (%).
2.2
2.2. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 2 Serum ferritin concentration: mean at endpoint (ng/ml).
2.3
2.3. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 3 Serum ferritin concentration: mean change from baseline (ng/ml).
2.4
2.4. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 4 Urinary iron excretion: mean over study (%).
2.5
2.5. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 5 Urinary iron excretion: mean at endpoint (mg/24h).
2.6
2.6. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 6 Liver iron concentration: mean at endpoint (mg/g dry weight).
2.7
2.7. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 7 Chelation efficiency (%).
2.8
2.8. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 8 Plasma NTBI: mean change from baseline (mM).
2.9
2.9. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 9 Total Iron excretion: mean at endpoint (mg/kg/day).
2.10
2.10. Analysis
Comparison 2 Deferiprone alone versus deferiprone and DFO in combination, Outcome 10 Adverse Events.
3.1
3.1. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 1 Left ventricular ejection fraction: mean at endpoint (%).
3.2
3.2. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 2 Serum ferritin concentration: ratio of geometric means at endpoint (ng/ml).
3.3
3.3. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 3 Serum ferritin concentration: ratio of geometric means at endpoint (ng/ml).
3.4
3.4. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 4 Serum ferritin concentration: mean change from baseline (ng/ml).
3.5
3.5. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 5 Urinary iron excretion: mean at endpoint (mg/24h).
3.6
3.6. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 6 Urinary iron excretion: mean over study (%).
3.7
3.7. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 7 Liver iron concentration: mean change from baseline.
3.8
3.8. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 8 Chelation efficiency (%).
3.9
3.9. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 9 Plasma NBTI: mean change from baseline (mM).
3.10
3.10. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 10 Total iron excretion: mean at endpoint (mg/kg/day).
3.11
3.11. Analysis
Comparison 3 Deferiprone and DFO in combination versus DFO alone, Outcome 11 Adverse events.
4.1
4.1. Analysis
Comparison 4 Deferiprone dose A versus deferiprone dose B, Outcome 1 Serum ferritin concentration: mean at endpoint (ng/ml).
See this image and copyright information in PMC

Update of

References

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Kontoghiorghes 1987 {published data only}
    1. Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, Barr J, Wonke B, Kourouclaris T, et al. Effective chelation of iron in beta thalassaemia with the oral chelator 1,2‐dimethyl‐3‐hydroxypyrid‐4‐one. British Medical Journal 1987;295(6612):1509‐12. - PMC - PubMed
Lai 2010 {published data only}
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Loebstein 1997 {published data only}
    1. Loebstein R, Dalal I, Nisbet‐Brown E, Berkovitch M, Meydan N, Andrews D, et al. Immune function in patients with beta‐thalassamia receiving the orally active iron‐chelating agent deferiprone. British Journal of Haematology 1997;98(3):597‐600. - PubMed
Marshall 2003 {published data only}
    1. Marshall R, Tricta F, Galanello R, Leoni G, Kirkland D, Minto S, et al. Chromosomal aberration frequencies in patients with thalassaemia major undergoing therapy with deferiprone and deferoxamine in a comparative crossover study. Mutagenesis 2003;18(5):457‐63. - PubMed
Nielsen 1995 {published data only}
    1. Nielsen P, Fischer R, Engelhardt R, Tondury P, Gabbe EE, Janka GE. Liver iron stores in patients with secondary haemosiderosis under iron chelation therapy with deferoxamine or deferiprone. British Journal of Haematology 1995;91(4):827‐33. - PubMed
Olivieiri 1993 {published data only}
    1. Olivieri N, Brittenham G, Koren G. Reduction in hepatic iron stores with the oral iron chelator L1 inpatients with transfusion‐dependent thalassemia and sickle cell disease: First three years of the Canadian trial [abstract]. Proceedings of the 35th Annual Meeting and Exposition of the American Society of Hematology; 1993 December 3‐7; St. Louis. 1993:1238.
Peng 2003 {published data only}
    1. Peng CT, Chow KC, Chen JH, Chiang YP, Lin TY, Tsai CH. Safety monitoring of cardiac and hepatic systems in beta‐thalassemia patients with chelating treatment in Taiwan. European Journal of Haematology 2003;70(6):392‐7. - PubMed
Peng 2006 {published data only}
    1. Peng CT, Wu KH, Tsai CC, Ysai CH. Deferirpone in patients with beta‐thalassamiea major for 4 years in the Chinese population in Taiwan. European Journal of Clinical Investigation 2004 Suppl 1;34:20‐61; Abstract 138.
    1. Peng CT, Wu KH, Tsai CH, Yang CP, Wang LW, Jang RC, et al. Study of deferiprone or deferoxamine versus combination therapy in iron‐loaded thalassaemia patients in Taiwan. Blood 2006;18 Suppl:Abstract 3736.
Pepe 2006 {published data only}
    1. Pepe A, Lombardi M, Positano V, Cracolici E, Capra M, Malizia R, et al. Evaluation of the efficacy of oral deferiprone in beta‐thalassaemia major by multislice multiecho T2*. European Journal of Haematology 2006;76(3):183‐92. - PubMed
Ricchi 2010 {published data only}
    1. Ricchi P, Ammirabile M, Spasiano A, Costantini S, Cinque P, Matola T, et al. Combined chelation therapy in thalassemia major with deferiprone and desferrioxamine: a retrospective study. European Journal of Haematology 2010;85(1):36‐42. - PubMed
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Tanner 2008 {published data only}
    1. Tanner MA, Galanello R, Dessi C, Smirth GC, Westwood MA, Agus A, et al. Combined chelation therapy in thalassaemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. Journal of Cardiovascular Magnetic Resonance 2008;10(1):12‐20. - PMC - PubMed
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Vlachaki 2007 {published data only}
    1. Vlachaki E, Ioannidou‐Papagiannaki E, Haralambidou‐Vranitsa SH, Perifanis V, Tsigga A, Klonizakis I, et al. Progenitor haemopoietic cells in the peripheral blood of thalassemic patients with desferioxamine or deferiprone chelation therapy [abstract]. Hematology 2005;90 Suppl 2:Abstract 1065.
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Wang 2006 {published data only}
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Zareifar 2009 {published data only}
    1. Zareifar S, Jabbari A, Cohan N, Haghpanah S. Efficacy of combined desferrioxamine and deferiprone versus single desferrioxamine therapy in patients with major thalassemia. Archives of Iranian Medicine 2009;12(5):488‐91. - PubMed

References to studies awaiting assessment

Alpendurada 2012 {published data only}
    1. Alpendurada F, Smith GC, Carpenter JP, Nair SV, Tanner MA, Banya W, et al. Effects of combined deferiprone with deferoxamine on right ventricular function in thalassemia major. Journal of Cardiovascular Magnetic Resonance 2012;14(1):8. [DOI: 10.1186/1532-429X-14-8] - DOI - PMC - PubMed
Aydinok 2012 {published data only}
    1. Aydinok Y, Evans P, Manz CY, Porter JB. Probing the origin of chelatable iron during deferiprone and combination therapies: insights from plasma NTBI and LPI determinations. ASH Annual Meeting Abstracts 2010;116(21):5158.
    1. Aydinok Y, Evans P, Manz CY, Porter JB. Timed non‐transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response. Haematologica 2012;97(6):835‐41. - PMC - PubMed
Badawy 2010 {published data only}
    1. Badawy S, Hassan TH, Hesham MAA, Badr MA. Evaluation of iron chelation therapy in beta‐thalassemic patients in Zagazig University Hospital. Pediatric Blood and Cancer; Proceedings of the 23rd Annual Meeting of the American Society of Pediatric Hematology/Oncology, ASPHO, Montreal, Canada. 2010:799‐800, Poster 124.
    1. Hassan T, Badr M, Hesham M, Badawy S. Evaluation of iron chelation therapy in beta‐thalassemia major patients in East Delta of Egypt. Haematologica. 2010 Suppl 2; Vol. 95:701, Abstract 1810.
Evans 2011 {published data only}
    1. Evans P, Aydinok Y, Manz C, Porter J. Origin of chelatable iron during deferiprone and combination therapies: Insights from plasma NTBI and LPI. American Journal of Hematology. 2011; Vol. 86:9: E84.
Jain 2011 {published data only}
    1. Jain R, Perkins J, Johnson S, Harimoorthy V, Desai P, Chudgar U, et al. A prospective study for determination of the mean red cell transfusion requirement compared on the basis of iron overload and type of chelation therapy in multiply transfused thalassaemia major patients. Transfusion Medicine 2011;21(1):46‐7.
Kompany 2009 {published data only}
    1. Kompany F, Mohammadi S, Sigari N, Hadizadeh N, Rezaie N, Gharibi FSM. Comparative efficacy of deferrioxamine and combination of deferiprone and deferrioxamine on echocardiographic indices in beta thalassemic patients. Scientific Journal of Kurdistan University of Medical Sciences 2009;14(2):21‐30.
Maggio 2012 {published data only}
    1. Maggio A, Capra M, Cuccia L, Gagliardotto F, Rigano P, Calvaruso G, et al. Long‐term use of deferiprone enhances significantly the left ventricular ejection function in thalassemia major. ASH Annual Meeting Abstracts; 53rd American Society of Hematology (ASH) Annual Meeting, 10‐13 December 2011, San Diego, USA 2011;118:21; Abstract 5302.
    1. Maggio A, Vitrano A, Lucania G, Capra M, Cuccia L, Gagliardotto F, et al. Long‐term use of deferiprone significantly enhances left‐ventricular ejection function in thalssemia major patients. American Journal of Hematology 2012;87(7):732‐3. - PubMed
Mirbehbahani 2012 {published data only}
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N0277104959 {published data only}
    1. Wonke B. A randomised controlled prospective trial using Ferriprox versus placebo and conventional intravenous and subcutaneous iron chelation. National Research register: N0277104959.
NCT00115349a {published data only}
    1. National Heart, Lung and Blood Institute (NHLBI). Combination therapy compared with single‐drug therapy in patients with cardiac diseases. ClinicalTrials.gov: NCT00115349.
Pantalone 2011 {published data only}
    1. Pantalone GR, Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, 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 beta‐thalassemia major patients. Hemoglobin 2011;35(3):206‐16. - PubMed
Pepe 2013 {published data only}
    1. Pepe A, Meloni A, Pepe P, Capra M, D'Ascola DG, Santodirocco M, et al. Prospective comparison on cardiac and hepatic iron and cardiac function by MR in thalssemia major patients treated with combination deferiprone‐desferrioxamine versus deferiprone and desferrioxamine in monotherapy. Blood 2011;118(21):Abstract.
    1. Pepe A, Meloni A, Rossi G, Cuccia L, D'Ascola GD, Santodirocco M, et al. Cardiac and hepatic iron and ejection fraction in thalassemia major: multicentre prospective comparison of combined deferiprone and deferoxamine therapy against deferiprone or deferoxamine monotherapy. http://www.jcmr‐online.com/content/pdf/1532‐429X‐15‐1.pdf (Accessed 01 August 2013). [DOI: 10.1186/1532-429X-15-1] - DOI - PMC - PubMed
    1. Pepe A, Meloni A, Rossi G, Ruffo GB, D'Ascola DG, Santodirocco M, et al. Cardiac iron and function by CMR in thalassemia major patients treated with combined deferiprone and desferrioxamine regimen versus monotherapies: a multi‐center, observational and prospective study. European Heart Journal 2012;33:805.
    1. Pepe A, Rossi G, Meloni A, Dell'Amico MC, Capra M, Caruso V, et al. Prospective comparison on cardiac iron and liver iron by MR in thalassemia major patients treated with combination deferiprone‐desferrioxamine versus deferiprone and desferrioxamine in monotherapy. ASH Annual Meeting Abstracts 2010;116(21):5164.
    1. Pepe A, Rossi G, Meloni A, Dell'Amico MC, Capra M, Caruso V, et al. Prospective comparison on cardiac iron and liver iron by MR in thalassemia major patients treated with combination deferiprone‐desferrioxamine versus deferiprone and desferrioxamine in monotherapy. Haematologica, Proceedings of the 15th Congress of the European Hematology Association, Barcelona, Spain 2010 Suppl 2;95:696 Abstract 1797.
Unal 2009 {published data only}
    1. Unal S, Hazirolan T, Beton B, Karabulut E, Gumruk F. The cardiac effects of desferrioxamine deferiprone combination therapy and desferrioxamine monotherapy in thalassemic patients. Haematologica 2009 Suppl 2;94:514‐5, Abstract 1295.

References to ongoing studies

EU_2009‐014666‐25 {published data only}
    1. Fondazione Franco e Piera Cutino (Sponsors). Sequential deferasirox‐deferiprone versus deferasirox or deferiprone multicentre randomized trial. EU Clinical Trials Register: 2009‐014666‐25 2010.
IRCT201110087677N1 {published data only}
    1. Akramipoor R. The comparative study of incidence of lens opacity between Osfereal and Deferoxamine in major thalassemia. Iranian Registry of Clinical Trials: IRCT20110087677N1.
NCT01511848 {published data only}
    1. Mohsen Saleh Elalfy, Ain Shams University. Study of efficacy, safety of combined deferasirox and deferiprone versus combined deferiprone and desferal in conditions of iron overload. ClinicalTrials.gov: NCT01511848.

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