review
Chelation treatment in sickle-cell-anaemia: much ado about nothing?
Gaetano Lucania,
Angela Vitrano,
Aldo Filosa,
Aurelio Maggio,
Gaetano Lucania
U.O.C. “Ematologia II con Talassemia”, A.O. “Villa Sofia-V. Cervello”, Palermo
Search for more papers by this authorAngela Vitrano
Dipartimento di Scienze Statistiche e Matematiche ‘S. Vianelli’, Università di Palermo, Palermo
Search for more papers by this authorAldo Filosa
U.O.S. Talassemia Pediatrica, A.O. Cardarelli, Napoli
Search for more papers by this authorAurelio Maggio
U.O.C. “Medicina Trasfusionale”, A.O. “Villa Sofia-V. Cervello”, Palermo, Italy
Search for more papers by this authorGaetano Lucania,
Angela Vitrano,
Aldo Filosa,
Aurelio Maggio,
Gaetano Lucania
U.O.C. “Ematologia II con Talassemia”, A.O. “Villa Sofia-V. Cervello”, Palermo
Search for more papers by this authorAngela Vitrano
Dipartimento di Scienze Statistiche e Matematiche ‘S. Vianelli’, Università di Palermo, Palermo
Search for more papers by this authorAldo Filosa
U.O.S. Talassemia Pediatrica, A.O. Cardarelli, Napoli
Search for more papers by this authorAurelio Maggio
U.O.C. “Medicina Trasfusionale”, A.O. “Villa Sofia-V. Cervello”, Palermo, Italy
Search for more papers by this authorAurelio Maggio, U.O.C. “Ematologia II con Talassemia”, A.O. “V. Cervello”, Palermo, Italy.E-mail: [email protected]
Summary
Blood transfusions may prevent and treat serious complications related to sickle-cell disease (SCD) when performed according to specific guidelines. However, blood transfusion requirements in SCD inevitably lead to increased body iron burden. An adequate chelation treatment may prevent complications and reduce morbidity and mortality. This review evaluates the effectiveness, safety and costs of chelation treatment. The included trials were examined according to the recommendations of the American College of Cardiology (ACC) and the American Heart Association (AHA). Overall, 14 trials and a total of 502 patients with SCD were included in this review. Deferoxamine alone (s.c. or i.v.), deferiprone alone or versus deferoxamine, deferasirox versus deferoxamine and combined treatment with deferoxamine plus deferiprone were included and evaluated in the analysis. Only two randomized clinical trials have been reported. The results of this analysis suggest that use of chelation treatment in SCD to date has been based on little efficacy and safety evidence, although it is widely recommended and practised. The cost/benefit ratio has not been fully explored. Further research with larger randomized clinical trials needs to be performed.
References
- Ballas, S.K. (2001) Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease. Seminars in Hematology, 38(1 Suppl 1), 30–36.
- Cappellini, M.D., Cohen, A., Piga, A., Bejaoui, M., Perrotta, S., Agaoglu, L., Aydinok, Y., Kattamis, A., Kilinc, Y., Porter, J., Capra, M., Galanello, R., Fattoum, S., Drelichman, G., Magnano, C., Verissimo, M., Athanassiou-Metaxa, M., Giardina, P., Kourakli Symeonidis, A., Janka-Schaub, G., Coates, T., Vermylen, C., Olivieri, N., Thuret, I., Opitz, H., Ressayre-Djaffer, C., Marks, P. & Alberti, D. (2006) A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood, 107(9), 3455–3462.
- Cappellini, M.D., Porter, J., El-Beshlawy, A., Li, C.K., Seymour, J.F., Elalfy, M., Gattermann, N., Giraudier, S., Lee, J.W., Chan, L.L., Lin, K.H., Rose, C., Taher, A., Thein, S.L., Viprakasit, V., Habr, D., Domokos, G., Roubert, B. & Kattamis, A.; EPIC Study Investigators (2010) Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica, 95, 557–566.
- Ceci, A., Felisi, M.G., Cappellini, M.D., Carnelli, V., De Sanctis, V., Galanello, R., Maggio, A., Masera, G., Piga, A., Schettini, F., Stefano, I. & Tricta, F. (2002) The safety and effectiveness of deferiprone in a large scale 3 years study in Italian patients. British Journal of Haematology, 118, 330–336.
- Cohen, A.R., Galanello, R., Piga, A., Dipalma, A., Vullo, C. & Tricta, F. (2000) Safety profile of the oral iron chelator deferiprone: a multi- centre study. British Journal of Haematology, 108, 305–312.
- Collins, A.F., Fassos, F.F., Stobie, S., Lewis, N., Shaw, D., Fry, M., Templeton, D.M., McClelland, R.A., Koren, G. & Olivieri, N.F. (1994) 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, 2329–2333.
- Darbari, D.S., Kple-Faget, P., Kwagyan, J., Rana, S., Gordeuk, V.R. & Castro, O. (2006) Circumstances of death in adult sickle cell disease patients. American Journal of Hematology, 81, 858–863.
- De Montalembert, M., Llados, A., Hannedouche, T. & Girot, R. (1989) Treatment of post-transfusion iron overload by deferoxamine. Archives Francaises de Pediatrie, 46, 99–105.
- Delea, T.E., Hagiwara, M., Thomas, S.K., Baladi, J.F., Phatak, P.D. & Coates, T.D. (2008) Outcomes, utilization, and costs among thalassemia and sickle cell disease patients receiving deferoxamine therapy in the United States. American Journal of Hematology, 83, 263–270.
- Drasar, E., Igbineweka, N., Vasavda, N., Free, M., Awogbade, M., Allman, M., Mijovic, A. & Thein, S.L. (2011) Blood transfusion usage among adults with sickle cell disease - a single institution experience over ten years. British Journal of Haematology, 152, 766–770.
- Elalfy, M.S., Abdin, I.A., El Safy, U.R., Ibrahim, A.S., Ebeid, F.S. & Salem, D.S. (2010) Cardiac events and cardiac T2* in Egyptian children and young adults with beta-thalassemia major taking deferoxamine. Hematology/Oncology and Stem Cell Therapy, 3, 174–178.
- Franchini, M., Gandini, G., De Gironcoli, M., Vassanelli, A., Borgna-Pignatti, C. & Aprili, G. (2000) Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood, 95, 2776–2779.
- Fung, E.B., Harmatz, P., Milet, M., Ballas, S.K., De Castro, L., Hagar, W., Owen, W., Olivieri, N., Smith-Whitley, K., Darbari, D., Wang, W. & Vichinsky, E.; Multi-Center Study of Iron Overload Research Group (2007) Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: a report from the multi-center study of iron overload. American Journal of Hematology, 82, 255–265.
- Galanello, R., Piga, A., Forni, G.L., Bertrand, Y., Foschini, M.L., Bordone, E., Leoni, G., Lavagetto, A., Zappu, A., Longo, F., Maseruka, H., Hewson, N., Sechaud, R., Belleli, R. & Alberti, D. (2006) 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, 873–880.
- Gulbis, B., Eleftheriou, A., Angastiniotis, M., Ball, S., Surrallés, J., Castella, M., Heimpel, H., Hill, A. & Corrons, J.L. (2010) Epidemiology of rare anemias in Europe. Advances in Experimental Medicine and Biology, 686, 375–396.
- Hoffbrand, A.V., AL-Refaie, F., Davis, B., Siritanakatkul, N., Jackson, B.F., Cochrane, J., Prescott, E. & Wonke, B. (1998) Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood, 91, 295–300.
- Kalpatthi, R., Peters, B., Kane, I., Holloman, D., Rackoff, E., Disco, D., Jackson, S., Laver, J.H. & Abboud, M.R. (2010) Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease. Pediatrics Blood and Cancer, 55, 1338–1342.
- Klocke, F.J., Baird, M.G., Lorell, B.H., Bateman, T.M., Messer, J.V., Berman, D.S., O’Gara, P.T., Carabello, B.A., Russell, Jr, R.O., Cerqueira, M.D., St. John Sutton, M.G., DeMaria, A.N., Udelson, J.E., Kennedy, J.W., Verani, M.S., Williams, K.A., Antman, E.M., Smith, Jr, S.C., Alpert, J.S., Gregoratos, G., Anderson, J.L., Hiratzka, L.F., Faxon, D.P., Hunt, S.A., Fuster, V., Jacobs, A.K., Gibbons, R.J. & Russell, R.O. (2003) ACC/AHA/ASNC Guidelines for the clinical use of cardiac radionuclide imaging, executive summary: a report of the American College of Cardiology/American Heart Association task force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radio- nuclide Imaging). Circulation, 108, 1404–1418.
- Krishnan, S., Setty, Y., Betal, S.G., Vijender, V., Rao, K., Dampier, C. & Stuart, M. (2010) Increased levels of the inflammatory biomarker C-reactive protein at baseline are associated with childhood sickle cell vasocclusive crises. British Journal of Haematology, 148, 797–804.
- Link, G., Konijn, A.M. & Hershko, C. (1999) Cardioprotective effect of alpha-tocopherol, ascorbate, deferoxamine, and deferiprone: mitochondrial function in cultured, iron-loaded heart cells. The Journal of Laboratory and Clinical Medicine, 133, 179–188.
- Lottenberg, R. & Hassel, K.L. (2005) An evidence based approach to the treatment of adults with sickle cell disease. Hematology, American Society of Hematology, Educational Programme, 58–65.
- Maggio, A. (2007) Light and shadows in the iron chelation treatment of haematological diseases. British Journal of Haematology, 138, 407–421.
- Meerpohl, J.J., Antes, G., Rücker, G., Fleeman, N., Niemeyer, C.M. & Bassler, D. (2010) Deferasirox for managing transfusional iron overload in people with sickle cell disease. Cochrane Database System Review, Issue 8, CD007477.
- Olivieri, NF. (2001) Progression of iron overload in sickle cell disease. Seminars in Hematology, 38(1 Suppl 1), 57–62.
- Porter, J.B. (2009) Pathophysiology of transfusional iron overload: contrasting patterns in thalassemia major and sickle cell disease. Hemoglobin, 33(Suppl 1), 37–45.
- Raphael, J.L., Bernhardt, M.B., Mahoney, D.H. & Mueller, B.U. (2009) Oral iron chelation and the treatment of iron overload in a pediatric hematology center. Pediatrics Blood and Cancer, 52, 616–620.
- Ritchie, J.C., Bateman, T.M., Bonow, R.O., Crawford, M.H., Gibbons, R.J., Hall, R.J., O’Rourke, R.A., Parisi, A.F. & Verani, M.S. (1995) Guidelines for the clinical use of cardiac radionuclide imaging: report of the American College of Cardiology/American Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures (Committee on Radionuclide Imaging), developed in collaboration with the American Society of Nuclear Cardiology. Journal of the American College of Cardiology, 25, 521–547.
- Setty, Y., Betal, S.G., Vijender, V., Rao, K., Dampier, C. & Stuart, M. (2010) Increased levels of the inflammatory biomarker C-reactive protein at baseline are associated with childhood sickle cell vasocclusive crises. British Journal of Haematology, 148, 797–804.
- Silliman, C.C., Peterson, V.M., Mellman, D.L., Dixon, D.J., Hambidge, K.M. & Lane, P.A. (1993) Iron chelation by deferoxamine in sickle cell patients with severe transfusion-induced hemosiderosis: a randomized, double-blind study of the dose-response relationship. The Journal of Laboratory and Clinical Medicine, 122, 48–54.
- Tsironi, M., Polonifi, K., Deftereos, S., Farmakis, D., Andriopoulos, P., Moyssakis, I. & Aessopos, A. (2005) Transfusional hemosiderosis and combined chelation therapy in sickle thalassemia. European Journal of Haematology, 75, 355–358.
- Vichinsky, E., Onyekwere, O., Porter, J., Swerdlow, P., Eckman, J., Lane, P., Files, B., Hassell, K., Kelly, P., Wilson, F., Bernaudin, F., Forni, G.L., Okpala, I., Ressayre-Djaffer, C., Alberti, D., Holland, J., Marks, P., Fung, E., Fischer, R., Mueller, B.U. & Coates, T.; Deferasirox in Sickle Cell Investigators (2007) A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. British Journal of Haematology, 136, 501–508.
- Voskaridou, E., Douskou, M., Terpos, E., Stamoulakatou, A., Meletis, J., Ourailidis, A., Papassotiriou, I. & Loukopoulos, D. (2005) Deferiprone as an oral iron chelator in sickle cell disease. Annals of Hematology, 84, 434–440.
- Walter, P.B., Harmatz, P. & Vichinsky, E. (2009) Iron Metabolism and Iron Chelation in Sickle Cell Disease. Acta Haematologica, 122, 174–183.
- Wood, J.C., Tyszka, J.M., Carson, S., Nelson, M.D. & Coates, T.D. (2004) Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease. Blood, 103, 1934–1936.
- Yusuf, B., McPhedran, P. & Brewster, U.C. (2008) Hypocalcemia in a dialysis patient treated with deferasirox for iron overload. American Journal of Kidney Disease, 52, 587–590.
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