Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction

Mark A Tanner, Renzo Galanello, Carlo Dessi, Gillian C Smith, Mark A Westwood, Annalisa Agus, Martina Pibiri, Sunil V Nair, J Malcolm Walker, Dudley J Pennell, Mark A Tanner, Renzo Galanello, Carlo Dessi, Gillian C Smith, Mark A Westwood, Annalisa Agus, Martina Pibiri, Sunil V Nair, J Malcolm Walker, Dudley J Pennell

Abstract

Background: In thalassemia major (TM), severe cardiac siderosis can be treated by continuous parenteral deferoxamine, but poor compliance, complications and deaths occur. Combined chelation therapy with deferiprone and deferoxamine is effective for moderate myocardial siderosis, but has not been prospectively examined in severe myocardial siderosis.

Methods: T2* cardiovascular magnetic resonance (CMR) was performed in 167 TM patients receiving standard subcutaneous deferoxamine monotherapy, and 22 had severe myocardial siderosis (T2* < 8 ms) with impaired left ventricular (LV) function. Fifteen of these patients received combination therapy with subcutaneous deferoxamine and oral deferiprone with CMR follow-up.

Results: At baseline, deferoxamine was prescribed at 38 +/- 10.2 mg/kg for 5.3 days/week, and deferiprone at 73.9 +/- 4.0 mg/kg/day. All patients continued both deferiprone and deferoxamine for 12 months. There were no deaths or new cardiovascular complications. The myocardial T2* improved (5.7 +/- 0.98 ms to 7.9 +/- 2.47 ms; p = 0.010), with concomitant improvement in LV ejection fraction (51.2 +/- 10.9% to 65.6 +/- 6.7%; p < 0.001). Serum ferritin improved from 2057 (CV 7.6%) to 666 (CV 13.2%) microg/L (p < 0.001), and liver iron improved (liver T2*: 3.7 +/- 2.9 ms to 10.8 +/- 7.3 ms; p = 0.006).

Conclusion: In patients with severe myocardial siderosis and impaired LV function, combined chelation therapy with subcutaneous deferoxamine and oral deferiprone reduces myocardial iron and improves cardiac function. This treatment is considerably less onerous for the patient than conventional high dose continuous subcutaneous or intravenous deferoxamine monotherapy, and may be considered as an alternative. Very prolonged tailored treatment with iron chelation is necessary to clear myocardial iron, and alterations in chelation must be guided by repeated myocardial T2* scans.

Trial registration: This trial is registered as NCT00103753.

Figures

Figure 1
Figure 1
Myocardial T2* improved significantly between baseline and 12 months. Standard error bars are shown. The p values shown are post-hoc analyses for 0–6 months, and 0–12 months.
Figure 2
Figure 2
Liver T2* improved significantly between baseline and 12 months. Standard error bars are shown. The p values shown are post-hoc analyses for 0–6 months, and 0–12 months.
Figure 3
Figure 3
There was a significant improvement in LV ejection fraction over 12 months. Standard error bars are shown. The p values shown are post-hoc analyses for 0–6 months, and 0–12 months.
Figure 4
Figure 4
LV end-systolic volume index decreased significantly over 12 months. Standard error bars are shown. The p values shown are post-hoc analyses for 0–6 months, and 0–12 months.
Figure 5
Figure 5
There was a significant reduction in serum ferritin over 12 months. The vertical axis shows the geometric mean of ferritin. Standard error bars are shown. The p values shown are post-hoc analyses for 0–6 months, and 0–12 months.

References

    1. Weatherall DJ, Clegg JB. The thalassaemia syndromes. 4. Oxford, England: Blackwell Science; 2001.
    1. Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, Martin M, Koren G, Cohen AR. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994;331:574–8. doi: 10.1056/NEJM199409013310903.
    1. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89:1187–93.
    1. Telfer P, Coen PG, Christou S, Hadjigavriel M, Kolnakou A, Pangalou E, Pavlides N, Psiloines M, Simamonian K, Skordos G, Sitarou M, Angastiniotis M. Survival of medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980–2004. Haematologica. 2006;91:1187–92.
    1. Modell B, Khan M, Darlison M. Survival in beta thalassaemia major in the UK: Data from the UK Thalassaemia Register. Lancet. 2000;355:2051–2. doi: 10.1016/S0140-6736(00)02357-6.
    1. Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, Yazdanpanah M, Wilson GJ, Schwartz A, Liu PP, Backx PH. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med. 2003;9:1187–94. doi: 10.1038/nm920.
    1. Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med. 2006;84:349–64. doi: 10.1007/s00109-005-0029-x.
    1. Ludwiczek S, Theurl I, Muckenthaler MU, Jakab M, Mair SM, Theurl M, Kiss J, Paulmichl M, Hentze MW, Ritter M, Weiss G. Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med. 2007;13:448–54. doi: 10.1038/nm1542.
    1. Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM, Pennell DJ. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron levels and ventricular function in beta thalassemia. Lancet. 2002;360:516–20. doi: 10.1016/S0140-6736(02)09740-4.
    1. Tanner MA, Galanello R, Dessi C, Westwood MA, Smith GC, Nair SV, Anderson LJ, Walker JM, Pennell DJ. Myocardial iron loading in patients with thalassaemia major on deferoxamine chelation. J Cardiovasc Magn Reson. 2006;8:543–7. doi: 10.1080/10976640600698155.
    1. Pennell DJ, Berdoukas V, Karagiorga M, Ladis V, Piga A, Aessopos A, Gotsis S, Tanner MA, Smith GC, Westwood MA, Wonke B, Galanello R. Randomized controlled trial of the effect of deferiprone or deferoxamine on myocardial iron and function in beta-thalassemia major. Blood. 2006;107:3738–44. doi: 10.1182/blood-2005-07-2948.
    1. Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, Roughton M, Assomull R, Nair SV, Walker JM, Pennell DJ. 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;115:1876–84. doi: 10.1161/CIRCULATIONAHA.106.648790.
    1. Origa R, Bina P, Agus A, Crobu G, Defraia E, Dessi C, Leoni G, Muroni PP, Galanello R. Combined therapy with deferiprone and desferrioxamine in thalassemia major. Haematologica. 2005;90:1309–14.
    1. Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and desferrioxamine. Br J Haematol. 1998;103:361–4. doi: 10.1046/j.1365-2141.1998.01002.x.
    1. Link G, Konijn AM, Breuer W, Cabantchik ZI, Hershko C. 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;138:130–8. doi: 10.1067/mlc.2001.116487.
    1. Davis BA, Porter JB. Long-term outcome of continuous 24-hour deferoxamine infusion via indwelling intravenous catheters in high-risk beta-thalassemia. Blood. 2000;95:1229–36.
    1. Anderson LJ, Westwood MA, Holden S, Davis B, Prescott E, Wonke B, Porter JB, Walker JM, Pennell DJ. Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance. Br J Haematol. 2004;127:348–55. doi: 10.1111/j.1365-2141.2004.05202.x.
    1. Westwood M, Anderson LJ, Firmin DN, Gatehouse PD, Lorenz CH, Wonke B, Pennell DJ. Interscanner reproducibility of cardiovascular magnetic resonance in the early diagnosis of myocardial iron overload. J Magn Reson Imaging. 2003;18:616–20. doi: 10.1002/jmri.10396.
    1. Tanner MA, He T, Westwood MA, Firmin DN, Pennell DJ. Thalassemia International Federation Heart T2* Investigators. Multi-center validation of the transferability of the magnetic resonance T2* technique for the quantification of tissue iron. Haematologica. 2006;91:1388–91.
    1. Maceira AM, Prasad SK, Khan M, Pennell DJ. Normalized left ventricular systolic and diastolic function by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2006;8:417–26. doi: 10.1080/10976640600572889.
    1. Maceira AM, Prasad SK, Khan M, Pennell DJ. Reference right ventricular systolic and diastolic function normalized to age, gender and body surface area from steady-state free precession cardiovascular magnetic resonance. Eur Heart J. 2006;27:2879–88. doi: 10.1093/eurheartj/ehl336.
    1. Westwood MA, Anderson LJ, Maceira AM, Shah FT, Prescott E, Porter JB, Wonke B, Walker JM, Pennell DJ. Normalized left ventricular volumes and function in thalassemia major patients with normal myocardial iron. J Magn Reson Imaging. 2007;25:1147–51. doi: 10.1002/jmri.20915.
    1. Porter JB. Practical management of iron overload. Br J Haematol. 2001;115:239–52. doi: 10.1046/j.1365-2141.2001.03195.x.
    1. Westwood M, Anderson LJ, Firmin DN, Gatehouse PD, Charrier CC, Wonke B, Pennell DJ. A single breath-hold multiecho T2* cardiovascular magnetic resonance technique for diagnosis of myocardial iron overload. J Magn Reson Imaging. 2003;18:33–9. doi: 10.1002/jmri.10332.
    1. He T, Gatehouse PD, Kirk P, Tanner MA, Smith GC, Keegan J, Mohiaddin RH, Pennell DJ, Firmin DN. Black-blood T2* technique for myocardial iron measurement in thalassemia. J Magn Reson Imaging. 2007;25:1205–9. doi: 10.1002/jmri.20929.
    1. Pennell DJ. Cardiovascular Magnetic Resonance. In: Zipes DP, Libby P, Bonow RO, Braunwald E, editor. Braunwald's Heart Disease: A textbook of cardiovascular medicine. Elsevier Saunders, USA; 2005. pp. 335–53.
    1. Olivieri NF, Snider MA, Nathan DG, et al. Survival following the onset of iron-induced cardiac disease in thalassaemia major. Blood (Abstract) 1995;86:250.
    1. Jessup M, Manno CS. Diagnosis and management of iron-induced heart disease in Cooley's anemia. Ann N Y Acad Sci. 1998;850:242–50. doi: 10.1111/j.1749-6632.1998.tb10481.x.
    1. Tamary H, Goshen J, Carmi D, Yaniv I, Kaplinsky C, Cohen IJ, Zaizov R. Long-term intravenous deferoxamine treatment for noncompliant transfusion-dependent beta-thalassemia patients. Isr J Med Sci. 1994;30:658–64.
    1. Cohen AR, Martin M, Schwartz E. Current treatment of Cooley's anemia. Intravenous chelation therapy. Ann N Y Acad Sci. 1990;612:286–92. doi: 10.1111/j.1749-6632.1990.tb24316.x.
    1. Davis BA, O'Sullivan C, Jarritt PH, Porter JB. Value of sequential monitoring of left ventricular ejection fraction in the management of thalassemia major. Blood. 2004;104:263–9. doi: 10.1182/blood-2003-08-2841.
    1. Origa R, Bina P, Agus A, Crobu G, Defraia E, Dessi C, Leoni G, Muroni PP, Galanello R. Combined therapy with deferiprone and desferrioxamine in thalassemia major. Haematologica. 2005;90:1309–14.
    1. Kattamis K, Ladis V, Berdousi H, Kelekis NL, Alexopoulou E, Papasotiriou I, Drakaki K, Kaloumenou I, Galani A, Kattamis C. Iron chelation treatment with combined therapy with deferiprone and deferioxamine: a 12-month trial. Blood Cells Mol Dis. 2006;36:21–5. doi: 10.1016/j.bcmd.2005.11.002.
    1. Wu KH, Chang JS, Tsai CH, Peng CT. Combined therapy with deferiprone and desferrioxamine successfully regresses severe heart failure in patients with beta-thalassaemia major. Ann Hematol. 2004;83:471–3. doi: 10.1007/s00277-003-0820-0.
    1. Tsironi M, Deftereos S, Andriopoulos P, Farmakis D, Meletis J, Aessopos A. reversal of heart failure in thalassaemia major by combined chelation therapy: a case report. Eur J Haematol. 2005;74:84–5. doi: 10.1111/j.1600-0609.2004.00335.x.
    1. Porcu M, Landis N, Salis S, Corda M, Orru P, Serra E, Usai B, Matta G, Galanello R. Effects of combined deferiprone and desferrioxamine iron chelating therapy in beta-thalassemia major end-stage heart failure: a case report. Eur J Heart Fail. 2007;9:320–2. doi: 10.1016/j.ejheart.2006.08.006.
    1. Piga A, Longo F, Consolati A, De Leo A, Carmellino L. Mortality and morbidity in thalassaemia with conventional treatment. In Proceedings of the third international conference on bone marrow transplantation in thalassaemia. Bone Marrow Transplantation. 1997;19(Supplement 2):11–3.
    1. Piga A, Caglioti C, Fogliacco E, Tricta F. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassaemia major: a retrospective analysis. Haematologica. 2003;88:489–96.
    1. Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, Ghilardi R, Piga A, Romeo MA, Zhao H, Cnaan A. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood. 2006;107:3733–7. doi: 10.1182/blood-2005-07-2933.
    1. Galanello R, Kattamis A, Piga A, Fischer R, Leoni G, Ladis V, Voi V, Lund U, Tricta F. 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;91:1241–3.
    1. Anderson LJ, Holden S, Davies B, Prescott E, Charrier C, Bunce NH, Firmin DN, Porter JB, Wonke B, Walker JM, Pennell DJ. Cardiovascular T2* (T2 star) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22:2171–9. doi: 10.1053/euhj.2001.2822.
    1. Wood JC, Tyszka JM, Carson S, Nelson MD, Coates TD. Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease. Blood. 2004;103:1934–6. doi: 10.1182/blood-2003-06-1919.
    1. Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE, Allen CJ, Farrell DE, Harris JW. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 1994;331:567–73. doi: 10.1056/NEJM199409013310902.
    1. Kolnagu A, Econoimides C, Eracleous E, Kontoghiorghes GJ. Low serum ferritin levels are misleading for detecting cardiac iron overload and increase the risk of cardiomyopathy in thalassaemia patients. The importance of cardiac iron overload monitoring using magnetic resonance imaging T2 and T2*. Hemoglobin. 2006;30(2):219–227. doi: 10.1080/03630260600642450.
    1. Anderson LJ, Westwood MA, Prescott E, Walker JM, Pennell DJ, Wonke B. Development of thalassemic cardiomyopathy despite low liver iron levels and meticulous compliance to desferrioxamine. Acta Haematol. 2006;115:106–8. doi: 10.1159/000089475.
    1. Maisel AS, Krishnaswany P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347:161–7. doi: 10.1056/NEJMoa020233.
    1. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS. Plasma natriuretic peptide levels and the risk of cardiovascular events and deaths. N Engl J Med. 2004;350:655–63. doi: 10.1056/NEJMoa031994.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren