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Thalassemia Workshop: Chelation Therapy

BTG 2013. Thalassemia Workshop: Chelation Therapy. Chi-Kong Li, MBBS, MD Department of Paediatrics Prince of Wales Hospital The Chinese University of Hong Kong. Transfusion therapy and iron loading in thalassemia. 1 blood unit contains 200 mg iron

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Thalassemia Workshop: Chelation Therapy

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  1. BTG 2013 Thalassemia Workshop:Chelation Therapy Chi-Kong Li, MBBS, MD Department of Paediatrics Prince of Wales Hospital The Chinese University of Hong Kong

  2. Transfusion therapy and iron loading in thalassemia • 1 blood unit contains 200 mg iron • A 60 kg thalassemia patient receiving 45 units of blood annually has transfusional iron intake of 9 g iron/year • 0.4 mg iron/kg body wt/day • In addition, up to 4 mg/day may be absorbed from the gut • Up to 1.5 g iron/year 200–250 mg iron: Whole blood: 0.47 mg iron/mL ‘Pure’ red cells: 1.16 mg iron/mL Rate of iron loading influences the therapeutic goal Porter JB. Br J Haematol 2001;115:239–252

  3. Transfusional Iron Overload in Thalassemia Transfusional Iron Death Cardiac Failure Hypoparathyroidism Hypothyroidism Diabetes Hypogonadism Cardiac arrhythmia Hepatic Fibrosis --> Cirrhosis

  4. Currently Marketed Iron Chelators Deferoxamine (Desferal ) Deferiprone (Ferriprox) Desferasirox (Exjade)

  5. Comparison of chelators

  6. Side effects of desferral local reactions, severe allergic reaction: rare yersinia enterocolitica infection Hearing: high tone deafness, Visual: night blindness, reduction of visual field & visual acuity, reduced growth velocity, skeletal lesions.

  7. Effect of DFO compliance on outcome 100 90 80 70 60 Survival 50 Infusions/year 40 300–365 30 225–300 150–225 20 75–150 10 0–75 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Years DFO = desferrioxamine. Gabutti V, Piga A. Acta Haematol. 1996;95:26-36.

  8. Deferiprone: oral tablet and suspension • GI and Joint complications • Agranulocytosis and Neutropenia • Neutropenia 1-3%, agranulocytosis <1% • Need Weekly blood counts • Discontinue therapy if ANC <1500/mm3 and confirm neutrophil count • Re-challenge only with caution

  9. Combined therapy of Desferrioxamine & Deferiprone Simultaneous use - may get drug interaction -shuttle Sequential (alternate) use - longer ‘protection time’ Agranulocytosis and Milder Neutropenia

  10. Advantages of Combined Chelation of desferral and deferiprone • Different iron pools of chelation • Increasing efficacy • Dose decrease  toxicity decrease • Better tolerability  better compliance • Quality of life improvement • Preventing NTBI accumulation • Use of oral chelators as “shuttling” agents

  11. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: retrospective analysis • treated for at least 4 years with deferiprone or deferoxamine January 1995 and March 2001 • None of the 54 patients treated with deferiprone died, • 4 of the 75 patients treated with deferoxamine died during the study period.  A. Piga et al; 2003, Thalassemia Centre, University of Torino

  12. 265 patients with β-thalassaemia major Monotherapy DFO or DFP, or combined DFP–DFO DFO alone (n = 124) DFP (n = 55) sequential DFP–DFO (n = 68),combined DFP–DFO (n = 18) 8/124 DFO developed arrhythmia, and 3/141 other chelators had arrhythmia 12 deaths, 7 of which were related to cardiac disease 6/7 had received DFO prior to death Survival analysis of patients initially randomizedto DFO + DFP vs monotherapy with DFO or DFP Maggio A, et al. Blood Cells Mol Dis. 2009 Feb 20].

  13. Monitoring of Iron overload Cardiac iron overload – cardiomyopathy - death

  14. Liver biopsy Quantitative assessment of liver iron content Good correlation with total body iron Invasive, not without risk, poor patient acceptance

  15. R2 MRI: a new measure for Liver Iron Content 300 250 Hereditary hemochromatosis 200 β-thalassemia β-thalassemia / hemoglobin E 150 Mean transverse relaxation rate <R2> (s-1) 50 Hepatitis 100 40 30 50 20 0.5 1.0 1.5 2.0 0 50 0 10 20 30 40 Biopsy iron concentration (mg.g-1 dry tissue) R2 MRI is a validated and standardized method for measuring LIC. This technique is now approved by TGA and FDA and in the EU St Pierre TG et al. Blood 2005;105:855–861

  16. Lack of Correlation: Liver and Cardiac Iron Liver Liver

  17. T2* MRI: emerging new standard for cardiac iron 90 80 70 60 50 Cardiac T2* value of 37 in a normal heart Left ventricular ejection fraction (%) 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Heart T2* (ms) Cardiac T2* value of 4 in a significantly iron overloaded heart Relationship between myocardial T2* values and left ventricular ejection fraction. Below a myocardial T2* of 20 ms, there was a progressive and significant decline in left ventricular ejection fraction (R=0·61, P<0·0001) Anderson LJ et al. Eur Heart J 2001;22:2171–2179,

  18. 80 70 60 50 Percentage of assessments with LVEF <56% 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 T2* Heart (ms) Cardiac T2* and risk for cardiac dysfunction Westwood MA et al. J Magn Reson Imaging 2005;7:46–47,

  19. Improvement in liver fibrosis with at least 3 years of deferasirox treatment Fibrosis score Improved by ≥2 Ishak stages Remained stable (no change or ±1) Missing Worsened by ≥2 Ishak stages 100 26.9 26.1 30.3 90 80 59.7 70 55.7 48.7 60 Patients (%) 50 40 30 20 15.8 10.0 6.0 10 8.2 7.3 5.3 0 Overall LIC responders LIC non-responders 82.6% of patients experienced either stabilization or improvement in fibrosis staging Improvements in fibrosis staging were observed in patients who met the LIC response criteria and those who did not Studies 107 and 107E Deugnier Y et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4274]

  20. Monotherapy of Desferasirox: MRI cardiac T2*, 3 year study Pennel DJ et al. Haematologica | 2012; 97(6)

  21. Causes of death : UK, Italy, Cyprus 7 6 uncertain 5 Others Cancer 4 Annual Death rate Iron overload 3 Infection 2 anemia 1 0 1950 - 1954 1955 - 1959 1960 - 1964 1965 - 1969 1970 - 1974 1975 - 1979 1980 - 1984 1985 - 1989 1990 - 1994 1995 - 1999 2000 - 2004 year Telfer et al, Haematologica 2006

  22. Summary • More accurate body iron assessment: MRI • liver and heart • Non-invasive, reproducible • Newer oral chelators improves compliance, reduce complications and mortality

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