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

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 Porter JB. Br J Haematol 2001;115:239–252 200–250 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

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

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

6. Comparison of chelators PropertyDFODeferiproneDeferasirox Usual dose (mg/kg/day) 25–607520–30 Route sc, iv (8–12 hours, 5 days/week) Oral 3 times daily Oral Once daily Half-life20–30 minutes3–4 hours12–16 hours ExcretionUrinary, fecalUrinaryFecal Adverse effects Local reactions, ophthalmologic, auditory, growth retardation, allergic Gastrointestinal disturbances, agranulocytosis/ neutropenia, arthralgia Gastrointestinal disturbances, rash, mild non-progressive creatinine increase, ophthalmologic, auditory StatusLicensed

7. 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.

9. Effect of DFO compliance on outcome Gabutti V, Piga A. Acta Haematol. 1996;95:26-36. Survival 0 60 80 50 40 30 20 10 70 90 100 0282624222018161412108642303234363840 Years 300–365 225–300 150–225 75–150 0–75 Infusions/year DFO = desferrioxamine.

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

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

12. 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

13. 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

14.  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 randomized to DFO + DFP vs monotherapy with DFO or DFP Maggio A, et al. Blood Cells Mol Dis. 2009 Feb 20].

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

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

17. R2 MRI: a new measure for Liver Iron Content 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 30 20 40 50 0.51.01.52.0 Biopsy iron concentration (mg.g -1 dry tissue) Mean transverse relaxation rate (s -1 ) 0 100 200 50 150 250 300 010203040 50 Hereditary hemochromatosis Hepatitis β -thalassemia β -thalassemia / hemoglobin E

18. Liver Lack of Correlation: Liver and Cardiac Iron

19. T2* MRI: emerging new standard for cardiac iron Anderson LJ et al. Eur Heart J 2001;22:2171–2179, Left ventricular ejection fraction (%) 0 50 70 40 30 20 10 60 80 90 0204060908010010305070 Heart T2* (ms) Cardiac T2* value of 37 in a normal heart 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)

20. Cardiac T2* and risk for cardiac dysfunction 0 50 70 40 30 20 10 60 80 1357101112131415161718199202468 T2* Heart (ms) Percentage of assessments with LVEF <56% Westwood MA et al. J Magn Reson Imaging 2005;7:46–47,

21. 100 Improvement in liver fibrosis with at least 3 years of deferasirox treatment  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 Fibrosis score 7.3 8.2 5.3 10.0 6.0 15.8 55.7 59.7 48.7 26.9 26.1 30.3 0 10 20 30 40 50 60 70 80 90 OverallLIC respondersLIC non-responders Patients (%) Worsened by ≥2 Ishak stages Remained stable (no change or ±1)Improved by ≥2 Ishak stages Missing Deugnier Y et al. Presented at ASH 2010 [Blood 2010;116(21):abst 4274] Studies 107 and 107E

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

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

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