1. Iron Overload in Chronic Anaemias Dick Wells MD, DPhil, FRCPC Director, Crashley Myelodysplastic Syndrome Research Laboratory Odette Cancer Centre

2. Preview Why we need iron The iron economy Why too much iron is a bad thing Pumping (out) iron Current recommendations for treatment of iron overload in MDS

3. Why we need iron Enzymes Oxygen transport –Haemoglobin (red blood cells) –Myoglobin (muscle cells) About 70% of the bodys iron is in these proteins

4. The iron economy

5. Adapted with permission from Andrews NC. N Engl J Med. 1999;341:1986–1995 Body Iron Distribution and Storage

6. We cope well with iron shortage… Iron deficiency is the most common deficiency state in the world –Blood loss –diet About 1000 mg of iron is stored as ferritin (1/3 of total body iron) Intestinal absorption of iron increases in response to deficiency

7. …but poorly with iron excess. Iron is excreted by shedding of intestinal cells There is no physiologic mechanism to excrete excessive iron

8. Blood transfusion overwhelms the iron balance Normal daily iron flux: 1-2 mg Each unit of PRBC: 200-250 mg

9. Summary: Iron is in a fine balance In normal circumstances, not much iron enters or leaves the body The body cannot increase its excretion of iron. Blood transfusions contain much iron, so patients who need frequent transfusions will build up excess iron.

10. Why too much iron is a bad thing

11. Dying RBC Reticuloendothelial System Free Iron Liver Heart Endocrine organs CIRRHOSIS ARRHYTHMIA HEART FAILURE DIABETES

12. Lessons from thalassaemia Hepatic fibrosis Cirrhosis Arrhythmia Hypogonadism Diabetes Hypothyroidism Hypoparathyroidism Cardiomyopathy

13. When does iron become a problem? Normally 2.5 – 3 grams of iron in the body. Tissue damage when total body iron is 7 – 15 grams –After 30-50 units of red blood cells

14. How do we know if theres too much iron? Serum ferritin concentration –Used in clinical practice globally Liver biopsy –Reference methodology (gold standard) Magnetic resonance imaging (MRI) –Investigational, potential for broad access

15. Serum Ferritin Concentration Easy Inexpensive Can be tricky – not purely iron –Inflammation (acute phase reactant) –Liver function abnormalities Not perfect marker in iron overload –What it lacks in accuracy it makes up for in part with world-wide availability

16. Liver Biopsy The Gold Standard Invasive Potentially risky Not often used in MDS Direct measurement of iron content

17. Magnetic Resonance Imaging Bright = high iron concentration; dark areas = low iron concentration

18. Iron overload impairs survival in MDS <1000 1000-1500 >2500 1500-2000 >1000 1000-1500 >2500 1500-2000 Proportion surviving 40 80 120 Survival time (months) Malcovati, Haematologica, 2006 RA, RARS, 5q- RCMD, RCMD-RS ? Ferritin

19. Summary: Too much iron is bad Iron overload caused by transfusions causes malfunction of the liver, heart, and endocrine organs. Problems may begin after 30 units of RBC (or even earlier) We use serum ferritin level to estimate iron levels –MRI might be better What can we do about it?

20. Iron chelation Out

21. Metal Chelator + Toxic Non-Toxic Chelate Outside the Body Metal What is Chelation Therapy?

22. How to chelate? Currently licensed in Canada: –Deferoxamine (Desferal) –Deferasirox (ICL670, Exjade) Alternative –Deferiprone (L1) Available on compassionate release

23. Deferoxamine: Mode of Action

24. Deferoxamine works! Survival of patients with thalassaemia No data like these are available for iron chelation in MDS

25. Challenges of Deferoxamine Subcutaneous/Intravenous route of administration –Expensive –Cumbersome –Uncomfortable Rapid metabolism (30 minute half-life) necessitates prolonged infusion (12-15 hours) Complications due to iron overload still occur due to poor compliance with therapy

26. Deferoxamine infusion

27. Common Side Effects of Deferoxamine Local reactions –Erythema (localized redness) –Induration (localized swelling) –Pruritus (itchiness) Ophthalmologic –Reduced visual acuity –Impaired color vision –Night blindness –Increased by presence of diabetes Hearing loss Zinc deficiency

28. Summary: Iron chelation and deferoxamine Chelation works by attaching a drug to iron, which allows the body to excrete it. Deferoxamine is awful stuff… –Inconvenient and uncomfortable to take –Many nasty side effects …but it works –Enormous extension of lifespan in thalassaemia.

29. ICL670: Deferasirox, Exjade n Oral, dispersible tablet n Taken once daily n Highly specific for iron n Chelated iron excreted mainly in faeces n Less than 10% excreted in the urine

30. Exjade works. Deferoxamine< 2525-3535-50 50 ICL6705102030 All doses in mg/kg/day g/L Deferoxamine 0107 ICL670 0107 ICL670 0108

31. Exjade is Generally Tolerable n The most common adverse events were mild and transient: –Nausea (10%) –Vomiting (9%) –Abdominal pain (14%) –Diarrhea (12%) –Skin rash (8%) n Rarely required discontinuation of drug n Reports of : n Kidney failure n Worsening of blood counts

32. Exjade is Available (…sort of) Health Canada approval received Oct 2006 –chronic iron overload in patients with transfusion- dependent anemias aged 6 years old and older. –chronic iron overload in patients with transfusion- dependent anemias aged 2 to 5 years old who cannot be adequately treated with deferoxamine Provincial formularies still need to decide whether to include Deferasirox.

33. What do the experts say?

34. Canadian Guidelines 2007 Why: to prevent end-organ complications of iron overload and extend lifespan Whom: transfusion-dependent patients with expected survival > 1 year or BMT candidates When: ferritin >1000, TfSat > 0.5 How: DSX 20 mg/kg/d or DFO 50 mg/kg/d 5/7; target ferritin<1000 Iron Overload in Myelodysplastic Syndromes: A Consensus Guideline. Submitted 2007

35. Summary Iron overload is an inevitable consequence of chronic RBC transfusion Iron toxicity affects the function of the liver, heart, and endocrine organs Chelation therapy should be offered to iron overloaded patients with life expectancy >1 year Desferal and Exjade are both effective.

36. Thank you!