Iron Overload in Chronic Anaemias

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 body’s iron is in these proteins

4. The iron economy

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

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. Normal daily iron flux: 1-2 mg Each unit of PRBC: Blood transfusion overwhelms the iron balance 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. Free Iron Reticuloendothelial System Dying RBC Liver Endocrine organs CIRRHOSIS Heart DIABETES ARRHYTHMIA HEART FAILURE

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

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 there’s 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 RA, RARS, 5q- RCMD, RCMD-RS <1000 >1000 1000-1500 1000-1500 Ferritin Ferritin 1500-2000 1500-2000 >2500 >2500 Proportion surviving ? 40 80 120 40 80 120 Survival time (months) Malcovati, Haematologica, 2006

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 Metal What is Chelation Therapy? Toxic Non-Toxic Chelator Chelator OutsidetheBody + “Chelate”

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 • Oral, dispersible tablet • Taken once daily • Highly specific for iron • Chelated iron excreted mainly in faeces • Less than 10% excreted in the urine

30. Exjade works. Deferoxamine 0107 ICL670 0107 ICL670 0108 g/L Deferoxamine < 25 25-35 35-50 ≥ 50 ICL670 5 10 20 30 All doses in mg/kg/day

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