Iron Overload in Chronic Anaemias

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

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. The iron economy is well-balanced. 70% 30%

6. We cope well with iron shortage… • Iron deficiency is the most common deficiency state in the world • Blood loss • dietary • 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

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 • Magnetic susceptometry (SQUID) • Investigational, very limited 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. 300 r = 0.98 250 200 150 Total body iron stores, mg/kg 100 50 0 0 5 10 15 20 25 Hepatic iron concentration, mg/g dry weight Liver Biopsy 25 patients with iron overload andcirrhosis  1 mg dry weight liver sample • LIC accurately reflects total body iron stores LIC = Liver iron concentration. Reprinted with permission from Angelucci E, et al. N Engl J Med. 2000;343:327-331.

17. Magnetic Susceptometry (SQUID) • Superconducting QUantum Interference Device • High-power magnetic field • Iron interferes with the field • Changes in the field are detected • Noninvasive, sensitive, and accurate • Limited availability • Superconductor requires high maintenance • Only 4 machines worldwide Photograph courtesy of A. Piga

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

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

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 • Alternatives • Deferiprone (L1) • Available on compassionate release • Deferasirox (ICL670, Exjade) • Undergoing accelerated review by Health Canada

23. Deferoxamine: Mode of Action

24. 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

25. Deferoxamine infusion

26. 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

27. Are we certain it helps? Survival of patients with thalassaemia

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. ICL670 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. ICL670 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 study drug • Mild increases in serum creatinine • No agranulocytosis observed

32. When can we have Exjade? • Already FDA-approved in the USA • Health Canada approval expected September 2006 • Provincial formularies will need to decide whether to include Exjade.

33. What do the experts say?

34. Recommended Treatment for Iron Overload in MDS • Why: to prevent end-organ complications of iron overload and extend lifespan • Whom: transfusion-dependent patients with expected survival > 1 year • When: after 25 units RBC transfused, ferritin >1000. • How: Desferal by subcutaneous infusion (for now); keep ferritin<1000

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 is the only drug currently available; Exjade will be available soon.

36. Thank you!