1. Thalassemia Center 1 Iron Overload in Chronic Anaemias

2. Thalassemia Center 2 We cope well with iron shortage…

3. Thalassemia Center 3 …but poorly with iron excess. There is no physiologic mechanism to excrete excessive iron

4. Thalassemia Center 4 Blood transfusion overwhelms the iron balance Normal daily iron flux: 1-2 mg Each unit of PRBC: 200-250 mg

5. Thalassemia Center 5 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.

6. Thalassemia Center 6 Why too much iron is a bad thing

7. Thalassemia Center 7 Dying RBC Free Iron Liver Heart Endocrine organs CIRRHOSIS ARRHYTHMIA HEART FAILURE DIABETES

8. Thalassemia Center 8 Lessons from thalassaemia

9. Thalassemia Center 9 When does iron become a problem? Tissue damage when total body iron is 7 – 15 grams –After 30-50 units of red blood cells

10. Thalassemia Center 10 How do we know if there’s too much iron? Serum ferritin concentration Liver biopsy Magnetic resonance imaging (MRI)

11. Thalassemia Center 11 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

12. Thalassemia Center 12 Iron chelation Out

13. Thalassemia Center 13 Metal Chelator + Toxic Non-Toxic “Chelate” Outside the Body Metal What is Chelation Therapy?

14. Thalassemia Center 14 How to chelate? –Deferoxamine –Deferiprone (L1) –Deferasirox (ICL670, Exjade)

15. Thalassemia Center 15 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

16. Thalassemia Center 16 Are we certain it helps? Survival of patients with thalassaemia

17. Thalassemia Center 17 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.

18. Thalassemia Center 18 ICL670: Deferasirox, Exjade n Oral, dispersible tablet n Taken once daily n Highly specific for iron

19. Thalassemia Center 19 ICL670 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 study drug n Mild increases in serum creatinine

20. Thalassemia Center 20 What do the experts say?

21. Thalassemia Center 21 Recommended Treatment for Iron Overload 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

22. Thalassemia Center 22 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 Desferal is the drug currently STOOD TEST OF TIME ; Exjade is available too.

23. Thalassemia Center 23 Thank you!