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

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

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

The iron economy

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

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

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

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

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.

Why too much iron is a bad thing

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

Lessons from thalassaemia

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 units of red blood cells

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

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

Liver Biopsy LIC = Liver iron concentration. Reprinted with permission from Angelucci E, et al. N Engl J Med. 2000;343: patients with iron overload and cirrhosis  1 mg dry weight liver sample Hepatic iron concentration, mg/g dry weight Total body iron stores, mg/kg r = 0.98 LIC accurately reflects total body iron stores

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

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

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

Iron chelation Out

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

How to chelate? Currently licensed in Canada: –Deferoxamine Alternatives –Deferiprone (L1) Available on compassionate release –Deferasirox (ICL670, Exjade) Undergoing accelerated review by Health Canada

Deferoxamine: Mode of Action

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

Deferoxamine infusion

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

Are we certain it helps? Survival of patients with thalassaemia

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.

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

ICL670 works. Deferoxamine< ≥ 50 ICL All doses in mg/kg/day  g/L Deferoxamine 0107 ICL ICL

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 n No agranulocytosis observed

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.

What do the experts say?

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

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.

Thank you!