Iron Overload Wells

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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: 

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

The iron economy is well-balanced.: 

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

We cope well with iron shortage…: 

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.: 

…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: 

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

Summary: Iron is in a fine balance: 

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: 

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: 

Lessons from thalassaemia

When does iron become a problem?: 

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

How do we know if there’s too much iron?: 

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: 

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 : 

Liver Biopsy LIC = Liver iron concentration. Reprinted with permission from Angelucci E, et al. N Engl J Med. 2000;343:327-331. 25 patients with iron overload and cirrhosis  1 mg dry weight liver sample LIC accurately reflects total body iron stores

Magnetic Susceptometry (SQUID): 

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: 

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

Summary: Too much iron is bad: 

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: 

Iron chelation Out

What is Chelation Therapy?: 

Chelator + Chelator Toxic Non-Toxic 'Chelate' Outside the Body What is Chelation Therapy?

How to chelate?: 

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: 

Deferoxamine: Mode of Action

Challenges of Deferoxamine: 

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: 

Deferoxamine infusion

Common Side Effects of Deferoxamine: 

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?: 

Are we certain it helps? Survival of patients with thalassaemia

Summary: Iron chelation and deferoxamine: 

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: 

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

ICL670 works.: 

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

ICL670 is Generally Tolerable: 

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

When can we have Exjade?: 

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?: 

What do the experts say?

Recommended Treatment for Iron Overload in MDS: 

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 andgt; 1 year When: after 25 units RBC transfused, ferritin andgt;1000. How: Desferal by subcutaneous infusion (for now); keep ferritinandlt;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 andgt;1 year Desferal is the only drug currently available; Exjade will be available soon.

Thank you!: 

Thank you!

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