Iron Overload in Chronic Anaemias

Dick Wells MD, DPhil, FRCPCDirector, 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:

200-250 mg200-250 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 organsCIRRHOSIS

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 30-50 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;343:327-331.

25 patients with iron overload andcirrhosis

1 mg dry weight liver sample

Hepatic iron concentration, mg/g dry weight

To

tal

bo

dy

iro

n s

tore

s, m

g/k

g

0 5 10 15 20 25

300

250

200

150

100

50

0

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

MetalChelatorChelator + ChelatorChelator

Toxic Non-Toxic

“Chelate”

Outsidethe

BodyMetal

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

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.

Deferoxamine < 25 25-35 35-50 ≥ 50ICL670 5 10 20 30

All doses in mg/kg/day

-3000

-2000

-1000

0

1000

2000

3000

4000

Desferal 0107

ICL670 0107

ICL670 0108

g/L

Deferoxamine 0107

ICL670 0107

ICL670 0108

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?

• 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!