CU-1 Iron Overload: Complications and Need for Therapy John B. Porter, MD Professor of Hematology University College, London, UK.

CU-1

Iron Overload: Complications and Iron Overload: Complications and Need for TherapyNeed for Therapy

John B. Porter, MDProfessor of HematologyUniversity College, London, UK

CU-2

Iron Distribution & Turnover In HumansIron Distribution & Turnover In Humans

Erythron 2g

Macrophages 0.6g

Transferrin 3mg 20-30 mg/day2-3mg/day

1-2 mg day

Gut

20-30mg/day

20-30 mg/day

Adapted with permission from Porter JB; Hematol/Oncol Clinics 2005; 19, 1-6. Andrews NC. N Engl J Med. 1999; 341:1986-1995.

Parenchyma0.3g

Liver1g

CU-3

Iron Loading From Blood TransfusionsIron Loading From Blood Transfusions

1 unit of blood contains approximately 200 mg of irona

– Normally, total body iron is approximately3 to 4 g

– Chronic transfusion-dependent patients have an iron excess of 0.3 to 0.7 mg/kg/day, equivalent to 4 to 10 g of iron per yearb

Iron accumulates with repeated blood transfusion

a Porter JB. Br J Haematol. 2001;115:239-252.b Andrews NC. N Engl J Med. 1999;341:1986-1995.

CU-4

Parenchyma

Hepatocytes

Hepatocytes

Parenchyma

Transfusional Iron OverloadTransfusional Iron Overload

Red

Erythron

Macrophages

Gut

Transfusion

20-40mg/day(0.3- 0.7 mg/kg/d)

NTBI

Transferrin

Adapted with permission from Porter JB; Hematol/Oncol Clinics 2005 19,1-6

CU-5

Organ Systems Affected byOrgan Systems Affected byIron OverloadIron Overload

Pituitary gland

Heart

Liver

Pancreas

Gonadal

• Iron overload results in non–transferrin-boundiron in the plasma

• Increased iron uptake into selective organs

• Generation of free hydroxyl radicals

Tissue damage

CU-6

Complications of Iron OverloadComplications of Iron Overload

Cardiomyopathy and cardiac failure

Hepatic cirrhosis

Diabetes mellitus

Impaired growth

Hypogonadism and infertility

Andrews NC. N Engl J Med. 1999;341:1986–1995

CU-7

Diseases Associated WithDiseases Associated WithTransfusional Iron OverloadTransfusional Iron Overload

β-thalassemiaOther chronic anemias

– Fanconi anemia (hypoplastic anemia)

– Diamond-Blackfan anemia (red cell aplasia)

– Congenital dyserythropoietic anemiasSickle cell anemiaAplastic anemiaMyelodysplastic syndromes (MDS)

Andrews NC. N Engl J Med. 1999;341:1986-1995.

CU-8

Initiation of Therapy for Iron OverloadInitiation of Therapy for Iron OverloadCurrent PracticeCurrent Practice

With repeated blood transfusions, iron rapidly accumulates in the body

– Chelation treatment is generally initiated after 10 to 20 transfusions or when serum ferritin > 1000 µg/L

– Alternatively, if iron loading is unclear, LIC may be measured

LIC = Liver iron concentration.Porter JB. Br J Haematol. 2001;115:239-252.

CU-9

Liver Iron Concentration Accurately Liver Iron Concentration Accurately Reflects Total Body Iron StoresReflects Total Body Iron Stores

Reprinted with permission from Angelucci E, et al. N Engl J Med. 2000;343:327-331.

Liver iron concentration (LIC), 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

• Stores calculated by

quantitative phlebotomy

• LIC measured from

biopsy samples ≥ 1 mg

dry weight in 25 patients

Body iron (mg/kg) = 10.6 x LIC (mg/g dry wt)

CU-10

HH heterozygotes

50403020100

50

100

150

200

250

Age, years

Hep

atic

iro

n, µ

mo

l/g w

et w

eig

ht

50

40

30

20

10

0

Hep

atic

iro

n, m

g/g

dry

wei

gh

t

Threshold for cardiac disease and early death

Increased risk of complications

Normal

Olivieri & Brittenham, 1997 Blood. 89; 739-761.

Thalassemia major

Liver Iron and Risk of Complications From Liver Iron and Risk of Complications From Iron OverloadIron Overload

0

CU-11

Plasma Ferritin as a Plasma Ferritin as a Monitor of Iron LoadingMonitor of Iron Loading

Relatively non-invasive Inexpensive Obtained as

routine laboratory assay

Values confounded by

– Inflammation

– Liver function

0 4000 8000 12000

24,000

12,000

8000

4000

0

Hepatic iron, µg Fe/g liver *

Pla

sma

ferr

itin

, µ

g/L

Brittenham et al. Am J Hematol. 1993;42:81.

Sickle cell anemia (n = 37)

Thalassemia major (n = 74)

CU-12

Liver Iron Concentration and Serum Liver Iron Concentration and Serum FerritinFerritin

Change in serum ferritin over time reflects change in LIC

– Sequential evaluation of ferritin levels provides a good index of chelation historya

Maintenance of serum ferritin < 2500 µg/L significantly correlates with cardiacdisease-free survivalb,c,d,e

a Gabutti V and Piga A. Acta Haematol. 1996;95:26-36.b Olivieri NF, et al. N Engl J Med. 1994;331:574-578. c Telfer PT, et al. Br J Haematol. 2000;110:971-977.d Davis BA, et al. Blood. 2004;104:263-269.e Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-1193.

CU-13

Cardiac Disease and % of Time WithCardiac Disease and % of Time WithSerum Ferritin > 2500 µg/LSerum Ferritin > 2500 µg/L

Olivieri, et al. N Engl J Med. 1994;331:574.

Assessments > 2500 µg/L

1.00

0.75

0.50

0.25

00 2 4 6 8 10 12 14 16

Years of chelation therapy

Pro

po

rtio

n w

ith

ou

tc

ard

iac

dis

ea

se

< 33%33% - 67%> 67%

CU-14

Ideal Properties of an Iron ChelatorIdeal Properties of an Iron Chelator

Control of body iron Prevention of iron mediated organ toxicity Simplicity and ease of administration Once daily oral administration Suitable for monotherapy Acceptable toxicity profile

– Iron free drug - dose relationship

– Iron complex - stable no redistribution of iron Simplicity and ease of monitoring

CU-15

Current Therapy for Iron OverloadCurrent Therapy for Iron Overload

Deferoxamine (Desferal®) is the only drug available in US to treat iron overload

Because of short half-life (20 minutes), must be given by continuous infusion

– 8 to 12 hours/day, 5 to 7 days/week

Compliance is poor because ofside effects and quality-of-life issues

Oral therapy is highly desirable

Porter JB and Huehns CR. Baillieres Clin Haematol. 1989;2:459-474.

CU-16

Compliance With Deferoxamine Infusions Compliance With Deferoxamine Infusions Is Related to Survival in ThalassemiaIs Related to Survival in Thalassemia

Kaplan-Meier analysis of survival in 257 consecutive thalassemic patientsaccording to the mean compliance with subcutaneous DFO therapy

Age, years

Su

rviv

al,

%

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

0 - 75

75 - 150

150 - 225

225 - 300

300 - 365

Gabutti V and Piga A. Acta Haematol. 1995;95:26-36.

Deferoxamineinfusions/year

CU-17

Summary of Medical NeedSummary of Medical Need

Transfusional therapy results in iron overload

Currently, the only approved therapy for iron overload in US is deferoxamine, which requires subcutaneous infusion for 8 to 12 hours, 5 to 7 times per week

– Compliance is an issue

– Many patients are not adequately treated

Treadwell MJ, et al. Pediatr Blood Cancer. 2005;44:500-507.Porter JB and Huehns CR. Baillieres Clin Haematol. 1989;2:459-474.

CU-18

Summary of Medical NeedSummary of Medical Need

Inadequately treated iron overload leads toorgan toxicity

– Related to lack of control of reactive iron, and deposition of iron in key tissues

– Developmental and endocrine dysfunction

– Cardiac dysfunction results in early death

Beutler E, et al. Hematology (Am Soc Hematol Educ Program). 2004:40-61.