iron overload in haemoglobinopathies

Dr Farrukh ShahConsultant haematologist

Joint Red cell disorders unitWhittington hospital and UCLH

Why?

Erythron

MacrophagesHepatocytes & other

parenchymaTransferrin

Transfusion

20-30mg/day(0,4 mg/kg/day)

NTBI

20-30mg/day

Iron turnover in transfusional overload

Gut

Sources of iron overload in haemoglobinopathy patients

• Dietary iron overload– Thalassaemia intermedia patients– Thalassaemia trait patients given oral iron to

correct anaemia • Intermittent transfusion

– Sickle cell anaemia– Thalassaemia intermedia

• Regular transfusion therapy

-Transfusional Iron Overload

– Normal total body iron (TBI) 3-5g – Transfusional iron overload

without chelation

• 1 unit of Packed Red Blood Cells (PRBC)= 200 mg Fe

• A patient receiving 2-4 units/month receives 4 to 10 grams of iron per year

• Porter JP. Br J Haematol. 2001;115:239-252.

Consequences of iron overload

Organ Systems Affected byIron 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

Fatal Complications of iron overload

• Cardiac– Dysrhythmias– Heart failure

• Infections• Liver

– iron overload, cirrhosis– viral hepatitis– failure

non fatal complications of iron overload

• Growth failure• Sexual development & fertility• Diabetes• Hypothyroidism• Hypoparathydroidism• Osteoporosis

Complication-free survival of Italian β-thalassaemia major patients

Borgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.

Surv

ival

pro

babi

lity

p < 0.000050

1.00

0.75

0.50

0.25

0 5 10 15 20 25 30

Age (years)

Birth cohort

1960–19641965–19691970–19741975–19791980–19841985–1997

HR = hazard ratio.

Monitoringiron overload

Why monitor

• For adequacy of treatment– Transfusion– Chelation

• For complications of chelation

Monitoring iron overload

• Tissue iron estimation– Ferritin– Liver iron– Cardiac iron

• Effects of iron overload on function– Heart– Endocrine

• Pituitary damage• Diabetes• Hypothyroidism• Hypoparathyroidism

Serum ferritin reflects

• Iron stores• Recent chelation and type of chelation• Inflammation • Tissue damage• Ascorbate status

Serum ferritin underestimates iron burden in β-thalassaemia intermedia

Origa R, et al. Haematologica. 2007;92:583-8.Taher A, et al. Haematologica. 2008;93:1584-5.

0 5 10 15 20 25 30 35

LIC (mg/g dry wt)

Ser

um

fer

riti

n (

μg

/L)

2,000

4,000

6,000

8,000

10,000

12,000

14,000

0

β-Thalassaemia intermedia

β-Thalassaemia major

Ser

um

fer

riti

n (

μg

/L)

0 5 10 15 20 25 30 35 40 45 50

LIC (mg/g dry wt)

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

10,000

0

β-Thalassaemia intermedia

β-Thalassaemia major

Relationship between cardiac T2* and cardiac failure

Kirk P, et al. Circulation. 2009;120:1961-8.

0

0.1

0.2

0.3

0.4

0.5

0.6

0 30 60 90 120 150 180 210 240 270 300 330 360

Prop

ortio

n of

pati

ents

de

velo

ping

car

diac

failu

re

Follow-up time (days)

< 6 ms

6–8 ms

8–10 ms

> 10 ms

Chelator effect on ferritin

Ang, Ai leen et al ASH 2010

N=84 DFO DFX DFP Median LIC (mg/kg dw) 5 (1.2-30.6) 4.8 (0.8-36.5) 5 (0.5-34.9) Median SF (µg/L) 1927 (1378-

5182) 1713 (312-6085)

1142 (133-2897)

Median SFaverage (µg/L) 2147 (950-6063) 2006 (773-7290)

1240 (230-2734)

Median SF/LIC (µgL-1/µgg-1)

523 (120-1562) 403 (52-1188) 181 (56-910)

Predicted LIC (95% confidence interval) (mg/kg dw) at: - SF 1000 µg/L - SF 2000 µg/L - SF 4000 µg/L

1.9 (0-4.9) 4.4 (2.8-5.9) 9.3 (5.1-13.5)

2.8 (1.9-3.7) 5 (4.2-5.8) 9.5 (7.3-11.6)

5.1 (3.2-6.9) 9.4 (6.8-12.0) 18 (11.1 -24.9)

Why is measurement of liver iron concentration (LIC) important?

• A patient’s LIC value is the best measure of total body iron stores

• A patient’s LIC value enables better informed decisions on when to

– Initiate chelation therapy– Increase chelation dose– Decrease chelation dose– Change mode of chelator delivery (e.g. iv mode)

Bo

dy

iro

n s

tore

s (m

g/k

g)

300

250

200

150

100

50

0

0 5 10 15 20 25

Hepatic iron concentration (mg/g dry wt)

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

Sample < 1 mg dry wt (n = 23)

Angelucci E, et al. N Engl J Med. 2000;343:327-31.

Liver iron concentration predicts total body iron stores

r = 0.83

Bo

dy

iro

n s

tore

s (m

g/k

g)

300

250

200

150

100

50

0

0 5 10 15 20 25

Hepatic iron concentration (mg/g dry wt)

r = 0.98

Sample > 1 mg dry wt (n = 25)

Example: FerriScan® measurements to monitor iron chelation therapy

Before chelation therapy intervention

Mean LIC = 16.0

After 12 months of chelation therapy intervention

Mean LIC = 1.6

Cardiac monitoring in Iron Overload

• Functional– LVEF

• Echo, MUGA, MRI

– Rhythmicity• Resting/Exercise ECG• 24h ECG

• Iron loading:• Low cardiac t2* associated with low LVEF

Severe cardiac ironMinimal liver iron.

Severe liver ironMinimal cardiac iron.

Discordance of liver and heart iron

0102030405060708090

100

Causes of death in β-thalassaemia major in the UK

Adapted from UK Thalassaemia Registry data from Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42.Thomas AS, et al. Blood. 2010;116:[abstract 1011].

Mortality rates per cohort

Patie

nts

(%)

Hepatitis C complicationsOther/unknownMalignancyInfectionBMT complicationAnaemiaIron overload

1950–19591960–19691970–19791980–19891990–19992000–2003Th

is cohort

BMT = bone marrow transplantation;CMR = cardiac magnetic resonance imaging

Absence of cardiac siderosis despite elevated LIC and serum ferritin in

Lebanese patients with SCD

Inati A, et al. Eur J Haematol. 2009;83:565-71.

50

45

40

35

30

25

20

15

10

5

0

0 1,000 2,000 3,000 4,000

Serum ferritin (µg/L)

High serum ferritin

Normal T2*

Card

iac

T2*

(mse

c)

p = NS

Sample size: 23 patients (17 SS, 6 ST)

Normal T2*

p = NS

Management of iron overload

Chelators in clinical use

• Desferrioxamine– 20- 40mg/kg/day 8-10h 5-6 x/week– start at 3y or ferritin ≥ 1000µg/L

• Deferiprone – (L1) 75 mg/kg/day in 3 divided doses

• Exjade (ICL670)– 20-30mg/kg/day once daily

• FSB0701 in phase 2

Effect of DFO IV infusion on removal and return of NTBI

( Porter et al, Blood 1996 )

544842363024181260- 6-

-1

0

1

2

3

4

5

6

7

NTBPI (µM)

DFO (µM)

Time (h)

NT

BI

or D

FO

(µ

M)

Compliance with deferoxamine and its impact on survival

Gabutti V, Piga A. Acta Hematol .1996;95:26-36.

50

0–20%

30 40

25

75

100

Cum

ulati

ve %

sur

viva

l

2010

20–40%

40–60%

60–80%

80–100%

Time (years)

300–365225–300150–22575–1500–75

Infusions/year

Complications of Desferrioxamine

• Immediate– Local skin reactions– Allergy

• Infection: yersinia, other G-• Dose related:

– Hearing problems– Eye complications– Growth retardation– Skeletal changes– rare

Deferiprone (Ferriprox®, L1)

● Indication (Europe)– ‘Treatment of iron overload in

patients with thalassaemia major when DFO therapy is contraindicated or inadequate’1

● Oral three times a day (short plasma half life)

● Decreases serum ferritin when baseline levels high

● Variable effects on liver iron

1. Ferriprox [package insert]. Apotex Europe Ltd, 20042. Pennell et al, Blood 2006 Vol 107; 3738-3744

Pharmacokinetics of deferiprone(Kontoghiorghes et al, 1990)

0 100 200 300 400

140

120

100

80

60

40

20

0

Time (minutes)

Glucuronide Deferiprone

Con

cent

ratio

n (µ

M)

t1/2 1.52 hours

Side effects

• Neutropenia: 3.9%• Agranulocytosis: 0.5-0.9%• Gastrointestinal: 3-33%• liver: 1-3% • Joint pains: 4-15%• Neurological complications in high doses

• High drop out rate:

– Ceci study 124/532

– Cohen study 103/187

Cardioprotective effect61patients DFO 43mg/kg/day for 5.7 days vrs DFP 92mg/kg/dayT2* and EF improved more in the DFP group

Pennell et al; Blood, 1 May 2006, Vol. 107, No. 9, pp. 3738-3744.

deferasirox Nick H, Current Medicinal Chemistry. 2003; 10: 1065-1076

• Tridentate iron chelator (high specificity)

• High therapeutic safety in animal data

• Lipophilic but protein bound

• Renal target in animal toxicology

• Long plasma half life in humans

• Excreted in faeces only

• Given as once daily drink

(dispersible tablet)

NNNN

NN

OHOHHOHO

OHOHOO

Safety profile over time in patients with β-thalassaemia major

Cappellini MD, et al. Blood. 2011;118:884-93.

Pat

ien

ts (

%)

Adverse event

10

8

6

4

2

0

9

7

5

3

1

Increased bloodcreatinine

Abdominalpain*

Nausea VomitingRash Diarrhoea

Year 1 (n = 296)Year 2 (n = 282)Year 3 (n = 234)Year 4 (n = 213)Year 5 (n = 196)

* Reports of abdominal pain and abdominal pain are combined and presented as abdominal pain.

Patients, n

< 10 ms 24 24 24 24

10–< 20 ms 47 47 47 44

All patients 71 71 71 68

Cardiac iron reduction with deferasirox: continued improvement in cardiac T2*

Pennell D, et al. Haematologica. 2012 Jan 22. [Epub ahead of print].CI = confidence interval; LOCF = last observation carried forward.

†p = 0.0012 versus baseline; ‡p < 0.001 versus baselineDashed line indicates normal cardiac T2* of ≥ 20 ms

10.5‡

7.78.6† 9.4‡

15.0

17.7‡

20.3‡

22.3‡

Baseline 12 24 36

Time (months)

Geo

met

ric m

ean

T2*

± 95

% C

I (m

s)

> 5–< 10 ms 10–< 20 ms All patients

0

5

10

20

30

15

25

17.1‡

15.6‡

13.9‡

12.0

Impact of monitoring on outcomes

A decade of cardiac monitoring at the UCLH/Whittington Hospital

• Cohort of 132 patients received first CMR 1999–2000

• 109 of these available for long-term CMR follow-up‒ follow-up median 9.2 years (range 7.0–10.6)‒ minimum CMR follow-up of 7 years‒ median age at first CMR 27.9 years (range 7.7–49.5)‒ 58 females, 51 males

Thomas AS, et al. Blood. 2010;116:[abstract 1011]. UCLH = University College London Hospital.

Cohort of 132 patients from UCLH/Whittington hospital

BaselineMedian 9 years follow-up

Pro

po

rtio

n o

f p

atie

nts

(%

)

70

50

30

10

0

60

40

20

T2* ≤ 20 ms T2* < 10 ms

60

23

17

7

p < 0.001

p < 0.001

Thomas AS, et al. Blood. 2010;116:[abstract 1011].

The proportion of patients with cardiac iron overload decreased 3-fold in a

decade

0102030405060708090

100

Causes of death in β-thalassaemia major in the UK

Adapted from UK Thalassaemia Registry data from Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42.Thomas AS, et al. Blood. 2010;116:[abstract 1011].

Mortality rates per cohort

Pat

ien

ts (

%)

Hepatitis C complicationsOther/unknownMalignancyInfectionBMT complicationAnaemiaIron overload

1950

–195

919

60–1

969

1970

–197

919

80–1

989

1990

–199

920

00–2

003

This

coho

rtBMT = bone marrow transplantation;CMR = cardiac magnetic resonance imaging

Ferriscan liver iron monitoringWhittington audit

• Ferriscan part of routine monitoring from December 2007

• 94 TM patients with at least 2 scans between January 2008-December 2011

Long term

Patient 1

• 30 year old TM• Arrives in UK as a highly skilled migrant • Heavy iron overload in arrival in 2008

– Marked skin deposition – Ferriscan liver iron >43mg/g/dw– No myocardial iron loading– Spontaneous puberty

• Initial treatment is deferiprone, agrees to start deferasirox

Patient 1

• Spontaneous conception on exjade! Around 9 months post arrival in UK!

• Immediately stops deferasirox• Healthy baby delivered in 2009• restarts deferasirox at 40mg/kg/day• Almost fully compliant initially

•In 2011 compliance becomes a challenge•Ferriscan bought forwards