iron overload in haemoglobinopathies dr farrukh shah consultant haematologist joint red cell...

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