iron overload in - PowerPoint Presentation

Slide1

iron overload in haemoglobinopathies

Dr Farrukh Shah

Consultant haematologist

Joint Red cell disorders unit

Whittington hospital and UCLHSlide2

Why?Slide3

Erythron

Macrophages

Hepatocytes

& other

parenchyma

Transferrin

Transfusion

20-30mg/day

(0,4 mg/kg/day)

NTBI

20-30mg/day

Iron turnover in

transfusional

overload

GutSlide4

Sources of iron overload in haemoglobinopathy

patients

Dietary iron overload

Thalassaemia intermedia patientsThalassaemia trait patients given oral iron to correct anaemia Intermittent transfusionSickle cell anaemiaThalassaemia intermedia Regular transfusion therapySlide5

-

Transfusional Iron Overload

Normal total body iron (TBI) 3-5g

Transfusional iron overload without chelation1 unit of Packed Red Blood Cells (PRBC)= 200 mg FeA patient receiving 2-4 units/month receives 4 to 10 grams of iron per year Porter JP. Br J Haematol. 2001;115:239-252.Slide6

Consequences of iron overloadSlide7

Organ Systems Affected by

Iron Overload

Pituitary gland

Heart

Liver

Pancreas

Gonadal

Iron overload results in n

on

–

transferrin

-b

ound

iron in the plasma

Increased iron uptake into selective organs

Generation of free hydroxyl radicals

Tissue damageSlide8

Fatal Complications of iron overload

Cardiac

Dysrhythmias

Heart failureInfectionsLiver iron overload, cirrhosisviral hepatitisfailureSlide9

non fatal complications of iron overload

Growth failure

Sexual development & fertility

DiabetesHypothyroidismHypoparathydroidismOsteoporosisSlide10

Complication-free survival of

Italian

β-

thalassaemia major patientsBorgna-Pignatti C, et al. Haematologica. 2004;89:1187-93.

Survival probability

p < 0.00005

0

1.00

0.75

0.50

0.25

0

5

10

15

20

25

30

Age (years)

Birth cohort

1960–1964

1965–1969

1970–1974

1975–1979

1980–1984

1985–1997

HR = hazard ratio.Slide11

Monitoring

iron overloadSlide12

Why monitor

For adequacy of treatment

Transfusion

ChelationFor complications of chelationSlide13

Monitoring iron overload

Tissue iron estimation

Ferritin

Liver ironCardiac ironEffects of iron overload on functionHeartEndocrinePituitary damageDiabetesHypothyroidismHypoparathyroidismSlide14

Serum ferritin reflects

Iron stores

Recent chelation and type of chelation

Inflammation Tissue damageAscorbate statusSlide15

Serum ferritin underestimates iron burden in

β

-

thalassaemia intermediaOriga R, et al. Haematologica. 2007;92:583-8.Taher A, et al. Haematologica. 2008;93:1584-5.05101520253035

LIC (mg/g dry wt)

Serum ferritin (μg/L)

2,000

4,000

6,000

8,000

10,00012,000

14,000

0

β

-Thalassaemia intermedia

β

-Thalassaemia major

Serum ferritin (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 majorSlide16

Relationship between cardiac T2* and cardiac failure

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

0

0.10.20.30.40.50.60306090120150

180210

240

270300

330

360Proportion of patients developing cardiac failure

Follow-up time (days)

< 6 ms

6–8 ms

8–10 ms

> 10 msSlide17

Chelator effect on ferritin

Ang

, Ai

leen et al ASH 2010N=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

(µ

g/L)

1927

(1378

-

5182)

1713

(312

-

6085)

1142

(

133

-

2897

)

Median SFaverage

(µ

g/L)

2147

(950

-

6063)

2006

(773

-

7290)

1240

(230

-

2734)

Median

SF/LIC

(µ

gL

-

1

/µ

gg

-

1

)

523

(120

-

1562)

4

03

(

5

2

-

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)

Slide18

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 therapyIncrease chelation doseDecrease chelation doseChange mode of chelator delivery (e.g. iv mode)Slide19

Body iron stores (mg/kg)

300

250

200150100500

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

Body iron stores (mg/kg)

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)Slide20

Example: FerriScan® measurements to monitor iron chelation therapy

Before chelation therapy intervention

Mean LIC = 16.0

After 12 months of chelation therapy interventionMean LIC = 1.6Slide21

Cardiac monitoring in Iron Overload

Functional

LVEF

Echo, MUGA, MRIRhythmicityResting/Exercise ECG24h ECG Iron loading:Low cardiac t2* associated with low LVEFSlide22

Severe cardiac iron

Minimal liver iron.

Severe liver iron

Minimal cardiac iron. Discordance of liver and heart ironSlide23

0

10

20

30405060708090100Causes of death in β-thalassaemia major in the UKAdapted 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

Patients (%)

Hepatitis C complications

Other/unknownMalignancyInfection

BMT complicationAnaemiaIron overload

1950–1959

1960–19691970–1979

1980–1989

1990–1999

2000–2003

This cohort

BMT = bone marrow transplantation;

CMR = cardiac magnetic resonance imagingSlide24

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. 504540353025201510500

1,000

2,0003,000

4,000Serum ferritin (µg/L)

High serum ferritin

Normal T2*

Cardiac T2* (msec)

p = NS

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

Normal T2*

p = NSSlide25

Management of iron overloadSlide26

Chelators in clinical use

Desferrioxamine

20- 40mg/kg/day 8-10h 5-6 x/week

start at 3y or ferritin ≥ 1000µg/LDeferiprone (L1) 75 mg/kg/day in 3 divided dosesExjade (ICL670)20-30mg/kg/day once dailyFSB0701 in phase 2Slide27
Slide28

Effect of DFO IV infusion on removal and return of NTBI

( Porter et al, Blood 1996 )

54

4842363024181260- 6

-

-1

0

1

2

3

4

5

6

7

NTBPI

(µ

M

)

DFO

(µ

M

)

Time (h)

NTBI or DFO

(µM)Slide29

Compliance with deferoxamine and its impact on survival

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

50

0–20%30

4025

75

100

Cumulative % survival

20

10

20–40%

40–60%

60–80%

80–100%

Time (years)

300

–

365

225

–

300

150

–

225

75

–

150

0

–

75

Infusions/yearSlide30

Complications of

Desferrioxamine

Immediate

Local skin reactionsAllergyInfection: yersinia, other G-Dose related:Hearing problemsEye complicationsGrowth retardationSkeletal changesrareSlide31

Deferiprone (Ferriprox

®

, L1)Indication (Europe)‘Treatment of iron overload in patients with thalassaemia major when DFO therapy is contraindicated or inadequate’1Oral three times a day (short plasma half life)Decreases serum ferritin when baseline levels highVariable effects on liver ironFerriprox [package insert]. Apotex Europe Ltd, 20042. Pennell et al, Blood 2006 Vol 107; 3738-3744Slide32

Pharmacokinetics of deferiprone

(Kontoghiorghes et al, 1990)

0 100 200 300 400

140

120

100

80

60

40

20

0

Time (minutes)

Glucuronide

Deferiprone

Concentration (µM)

t

1/2

1.52 hoursSlide33

Side effects

Neutropenia: 3.9%

Agranulocytosis: 0.5-0.9%

Gastrointestinal: 3-33%liver: 1-3% Joint pains: 4-15%Neurological complications in high dosesHigh drop out rate: Ceci study 124/532 Cohen study 103/187Slide34

Cardioprotective effect

61patients DFO 43mg/kg/day for 5.7 days vrs DFP 92mg/kg/day

T2* and EF improved more in the DFP group

Pennell et al; Blood, 1 May 2006, Vol. 107, No. 9, pp. 3738-3744.Slide35

deferasirox

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

Tridentate iron chelator (high specificity)High therapeutic safety in animal dataLipophilic but protein boundRenal target in animal toxicology Long plasma half life in humansExcreted in faeces onlyGiven as once daily drink (dispersible tablet)NNNOHHOOH

OSlide36

Safety profile over time

in patients with

β-thalassaemia majorCappellini MD, et al. Blood. 2011;118:884-93.Patients (%)Adverse event10864209

7

53

1

Increased blood

creatinine

Abdominal

pain*

Nausea

Vomiting

Rash

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.Slide37

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 baseline

Dashed line indicates normal cardiac T2* of ≥

20 ms

10.5

‡

7.7

8.6

†

9.4

‡

15.0

17.7

‡

20.3

‡

22.3

‡

Baseline

12

24

36

Time (months)

Geometric mean T2*

± 95% CI (ms)

> 5

–< 10 ms

10

–< 20 ms

All patients

0

5

10

20

30

15

25

17.1

‡

15.6

‡

13.9

‡

12.0Slide38

Impact of monitoring on outcomes Slide39

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-upfollow-up median 9.2 years (range 7.0–10.6)minimum CMR follow-up of 7 yearsmedian age at first CMR 27.9 years (range 7.7–49.5)58 females, 51 malesThomas AS, et al. Blood. 2010;116:[abstract 1011]. UCLH = University College London Hospital.Slide40

Cohort of 132 patients from UCLH/Whittington hospital

Baseline

Median 9 years follow-up

Proportion of patients (%)70503010

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 decadeSlide41

0

10

20

30405060708090100Causes of death in β-thalassaemia major in the UKAdapted 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

Patients (%)

Hepatitis C complications

Other/unknownMalignancyInfection

BMT complicationAnaemiaIron overload

1950–1959

1960–1969

1970–1979

1980–19891990–1999

2000–2003

This cohort

BMT = bone marrow transplantation;

CMR = cardiac magnetic resonance imagingSlide42

Ferriscan

liver iron monitoring

Whittington audit

Ferriscan part of routine monitoring from December 200794 TM patients with at least 2 scans between January 2008-December 2011Slide43

Long termSlide44
Slide45

Patient 1

30 year old TM

Arrives in UK as a highly skilled migrant

Heavy iron overload in arrival in 2008Marked skin deposition Ferriscan liver iron >43mg/g/dwNo myocardial iron loadingSpontaneous pubertyInitial treatment is deferiprone, agrees to start deferasiroxSlide46

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/dayAlmost fully compliant initiallySlide47
Slide48

In 2011 compliance becomes a challenge

Ferriscan

bought forwards