1

Iron Chelation Basics

John B. Porter, MA, MD, FRCP

ProfessorDepartment of HaematologyUniversity College LondonLondon, United Kingdom

2

NTBI = non–trasnsferrin-bound iron; LIP = labile iron pools.1. Porter J. Hematol/Oncol Clinics. 2005;19:7.2. Porter JB. Am J Hematol. 2007;82:1136.

Goals of Chelation Treatment

Iron balance with “safe” tissue iron levels– 0.4–0.5 mg/kg day excretion1

– Slow process2

– Finite chelatable iron pools2

– Prevention of heart and endocrine damage Detoxification of iron

– Extracellular (NTBI)– Intracellular (LIP)– Iron-chelate complex

3

The Challenge of Iron Chelation—A Question of Balance

Too much iron Too much chelator

Uncoordinated iron Free-radical generation Organ damage Growth failure Organ failure Cardiac death

Uncoordinated chelator Inhibition of

metalloenzymes Neurotoxicity Growth failure Bone marrow toxicity

4

Properties of an Ideal Chelator

To control body iron– High chelating efficiency

– High and specific affinity for Fe3+ To minimize iron toxicity

– 24-hour coverage

– Slow metabolism and elimination rate

– Good tissue penetration with stable iron complex Acceptable toxicity-efficacy profile

– Clear drug-dose relationship to efficacy and toxicity

– No iron redistribution Simplicity and ease of monitoring Patient acceptance/compliance

– Oral bioavailability

– Suitable for monotherapy

5

BidentateTridentate Hexadentate

O O

O

O

O O

FFee

O

O

O O

O

O

FFeeO

O

O

O

O

OFFe e

Adapted from Porter JB, et al. Baillieres Clin Haematol. 1989;2:257.

How Chelators Bind Iron

Desferrioxamine (DFO) Deferiprone (DFP)Deferasirox (DFS)

6

Chelatable Iron Pools

For iron balance

– Plasma iron turnover pools

– Intrahepatic pools

For iron detoxification

– Plasma iron toxic pools (NTBI)

– Intraparenchymal iron toxic pools

eg, heart, liver, endocrine, joints

NTBI = non–transferrin-bound iron.

7

Bile

Macrophage

Urine

Labile Fe

Storage Fe

Hepatocyte

FeFe Fe

Fe

Fe

Fe

Fe

Fe

FeFe

FeFe

Fe

Fe

Plasma

Faeces

Kidney

Chelatable Pools and Excretion Pathways with DFO

Fe

With permission from Cohen AR, Porter JB. In: Steinberg MH, et al, editors. Disorders of hemoglobin:genetics, pathophysiology, and clinical management. Cambridge: Cambridge University Press; 2001.

DFO = desferrioxamine.

8

Transferriniron

Lysosomaldegradation

LV

DC

CNon-transferriniron

Organelle damage

Ironproteins

Free-radical generation

Ferritin

LVDCC = L-type voltage-dependent calcium channel.With permission from Porter JB. Am J Hematol. 2007;82:1136.

Decreasing Cellular Toxicity with Chelators

Labile iron pool

9

Chelatable Iron Pools Prevention of Accumulation More Efficient

than Removal of Stored Iron

100%

30%

Normal: No NTBI produced

Subsequent formation of

NTBI in plasma

Fe

FeFe

FeFe

FeFe

Iron overload

Transferrin saturation occurs

due to frequent blood transfusions

Uncontrolled iron loading of

organs, such as:

Chelators may prevent iron uptake into these tissues Chelation of storage iron is slow and inefficientCourtesy of Dr. J. Porter.

10

63 ± 6.4

62 ± 7.9

61 ± 8.1

52 ± 7.1

10.3 ± 9.2

6.9 ± 5.3

3.4 ± 1.8

1.8 ± 1.0

8.1 ± 2.8

7.5 ± 2.5

6.9 ± 2.1

5.1 ± 1.9

.03.001.01.003P-value

2.1 ± 1.512 months

2.9 ± 1.96 months

6.0 ± 5.63 months

9.6 ± 4.3Baseline

61–81<1.6>19 >20 Normal range

LVEF (%)Liver Iron (mg/g dw)

Liver T2* (ms)

Myocardial T2* (ms)

dw = dry weight; LVEF = left ventricular ejection fraction.

With permission from Anderson LJ, et al. Br J Haematol. 2004;127:348.

* Desferrioxamine Data

Chelation Therapy Removes Liver Iron Faster than Heart Iron*

11

Desferrioxamine Therapy for Iron Overload

Available for > 3 decades with improving survival

Hexadentate molecule not absorbed from gut

Short half-life (20 min), so must be given by continuous infusion

– 8 –12 h/d, 5 – 7 d/w (40–50 mg/kg SC)

Commenced after 15–20 transfusions or when ferritin >1000 µg/L

Audiometric, retinopathic, and growth effects at high doses and low iron loading

Compliance often is poor, leading to variable outcome

Porter JB, Huehns CR. Baillieres Clin Haematol. 1989;2:459. Courtesy of Dr. J. Porter

12Reprinted from Porter JB, et al. Blood. 1996;88:705, with permission from the American Society of Hematology.

544842363024181260-6 -1

0

1

2

3

4

5

6

7

Time (hours)

NT

BI

or

DF

O (

µM

)

DFO–Control of Plasma NTBI Levels

DFO (µM)

NTBI (µM)

Intravenous continuous infusion

DFO = desferrioxamine, NTBI = non–transferrin-bound iron.

13

Efficacy of DFO - early history Sephton Smith 1962 IM bolus— Urine Fe excretion inc. with dose, no oral effect

1964 Fe excretion inc. with Tf sat, age, transfusions

Barry 1974 Daily IM bolus reduces mortality,

stabilises hepatic iron & fibrosis

Propper, Hussain 1976 Iron balance with 24-h SC infusions using portable devices

Pippard 1978 Iron balance achievable with 12-h SC infusions

Pippard 1982 Faecal excretion important (≥50%)

Freeman 1983 SC therapy improves asymptomatic cardiac disease

Marcus 1984 Intensive IV therapy reverses symptomatic cardiac failure

Wolfe 1985 Long-term SC therapy reduces incidence of cardiac disease

Zurlo 1989 Survival improved in TM cohorts if SC therapy started early

Bronspiegel-

Weintrob 1990 SC therapy started before age 10 y reduces hypogonadism

Olivieri 1994 Long-term control of ferritin reduces heart disease

Brittenham 1994 Compliance long-term protects against diabetes mellitus, cardiac disease and mortality

Davis BA, Porter JB. Adv Exp Med Biol. 2002;509: 91.

14

Reprinted from Borgna-Pignatti C, et al. Haematologica. 2004;891:187, with permission from theFerrata Storti Foundation, Pavia, Italy.

Su

rviv

al P

rob

ab

ility

P < .00005

0

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

DFO = desferrioxamine; TM = thalassaemia major.

DFO–Improved Survival in TM

15

DFO–Decline in Complications

Patients with thalassaemia major born after 1960 (n = 977)

With permission from Porter JB. Am J Hematol. 2007;82:1136.

*DFO IM, 1975; †DFO SC, 1980.In 1995, 121 patients switched to deferiprone (censored at this time).

DFO = desferrioxamine.

Death at age 20 years 5% 1%

Hypogonadism 64.5% 14.3%

Diabetes 15.5% 0.8%

Hypothyroidism 16.7% 4.9%

Birth 1970-1974* Birth 1980-1984†

16

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

.

Iron Balance Over 1 Year with DFO SC x 5/Week

With permission from Cohen AR, et al. Blood. 2008;111:583.

Initial DFO dose (mg/kg/d) <25 25 to <35 35 to <50 ≥50

100%

0%

100%

Increase

Decrease

<0.3 0.3–0.5 >0.5

Iron Intake (mg/kg/d)

17

Desferal [package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006.Porter JB, Huehns ER. Bailliere’s Clin Haematol.1989;2:459.

Unwanted Effects of Desferrioxamine

Effect

– Retinopathy

– Ototoxicity

– CNS, coma

– Growth retardation

– Bony changes

– Yersinia infection

– Sensitivity

– Misc (pulmonary fibrosis)

Contributing factor

– Dose

– Dose, ferritin, therapeutic index

– Iron status, other drugs

– Dose, age <3 y, ferritin <1000 ug≠L

– Age, dose, ferritin

– Natural siderophore

– Intermittent use

– Very high dose (short term)

181. Desferal [Package insert]. East Hanover, NJ: Novartis Pharmaceuticals, 2006.

How to Minimize Desferrioxamine’s Unwanted Effects?

Avoid >40 mg/kg mean daily dose when growing1

Avoid >50 mg/kg mean daily dose in routine use Avoid starting too early Dose adjustment as ferritin falls

– Adjust mean daily dose downwards

– Try NOT to reduce frequency of treatment

– Keep therapeutic index <.025 (dose mg/kg / ferritin µg/L)

Monitor regularly for toxic effects

19

DesferrioxamineSummary of Advantages and Disadvantages Advantages

– Recognized first-line treatment in iron overload

– Long-term experience and data—reduced morbidity and mortality

– Effective in maintaining near-normal iron stores Specific affinity for iron with high chelating efficiency Achieves negative iron balance

– Reversal of cardiac disease with intensive therapy Disadvantages

– Requires maximum exposure for optimal outcome

– Not absorbed from GI tract

– Rapidly eliminated—30-minute half-life requires prolonged infusions

– Requires parenteral infusion

– Challenges—compliance

– Dose-dependent adverse events limit achievable goals Ear, eye, bone toxicity

Deferiprone History

– Patented 1982; licensed in EU 1999 Pharmacology

– Bidentate, short plasma half-life — given TID

– Rapidly glucuronidated, low efficiency (7%)

– Urine excretion Efficacy

– Indicated for treatment of iron overload in patients with thalassaemia major

when desferrioxamine therapy is contraindicated or inadequate1

– May be less effective than desferrioxamine in reducing LIC

– Possible cardioprotective effect 2

Side effects– Neutropaenia/agranulocytosis (weekly neutrophil count recommended1)

– Nausea, vomiting, abdominal pain

– Arthralgia and arthritis (variable 6%–39%)

CH3

CH3

OH

N

O

EU = European Union; LIC = liver iron concentration.1. Ferriprox® [Summary of Product Characteristics]. Apotex Europe Ltd.

1999.2. Anderson LJ, et al. Lancet. 2002;360:516.

20

21

DW = dry weight; FU = follow-up; LIC = liver iron concentration.

1. Olivieri N, et al. N Engl J Med. 1995;332:918.2. Olivieri N, et al. N Engl J Med. 1998;339:417.3. Töndury P, et al. Br J Haematology. 1998;101:413.4. Del Vecchio GC, et al. Acta Haematologica. 2000;104:99. 5. Mazza P, et al. Haematologica. 1998;83:496.6. Hoffbrand AV, et al. Blood. 1998;91:295.

Percentage Deferiprone Patients with Liver Iron >7 or >15 mg/g DW After 1-4 Years of Treatment

FU LIC LIC

Publication n Years % >7 % >15

Olivieri, 19951 21 3 52 10

Olivieri, 19982 19 4.6 65 39

Tondury, 19983 7 8 53 18

Del Vecchio, 20004 13 1 64 11

Mazza,19985 20 1–3 85 65

Hoffbrand,19986 51(17) 2–4 88 53

22

Cardioprotective Effect of Deferiprone Monotherapy?

Author n Data

Piga, 2003 1 54 DFP more effective than DFO inpreventing cardiac disease (retrospective)

Anderson, 2002 2 15 DFP more effective than DFO in reducing cardiac T2* (retrospective control)

Maggio, 2002 3 71 Similar decrease in cardiac MRI by both drugs

Hoffbrand, 1998 4 51 4 died of cardiac causes

Ceci, 2002 5 532 9 died of heart failure

1. Piga A, et al. Haematologica. 2003;88:489.2. Anderson LJ, et al. Lancet. 2002;360:516.3. Maggio A, et al. Blood Cell Mol Dis. 2002;28:196.4. Hoffbrand AV, et al. Blood. 1998;91:295.5. Ceci A, et al. Br J Haematol. 2002;118:330.

23

Prospective Comparison of DFO vs DFP Effect on Myocardial T2*

Myo

card

ial T

2*

(geo

met

ric m

ean

± S

EM

)

DFP (delta 3.5 ms; n = 29)

DFO (delta 1.7 ms; n = 32)

Reprinted from Pennell DJ, et al. Blood. 2006;107:3738, with permission from theAmerican Society of Hematology

DFP 92 mg/kg orally DFO 43 mg/kg x 5.7 SC

12

13

14

15

16

17

18

Baseline 6 Months 12 Months

DFO = desferrioxamine; DFP = deferiprone; SEM = standard error of the mean.

24

How to Minimize Deferiprone’s Unwanted Effects

Frequent monitoring of white count (1–2 weeks)– Avoid exposure if stem cell disorder or neutropaenia

Monitor liver function, liver iron, and histology Monitor serum zinc Avoid exceeding recommended dose?

– Is agranulocytosis dose related? Avoid exposure at young age? Role of dose adjustment? Use of other chelators concomitantly?

25

DeferiproneSummary of Advantages and Disadvantages Advantages

– Orally active

– Enhanced removal of cardiac iron

– Increased effectiveness when combined with desferrioxamine Disadvantages

– Short plasma half-life and rapid inactivation by metabolism

– Administered 3 times daily—may negatively impact patient compliance and outcome

– May not achieve negative iron balance at 75 mg/kg/day

– Risk of agranulocytosis and need for weekly blood counts

– Limited data Data in thalassaemia patients but limited use for other indications Relationship of dose to tolerability and efficacy Effects of combined therapy on tolerability

– Second-line therapy in thalassaemia major

26

Potential Value of 24-Hour Chelation

Minimizes exposure to labile iron – In tissues

– In plasma Continuous capture of iron released from

– Red cell catabolism in macrophages

– Ferritin catabolism (mainly in liver) Minimizes new cellular uptake of NTBI

27

Effects of Monotherapy and Combined Therapy on LPI

DFO 40 mg/kg/d given at night– Effectively removes LPI at night

– No protection during the day DFP 75 mg/kg/d given during the day

– Intermittent decrease in LPI during the day

– Rebound effect at night DFO 40mg/kg/d given at night + DFP 75

mg/kg/d given during the day– Provides 24 hour protection against LPI

Cabantchik ZI, et al. Best Pract Res Clin Hematol. 2005;18:277.

28

India5

2004

Lebanon4

2003

Malaysia3

2000

Turkey2

1999

London1

1998

CenterYear

Not doneMax decreaseNS from DFOLess decrease

52-

-7575

1230Rand

Not doneFall in both6/11 ≥ 2500 final

52

-75

121411

Rand

No significant fall7/9 ≥ 15 mg/g

7/9 ≥ 2500275–85129Obs

LIC 19% decrease6/7 ≥ 15 mg/g

30% decrease4/7 ≥ 2500 final

275 (4/7)

67Obs

Not done1/5 ≥ 2500 final2–688–1106–155Obs

LIC(Total Excretion)

Ferritin(μg/L)

Days DFO

DFP dose(mg/kg/d)

MonthsNDesign

Combinations of DFO and DFP

1. Wonke B, et al. Br J Haematol. 1998;103:361. 2. Aydinok Y, et al. Acta Haematol. 1999;102:17. 3. Balveer K, et al. Med J Malaysia. 2000;55:493. 4. Mourad FH, et al. Br J Haematol. 2003;121:187. 5. Gomber S, et al. Indian Pediatrics. 2004;41:21.

Obs = observational; Rand = randomised.

29

Combinations of DFO and DFP

*SignificantObs = observational; Simul = simultaneous; Seq = sequential.

1. Origar, et al. Haematologica. 2005;90:1309. 2. Kattamis A, et al. Blood Cells Mol Dis. 2006;36:21. 3. Galanello R, et al. Haematologica. 2006;91:1241. 4. Farmaki K, et al. Br J Haematol. 2006;134:438.

Center Year

N Design Months Regimen

DFP Dose (mg/kg)

DFO Dose mg/kg Duration

Ferritin LIC Other

Sardinia1

200579 Obs ±

Simul31 mean 25 TID x 7 40

(x2-6)/7d, 8-24 h

Ferritin fall from high*

LIC not done

4% agranulocytosis8% neutropaeniaImproved LVEF Echo*

Greece2

200650 ObsSimul

12 25 mg TID x 4/7

25mg BID x 3/7 30-55, 3/7 d 8 hFerritin fall*LIC not done

4 agranuloytosis/100 pt yT2 heart improvedLV shortening fraction incr

3 Centres3 2006

3030

RandSeq

12 -25mg TID x 7

33 x 5/7 d, 8 h33 x 2/7 d, 8 h

Ferritin ± decr sameLIC ± decr same

7% AEs24% AEs2 neutropaenia

Greece4 2006

42ObsSeq

3-4 y 25-30mg TID 20-40 x 2-6 d8-12 h

Ferritin fall*Liver MRI improve*

AEs not reportedImproved GTT*Improved insulin secr*

30

Prospective Randomized Comparison of DFO Monotherapy vs Combination Therapy with DFP

Design

65 adult patients with TM

Mild to moderate T2* shortening (8–20 ms)

Normal heart function (LVEF >56%)

Pretreatment with SC DFO 30–40 mg/kg/night x5

Randomised to

• SC DFO monotherapy 43 mg/kg x5/week

• Placebo or deferiprone 75 mg/kg/day

Outcome

Improvement better in combined arm for

T2* (see graph)

Ferritin (-233 vs -976 µg/L)

LV function (0.6% vs 2.6%)

DFO = desferrioxamine; DFP = deferiprone; TM = thalassaemia major; LVEF = left ventricular ejection fraction. With permission from Tanner M, et al. Circulation. 2007;115:1876.

0 6 12

Months

0

1

2

3

4

5

6

7

8

Ch

ang

e in

Hea

rt T

2* (

ms)

Between groups:P = .02

CombinedDesferrioxamine

31

Deferasirox (ICL670) Tridentate iron chelator (high specificity)1

High therapeutic safety in animal data Lipophilic but protein bound1

Renal target in animal toxicology Long plasma half-life in humans1

Primarily excreted in faeces1

Given as once-daily drink1 Prospective 1-y phase II/III studies in wide range of

anaemias, including (TM2,4,5, SCD3, MDS4, DBA4) Randomised 1-y comparison with DFO in adult TM2 (n

= 586), children with TM2,3, and adults and children with SCD3 (n = 195)

Licensed in US, EU for treatment of iron overload, including children

1. EXJADE [Package Insert]. East Hanover, NJ:Novartis Pharmaceuticals 2007

2. Cappellini MD, Blood. 2006;107:3455.

3. Vichinsky E, Br J Haematol. 2007;136:501.

4. Porter J. Eur J Haematol. 2008; 80: 168.5. Piga A. Haematologica. 2006; 91:873.

N N

N

OH HO

OHO

32

0

20

40

60

80

100

0 4 8 12 16 20 24Time Postdose with Deferasirox 20 mg/kg/day (hours)

Pla

sma

Co

nce

ntr

atio

n I

ron

-Fre

e D

efer

asir

ox

(µm

ol/

L)

Degree of constant chelation coverage with 20 mg/kg dose

24-Hour Chelation Coverage After Repeated Daily Dosing

Mean values of measurements taken on weeks 2, 4, 8, and 12 are presented

With permission from Piga A, et al. Haematologica. 2006;91:873.

Steady-state levels with daily deferasirox

33

LPI After Single and Multiple Deferasirox Dosing in β-thalassaemia

Adapted from Daar S, et al. Haematologica. 2006;91:13, with permission from theFerrata Storti Foundation, Pavia, Italy.

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Baseline Week 4 Week 16

Mea

n L

PI

(µm

ol/

L)

Predose (n = 13) 2 hours postdose (n = 13)

P < .0001* P = .0119*

*Vs predose

P = .0187P = .0007Washout

P = .1948*

Once-daily administration of deferasirox provides 24-hour chelation coverage and cumulative reduction in peak LPI with multiple dosing

20 mg/kg/day

34

Desferrioxamine: 13% (10%–17%) efficient when given at 25–50 mg/kg over 8–10 hours, 5 times per week1

Deferiprone: 4% of administered dose eliminated in urine bound to iron at 25 mg/kg/day, 3 times daily2

Deferasirox: 27% of drug eliminated in iron-bound form when given at10–30 mg/kg/day, once daily1

1. Porter J, et al. Blood. 2005;106:abstr 2690.2. Hoffbrand V, et al. Blood. 2003;102:17.

Efficiency of Chelation Therapy Definition

– Proportion of administered drug that is eliminated in iron-bound forms

How calculated

– Formal iron balance studies

– Iron excretion or change in body iron (LIC) relative to dose and transfusion rate

35

5 10 20 30

n = 325; R = 0.63

Ch

ang

e in

LIC

(m

g F

e/g

dw

)

-30

-25

-20

-15

-10

-5

0

5

10

15

20

Change in Ferritin (µg/mL)

-7500 -6250 -5000 -3750 -2500 -1250 0 1250 2500 3750 5000

Novartis data on file.

Deferasirox Dosing EffectsDose-dependent change in ferritin predicts change in LIC,

with zero change at dose of 10 mg/kg/day

Deferasirox, mg/kg/day

36

Iron Excretion and DoseComparison over 1 Year with DFO

Deferasirox

Deferasirox

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0 5 10 15 20 25 30

Mea

n T

ota

l B

od

y Ir

on

Exc

reti

on

± S

D(m

g F

e/kg

/d)

Average transfusional iron intake in thalassemia

Actual doses, mg/kg/d

Average transfusional iron intake in MDS 12

Average t ransfusional iron intake in SCD 11

, F o 5 d wD O n / k0 3 4 500 1 2 0 0 0 60

DFO

With permission from Cohen AR, et al. Blood. 2008;111;583.

Thalassaemia major, n=541

37

Iron Intake, Dose, and Outcome with Deferasirox

n = 11 44 42 63

Increase

Decrease

Proportion of patients with increase or decrease of LIC

Deferasirox dose (mg/kg/d) 5 10 20 30

Iron Intake (mg/kg/d)

1 10 19 17

>0.5(>4 units/mo)

0.3–0.5(2–4 units/mo)

3 14 16

28

<0.3(<2 units/mo)

100%

100%

0%

Reprinted from Cohen AR, et al. Blood. 2008;111;583, with permission from theAmerican Society of Hematology.

38

Change in Cardiac T2* in Studies 0107 and 0108 in UCLH Patients at Doses

10, 20, 30 mg/kg/day (n = 22)

With permission from Porter JB, et al. Blood. 2005;106: abstr 3600.

0

10

20

30

40

50

60

1

Pre Post 1 y

20.0 ±2.0 gm = 18.0

26.4±2.8 (gm = 23.1)

P = .0026

16 thalassaemias

6 other anaemias

Car

diac

T2*

ms

9 thalassaemia major patients randomized to DFO arm; T2* pre = 18.1, post = 21.1 (not shown)

39

Generally well tolerated over a range of transfusion-dependent anaemias1,2,3,4

Most common treatment-related adverse events were mild to moderate, transient

gastrointestinal disturbances and skin rash1,2,3

No drug-induced agranulocytosis, neutropaenia, or arthralgia

Mild, nonprogressive, dose-dependent elevations in serum creatinine (>33% above

baseline in 36% of patients, in 10% managed by dose adjustment)1,2,3

– No increase of incidence or progression in extension studies

2 cases of suspected drug-related hepatitis1

Cataract/lens opacities: 2 patients discontinued — 2 with DFO also1

30 mg/kg/day generally well tolerated in children as young as 2 years4

Sexual and physical development proceeded within normal parameters4

Tolerability and Unwanted Effects of Deferasirox in Adults and Children During Prospective Studies

1. Cappellini MD, Blood. 2006;107:3455. (Study 107, randomised vs DFO in TM, n= 586).

2. Vichinsky E, Br J Haematol. 2007;136:501. (Study, 108…randomised vs DFO in sickle, n= 195)

3. Porter J. Eur J Haematol, 2008;80:168. (Study 109… n TM n= 85, MDS n=47, DBA n=30, other=22) 4. Piga A. Haematologica, 2006;91:873. (Study 106…randomised vs DFO in TM paediatric, n=71)

40

DeferasiroxSummary of Advantages and Disadvantages

Advantages – Orally active with long plasma half-life

– Generally well tolerated over a range of transfusion-dependent anaemias

– Once-daily administration Ease of administration, 24-h chelation, increased chelation efficiency

– Clear dose response effect on iron balance

– Demonstrated equivalency to desferrioxamine at higher doses

– Prospective studies in MDS, thalassaemia, SCD, other anaemias

– Ferritin trend follows trend in LIC and hence iron balance

– Licensed as first-line treatment in iron overload Disadvantages

– Long-term data less than 5 years follow-up

– Need to monitor renal function

– Limited data on cardiac effects

– Not all patients achieve negative iron balance at highest recommended dose

41

Conclusions Most of body iron is not directly available for chelation

Chelatable iron pools result from continuous turnover of

– Catabolised red cells (in macrophages)

– Catabolised storage iron (ferritin and haemosiderin, mainly in hepatocytes)

Toxic (labile) iron pools are small, transient, and constantly turned over

Iron chelation protects by

– Decreasing absolute levels of storage iron (slow)

– Detoxifying labile iron in cells or plasma (fast)

– Preventing continuous distribution of iron to key tissues via plasma NTBI

Chelation must detoxify iron without producing chelator toxicity

4 decades of clinical experience show chelation is an effective modality

Extensive clinical experience with 3 chelators now available