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Iron Chelation Basics . John B. Porter, MA, MD, FRCP Professor Department of Haematology University College London London, United Kingdom. Goals of Chelation Treatment . Iron balance with “safe” tissue iron levels 0.4–0.5 mg/kg day excretion 1 Slow process 2

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iron chelation basics
Iron Chelation Basics

John B. Porter, MA, MD, FRCP

ProfessorDepartment of HaematologyUniversity College LondonLondon, United Kingdom

goals of chelation treatment
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

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.

the challenge of iron chelation a question of balance
Uncoordinated iron

Free-radical generation

Organ damage

Growth failure

Organ failure

Cardiac death

Uncoordinated chelator

Inhibition of metalloenzymes

Neurotoxicity

Growth failure

Bone marrow toxicity

The Challenge of Iron Chelation—A Question of Balance

Too much iron

Too much chelator

properties of an ideal chelator
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
how chelators bind iron

O

O

O

O

O

O

O

O

O

Fe

O

O

O

O

O

O

O

O

O

How Chelators Bind Iron

Desferrioxamine (DFO)

Deferiprone (DFP)

Deferasirox (DFS)

Hexadentate

Bidentate

Tridentate

Fe

Fe

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

chelatable iron pools
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.

chelatable pools and excretion pathways with dfo

Fe

Fe

Fe

Fe

Fe

Fe

Fe

Fe

Fe

Fe

Fe

Fe

Chelatable Pools and Excretion Pathways with DFO

Plasma

Bile

Storage Fe

Macrophage

Fe

Labile Fe

Fe

Fe

Hepatocyte

Kidney

Faeces

Urine

DFO = desferrioxamine.

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.

decreasing cellular toxicity with chelators

Ferritin

Non-transferrin

iron

LVDCC

Labile

iron pool

Lysosomal

degradation

Free-radical generation

Iron

proteins

Organelle damage

Decreasing Cellular Toxicity with Chelators

Transferrin

iron

LVDCC = L-type voltage-dependent calcium channel.

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

chelatable iron pools prevention of accumulation more efficient than removal of stored iron
Chelatable Iron Pools Prevention of Accumulation More Efficient than Removal of Stored Iron

Uncontrolled iron loading of organs, such as:

Transferrin saturation occurs due to frequent blood transfusions

Subsequent formation of NTBI in plasma

Normal: No NTBI produced

Iron overload

100%

Fe

Fe

Fe

Fe

Fe

Fe

Fe

30%

Chelation of storage iron is slow and inefficient

Chelators may prevent iron uptake into these tissues

Courtesy of Dr. J. Porter.

chelation therapy removes liver iron faster than heart iron
Chelation Therapy Removes Liver Iron Faster than Heart Iron*

Myocardial T2* (ms)

Liver T2* (ms)

Liver Iron

(mg/g dw)

LVEF (%)

Normal range

>20

>19

<1.6

61–81

Baseline

5.1 ± 1.9

1.8 ± 1.0

9.6 ± 4.3

52 ± 7.1

3 months

6.9 ± 2.1

3.4 ± 1.8

6.0 ± 5.6

61 ± 8.1

6 months

7.5 ± 2.5

6.9 ± 5.3

2.9 ± 1.9

62 ± 7.9

12 months

8.1 ± 2.8

10.3 ± 9.2

2.1 ± 1.5

63 ± 6.4

P-value

.003

.01

.001

.03

* Desferrioxamine Data

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

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

desferrioxamine therapy for iron overload
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

dfo control of plasma ntbi levels

Intravenous continuous infusion

7

DFO (µM)

6

5

4

3

NTBI (µM)

2

1

0

-1

DFO–Control of Plasma NTBI Levels

NTBI or DFO (µM)

-6

0

6

12

18

24

30

36

42

48

54

Time (hours)

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

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

slide13

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 1989Survival 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.

dfo improved survival in tm

1960–1964

1965–1969

1970–1974

1975–1979

1980–1984

1985–1997

DFO–Improved Survival in TM

1.00

0.75

Birth cohort

Survival Probability

0.50

0.25

P < .00005

0

0

5

10

15

20

25

30

Age (years)

DFO = desferrioxamine; TM = thalassaemia major.

Reprinted from Borgna-Pignatti C, et al. Haematologica. 2004;891:187, with permission from the

Ferrata Storti Foundation, Pavia, Italy.

dfo decline in complications
DFO–Decline in Complications

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

*DFO IM, 1975; †DFO SC, 1980.

In 1995, 121 patients switched to deferiprone (censored at this time).

DFO = desferrioxamine.

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

slide16

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

.

Initial DFO dose (mg/kg/d)

<25 25 to <35 35 to <50 ≥50

100%

Increase

0%

Decrease

100%

<0.3

0.3–0.5

>0.5

Iron Intake (mg/kg/d)

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

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)

Unwanted Effects of Desferrioxamine

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

Porter JB, Huehns ER. Bailliere’s Clin Haematol.1989;2:459.

how to minimize desferrioxamine s unwanted effects
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

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

desferrioxamine summary of advantages and disadvantages
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

O

OH

N

CH

3

CH

3

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%)

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

percentage deferiprone patients with liver iron 7 or 15 mg g dw after 1 4 years of treatment
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

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.

cardiopr o tective e ffect of d eferiprone m onotherapy
Cardioprotective Effect of Deferiprone Monotherapy?
  • Piga A, et al. Haematologica. 2003;88:489.
  • Anderson LJ, et al. Lancet. 2002;360:516.
  • Maggio A, et al. Blood Cell Mol Dis. 2002;28:196.
  • Hoffbrand AV, et al. Blood. 1998;91:295.
  • Ceci A, et al. Br J Haematol. 2002;118:330.
prospective comparison of dfo vs dfp effect on myocardial t2
Prospective Comparison of DFO vs DFP Effect on Myocardial T2*
  • DFP 92 mg/kg orally
  • DFO 43 mg/kg x 5.7 SC

18

17

DFP (delta 3.5 ms; n = 29)

16

DFO (delta 1.7 ms; n = 32)

Myocardial T2* (geometric mean ± SEM)

15

14

13

12

Baseline

6 Months

12 Months

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

Reprinted from Pennell DJ, et al. Blood. 2006;107:3738, with permission from the

American Society of Hematology

how to minimize deferiprone s unwanted effects
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?
deferiprone summary of advantages and disadvantages
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
potential value of 24 hour chelation
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
effects of monotherapy and combined therapy on lpi
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.

combinations of dfo and dfp
Combinations of DFO and DFP

Center

Year

N

Design

DFP dose(mg/kg/d)

Days DFO

Ferritin

(μg/L)

LIC

(Total Excretion)

Months

6–15

London1

1998

5

Obs

88–110

2–6

1/5 ≥ 2500 final

Not done

Turkey2

1999

7

Obs

75

(4/7)

2

30% decrease

4/7 ≥ 2500 final

LIC 19% decrease

6/7 ≥ 15 mg/g

6

2

Malaysia3

2000

9

Obs

12

75–85

7/9 ≥ 2500

No significant fall

7/9 ≥ 15 mg/g

-

75

Lebanon4

2003

12

5

2

Fall in both

6/11 ≥ 2500 final

Not done

14

11

Rand

-

75

75

India5

2004

5

2

-

12

Max decrease

NS from DFO

Less decrease

Not done

30

Rand

Obs = observational; Rand = randomised.

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.

combinations of dfo and dfp29
Combinations of DFO and DFP

*Significant

Obs = 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.

prospective randomized comparison of dfo monotherapy vs combination therapy with dfp

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%)

8

Combined

Desferrioxamine

7

Between groups:P = .02

6

5

4

Change in Heart T2* (ms)

3

2

1

0

0

6

12

Months

DFO = desferrioxamine; DFP = deferiprone; TM = thalassaemia major; LVEF = left ventricular ejection fraction.

With permission from Tanner M, et al. Circulation. 2007;115:1876.

deferasirox icl670
Deferasirox (ICL670)

OH

O

  • 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

N

N

N

OH

HO

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.

24 hour chelation coverage after repeated daily dosing
24-Hour Chelation Coverage After Repeated Daily Dosing

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

Steady-state levels with daily deferasirox

100

80

Plasma Concentration Iron-Free Deferasirox (µmol/L)

60

40

20

Degree of constant chelation coverage with 20 mg/kg dose

0

0

4

8

12

16

20

24

Time Postdose with Deferasirox 20 mg/kg/day (hours)

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

lpi after single and multiple deferasirox dosing in thalassaemia
LPI After Single and Multiple Deferasirox Dosing in β-thalassaemia

2.0

2 hours postdose (n = 13)

Predose (n = 13)

1.8

20 mg/kg/day

1.6

1.4

1.2

Mean LPI (µmol/L)

1.0

0.8

0.6

0.4

P < .0001*

P = .0119*

P = .1948*

0.2

0

P = .0187

Washout

P = .0007

Week 16

Baseline

Week 4

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

*Vs predose

Adapted from Daar S, et al. Haematologica. 2006;91:13, with permission from the

Ferrata Storti Foundation, Pavia, Italy.

efficiency of chelation therapy
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
  • 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.

slide35
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

5 10 20 30

20

15

10

n = 325; R = 0.63

5

0

Change in LIC (mg Fe/g dw)

-5

-10

-15

-20

-25

-30

-7500

-6250

-5000

-3750

-2500

-1250

0

1250

2500

3750

5000

Change in Ferritin (µg/mL)

Novartis data on file.

iron excretion and dose comparison over 1 year with dfo

D

F

O

0

1

0

2

0

3

0

4

0

5

0

6

0

D

F

O

,

o

n

5

d

/

w

k

Iron Excretion and DoseComparison over 1 Year with DFO

D

e

f

e

r

a

s

i

r

o

x

Thalassaemia major, n=541

0

.

8

0

.

7

0

.

6

0

.

5

Mean Total Body Iron Excretion ± SD

(mg Fe/kg/d)

A

v

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r

a

g

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

iron intake dose and outcome with deferasirox

Deferasirox dose (mg/kg/d)

1

3

10

14

19

16

17

28

>0.5

(>4 units/mo)

<0.3

(<2 units/mo)

20

30

5

10

Iron Intake, Dose, and Outcomewith Deferasirox

Proportion of patients with increase or decrease of LIC

100%

Increase

n =

11

44

42

63

0%

Decrease

0.3–0.5

(2–4 units/mo)

100%

Iron Intake (mg/kg/d)

Reprinted from Cohen AR, et al. Blood. 2008;111;583, with permission from the

American Society of Hematology.

change in cardiac t2 in studies 0107 and 0108 in uclh patients at doses 10 20 30 mg kg day n 22
Change in Cardiac T2* in Studies 0107 and 0108 in UCLH Patients at Doses10, 20, 30 mg/kg/day (n = 22)

60

P = .0026

50

16 thalassaemias

6 other anaemias

40

Cardiac T2* ms

26.4

±2.8

(gm = 23.1)

30

20

20.0

±2.0

gm = 18.0

10

0

Post 1 y

Pre

1

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

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

tolerability and unwanted effects of deferasirox in adults and children during prospective studies
Tolerability and Unwanted Effects of Deferasirox in Adults and Children During Prospective Studies
  • 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

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)

deferasirox summary of advantages and disadvantages
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
conclusions
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