IRON CHELATION

Maria Domenica CappelliniUniversity of Milan

3° European Symposium on Rare Anaemias

1° Spanish Thalassemia meeting for Patients and Health Professional

Madrid 19-20 November 2010

Iron is essential

● Transport and O2 exchange– haemoglobin and myoglobin

● Respiratory chain– complex I and III

● Metabolic reactions– haem synthesis (FECH) – Fe/S cluster (IRPs)

● DNA synthesis and repair– ribonucleotide reductase– endonuclease III

● Cell growth and proliferation

● Ability to transfer electrons

● Production of free O2 radicals

Fenton reaction:

Fe2+ + H2O2 Fe3+ + OH− + .OH

Iron is toxic

FECH = ferrochelatase; IRP = iron-regulatory protein.

y

Fe2Tf

Tf Fe

+

ROS

Mitochondrialdamage DNA damage

Lipidperoxidation

Protein damage

Lysosomes

Transferrin and non-transferrin-bound iron (NTBI)

NTBI appears in plasma when transferrin is almost completely saturated (saturation > 60–70%); it is taken up by cells* and is highly toxic

*Through L-type calcium-dependent channels.

ROS = reactive oxygen species; Tf = transferrin. Cabantchik ZI, et al. Best Pract Res Clin Haematol. 2005;18:277-87.

MetalChelatorChelator +

Toxic

Non-toxic

“Chelation”

Excretion

Metal

What is chelation therapy?

Chelator

60 70 90 2005

1968FDA

19952004

EMEA

2005-FDA2006-EMEA

Chelator Chelator

toxictoxic Non toxicNon toxic

excretionexcretion

Goals of iron chelation therapy

The primary goals of iron chelation therapy are to remove excess iron and to provide protection from the effects of (labile) toxic iron

Transfusions and iron intake

Ironchelationtherapy

Iron stores

Targets:Maintenance of body iron

Reduction of body iron in excess

Overview of iron chelators

Property Deferoxamine Deferiprone Deferasirox

Usual dose 20–60 mg/kg/day 75–100 mg/kg/day 10–30 mg/kg/day

Route s.c., i.v.8–12 h, 5 days/week

Oral3 times daily

Oralonce daily

Half-life 20–30 min 2–3 h 8–16 h

Excretion Urinary, faecal Urinary Faecal

Deferasirox Summary of Product Characteristics.Deferiprone Summary of Product Characteristics.

Deferoxamine Summary of Product Characteristics.Please refer to prescribing information in your country of practice.

Current indications of the available iron chelators

● Deferoxamine– treatment of acute iron intoxication and chronic iron overload due to

transfusion-dependent anaemias● Deferiprone

– treatment of iron overload in patients with β-thalassaemia major when deferoxamine therapy is contraindicated or inadequate

● Deferasirox– treatment of chronic iron overload due to frequent blood transfusions in

patients with β-thalassaemia major aged 6 years and older– treatment of chronic iron overload due to blood transfusions when

deferoxamine therapy is contraindicated or inadequate in the following patients groups

• patients with other anaemias• patients aged 2–5 years• patients with β-thalassaemia major with iron overload due to infrequent

blood transfusions

Please refer to prescribing information in your country of practice.

Deferasirox Summary of Product Characteristics.Deferiprone Summary of Product Characteristics.

Deferoxamine Summary of Product Characteristics.

Iron Chelation with Deferioxamine

1962 1967 1972 1977 1982 1987 1992 1999 2002 2007 2009……………

Deferioxamine im (Sephton -Smith 20 mg/Kg)

Deferioxamine sc ( Propper:25-45 mg/Kg)

Deferioxamine iv

PROGNOSIS (yrs)PROGNOSIS (yrs)7-107-10 16-2016-20 openopen

Iron chelation therapy with deferoxamine

● In clinical use since the 1970s, DFO has had an impact on survival and iron-overload-related complications if– initiated within 2–3 years of start of transfusions– administered regularly and in adequate doses

• to achieve a negative iron balance in patients with average transfusion requirements, a dose of 50 mg/kg/day for at least 5 days a week is required

● Intensive chelation with DFO (continuous 24-h s.c. or i.v. infusions) are indicated for– persistently high serum ferritin levels– LIC > 15 mg/g dry wt– significant heart disease (cardiac dysrhythmias, ↓ LVEF,

cardiac T2* < 6 ms)

Cappellini MD. Semin Hematol. 2005;42 Suppl 1:S19-S21.Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.

Survival in β-thalassaemia major

● Risk factors for mortality in β-thalassaemia major include: serum ferritin levels > 2,500 μg/L (HR: 3.7); arrhythmia (HR: 2.4); male sex (HR: 1.9); and heart failure (HR: 11.3)

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

Surv

ival

pro

babi

lity

(p < 0.00005)

0

1.00

0.75

0.50

0.25

0 5 10 15 20 25 30Age (years)

Birth cohort

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

Surv

ival

pro

babi

lity

(p = 0.0003)

0

1.00

0.75

0.50

0.25

0 5 10 15 20 25 30Age (years)

MalesFemales

HR = hazard ratio.

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

Compliance to chelation improves survival in patients with β-thalassaemia major

Surv

ival

(%)

0

60

80

50

40

30

20

10

70

90

100

0 282420161284 32 36 40Years

300–365225–300150–22575–1500–75

Infusions/year

Safety profile of deferoxamine

● Risk of over-chelation2,3

– there is a link between risk of deferoxamine toxicity and low iron stores

– the aim is to keep the therapeutic index < 0.025 at all times.2 This seems to be especially important in patients with serum ferritin levels < 1,000 µg/L or with diabetes

– the therapeutic index was initially used with regard to audiometric toxicity. It is also used to limit retinal toxicity and recommended for skeletal toxicity3

● Adverse events associated with deferoxamine1

– local reactions– high-frequency hearing loss– retinopathy– allergy– poor growth – gastrointestinal symptoms– Yersinia infections

1. Cunningham MJ, et al. Blood. 2004;104:34-9.2. Porter JB, et al. Br J Haematol. 1989;73:403-9.

3. Davis BA, Porter JB. Adv Exp Med Biol. 2002;509:91-125.

mean daily dose of deferoxamine (mg/kg)serum ferritin (µg/L)Therapeutic index =

Causes of death in patients with β-thalassaemia major

*Accident, renal failure, HIV/AIDS, familial autoimmune disorder, anorexia, haemolytic anaemia, thrombocytopenia.Borgna-Pignatti C, et al. Ann N Y Acad Sci. 2005;1054:40-7.

6.8

1.8

6.8

4.1

4.1

3.6

3.2

2.7

50.8

6.6

14.8

3.3

3.3

3.3

8.2

9.7

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Heart failure

ArrhythmiaMyocardial

infarction

Infection

Cirrhosis

Thrombosis

Malignancy

Diabetes

Unknown

Other*

60.2

6.7

%

All patients (n = 1,073)Patients born after 1970 (n = 720)

IRON CHELATION HISTORY

1962 1967 1972 1977 1982 1987 1992 1999 2002 2007 2009……………

Desferioxamine im (Sephton -Smith 20 mg/Kg)

Desferioxamine sc ( Propper:25-45 mg/Kg)

Deferiprone

Desferioxamine iv

PROGNOSIS (yrs)PROGNOSIS (yrs)7-107-10 16-2016-20 openopen

Iron chelation therapy with deferiprone

● The European Union granted marketing approval for deferiprone in 1999 under the “exceptional circumstances” policy that requires further studies. Deferiprone achieved full-marketing authorization in Europe in April 2002

● In Europe, deferiprone is licensed for second-line treatment in patients unable to use DFO or when DFO has been inadequate– there are limited data available on the use of deferiprone in children 6–

10 years of age, and no data on deferiprone use in children < 6 years of age

● Standard dose is 75 mg/kg/day in 3 divided doses, with a maximum dose of 100 mg/kg/day

● Weekly blood counts are required throughout treatment● Treatment should be stopped during pregnancy

Deferiprone Summary of Product Characteristics.

Effect of deferiprone therapy on serum ferritin levels

1,0001,5002,0002,5003,0003,5004,0004,5005,0005,5006,000

Initial Final

10 studies (11–162 patients); duration 6–> 58 months

p range < 0.05–< 0.001Green lines are not significant

Hoffbrand V, et al. Blood. 2003;102:17-24.

Seru

m fe

rriti

n (μ

g/L)

Car

diac

T2*

(g

eom

etric

mea

n ±

SEM

)

DFP (change 3.5 ms; n = 29; p < 0.001)

DFO (change 1.7 ms; n = 32; p < 0.001)

SEM = standard error of the mean.

DFP 92 mg/kg/day orally

12

13

14

15

16

17

18

Baseline 6 months 12 months

Prospective improvement in cardiac T2* with DFO and DFP monotherapy

DFO 43 mg/kg/day x 5.7 s.c.

Time (months)

Pennell DJ, et al. Blood. 2006;107:3738-44.

Combination therapy:DFO and deferiprone

● A variety of regimens combining DFO and deferiprone have been used by clinicians– usually when monotherapy with either chelator has failed to

control the iron burden or its effects

● Most regimens comprised deferiprone daily plus DFO with varying frequency and dosing– most used relatively low and intermittent DFO doses and daily

deferiprone

Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.

0

2

4

6

8

10

12

14

16

18

20

0 6 12

DFO alone versus DFO + DFP combination treatment

Liver T2*

Myocardial T2*

p = 0.01

p < 0.001

p < 0.001

p = 0.001Between groups

p = 0.02

Between groups p < 0.001

T2* (

geom

etric

mea

n ±

SEM

)

Tanner MA, et al. Circulation. 2007;115:1876-84.Time (months)

DFO (n = 33)Combined (n = 33)

Intensive combined chelation

● Intensive combined chelation normalized iron load in thalassemia patients

● Intensive combined chelation prevented and reversed cardiac and multiple endocrine complications

Farmaki K. Et al. Br.J.haematol. 2010

● Formal safety data on intensive combined chelation are limited

Simultaneous use

Sequential (alternate) use

Simultaneous versus sequential

Most regimens comprised deferiprone daily plus DFO with varying frequency

Combination therapy DFO and deferiprone

● TIF-guidelines:– The studies suggest that some combined regimens can control

iron overload in the liver and heart where monotherapy (deferiprone or deferoxamine) is not having the desired effects.

– In general, if a patient is not doing well with monotherapy, combined treatment offers an additional approach (as does intensive therapy with at least 50 mg/kg/day of deferoxamine for as many hours a day as is practicable).

– For patients with very high levels of heart iron or cardiac dysfunction, 24-hour treatment with deferoxamine and daily therapy with deferiprone should be strongly considered

– Formal safety data on combination treatment are limited, although agranulocytosis may be more frequent with combination therapy (particularly simultaneous regimens)

Guidelines for the clinical management of thalassaemia. 2nd rev ed. TIF 2008.

IRON CHELATION HISTORY

1962 1967 1972 1977 1982 1987 1992 1999 2002 2007 2009……………

Desferioxamine im (Sephton -Smith 20 mg/Kg)

Desferioxamine sc ( Propper:25-45 mg/Kg)

Deferiprone

Deferasirox

Desferioxamine iv

PROGNOSIS (yrs)PROGNOSIS (yrs)7-107-10 16-2016-20 openopen

Study103

Study 104 (12 days)

Phase I

LPLV Jan 2008Study 105(48 weeks)

Phase II

LPLV Dec 2008Study 108 (1 year)

Phase III LPLV Nov 2008Study 107 (1 year)

Deferasirox clinical development: completed

Phase IV/GMA

Single-dose, safety and tolerability study in 24 adult β-thalassaemia patients

Multiple-dose iron balance study in 24 adult β-thalassaemia patients

Randomized deferasirox vs DFO safety and LIC study in 71 adult β-

thalassaemia patients

Single-arm safety and LIC study in 40 paediatric β-thalassaemia patients

Single-arm LIC and tolerability study in 184 paediatric/adult patients with

β-thalassaemia, MDS, rare anaemias

Randomized deferasirox vs DFO LIC and tolerability study in

586 paediatric/adult β-thalassaemia patients

Open-label, single-arm efficacy/safety trial in 252 previously inadequately

treated paediatric/adult β-thalassaemia patients

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

LPLV Feb 2008Study 106 (48 weeks)

May 2008Study 2402(1 year)

GMA = Global Medical Affairs; LPLV = last patient, last visit.

Phase II

LPLV Feb 2010Study 109(1 year)

Deferasirox clinical development: ongoing

Phase IV

Randomized deferasirox vs DFO safety and LIC study in

195 paediatric/adult SCD patients

Open-label, single-arm efficacy/safety in

1744 paediatric/adult patients with various transfusion-

dependent anaemias

2003 2004 2005 2006 2007 2008 2009 2010 2011

June 2009

Randomizeddeferasirox vs DFO efficacy

and safety trial in 192 patients with myocardial

iron overload

May 2011Study 2206(1 year)

Oct 2008

Open-label, dose-escalation safety and efficacy trial of deferasirox in 49 patients

with hereditary haemochromatosis

Study 2409(1 year)

Study 2202

● What has been observed● What has been learned

Dose-dependent changesin iron burden

● Neutral iron balance was achieved over 1 year with 20 mg/kg/day and negative iron balance with 30 mg/kg/day

Deferasirox 5 10 20 30

Cha

nge

in s

erum

ferr

itin

(μg/

L)

DFO < 25 25–35 35–50 ≥ 50DFO < 25 25–35 35–50 ≥ 50Deferasirox 5 10 20 30

Deferasirox (n = 296)Deferasirox (n=268)DFO (n = 290)DFO (n=273)

−20

−15

−10

−5

0

5

10

Cha

nge

in L

IC (m

g Fe

/g d

ry w

t)

−3,000

−2,500

−2,000

−1,500

−1,000

−500

0

500

1,000

1,500

2,000

2,500LIC

Planned starting dose (mg/kg/day) Planned starting dose (mg/kg/day)

Serum ferritin

Cappellini MD, et al. Blood. 2006;107:3455-62.

Study 107

Deferasirox dose-related reductions in LIC support tailored therapy

Deferasirox dose (mg/kg/day)

-18-16-14-12-10-8-6-4-202468

10

Cha

nge

in L

IC (m

g Fe

/g d

w)

Iron intake: < 0.3 mg/kg/day(< 2 units/month)

0.3–0.5 mg/kg/day(2–4 units/month)

> 0.5 mg/kg/day(> 4 units/month)

Studies 106, 107, 108 and 109dw = dry weightData on file

10 20 30 10 20 30 10 20 30

≥ 20–< 30 mg/kg/day (n = 614)

20.6 23.6 26.2

28.3

< 20 mg/kg/day (n = 193)

18.6

17.617.5

17.8

Baseline 3 6 9 12

Changes in serum ferritin reflect dose adjustments and iron intake in β-thalassaemia major

28.126.2

24.021.2

All patients (n = 937)≥ 30 mg/kg/day (n = 130)

39.0

36.5

33.5

29.0

Time (months)

Med

ian

chan

ge fr

om b

asel

ine

in

seru

m fe

rriti

n le

vels

(µg/

L)

200

0

−200

−400

−600

−800

−1,000Values represent mean dose at each time point

Mean iron intake mg/kg/day

0.36

0.460.390.43

Study 2409/EPICCappellini MD, et al. Haematologica 2009.

Effect of Deferasirox (Exjade®) on Labile Plasma Iron Levels in Heavily Iron-overloaded Patients with

Transfusion-dependent Anemias

● 1602 patients: thalassemia, n=1029; MDS, n=305; AA, n=104; SCD, n=79; rare anemias, n=42; other conditions requiring transfusion, n=43

0

0.5

1.0

1.5

2.0

2.5

3.0

Baseline Week 12 Week 28 Week 52

Mea

n LP

I + S

D (µ

mol

/L)

Pre-administration Post-administration

*P<0.0001 versus pre-administration at same time pointNOTE: Dotted line represents the normal threshold for LPI (<0.4 µmol/L) Porter et al [#3881]ASH 2009

(n=838) (n=816) (n=1311) (n=1312) (n=1215) (n=1206) (n=1103) (n=1079)

*

* *

*

Normalthreshold

All patients

Deferasirox therapy forup to 5 years: LIC

● LIC significantly decreased in patients with β-thalassaemia major ● Proportion of patients with LIC <7 mg Fe/g dw increased from 35% (n=142) to

45% (n=183) during deferasirox treatment

Cappellini et al. submitted

Mea

n LI

C (m

g Fe

/g d

w)

Deferasiroxcohort

Crossovercohort

Time (year)BL 1* 5*

P<0.001

BL 1* 4*

P<0.001

P=0.003P<0.001

02468

10121416

Deferasirox cohort: 5 years deferasirox

Crossover cohort: 1 year DFO (core not shown) 4 years deferasirox (extension)

*at least 1, 4 or 5 years of deferasirox treatmentBL (baseline) = at start of deferasirox treatment

P-values for absolute change

Study 107E

Patients with transfusion-dependent anaemias

Experience with deferasirox

> 30 mg/kg/day: serum ferritin

Studies 107–109 & 2402

Taher A, et al. Br J Haematol. 2009;147:752-9.

Rel

ativ

e (%

) cha

nge

in

seru

m fe

rriti

n (µ

g/L)

Time (months)

−9 −6 −3 Baseline 3 6 9 12 15 18

Dose escalation to > 30 mg/kg/day

100

50

0

−50

−100

Deferasirox : safety profile

Adverse event Frequency (% patients)

Observations

Non-progressive increase in serum creatinine

36 Mild, mostly within normal range; dose-dependent, often resolve spontaneously; may be sometimes alleviated by dose reduction

Gastrointestinal disturbance(nausea, vomiting, diarrhoea, abdominal pain)

26 Dose-dependent, mostly mild to moderate, generally transient and self-limiting even with continued therapy

Skin rash 7 Dose-dependent, mostly mild to moderate, generally transient and self-limiting with continued therapy

Elevation in liver transaminases 2 Most patients had elevated levels prior to deferasirox treatmentElevations > 10 x upper limit of normal (ULN) were uncommon (0.3%)

High-frequency hearing loss and lenticular opacities

≤ 1 Uncommonly observed with patients taking deferasirox

Safety profile over time in patients with β-thalassaemia major

Cappellini MD, et al. Blood. 2008;112:[abstract 5411].

*Reported adverse events include rash, erythematous rash, macular rash, maculopapular rash, papular rash, and pruritic rash.

The frequency of investigator-assessed adverse events* decreased over the years on deferasirox

Studies 105E–108E

Patie

nts

(%)

0123456789

10

Increasedblood

creatinine

Nausea Rash Vomiting Diarrhoea Abdominalpain

Abdominalpain

(upper)

Year 1

Year 4

Year 2

Year 5

Year 3

Continued improvement in cardiac T2* with deferasirox therapy over 2 years

11,213

15,714,6

17,5

20,4

7,3 8,19,5

0

5

10

15

20

25

Baseline 12 24

Geo

met

ric m

ean

card

iac

T2* (

ms) All patients (n = 101) 10–< 20 ms (n = 62) > 5–< 10 ms (n = 39)

Mean actual dose (mg/kg/day): 33.1 in core 1-year phase; 36.1 during extension

*

*

*

*

*

*

*p < 0.001

LVEF remained stable in both groups throughout 2-year follow-up periodPennell DJ, et al. submitted.LVEF = left-ventricular ejection fraction.

Time (months)

Time (months)

Geo

met

ric m

ean

card

iac

T2* ±

CV

(ms)

Time (months)

Mean change = +1.8% p < 0.001

Change in cardiac T2* Change in LVEF

Pennell DJ, et al. Blood. 2009 Dec 8

Deferasirox treatment over 1 year prevented accumulation of cardiac iron and increased LVEF in β-thalassaemia major patients

with normal cardiac iron levels and function

Cardiac iron prevention

32 32.5

0

5

10

15

20

25

30

35

40

Baseline 12 Baseline 12M

ean

LVEF

± S

D (%

)

69.667.7

5658606264666870727476

All patients (n = 75)

Mean change = +2% p = 0.57

All patients (n = 75)

CV = coefficient of variation; SD = standard deviation.

Summary

● Core clinical trials have shown that deferasirox provides 24-hour coverage and reduces serum ferritin and LIC in a dose-dependent manner

● Doses of deferasirox > 30 mg/kg/day achieve a negative iron balance with a manageable safety profile

● Long-term follow-up has revealed that deferasirox is well tolerated and serum ferritin levels < 1,000 µg/L are attainable and do not increase adverse events

● Administration of deferasirox to β-thalassaemia patients with prior history of iron chelation therapy improves satisfaction with therapy and quality of life

Thalassemia International Federation guidelines for iron chelation in β-thalassemia major

Deferasirox (Exjade®)

● 20 mg/kg/day starting dose in averagely transfused patients

● 30 up to 40mg/kg/day in patients with pre-existing high levels of iron loading

● 10–15 mg/kg/day for newly diagnosed patients with low levels of iron loading

DFO(Desferal®)

● 20–40 mg/kg for children, ≤50–60 mg/kg for adults

● In pediatric patients <3 years of age, recommend reduced dose and monitoring of growth and bone development

Deferiprone(Ferriprox®)

● 75/100 mg/kg/day

● May be combined with DFO if DFO monotherapy is ineffective or in presence of severe cardiac siderosis

1http://www.thalassaemia.org.cy/archive.asp

Iron chelation must be

TAILOREDaccording to iron intake and pre-existing iron load

Reduction

of body iron

Maintenance of body iron

Iron chelation must be

TAILOREDaccording to iron intake and pre-existing iron load

Reduction

of body iron

Maintenance of body iron

DFO at proper doseCombinatio therapyDfx 30-40mg/kg/die

COMPLIANCE

COMPLIANCE

Conclusions

● Randomized, controlled trials comparing deferiprone and deferasirox monotherapy are needed

● Similarly, carefully controlled comparison of combination therapies (DFP-DFO, DFX-DFO, DFX-DFP) must also be evaluated