update on iron toxicity in myelodysplastic syndromes: i. myelodysplastic syndromes update...

Update on Iron Toxicity in Myelodysplastic Syndromes:

I. Myelodysplastic Syndromes Update

Aristoteles Giagounidis, MD, PhDDepartment of Haematology and Oncology

St. Johannes Hospital Duisburg, Germany

Cumulative Survival of 1806 Untreated Patients with Primary MDS

(Düsseldorf MDS Registry, 1970–2003)

YearsGraphic courtesy of Dr. U. Germing.

20

0.6

0.4

0.2

0.0

0.8

1.0

4 6 8 10 12 14 16 18 20

Cu

mu

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ve S

urv

ival

ScoreScore

Prognostic Variable

0 0.5 1.0 1.5 2.0

BM blasts (%) <5 5–10 –– 11–20 21–30

Karyotype Gooda Intermediateb Poorc –– ––

Cytopaeniad 0/1 2/3 –– –– ––

aGood: normal, -Y, del(5q), del(20q); bIntermediate: other abnormalities not seen in “good” or “poor”; cPoor: complex (≥3 abnormalities) or chromosome 7 anomalies; dHaemoglobin <10 g/dL, absolute neutrophil count <1.5 109/L, platelet count < 100 109/L.

International Prognostic Scoring System (IPSS)

Graphic on top: with permission from Greenberg P, et al. Blood. 1997;89:2079-2088.

ScoreScore Risk SubgroupRisk Subgroup Median Survival (Y)Median Survival (Y)

0 Low 5.7

0.5–1.0 Intermediate-1 3.5

1.5–2.0 Intermediate-2 1.2

≥2.5 High 0.4

Prognosis of MDS according to the IPSS

Su

rviv

al (

%)

LowInt-1Int-2High

Survival AML evolution

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Time (years)

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

AM

L E

volu

tio

n (

%)

Time (years)

LowInt-1Int-2High

With permission from Greenberg P, et al. Blood. 1997;89:2079-2088.

ScoreScore

Parameter 0 1 2 3

WHO category RA, RARS, 5q– RCMD, RCMD-RS RAEB-1 RAEB-2

Karyotype Gooda Intermediateb Poorc ––

Transfusion Yes Regular –– ––

aGood: normal, -Y, del(5q), del(20q); bIntermediate: other abnormalities not seen in “good” or “poor”; cPoor: complex (≥3 abnormalities) or chromosome 7 anomalies; dmedian survival.

With permission from Malcovati L, et al. Blood. 2005;106:abstract 788.

WHO Classification-Based Prognostic Scoring System (WPSS)

ScoreScore Risk Risk SubgroupSubgroup

Survival, Italian Cohort Survival, Italian Cohort (m)(m)

Survival, German Survival, German Cohort (m)Cohort (m)

0 Very low 103 141

1 Low 72 66

2 Intermediate 40 48

3–4 High 21 26

5–6 Very high 12 9

Survival and Risk of Leukaemic Progression According to WPSS at

Diagnosis

With permission from Malcovati L, et al. J Clin Oncol. 2007;25:3503-3510.

Overall Survival(P <.001)

Risk of AML Evolution(P <.001)

Abbreviation: AML, acute myeloid leukaemia.Abbreviation: AML, acute myeloid leukaemia.

ComorbidityComorbidity ScoreScore

Cardiac disease 2

Moderate-to-severe hepatic disease

1

Severe pulmonary disease

1

Renal disease 1

Solid tumour 1

TotalTotalScore Score

RiskRisk 2-Y Risk of 2-Y Risk of Nonleukaemic Nonleukaemic

DeathDeath

0 Low 24

1–2 Inter-mediate

42

>2 High 61

MDS-Specific Comorbidity Index

To predict the impact of extra-haematologic comorbidities on survival of patients with MDS

Left graphic: with permission from Della Porta MG, et al. Blood. 2008;112:abstract 2677.

MDS Therapeutic Options

• Best supportive care, including iron chelation

• Haematopoietic growth factors

• Immunosuppressive therapy

• Differentiation agents

• Farnesyltransferase inhibitors

• Thalidomide/lenalidomide

• Arsenic trioxide

• Low-dose chemotherapy

• Epigenetic treatment

• Intensive chemotherapy

• Allogeneic stem cell transplantation

´

Low Risk

High Risk

Pro

gn

os

is

1 unit PRC

200–250 mg

1–2 mg

DailyLosses

Iron Imbalance in Chronically Transfused Patients

2 units/month

Iron Accumulation Due to Transfusion Therapy

Serum ferritin~1000 μg/L

Moderate transfusion requirement

Normal body iron: 3–4 g No physiologic mechanism to

excrete excess of iron

24 units/year

≥5 g iron/year

Gattermann N. Hematol Oncol Clin North Am. 2005;19(suppl 1):13-17.

Impact of Transfusion Dependency on Nontransplant Candidates

With permission from Cazzola M, et al. N Engl J Med. 2005;352:536-538.

Transfusion-independent

Transfusion-dependent

Survival Time (months)

Cu

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rop

ort

ion

Su

rviv

ing

0.0

0.1

0.2

0.30.4

0.5

0.60.7

0.80.9

1.0

0 20 40 60 80 100 120 140

N = 374

P = .005

RA, RARS, or 5q–(HR = 1.42, P <.001)

RCMD or RCMD-RS(HR = 1.33, P = .07)

With permission from Malcovati L, et al. Haematologica. 2006;91:1588-1590.

Overall Survival of Transfusion-Dependent MDS Patients Based on Ferritin Level

180

Cu

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ion

Su

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ing

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160

Cu

mu

lati

ve P

rop

ort

ion

Su

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ing

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180Survival Time (months) Survival Time (months)

Serum ferritin (μg/L)1000 150020002500

Serum ferritin (μg/L)1000 150020002500

Abbreviations: RA, refractory anaemia; RARS, RA with ringed sideroblasts; RCMD, refractory cytopaenia with multilineage dysplasia; RS, ringed sideroblasts.

Independent Impact of Iron Overload and Transfusion Dependency on Survival and

Leukemic Evolution in Patients with Myelodysplastic Syndrome

Sanz G, Nomdedeu B, Such E, Bernal T, Belkaid M, Ardanaz MT, Marco V, Pedro C, Ramos F, del Cañizo C, Luño E, Cobo F, Carbonell F, Gomez

V, Muñoz JA, Amigo ML, Bailen A, Bonanad B, Tormo M, Andreu R, Arrizabalaga B, Arilla MJ, Bueno J, Requena MJ, Bargay J, Sanchez J,

Senent L, Arenillas L, de Paz R, Xicoy B, Duarte R, Cervera J.

(Spanish Registry of MDS)

50th Annual Meeting of the American Society of Hematology

San Francisco, California8 December 2008

Overall Survival in Patients with MDS by RBC Transfusion Dependency

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

Years from diagnosis

No RBC Transfusion Dependency

RBC Transfusion DependencyP <.0001

With permission from Sanz G, et al. 50th Annual American Society of Hematology Meeting; December 6-9, 2008. Abstract 640.

N = 2241

Pro

bab

ility

of

Su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

Years from Diagnosis

No RBC Transfusion Dependency

RBC Transfusion Dependency

P <.0001


N = 2241

Leukaemia-Free Survival in Patients with MDS by RBC Transfusion Dependency

Pro

bab

ility

of

Su

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al

Prognostic Impact of Development of Iron Overload is Independent of WPSS Score

Overall SurvivalLeukaemia-Free

Survival

VariableVariableaa HRHR P-P-valuevalue

Iron overload 4.34 <.001

WPSS 1.60 <.001

VariableVariableaa HRHR PP-value-value

WPSS 2.24 <.001

Iron overload 2.13 <.001

aMultivariate analyses, including WPSS and development of iron overload (time-dependent) (n = 580). Cases with less than 3 serum ferritin measurements were excluded.


Overall Survival in Patients with MDS by Serum Ferritin Level

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20


Ferritin <1000 ng/mL

Ferritin 1000 ng/mLP <.0001


N = 762P

rob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20


Ferritin <1000 ng/mL

Ferritin 1000 ng/mL

P <.0001


N = 762

Leukaemia-Free Survival in Patients with MDS by Serum Ferritin LevelP

rob

abili

ty

Impact of Iron Chelation on Survival in MDS

40 mo(0.7–224)

Not reachedat 160 mo

Median overall survivalfor Low or Int-1 IPSS

(P <.03)

“Although we were not able to demonstratea decrease in organ dysfunction in patients receiving ICT for MDS,

there was a significant improvement inoverall survival”

First data to document improvement in clinical outcome

in patients with MDS receiving ICT

2828Serum ferritin Serum ferritin

≥ 2000 ≥ 2000 μμg/Lg/L

2222Clinical evidence Clinical evidence of iron overloadof iron overload

1818DFO DFO

ICT therapyICT therapy

1010No ICTNo ICT

Retrospective review of 178 patients

(36 RA, 42 RARS, 28 RAEB, 16 RAEB-T or AML, 25 CMML, 31 other)

Abbreviations: CMML, chronic myelomonocytic leukaemia; DFO, desferroxamine; ICT, iron chelation therapy; RAEB, refractory anaemia with excess blasts; RAEB-T, RAEB in transformation; RARS, RA with ringed sideroblasts.Leitch HA, et al. Blood. 2006;108:abstract 249. Graphic courtesy of Dr. N. Gattermann.

Su

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istr

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n F

un

ctio

n

0.00

0.25

0.50

0.75

1.00

Time from Diagnosis to Death (months)

0 50 100 150 200 250

Iron chelation therapy

No iron chelation therapy

Median survival: 63 months (whole group); 115 months for chelated vs 51 months for nonchelated patients (P <.0001)

Iron Chelation May Improve Survival in MDS Patients

With permission from Rose C, et al. Blood. 2007;110:abstract 249.

Deferasirox in Patients with Transfusion-Dependent MDS

EPIC Trial• Design

– 1-year, multicenter, open-label, single-arm, trial

– Deferasirox 10–30 mg/kg/d for 12 months

– Primary efficacy endpoint was change in serum ferritin at 12 months

• Study population, N = 341– Median age 68 years

– Baseline serum ferritin 2730 ng/mL

– Mean transfusion dependency duration 3.6 years

– Mean blood received in previous year 116.4 mL/kg

– Previous chelation 52%

• Drug-related adverse effects, all grades– Diarrhea 32%, nausea 13%, abdominal pain 15%, vomiting 8%, and

rash 7%

• Conclusion: Significant reductions in serum ferritin levels over 1-year treatment with dose adjustments based on ferritin trends and safety markers

Gattermann N, et al. Blood. 2008;112:abstract 633.Gattermann N, et al. Blood. 2008;112:abstract 633.

2730

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28022635 2501

0

500

1000

1500

2000

2500

3000

3500

4000

0 3 6 9 12

Month

EPICUS03

Ser

um

Fer

riti

n (

ng

/mL

)S

eru

m F

erri

tin

(n

g/m

L)

Change in Serum Ferritin Levels with Deferasirox in MDS

EPIC1 and US032 Studies

1. Gattermann N, et al. Blood. 2008;112:abstract 633. 2. List AF, et al. Blood. 2007;110:abstract 1470.1. Gattermann N, et al. Blood. 2008;112:abstract 633. 2. List AF, et al. Blood. 2007;110:abstract 1470.

Patients (n) 53 34 28 19 13

Months from Baseline

0

0.4

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0.8

1.0

Baseline 6 9 12

Lab

ile P

lasm

a Ir

on

(m

ol/L

)

3

0.4

Threshold of Normal Labile Plasma Iron

With permission from List AF, et al. Blood. 2007;110:abstract 1470.

Deferasirox in Patients with MDS–Study US03Change of Labile Plasma Iron Over 12 Months

24

Elevated Pretransplant Serum Ferritin May Impact Prognosis of Haemopoietic Stem Cell Transplant

(HSCT) in Patients with MDS

• In HSCT, iron overload may increase treatment-related mortality

• The hazard ratio for mortality associated with serum ferritin ≥2515 μg/L was 2.6 (P =.003)

• Serum ferritin is an independent prognostic marker in MDS patients undergoing HSCT

• Iron chelation therapy has a possible role in the pre- and posttransplant setting

Armand P, et al. Blood. 2007;109:4586-4588.

Time from Transplantation (years)

Ove

rall

Su

rviv

al (

%)

P <.001

Serum ferritin 1st–3rd quartileSerum ferritin highest quartile

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Tre

atm

ent-

Rel

ate

d

mo

rtal

ity

(%

)

P = .005


0

20

40

60

80

100

0 1 2 3 4 5 6 7 8Time from Transplantation (years)

DF

S (

%)

P <.001


0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Rel

ap

se (

%)

P = .7


0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Outcomes According to Pretransplant Serum Ferritin Level in MDS Patients Undergoing HSCT

Abbreviations: DFS, disease-free survival; HSCT, haemopoietic stem cell transplant.With permission from Armand P, et al. Blood. 2007;109:4586-4588.

Deferasirox Dosing by Transfusion Requirements and Therapeutic Goals

Initial recommended dose 20 mg/kg/day

For patients receiving pRBCs >14 mL/kg/month(~4 adult units)

30 mg/kg/dayto reduce body iron

For patients receiving pRBCs >7 mL/kg/month(~2 adult units)

10 mg/kg/dayto maintain body iron

Numerically half the dose of desferrioxamine

For patients well managed on desferrioxamine

Exjade. Summary of Product Characteristics. West Sussex, UK: Novartis Europharm Ltd; 2006.Exjade. Summary of Product Characteristics. West Sussex, UK: Novartis Europharm Ltd; 2006.

Update on Iron Toxicity in Myelodysplastic Syndromes:

II. Cardiac Iron Update

Alberto Roghi, MDProfessor

Director, Cardiac Magnetic Resonance Unit Department of Cardiology A.De Gasperis Azienda Ospedaliera Niguarda Ca’Granda

Milan, Italy

XX

With permission from Oudit GY, et al. J Mol Med. 2006;84:349-364. With permission from Oudit GY, et al. J Mol Med. 2006;84:349-364.

Non–transferrin-Bound Iron Transport by L-Type Ca2+ Channels in the Heart

Abbreviations: Dcytb, duodenal cytochrome B; DMT1, dimetal transporter 1.

Longitudinal Heart and Liver Iron Time Courses in 38 Thlassaemia Major Patients

With permission from Noetzli LJ, et al. Blood. 2008;112:2973-2978. Abbreviation: HIC, hepatic iron concentration.

Various Iron Loading States

Graphic courtesy of Dr. A. Roghi.Graphic courtesy of Dr. A. Roghi.

Iron overload

Hypoxia Infections

Endocrinopathies

OXIDATIVE STRESS

Endothelial dysfunction

Myocardial impairment

Hypercoagulability

Graphic courtesy of Dr. A. Roghi.Graphic courtesy of Dr. A. Roghi.

Relationship Between Iron Overload, Oxidative Stress, and Calcium Channels

in Myocardial Cells

With permission from Oudit GY, et al. J Mol Med. 2006;84:349-364. With permission from Oudit GY, et al. J Mol Med. 2006;84:349-364.

Abbreviations: NCX, sodium-calcium exchanger; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; SERCA2a, sarcoplasmic reticulum Ca 2+ ATPase isoform 2.

Vasodilator Impairment of Aortic Ring by Iron Overload

Response to Nitroglycerine

Response to Acetylcholine

With permission from Day SM, et al. Circulation. 2003;107:2601-2606.

Iron n = 3Control n = 2

Cardiac failureInfectionHaemorrhageHepatic cirrhosisNot identified

Nonleukaemic Causes of Death and Relationship to Iron Overload

51%31%

8%

8% 2%

Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603.

Death in low-risk myelodysplastic syndromes – cardiac failure is more common in transfused than nontransfused patients (P = .01)

N = 467

Overall Survival(HR = 1.91; P <.001)

Leukaemia-Free Survival(HR = 1.84; P = .001)

180

Cu

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Transfusion-dependent

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160

Cu

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0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180Survival Time (months) Survival Time (months)

Transfusion-independentTransfusion-dependent

With permission from Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603.Abbreviation: HR, hazard ratio.

Survival of Patients with Myelodysplastic Syndromes According to Transfusion Dependence

Iron Chelation Therapy May Improve Survival in Patients with MDS

With permission from Rose C, et al. Blood. 2007;110:abstract 249.

Conclusions

• Chronic transfusion dependence in MDS may lead to significant iron overload and may contribute to increased morbidity and mortality

• Non–transferrin-bound iron causes oxidative stress and is deleterious to different organ systems, including liver and heart

• Both RBC transfusions and high ferritin levels independently worsen overall survival in patients with MDS

• Iron chelation with deferasirox consistently reduced serum ferritin levels and labile plasma iron levels in EPIC and US03 trials

• Effective iron chelation may improve overall survival in patients with low and intermediate-1 risk MDS

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