Transcript Iron Deficiency & Clinical Sequelae, Diagnosis

Update on Iron Toxicity in
Myelodysplastic Syndromes:
I. Myelodysplastic Syndromes
Update
Aristoteles Giagounidis, MD, PhD
Department of Haematology and Oncology
St. Johannes Hospital
Duisburg, Germany
Cumulative Survival of 1806
Untreated Patients with Primary MDS
(Düsseldorf MDS Registry, 1970–2003)
1.0
Cumulative Survival
0.8
0.6
0.4
0.2
0.0
0
2
4
Graphic courtesy of Dr. U. Germing.
6
8
10
Years
12
14
16
18
20
International Prognostic Scoring System (IPSS)
Score
Prognostic
Variable
0
0.5
1.0
1.5
2.0
BM blasts (%)
<5
5–10
––
11–20
21–30
Gooda
Intermediateb
Poorc
––
––
0/1
2/3
––
––
––
Karyotype
Cytopaeniad
Score
Risk Subgroup
Median Survival (Y)
Low
5.7
0.5–1.0
Intermediate-1
3.5
1.5–2.0
Intermediate-2
1.2
High
0.4
0
≥2.5
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.
Graphic on top: with permission from Greenberg P, et al. Blood. 1997;89:2079-2088.
Prognosis of MDS according
to the IPSS
Survival
AML evolution
Low
Int-1
Int-2
High
AML Evolution (%)
100
90
Survival (%)
80
70
60
50
40
30
20
100
90
80
70
60
50
40
30
20
10
0
Low
Int-1
Int-2
High
10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Time (years)
With permission from Greenberg P, et al. Blood. 1997;89:2079-2088.
Time (years)
WHO Classification-Based Prognostic
Scoring System (WPSS)
Score
Parameter
WHO category
Karyotype
Transfusion
Score
0
1
2
3
RA, RARS, 5q–
RCMD, RCMD-RS
RAEB-1
RAEB-2
Gooda
Intermediateb
Poorc
––
Yes
Regular
––
––
Risk
Subgroup
Survival, Italian Cohort
(m)
Survival, German
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
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.
aGood:
Survival and Risk of Leukaemic
Progression According to WPSS at
Diagnosis
Overall Survival
(P <.001)
Risk of AML Evolution
Abbreviation: AML, acute myeloid leukaemia.
With permission from Malcovati L, et al. J Clin Oncol. 2007;25:3503-3510.
(P <.001)
MDS-Specific Comorbidity Index
To predict the impact of extra-haematologic
comorbidities on survival of patients with MDS
Comorbidity
Score
Total
Score
Risk
2-Y Risk of
Nonleukaemic
Death
Low
24
Cardiac disease
2
Moderate-to-severe
hepatic disease
1
0
Severe pulmonary
disease
1
1–2
Intermediate
42
Renal disease
1
Solid tumour
1
>2
High
61
Left graphic: with permission from Della Porta MG, et al. Blood. 2008;112:abstract 2677.
MDS Therapeutic Options
Prognosis
Low Risk
High Risk
´
•
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
Iron Imbalance in Chronically Transfused
Patients
Daily
Losses
1–2 mg
1 unit PRC
200–250 mg
Iron Accumulation Due
to Transfusion Therapy
Moderate transfusion requirement
2 units/month
24 units/year
≥5 g iron/year
Serum ferritin
~1000 μg/L
Normal body iron: 3–4 g
No physiologic mechanism to
excrete excess of iron
Gattermann N. Hematol Oncol Clin North Am. 2005;19(suppl 1):13-17.
Cumulative Proportion Surviving
Impact of Transfusion Dependency
on Nontransplant Candidates
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Transfusion-independent
N = 374
P = .005
Transfusion-dependent
0
20
40
60
80
100
Survival Time (months)
With permission from Cazzola M, et al. N Engl J Med. 2005;352:536-538.
120
140
1.0
RA, RARS, or 5q–
RCMD or RCMD-RS
(HR = 1.42, P <.001)
(HR = 1.33, P = .07)
Serum ferritin (μg/L)
1000
1500
2000
2500
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Cumulative Proportion Surviving
Cumulative Proportion Surviving
Overall Survival of Transfusion-Dependent
MDS Patients Based on Ferritin Level
1.0
Serum ferritin (μg/L)
1000
1500
2000
2500
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0
0
20 40 60 80 100 120 140 160 180
Survival Time (months)
0
20 40 60 80 100 120 140 160 180
Survival Time (months)
Abbreviations: RA, refractory anaemia; RARS, RA with ringed sideroblasts; RCMD, refractory cytopaenia with
multilineage dysplasia; RS, ringed sideroblasts.
With permission from Malcovati L, et al. Haematologica. 2006;91:1588-1590.
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, California
8 December 2008
Overall Survival in Patients with MDS by RBC
Transfusion Dependency
Probability of Survival
1.0
N = 2241
0.8
0.6
No RBC Transfusion Dependency
0.4
0.2
RBC Transfusion Dependency
P <.0001
0.0
0
5
10
15
20
Years from diagnosis
With permission from Sanz G, et al. 50th Annual American Society of Hematology Meeting;
December 6-9, 2008. Abstract 640.
25
Leukaemia-Free Survival in Patients with MDS by
RBC Transfusion Dependency
N = 2241
Probability of Survival
1.0
No RBC Transfusion Dependency
0.8
0.6
RBC Transfusion Dependency
0.4
0.2
P <.0001
0.0
0
5
10
15
20
25
Years from Diagnosis
With permission from Sanz G, et al. 50th Annual American Society of Hematology Meeting;
December 6-9, 2008. Abstract 640.
Prognostic Impact of Development of Iron
Overload is Independent of WPSS Score
Overall Survival
Variablea
HR
P-value
Leukaemia-Free
Survival
Variablea
HR
Iron overload 4.34 <.001
WPSS
WPSS
Iron overload 2.13
1.60 <.001
P-value
2.24 <.001
aMultivariate
<.001
analyses, including WPSS and development of iron overload (time-dependent) (n = 580).
Cases with less than 3 serum ferritin measurements were excluded.
With permission from Sanz G, et al. 50th Annual American Society of Hematology Meeting;
December 6-9, 2008. Abstract 640.
Overall Survival in Patients with MDS
by Serum Ferritin Level
N = 762
1.0
Probability
0.8
Ferritin <1000 ng/mL
0.6
0.4
0.2
Ferritin 1000 ng/mL
P <.0001
0.0
0
5
10
15
20
Years from Diagnosis
With permission from Sanz G, et al. 50th Annual American Society of Hematology Meeting;
December 6-9, 2008. Abstract 640.
Leukaemia-Free Survival in Patients with MDS
by Serum Ferritin Level
1.0
N = 762
Ferritin <1000 ng/mL
Probability
0.8
0.6
Ferritin 1000 ng/mL
0.4
0.2
P <.0001
0.0
0
5
10
15
20
Years from Diagnosis
With permission from Sanz G, et al. 50th Annual American Society of Hematology Meeting;
December 6-9, 2008. Abstract 640.
Impact of Iron Chelation on
Survival in MDS
Retrospective review
of 178 patients
(36 RA, 42 RARS, 28 RAEB,
16 RAEB-T or AML, 25 CMML, 31 other)
“Although we were not able to demonstrate
a decrease in organ dysfunction
in patients receiving ICT for MDS,
there was a significant improvement in
overall survival”
First data to document improvement
in clinical outcome
in patients with MDS receiving ICT
28
Serum ferritin
≥ 2000 μg/L
22
Clinical evidence
of iron overload
18
DFO
ICT therapy
10
No ICT
Median overall survival
for Low or Int-1 IPSS
Not reached
at 160 mo
40 mo
(0.7–224)
Abbreviations: CMML, chronic myelomonocytic leukaemia; DFO,
desferroxamine; ICT, iron chelation therapy; RAEB, refractory anaemia with
(P <.03)
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.
Iron Chelation May Improve Survival
in MDS Patients
Median survival: 63 months (whole group); 115
months for chelated vs 51 months for
nonchelated patients (P <.0001)
Survival Distribution Function
1.00
0.75
0.50
Iron chelation therapy
0.25
No iron chelation therapy
0.00
0
50
100
150
200
Time from Diagnosis to Death (months)
With permission from Rose C, et al. Blood. 2007;110:abstract 249.
250
Deferasirox in Patients with TransfusionDependent MDS
• Design
EPIC Trial
– 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.
Change in Serum Ferritin Levels with
Deferasirox in MDS
EPIC1 and US032 Studies
Serum Ferritin (ng/mL)
4000
3397
3500
3000
3057
2802
2730
2358
2500
2210
2635
2076
2000
2501
1904
1500
EPIC
US03
1000
500
0
0
3
6
9
12
Month
1. Gattermann N, et al. Blood. 2008;112:abstract 633. 2. List AF, et al. Blood. 2007;110:abstract 1470.
Deferasirox in Patients with MDS–Study US03
Change of Labile Plasma Iron Over 12 Months
Patients (n)
53
34
28
19
13
Labile Plasma Iron (mol/L)
1.0
0.8
0.6
Threshold of Normal Labile Plasma Iron
0.4
0.4
0
Baseline
3
6
Months from Baseline
With permission from List AF, et al. Blood. 2007;110:abstract 1470.
9
12
24
Elevated Pretransplant Serum Ferritin May Impact
Prognosis of Haemopoietic Stem Cell Transplant
(HSCT) in Patients with MDS
• In HSCT, iron overload may increase treatmentrelated 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.
60
40
P <.001
20
0
1
2
3
4
5
6
80
7
60
40
P = .005
20
0
80
60
40
P <.001
20
0
8
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
100
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
100
DFS (%)
80
0
Treatment-Related
mortality (%)
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
100
100
Relapse (%)
Overall Survival (%)
Outcomes According to Pretransplant Serum Ferritin
Level in MDS Patients Undergoing HSCT
80
0
1
2
3
4
5
6
7
8
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
60
40
20
P = .7
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
Time from Transplantation (years)
Time from Transplantation (years)
Abbreviations: DFS, disease-free survival; HSCT, haemopoietic stem cell transplant.
With permission from Armand P, et al. Blood. 2007;109:4586-4588.
0
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/day
to reduce body iron
For patients receiving
pRBCs >7 mL/kg/month
(~2 adult units)
10 mg/kg/day
to maintain body iron
For patients well managed on
desferrioxamine
Numerically half the
dose of desferrioxamine
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, MD
Professor
Director, Cardiac Magnetic Resonance Unit
Department of Cardiology A.De Gasperis
Azienda Ospedaliera Niguarda Ca’Granda
Milan, Italy
Non–transferrin-Bound Iron Transport by
L-Type Ca2+ Channels in the Heart
X
Abbreviations: Dcytb, duodenal cytochrome B;
DMT1, dimetal transporter 1.
With permission from Oudit GY, et al. J Mol Med. 2006;84:349-364.
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.
Endocrinopathies
Iron overload
Hypoxia
Infections
OXIDATIVE STRESS
Myocardial
impairment
Hypercoagulability
Graphic courtesy of Dr. A. Roghi.
Endothelial
dysfunction
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.
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
Iron n = 3
Control n = 2
Response to
Nitroglycerine
Response to
Acetylcholine
With permission from Day SM, et al. Circulation. 2003;107:2601-2606.
Nonleukaemic Causes of Death and
Relationship to Iron Overload
N = 467
8%
2%
8%
Cardiac failure
Infection
Haemorrhage
Hepatic cirrhosis
Not identified
31%
51%
Death in low-risk myelodysplastic syndromes – cardiac failure is more
common in transfused than nontransfused patients (P = .01)
Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603.
Survival of Patients with Myelodysplastic
Syndromes According to Transfusion Dependence
1.0
Transfusion-independent
Transfusion-dependent
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Leukaemia-Free Survival
(HR = 1.84; P = .001)
Cumulative Proportion Surviving
Cumulative Proportion Surviving
Overall Survival
(HR = 1.91; P <.001)
1.0
Transfusion-independent
Transfusion-dependent
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0
0
20 40 60 80 100 120 140 160 180
0
20 40 60 80 100 120 140 160 180
Survival Time (months)
Abbreviation: HR, hazard ratio.
With permission from Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603.
Survival Time (months)
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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