Transcript Iron Deficiency & Clinical Sequelae, Diagnosis

Overview of
Myelodysplastic Syndromes
with Focus on Iron Overload
Norbert Gattermann, MD, PhD
Professor
Department of Haematology,
Oncology, and Clinical Immunology
Heinrich-Heine-University
Düsseldorf, Germany
Myelodysplastic Syndromes (MDS)–Age at Diagnosis
Patients in the Düsseldorf Registry
700
Number of Patients
600
N = 3125
500
400
300
200
100
0
20
30
40
50
60
70
Age (years)
Düsseldorf MDS Registry. Graphic courtesy of Dr. U. Germing.
80
90
MDS–Incidence by Age and Gendera
Patients in the Düsseldorf Registry
Age Group (Y)
aCases
All Patients
Male
Female
<30
0.4
0.5
0.2
30–39
0.4
0.3
0.5
40–49
1.3
1.2
1.4
50–59
2.8
3.5
2.2
60–69
8.7
11.4
6.2
70–79
24.5
38.8
17.2
80–89
31.3
53.6
23.6
≥90
15.9
28.2
13.1
All ages
4.9
5.5
4.4
per 100,000 population/year.
Düsseldorf MDS Registry. Graphic courtesy of Dr. U. Germing.
MDS Pathophysiology
Clonal Expansion Plus Ineffective Haematopoiesis
Bone Marrow
Peripheral Blood
Oncogene Activation
Growth Advantage
Ineffective
Functional Impairment,
Haematopoiesis Decreased Life Span
Graphic courtesy of Dr. N. Gattermann.
Excessive
Apoptosis
Apoptosis in MDS
Intrinsic and Extrinsic Causes?
Primary Defect
(Intrinsic)
Excessive
Apoptosis
Pro-apoptotic
Cytokines 
Graphic courtesy of Dr. N. Gattermann.
Activated
Macrophages
Impaired Production of Blood Cells
High
Apoptotic Activity
Impaired
Differentiation
Early MDS
Advanced MDS
(Low risk)
(High risk)
Graphic courtesy of Dr. N. Gattermann.
MDS Pathophysiology
Clonal Evolution Toward Acute Myelogenous Leukaemia
Normal
Haematopoiesis
Clonal
Clonal
Haematopoiesis Evolution
Oncogene Activation
Growth Advantage
MDS
Graphic courtesy of Dr. N. Gattermann.
Leukaemia
Incidence of Chromosomal Anomaliesa in Patients
with MDS and an Abnormal Karyotype
30
Frequency (%)
n = 1080b
25
20
15
10
aIsolated
t(7q)
del(11q)
del(12p)
t(5q)
+11
+1/+1q
-21
inv/t(3q)
+21
-13/del(13q)
+Mar
-17/del(17p)
-Y
-5
del(20q)
-18/del(18q)
+8
-7/del(7q)
0
del(5q)
5
or in combination with 1 additional anomaly or complex anomalies. bTotal data set, 2124; cytogenic analysis in 2072.
Haase D, et al. Blood. 2007;110:4385-4395. Graphic courtesy of Dr. D. Haase.
Cytogenetic Anomalies—Only Part
of the MDS Story
• Useful for making the diagnosis
• Useful for prognostication
• Useful for treatment decisions
•
•
•
•
•
Identified in about 50% of patients1
Not specific for MDS
Explanation for excessive apoptosis?
Explanation for genomic instability?
Explanation for dysplastic features?
1. Haase D, et al. Blood. 2007;110:4385-4395.
MDS–Dysplastic Features in Blood
and Bone Marrow
Erythropoiesis
Granulopoiesis
Thrombopoiesis
Blood
Anisocytosis
Poikilocytosis
Macrocytosis
Basophilic stippling
Dimorphic blood film
Pappenheimer bodies
Nucleated red cells
Pseudo-Pelger anomaly
Hypersegmented nuclei
Nuclei of bizarre shape
Chromatin clumping
Hypogranularity
Monocytosis
Blast cells, Auer rods
Thrombocytopenia
Giant platelets
Agranular platelets
Micromegakaryocytes
Bone
marrow
Megaloblastic cells
Nuclear fragmentation
Internuclear bridges
Multinuclearity
Vacuolization
Positive PAS staining
Ring sideroblasts
Increased blast cells
Hypogranular
Promyelocytes
Hypogranular myelocytes
Partial MPO defect
Increase of promonocytes
Lack of mature neutrophils
Abnormal neutrophils
Larger megakaryocytes
with nonlobed nuclei
Reduction of MEG
Mononuclear MEG
Multinucleated MEG
MEG with botryoid
nuclei
Abbreviations: MEG, megakaryocyte; MPO, myeloperoxidase; PAS, Periodic Acid-Schiff.
Graphic courtesy of Dr. N. Gattermann.
WHO Classification of MDS
Patients in the Düsseldorf Registry
%
MDS
Blood
Bone Marrow
3.7
5q– syndrome
• Anaemia
• Blasts <5%
• Platelets normal to increased
8.8
RA
• Anaemia
• Blasts ≤1%
• Megakaryocytes normal to increased
• Blasts <5%
• No Auer rods
• Isolated del(5q)
• Dyserythropoiesis only
• Blasts <5%
• Ringed sideroblasts <15%
7.8
RARS
• Anaemia
• Blasts ≤1%
31.0
RCMD
• Cytopaenia of ≥2 lineages
• Blasts ≤1%
• Monocytes <1000/µL
15.4
RCMD-RS
• Cytopaenia of ≥2 lineages
• Blasts ≤1%
• Monocytes <1000/µL
15.0
RAEB I
• Cytopaenia of ≥2 lineages
• Peripheral blood blasts ≤5%
• Monocytes <1000/µL
• Dyserythropoiesis only
• Blasts <5%
• Ringed sideroblasts <15%
• >10% of cells per lineage dysplastic
• No Auer rods
• Blasts <5%
• Ringed sideroblasts <15%
• >10% of cells per lineage dysplastic
• No Auer rods
• Blasts <5%
• Ringed sideroblasts ≥15%
• Unilinear or multilinear dysplasia
• No Auer rods
• Blasts 5%–9%
18.3
RAEB II
• Cytopaenia of ≥2 lineages
• Peripheral blood blasts ≤19%
• ± Auer rods
• Unilinear or multilinear dysplasia
• ± Auer rods
• Blasts 10%–19%
Düsseldorf MDS Registry. Graphic courtesy of Dr. U. Germing.
Cumulative Survival of MDS Patients
According to WHO Type
Abbreviations: RA, refractory anaemia; RAEB, refractory anaemia with excess blasts; RARS, refractory
anaemia with ring sideroblasts; RCMD, refractory cytopaenia with multilineage dysplasia; RSCMD,
refractory sideroblastic cytopaenia with multilineage dysplasia.
Germing U, et al. Leuk Res. 2000;24:983-992.
Graphic reflects updated data and is courtesy of Dr. U. Germing.
International Prognostic Scoring System
(IPSS)
Score
Prognostic
variable
0
0.5
1.0
1.5
2.0
Medullary
blasts (%)
<5
5–10
––
11–20
21–30
Karyotype
Gooda
Intermediateb
Poorc
––
––
Cytopaenia
0/1
2/3
––
––
––
Low risk
Intermediate-1
Intermediate-2
High risk
0
0.5–1.0
1.5–2.0
≥2.5
points
points
points
points
aGood: normal, -Y, del(5q), del(20q). bIntermediate: other abnormalities not seen in “good” or “poor.”
cPoor: complex (≥3 abnormalities) or chromosome 7 anomalies.
With permission from Greenberg P, et al. Blood. 1997;89:2079-2088.
The IPSS Applied to Patients in the
Düsseldorf MDS Registry
1.0
31%
Cumulative Survival
.8
39%
20%
10%
n = 550
.6
Risk Survival
Group (months)
Low
71
Int-1
31
Int-2
15
High
8
Low
.4
Int 1
.2
High
Int 2
0.0
0
48
24
96
72
144
120
192
168
240
216
Months
Düsseldorf MDS Registry. Graphic courtesy of Dr. U. Germing.
288
264
336
312
360
WHO Classification-Based Prognostic
Scoring System (WPSS)
Score
Prognostic
Variable
WHO category
Karyotype
Transfusion
requirement
0
1
RA, RARS, RCMD, RCMD5q–
RS
2
3
RAEB-1
RAEB-2
Gooda
Intermediateb
Poorc
––
Yes
Regular
––
––
Very low risk
Low risk
Intermediate
High risk
Very high risk
0
1
2
3–4
5–6
points
points
points
points
points
aGood: normal, -Y, del(5q), del(20q). bIntermediate: other abnormalities not seen in “good” or “poor.”
cPoor: complex (≥3 abnormalities) or chromosome 7 anomalies.
With permission from Malcovati L, et al. Blood. 2005;106:abstract 788.
WPSS at Diagnosis Applied to
Patients in the Düsseldorf MDS Registry
Overall Survival
Risk of AML Evolution
(P <.001)
(P <.001)
Malcovati L, et al. J Clin Oncol. 2007;25:3503-3510. Graphic courtesy of Dr. U. Germing.
MDS–Treatment Options
Low Risk
• Best supportive care, including iron chelation
• Growth factors
• Immunosuppressive treatment
• Differentiation induction
• Farnesyltransferase inhibitors
Prognostic
Group
• Thalidomide/lenalidomide
• Arsenic trioxide
• Low-dose chemotherapy
• Epigenetic treatment
• Intensive chemotherapy
High Risk
• Allogeneic stem cell transplantation
Iron Imbalance in Transfusion-Dependent
Patients
Approximately 80% of MDS patients have a haemoglobin <10 g/dL at
diagnosis1 and the majority become transfusion-dependent
Daily
Losses
1–2 mg
1 unit PRC
200–250 mg
Abbreviation: PRC, packed red cells.
1. Sanz GF, et al. Blood. 1989;74:395-408. Graphic courtesy of Dr. N. Gattermann.
Consequence of Ineffective Erythropoiesis–Increased
Intestinal Iron Uptake
Duodenum
Unrestrained
intestinal
iron absorption
Suppressed
hepcidin
expression
in the liver
Liver
Normal
daily iron
uptake
~1 mg
Increased
GDF15
in the serum
Other cells
in the body
Urine, faeces,
nails, hair, skin
Erythroblasts
Ineffective
erythropoiesis
Graphic courtesy of Dr. N. Gattermann.
Daily losses
~1 mg
Transferrin
Haemoglobin
(1.7–2.4 g)
Macrophages
(0.5–1.5 g)
Blood losses
(eg, menstrual)
MDS–Serum Ferritin at Diagnosis
8000
7794
Serum Ferritin (ng/mL)
6980
N = 650
6000
5000
4176
3839
4000
3526
2000
2500
2284
1980
1800
1500
1290
2555
2283
2000
1749
2980
2690
1830
1590
2000
2500
2136
2000
1309
0
RA
RARS
RAEB
RAEB-T
CMML
Abbreviations: RA, refractory anaemia; RAEB, RA with excess blasts; RA with excess blasts in
transformation; RARS, RA with ring sideroblasts; CMML, chronic myelomonocytic leukaemia.
Data on file. Düsseldorf MDS Registry. Graphic courtesy of Dr. N. Gattermann.
Most Important Cause of Iron Overload in
MDS–Transfusion Therapy
• Medium transfusion
dependence
– 2 units/month
– 24 units/year
– About 100 units/4 years
• Heavy transfusion
dependence
– 4 units/month
– 48 units/year
– About 100 units/2 years
100 units = ≥20 g iron
Total body iron in normal person
3–4 g
200–250 mg
iron
Impact of Transfusion Dependency
on Nontransplantation Candidates
Cumulative Proportion Surviving
Cumulative probability of survival among patients given a diagnosis of MDS in
Pavia, Italy from 1992–2002
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)
120
140
Cazzola M, et al. N Engl J Med. 2005;352:536-538. Copyright © 2005. Massachusetts Medical Society. All
rights reserved
Transfusion Dependency—A Risk Factor
Independent of Cytogenetic Risk Group
Not transfusion-dependent
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 20 40 60 80 100 120
Intermediate
0 20 40 60 80 100 120
Months
aOnly
isolated del 5q.
With permission from Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603.
Cumulative Proportion Surviving
Gooda
Cumulative Proportion Surviving
Cumulative Proportion Surviving
Transfusion-dependent
Poor
0 20 40 60 80 100 120
Survival of Patients with MDS According to
Transfusion Dependency
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
Survival Time (months)
0
20 40 60 80 100 120 140 160 180
Survival Time (months)
Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603. Graphic courtesy of Dr. N. Gattermann.
Overall Survival in Patients with MDS by RBC
Transfusion Dependency
Probability
N = 2241
No RBC Transfusion Dependency
P <.0001
RBC Transfusion Dependency
With permission from Sanz G, et al. Abstract 640. Presented at: 50th Annual American Society
of Hematology Meeting, December 6-9, 2008, San Francisco, California.
Leukaemia-Free Survival in Patients with MDS by
RBC Transfusion Dependency
With permission from Sanz G, et al. Abstract 640. Presented at: 50th Annual American Society
of Hematology Meeting, December 6-9, 2008, San Francisco, California.
Prognostic Impact of Development of Iron
Overload is Independent of WPSS Score
Overall Survival
Variablea
Leukaemia-Free
Survival
Variablea
HR
Iron overload 4.34 <.001
WPSS
2.24 <.001
WPSS
Iron overload 2.13 <.001
aMultivariate
HR
P-value
1.60 <.001
P-value
analyses including WPSS and development of iron overload (time-dependent) (n = 580).
Cases with <3 serum ferritin measurements were excluded.
With permission from Sanz G, et al. Abstract 640. Presented at: 50th Annual American Society of
Hematology Meeting, December 6-9, 2008, San Francisco, California.
Overall Survival in Patients with MDS
by Serum Ferritin Level
Probability
n = 762
With permission from Sanz G, et al. Abstract 640. Presented at: 50th Annual American Society of
Hematology Meeting, December 6-9, 2008, San Francisco, California.
Leukaemia-Free Survival in Patients with MDS
by Serum Ferritin Level
Probability
n = 761
With permission from Sanz G, et al. Abstract 640. Presented at: 50th Annual American Society of
Hematology Meeting, December 6-9, 2008, San Francisco, California.
Complications of Iron Overload
• Heart
– Heart failure, arrhythmias
• Liver
– Fibrosis, cirrhosis, cancer
• Endocrine tissues
– Diabetes mellitus
Development of Diabetes
During 3-Year Follow-Up
100%
P = .0001
80%
P = .02
60%
40%
20%
43%
48%
33%
32%
33%
0%
MDS
Patients
Overall
Medicare
Population
MDS Patients:
Received RBC
Transfusions
MDS Patients: Overall
No RBC
Medicare
Transfusions Population
Goldberg SL, et al. Abstract 636. Presented at: 50th Annual American Society of Hematology Meeting,
December 6-9, 2008, San Francisco, California. Graphic courtesy of Dr. N. Gattermann.
Development of Cardiac Complications
During 3-Year Follow-Up
100%
P = .001
P = .002
80%
60%
40%
80%
80%
20%
42%
69%
42%
0%
MDS
Patients
Overall
Medicare
Population
MDS Patients:
Received RBC
Transfusions
MDS Patients: Overall
Medicare
No RBC
Transfusions Population
Goldberg SL, et al. Abstract 636. Presented at: 50th Annual American Society of Hematology Meeting,
December 6-9, 2008, San Francisco, California. Graphic courtesy of Dr. N. Gattermann.
Patients with Cardiac Iron (%)
Relation of Cardiac Iron Deposits
to Amount of Blood Transfused
100
90
80
131 transfused adult patients
• 101 leukaemias
• 30 other anaemias
70
60
50
40
30
20
10
0
26Š50
51Š75
76Š100
101Š200
201Š300
Units of Blood Transfused
Buja LM, et al. Am J Med. 1971;51:209-221. Graphic courtesy of Dr. N. Gattermann.
Consequences of Iron-Mediated Toxicity
During Iron Overload
Increased LPI or “Free” Iron
Hydroxyl Radical Generation
Lipid Peroxidation
Organelle Damage
Lysosomal Fragility
TGF-β1
Collagen Synthesis
Enzyme Leakage
Cell Death
Fibrosis
Abbreviations: LPI, labile plasma iron; TGF, transforming growth factor.
With permission from Cohen AR, et al. In: Disorders of Hemoglobin. Steinberg MH, et al, eds. Cambridge
University Press; 2001:979-1027.
Which Patients with MDS May Benefit
from Chelation Therapy?
Cumulative Survival of MDS Patients
According to WHO Type
Abbreviations: RA, refractory anaemia; RAEB, refractory anaemia with excess blasts; RARS, refractory anaemia with ring
sideroblasts; RCMD, refractory cytopaenia with multilineage dysplasia; RSCMD, refractory sideroblastic cytopaenia with
multilineage dysplasia.
Germing U, et al. Leuk Res. 2000;24:983-992.
Graphic reflects updated data and is courtesy of Dr. U. Germing.
Survival of RCMD + RSCMD Patients
According to IPSS
(Düsseldorf MDS Registry)
MDS type: RA
n
131
IPSS score
Median survival
(months)
RARS RCMD RSCMD RAEBI RAEBII 5q146
420
247
200
Low
Int-1
Int-2
High
36%
50%
13%
1%
62
36
12
7
Düsseldorf MDS Registry. Graphic courtesy of Dr. N. Gattermann.
211
41
Requirement for Iron Chelator Therapy
in Patients with MDS
(Crude Estimate)
Median Survival
~ 20% of MDS patients
(RA + RARS)
~6 years
~ 15% of MDS patients
(RCMD ± RS)
5–6 years
36% low-risk
~ 20% of MDS patients
(RCMD ± RS)
50% int-1
Düsseldorf MDS Registry. Graphic courtesy of Dr. N. Gattermann.
3 years
Iron Overload in MDS Consensus Meeting
Nagasaki, Japan – May 11, 2005
•
Transfusion-dependent patients
•
Low-risk MDS: IPSS low or Int-1
•
WHO-type RA and RARS and 5q-
patients who
•
Candidates for allografting
might benefit
•
Patients with documented stable
from the
•
Profile of
disease
other evidence of significant tissue
treatment of iron
overload
Ferritin levels >1000–2000 ng/mL or
iron overload
•
Absence of comorbidities severely
limiting prognosis
Gattermann N. Hematol Oncol Clin North Am. 2005;19(suppl 1):18-25.
The Relative Importance of Iron Overload
in MDS Morbidity
Iron chelation
Complications of
chronic anaemia
Complications of
marrow failure
Clinical
problems
in MDS
Leukaemic
transformation
Graphic courtesy of Dr. N. Gattermann.
Problems of
aging
Concomitant
diseases
Conclusions
• Iron overload in MDS starts before patients become
transfusion-dependent, but its most important cause is
chronic transfusion therapy
• Transfusion therapy is associated with decreased
likelihood of survival
– Iron overload represents an independent prognostic factor
• Cardiac iron overload, which is detectable after about
75 units of red blood cells, appears to contribute to
cardiac complications in MDS patients
• Retrospective data suggest improved survival with iron
chelation therapy
– Patients with lower-risk MDS are most likely to benefit
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