Overview of Myelodysplastic Syndromes with Focus on Iron Overload Norbert Gattermann, MD, PhD Professor Department of Haematology, Oncology, and Clinical

Overview of Myelodysplastic Syndromes with Focus on Iron Overload

Norbert Gattermann, MD, PhDProfessor

Department of Haematology,Oncology, and Clinical Immunology

Heinrich-Heine-UniversityDüsseldorf, Germany

Myelodysplastic Syndromes (MDS)–Age at Diagnosis

Patients in the Düsseldorf Registry700

600

500

400

300

200

100

0

706050403020 80 90

Düsseldorf MDS Registry. Graphic courtesy of Dr. U. Germing.

Age (years)

Nu

mb

er

of

Pa

tie

nts N = 3125

Age Group (Y) 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

MDS–Incidence by Age and Gendera

Patients in the Düsseldorf Registry

aCases per 100,000 population/year.


Oncogene Activation

Growth Advantage

IneffectiveHaematopoiesis

Functional Impairment,Decreased Life Span

ExcessiveApoptosis

Bone Marrow Peripheral Blood

MDS PathophysiologyClonal Expansion Plus Ineffective Haematopoiesis

Graphic courtesy of Dr. N. Gattermann.

Apoptosis in MDS Intrinsic and Extrinsic Causes?

Primary Defect(Intrinsic)

ExcessiveApoptosis

ActivatedMacrophages

Pro-apoptoticCytokines


High Apoptotic Activity

ImpairedDifferentiation

Early MDS(Low risk)

Advanced MDS(High risk)

Impaired Production of Blood Cells


Oncogene Activation

Growth Advantage

NormalHaematopoiesis

ClonalHaematopoiesis

ClonalEvolution

LeukaemiaMDS

MDS PathophysiologyClonal Evolution Toward Acute Myelogenous Leukaemia


Incidence of Chromosomal Anomaliesa in Patients with MDS and an Abnormal Karyotype

0

5

10

15

20

25

30d

el(

5q

)

-7/d

el(

7q

)

+8

-18

/de

l(1

8q

)

de

l(2

0q

)

-5 -Y

-17

/de

l(1

7p

)

+2

1

inv

/t(3

q)

-13

/de

l(1

3q

)

-21

t(5

q)

+1

1

+1

/+1

q

de

l(1

2p

)

de

l(1

1q

)

t(7

q)

+M

ar

Fre

qu

ency

(%

)

Haase D, et al. Blood. 2007;110:4385-4395. Graphic courtesy of Dr. D. Haase.

n = 1080b

aIsolated or in combination with 1 additional anomaly or complex anomalies. bTotal data set, 2124; cytogenic analysis in 2072.

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.

ErythropoiesisErythropoiesis GranulopoiesisGranulopoiesis ThrombopoiesisThrombopoiesis

Blood AnisocytosisPoikilocytosisMacrocytosisBasophilic stipplingDimorphic blood filmPappenheimer bodies Nucleated red cells

Pseudo-Pelger anomalyHypersegmented nucleiNuclei of bizarre shapeChromatin clumpingHypogranularityMonocytosisBlast cells, Auer rods

ThrombocytopeniaGiant plateletsAgranular plateletsMicromegakaryocytes

Bone marrow

Megaloblastic cellsNuclear fragmentationInternuclear bridgesMultinuclearityVacuolizationPositive PAS stainingRing sideroblasts

Increased blast cellsHypogranular PromyelocytesHypogranular myelocytesPartial MPO defectIncrease of promonocytesLack of mature neutrophilsAbnormal neutrophils

Larger megakaryocytes with nonlobed nuclei

Reduction of MEGMononuclear MEGMultinucleated MEGMEG with botryoid

nuclei

MDS–Dysplastic Features in Blood and Bone Marrow

Graphic courtesy of Dr. N. Gattermann.Abbreviations: MEG, megakaryocyte; MPO, myeloperoxidase; PAS, Periodic Acid-Schiff.

WHO Classification of MDSPatients in the Düsseldorf Registry

%% MDSMDS BloodBlood Bone MarrowBone Marrow

3.7 5q– syndrome • Anaemia• Blasts <5%• Platelets normal to increased

• Megakaryocytes normal to increased• Blasts <5%• No Auer rods• Isolated del(5q)

8.8 RA • Anaemia• Blasts ≤1%

• Dyserythropoiesis only• Blasts <5%• Ringed sideroblasts <15%

7.8 RARS • Anaemia • Blasts ≤1%

• Dyserythropoiesis only• Blasts <5% • Ringed sideroblasts <15%

31.0 RCMD • Cytopaenia of ≥2 lineages• Blasts ≤1% • Monocytes <1000/µL

• >10% of cells per lineage dysplastic• No Auer rods • Blasts <5% • Ringed sideroblasts <15%

15.4 RCMD-RS • Cytopaenia of ≥2 lineages• Blasts ≤1%• Monocytes <1000/µL

• >10% of cells per lineage dysplastic• No Auer rods • Blasts <5%• Ringed sideroblasts ≥15%

15.0 RAEB I • Cytopaenia of ≥2 lineages• Peripheral blood blasts ≤5% • Monocytes <1000/µL

• 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%


Cumulative Survival of MDS PatientsAccording to WHO Type

Germing U, et al. Leuk Res. 2000;24:983-992. Graphic reflects updated data and is courtesy of Dr. U. Germing.

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.

ScoreScore

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 –– –– ––

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

Low risk 0 pointsIntermediate-1 0.5–1.0 pointsIntermediate-2 1.5–2.0 pointsHigh risk ≥2.5 points

International Prognostic Scoring System (IPSS)

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

360336

312288

264240

216192

168144

12096

7248

240

Cu

mu

lati

ve S

urv

ival

1.0

.8

.6

.4

.2

0.0

Risk Survival Group (months)

31% Low 7139% Int-1 3120% Int-2 1510% High 8

Months

The IPSS Applied to Patients in the Düsseldorf MDS Registry

Low

Int 1

Int 2High


n = 550

ScoreScore

Prognostic Variable

0 1 2 3

WHO category RA, RARS, 5q–

RCMD, RCMD-RS

RAEB-1 RAEB-2

Karyotype Gooda Intermediateb Poorc ––

Transfusion requirement

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.

WHO Classification-Based Prognostic Scoring System (WPSS)

Very low risk 0 pointsLow risk 1 pointsIntermediate 2 pointsHigh risk 3–4 pointsVery high risk 5–6 points

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

Overall Survival(P <.001)

Risk of AML Evolution(P <.001)

WPSS at Diagnosis Applied toPatients in the Düsseldorf MDS Registry

Malcovati L, et al. J Clin Oncol. 2007;25:3503-3510. Graphic courtesy of Dr. U. Germing.

MDS–Treatment Options

• Best supportive care, including iron chelation

• Growth factors

• Immunosuppressive treatment

• Differentiation induction

• Farnesyltransferase inhibitors

• Thalidomide/lenalidomide

• Arsenic trioxide

• Low-dose chemotherapy

• Epigenetic treatment

• Intensive chemotherapy

• Allogeneic stem cell transplantation

Low Risk

High Risk

PrognosticGroup

1 unit PRC

200–250 mg

1–2 mg

DailyLosses

Iron Imbalance in Transfusion-Dependent Patients

Abbreviation: PRC, packed red cells.

Approximately 80% of MDS patients have a haemoglobin <10 g/dL at

diagnosis1 and the majority become transfusion-dependent

1. Sanz GF, et al. Blood. 1989;74:395-408. Graphic courtesy of Dr. N. Gattermann.

Erythroblasts

Blood losses(eg, menstrual)

Normal daily iron uptake~1 mg

Transferrin

Other cells in the body

Daily losses~1 mg

Urine, faeces,nails, hair, skin

Duodenum

Ineffective erythropoiesis

Unrestrainedintestinal

iron absorption

Suppressedhepcidin

expressionin the liver

IncreasedGDF15

in the serum Macrophages(0.5–1.5 g)

Haemoglobin(1.7–2.4 g)

Liver

Consequence of Ineffective Erythropoiesis–Increased Intestinal Iron Uptake


MDS–Serum Ferritin at Diagnosis

RA RARS RAEB RAEB-T CMML

0

2000

4000

6000

8000

Ser

um

Fer

riti

n (

ng

/mL

)

129015001800 1749

20002283

15901830

2000

2690

1309

2000198022842500 2555

38394176

3526

7794

2980

6980

2136

2500

5000

Data on file. Düsseldorf MDS Registry. Graphic courtesy of Dr. N. Gattermann.

Abbreviations: RA, refractory anaemia; RAEB, RA with excess blasts; RA with excess blasts in transformation; RARS, RA with ring sideroblasts; CMML, chronic myelomonocytic leukaemia.

N = 650

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

200–250 mg iron

100 units = ≥20 g iron

Total body iron in normal person 3–4 g

Impact of Transfusion Dependency on Nontransplantation Candidates

Cazzola M, et al. N Engl J Med. 2005;352:536-538. Copyright © 2005. Massachusetts Medical Society. All rights reserved

Cumulative probability of survival among patients given a diagnosis of MDS in Pavia, Italy from 1992–2002

Cumulative probability of survival among patients given a diagnosis of MDS in Pavia, Italy from 1992–2002

Transfusion-Independent

Transfusion-Dependent

Survival Time (months)

Cu

mu

lati

ve P

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

Transfusion Dependency—A Risk Factor Independent of Cytogenetic Risk Group

Not transfusion-dependent

Transfusion-dependent

aOnly isolated del 5q.

1.00.90.80.70.60.50.40.30.20.1

0 20 40 60 80 100 120

Gooda

Months

Intermediate

20 40 60 80 100 120

Poor

0 20 40 60 80 100 120Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

0

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

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

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

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

180

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing Transfusion-independent

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

mu

lati

ve P

rop

ort

ion

Su

rviv

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)

Transfusion-independentTransfusion-dependent

Malcovati L, et al. J Clin Oncol. 2005;23:7594-7603. Graphic courtesy of Dr. N. Gattermann.

Survival of Patients with MDS According to Transfusion Dependency

Overall Survival in Patients with MDS by RBC Transfusion Dependency

No RBC Transfusion Dependency

RBC Transfusion DependencyP <.0001

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.

N = 2241

Pro

bab

ility


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

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

Overall SurvivalLeukaemia-Free

Survival

Variablea HR P-value

Iron overload 4.34 <.001

WPSS 1.60 <.001

Variablea HR P-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 <3 serum ferritin measurements were excluded.


Overall Survival in Patients with MDS by Serum Ferritin Level


n = 762P

rob

abili

ty


n = 761

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

rob

abili

ty

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%

80%

60%

40%

20%

0%

43%43%33%33%

48%48%32%32% 33%33%

MDSPatients

Overall Medicare

Population

Overall Medicare

Population

MDS Patients:Received RBCTransfusions

MDS Patients:No RBC

Transfusions

P = .0001 P = .02

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 ComplicationsDuring 3-Year Follow-Up

100%

80%

60%

40%

20%

0%

80%80%

42%42%

80%80%69%69%

42%42%

MDSPatients

Overall Medicare

Population

Overall Medicare

Population

MDS Patients:Received RBCTransfusions

MDS Patients:No RBC

Transfusions

P = .001 P = .002

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.

0

10

20

30

40

50

60

70

80

90

100

26–50 51–75 76–100 101–200 201–300

131 transfused adult patients• 101 leukaemias• 30 other anaemias

Relation of Cardiac Iron Depositsto Amount of Blood Transfused

Buja LM, et al. Am J Med. 1971;51:209-221. Graphic courtesy of Dr. N. Gattermann.

Pat

ien

ts w

ith

Car

dia

c Ir

on

(%

)

Units of Blood Transfused

Increased LPI or “Free” Iron

Cell Death Fibrosis

Organelle Damage TGF-β1

Hydroxyl Radical Generation

Lipid Peroxidation

Lysosomal Fragility

Enzyme LeakageCollagen Synthesis

Abbreviations: LPI, labile plasma iron; TGF, transforming growth factor.

Consequences of Iron-Mediated Toxicity During Iron Overload

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 PatientsAccording to WHO Type

Germing U, et al. Leuk Res. 2000;24:983-992. Graphic reflects updated data and is courtesy of Dr. U. Germing.

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.

Survival of RCMD + RSCMD Patients According to IPSS

(Düsseldorf MDS Registry)

MDS type: RA RARS RCMD RSCMD RAEBI RAEBII 5q-

n 131 146 420 247 200 211 41

IPSS score Low Int-1 Int-2 High

36% 50% 13% 1%

Median survival(months) 62 36 12 7

Düsseldorf MDS Registry. Graphic courtesy of Dr. N. Gattermann.

Requirement for Iron Chelator Therapy in Patients with MDS

(Crude Estimate)

~ 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) 3 years 50% int-1

Median Survival

Düsseldorf MDS Registry. Graphic courtesy of Dr. N. Gattermann.

Profile of

patients who

might benefit

from the

treatment of iron

overload

Gattermann N. Hematol Oncol Clin North Am. 2005;19(suppl 1):18-25.

Iron Overload in MDS Consensus MeetingNagasaki, Japan – May 11, 2005

• Transfusion-dependent patients

• Low-risk MDS: IPSS low or Int-1

• WHO-type RA and RARS and 5q-

• Candidates for allografting

• Patients with documented stable

disease

• Ferritin levels >1000–2000 ng/mL or

other evidence of significant tissue

iron overload

• Absence of comorbidities severely

limiting prognosis

The Relative Importance of Iron Overload in MDS Morbidity

Clinicalproblemsin MDS

Concomitantdiseases

Complications ofchronic anaemia

Problems ofaging

Complications ofmarrow failure

Leukaemictransformation

Iron chelation


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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Overview of Myelodysplastic Syndromes with Focus on Iron Overload Norbert Gattermann, MD, PhD Professor Department of Haematology, Oncology, and Clinical