Reinhard STAUDER M.D., M.Sc.Division of Haematology and OncologyInnsbruck Medical University, Austria

The relevance of comorbidities in myelodysplastic syndromes

The relevance of comorbidities in myelodysplastic syndromes

λ Age adjusted evaluation and statistical analysis

λ Individualized treatment based on assessment

Implementation of principles of geriatriconcology in myelodysplastic syndromesImplementation of principles of geriatriconcology in myelodysplastic syndromes

Decision making in MDSDecision making in MDS

λ 80 year old MDS patient

Age-adjusted life expectancy (years)Age-adjusted life expectancy (years)

Remaining life years at a given age x

Statistics Austria 2006

Age x Female Male

0 82,68 77,13

60 24,90 21.04

70 16,40 13,62

80 9,02 7,55

90 4,21 3,68

100 1,74 1,62

RS

Standardised mortality rate (SMR)Standardised mortality rate (SMR)

Morel et al., 1996

29Male

.002

50Female

pMedianSurvival

(mo)

Standardised mortality rate (SMR)Standardised mortality rate (SMR)

Morel et al., 1996

3,6729Male

n.s.

3,64

.002

50Female

p

Standard. mortality

rate(SMR)

pMedianSurvival

(mo)

Outcome in a given patientOutcome in a given patient

λ SEEDλ SOIL

Paget 1889

MDS - Individualised therapyMDS - Individualised therapy

SEEDDisease biologyBM-blastsCytogeneticsCytopeniaSerum LDH

SOILPatientAgeComorbiditiesFunctional capacitiesCognitionQoLSocial supportNutritional status

DECISIONTherapy ?

Which and when ?

Transfusion dependencySerumferritin

“...any distinct clinical entity that has existed or may

occur during the clinical course of a patient who has a

condition under study.”

Feinstein, 1970

RS

Comorbidity - DefinitionComorbidity - Definition

Impact of comorbidity on survivalImpact of comorbidity on survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25 30 35 40 45

Prop

ortio

n Su

rviv

ing

Survival Duration (Months)

Severe

Moderate

Mild

None

n=3378, p < 0.001

Yancik, 1998

Disease Pointsλ Myocardial infarction 1λ Congestive heart failure 1λ Peripheral vascular disease 1λ Cerebrovascular disease (except hemiplegia) 1λ Dementia 1λ Chronic pulmonary disease 1λ Connective tissue disease 1λ Ulcerative disease 1λ Mild liver disease 1λ Diabetes (without complications) 1λ Hemiplegia (or paraplegia) 2λ Moderate or severe renal disease 2λ Diabetes with end organ damage 2λ 2nd solid tumour (non metastatic) 2λ Leukaemia 2λ Lymphoma (NHL & Hodgkin), multiple myeloma 2λ Moderate or severe liver disease 3λ 2nd metastatic solid tumour 6λ AIDS 6

TOTAL SCORE

Charlson Comorbidity ScaleCharlson Comorbidity Scale

Charlson, 1987

Categories(points)

5948258Death due to cm (%)

855226121-year mortality (%)

≥53-41-20Outcome

Advantage: valid, simple, wide used, obainable retrospectively from chartsDisadvantage: tumours represent relevant item, floor effect, relevant cm not included

Categories (points)

.0251535Median survival (mo)Int I, II (IPSS) group

p≥ 31-20Outcome in MDS

Pelz Abstract 2007

In MDS differentiates risk groups(particularly in low rsik)

Prognostic factor independent from IPSS

Overall survivalCCI

Sorror 2004Diaconescu

2004

Applied in hematopoietic cell transplantation (HCT)

High CM predicts high non-relapse mortality (NRM) and toxicity

Toxicity, survival, mortalityAdapted CCICharlson

Comorbidity Index (CCI)

RefComment EndpointItemsTest

Application of comorbidity scores in MDS

3Hepatic, moderate/severe

Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI)

SCORECOMORBIDITY

1Inflammatory bowel disease

1Obesity

1Infection

1Psychiatric disturbance

2Peptic ulcer

2Rheumatologic

1Diabetes

3Prior solid tumor

2Moderate/severe renal

1Hepatic, mild

3Severe pulmonary

2Moderate pulmonary

0Mild pulmonary

1Cerebrovascular diesease

3Heart valve disease (except mitral valve prolapse)

1Atrial fibrillation or flutter; Sick sinus syndrome, or ventricular arrhythmias

1Coronary artery disease,congestive heart failure,myocardial infarction, or EF ≤ 50%

Total Score: 0...low; 1-2...intermediate; ≥ 3...high risk According to Sorror et al.; Blood, 2005

.0012,041,611Relapse/Progresion (HR)

MDS - Individualised therapyMDS - Individualised therapy

SEEDDisease biologyBM-blastsCytogeneticsCytopeniaSerum LDH

SOILPatientAgeComorbiditiesFunctional capacitiesCognitionQoLSocial supportNutritional status

DECISIONTherapy ?

Which and when ?

Transfusion dependencySerumferritin

Pelz Abstract 2007

In MDS differentiates risk groups(particularly in low rsik)

Prognostic factor independent from IPSS

Overall survivalCCI

Artz 2006KFS & PS predict OS

Combination of KFS & PS is developed

OS, TRM in 105 RIC-HCT patients

Parallel evaluation CM Composite (CM & function)Function

Charlson Comorbidity Index (CCI) Kaplan-Feinstein Scale (KFS)

ECOG Performance Status (PS)

Sorror 2004Diaconescu

2004

Applied in hematopoietic cell transplantation (HCT)

High CM predicts high non-relapse mortality (NRM)

Toxicity, survival, mortalityAdapted CCICharlson

Comorbidity Index (CCI)

ReferenceComment EndpointItemsTest

Application of comorbidity scores in MDS

Sorror20052007

In HCT more sensitive and better predictor of survival than CCI

2-yr non-relapse mortality (NRM)

and survival in training set of 708 and

validation set of 347 HCT patients

Modified based on CCI• New items obesitas, psychiatric

or infectious problems • Refined definitions like cardiac,

pulmonary or hepatic function

Hematopoietic Cell Transplantation-specific Comorbidity Index

(HCT-CI)

MDS and comorbidity (cm)MDS and comorbidity (cm)

λ CM should be integrated in decision algorithms in MDS, particularly in low risk and in elderly

λ Age per se should not be used as surrogate marker for cmλ Valid data are available for cm scoring in HCTλ In Non-HCT MDS cm has to be evaluated as a prognostic

factor for survival and leukemia transformation (studies usingCCI & HCT-CI are underway) IPSS,WPSS → CM PSS ???

λ The predictive power of cm-scores concerning tolerance and effectiveness of therapies should be analysed.

Societe internationaled’oncologie geriatrique

Score value

21-30

2,0

2/30/1Cytopenia

PoorIntermediateGoodKaryotype

11-20....5-10

MDS WPSS-Klassifikation (WHO based PSS)MDS WPSS-Klassifikation (WHO based PSS)

λ Five distinct risk groupsλ Significantly different OS

and probability of leukemiaevolution (p

MDS and comorbidity (cm)MDS and comorbidity (cm)

λ Why is CM relevant Therapy tolerance (Increased cm increases toxicity of therapies). Tendency to succumb to complications especially those related to

infections and cytopenias

Satariano1994

Simple, qualitative valuation3-yr survival in 936 breast cancer patients based on

SEER registry

Myocardial infarction, other types of heart disease, diabetes, other forms of cancer and

respiratory, gallbladder, liver conditionsSatariano

Kaplan-Feinstein 1974

Composite index5-yr survival in diabetes mellitus

12 ailments weighted including functional activity (“locomotive impairment”), “alcohol”

and “miscellaneous”Kaplan-Feinstein

Charlson1987

Simple most widely used in oncology; under-detects significant

ailments like anemia, decreased lung function

1-yr mortality in hospitalized internal medicine patients

19 conditions weighted 1-6CharlsonComorbidity Index (CCI)

ReferenceComment EndpointItemsIndex

Comorbidity scales in geriatric oncology

Charlson1994

Composite index5-yr mortality in surgery patients

Each decade 50+, add 1 pointCCI age

Greenfield 1987

Composite index2-yr survival in breast cancer patients

Includes 14 diseases (0-4) and a functional index of 12 conditions (0-2)

Index Of Coexisting Disease

(ICED)

Lee2006

So far not validated in oncology patients

4-yr mortality established in community-dwelling US

adults

Composite index based on 12 items (age, sex, self-reported comorbidity, functional measures)Prognostic Index

Linn 1968

Detailed and comprehensive list of diseases

13 organ systems weighted 0-4Cumulative Illness Rating Scale

(CIRS)

Adapted for elderly Miller 1992

14 organ systems rated 0-4 (weighted) Geriatric outpatientsCumulative Illness Rating Scale-

geriatric (CIRS-G)

NCCN2006

Decision making - Life expectancy ?Decision making - Life expectancy ?

λλ Medianes Alter: 76aMedianes Alter: 76aλλ 85% der Patienten über 60 Jahre85% der Patienten über 60 Jahreλλ 1/3 der Patienten über 80 Jahre1/3 der Patienten über 80 Jahreλλ Dunkelziffer ?Dunkelziffer ?

InzidenzInzidenz / / PrävalenzPrävalenz ⇑⇑ Demographische ÄnderungenDemographische Änderungen Überleben von Primärtumoren Überleben von Primärtumoren →→ tt--MDSMDS Verbesserte Diagnostik und Vigilanz.Verbesserte Diagnostik und Vigilanz.

0,494,33

16,10

31,65

05

101520253035

0-59 60-69 70-79 >80Alter (in Jahren)

Inzi

denz

/100

.000

/a

Stauder & Rocco

MDS und ÄltereMDS-Register Tirol 1995-2000

MDS und ÄltereMDS-Register Tirol 1995-2000

Lenalidomid

MDS Low-grade und Intermediate I

Anämie, Leukozytopenie, Thrombopenie

Epo ± G-CSF

ATG/CSA

Valproat? Klin. Studie

Del(5q)

Supportive Therapie, Transfusionstherapie ± Eisenchelation

Epo < 500 Epo > 500

Hypoplast.HLADR15

60+

Spender

MDS High-grade und Intermediate II

Allo-SCTmyeloablativ

oder RIC

IntensiveChemotherapie

ø Spender

MDS - Individualisierte TherapieMDS - Individualisierte Therapie

SEED (SAAT)ERKRANKUNGKM-BlastenZytogenetikZytopenieSerum LDH etc.

SOIL (SCHOLLE)PATIENTAlterFunktioneller StatusKomorbiditätKognitionQoLSoziale SituationErnährungssituation

ENTSCHEIDUNGTherapie ja/nein ?Wie und wie viel ?

TransfusionsbedarfSerumferritin

Score value

21-30

2,0

2/30/1Cytopenia

PoorIntermediateGoodKaryotype

11-20....5-10

MDS – Age IPSSMDS – Age IPSS

Greenberg et al., 1997

≤

MDS –Age and Survivalin IPSS subgroups

MDS –Age and Survivalin IPSS subgroups

Kuendgen et al., 2006

IPSS Low & Int-1p

MDS – AlterMDS – Alter

λ Wer früher stirbt ist länger tot.

Age per se as a risk factor for survival and leukemia transformation in MDS

NR Advanced age

Wie war das gleich mit der Lebenserwartung ?Wie war das gleich mit der Lebenserwartung ?

λ 80 jährige Patientin mit MDS

Lebenserwartung in Jahren ab der Geburt im Jahre

Wie war das gleich mit der Lebenserwartung ?Wie war das gleich mit der Lebenserwartung ?

Statistik Austria

Jahr Frauen Männer

1961 72,84 66,47

1971 73,67 66,64

1981 76,41 69,28

1991 79,05 72,41

2001 81,86 75,91

Alle 10 Jahre Anstieg um ca. 2,5 Jahre

2005 82,24 76,65

Wie war das gleich mit der Lebenserwartung ?Wie war das gleich mit der Lebenserwartung ?

Altersbezogene Lebenserwartung in Jahren

Sterbetafel 2000/02 Österreich - Statistik Austria

Alter x Frauen Männer

0 75,51

60

70

80

90

100

?

81,48

Wie war das gleich mit der Lebenserwartung ?Wie war das gleich mit der Lebenserwartung ?

Altersbezogene Lebenserwartung in Jahren

Sterbetafel 2000/02 Österreich - Statistik Austria

Alter x Frauen Männer

0 81,48 75,51

60 24,03 19,99

70 15,58 12,73

80 8,50 7,04

90 3,86 3,41

100 1,74 1,62

MDS - AgeMDS - Age

Morel et al., 1996

29Male

.002

50Female

pMedianSurvival

(mo)

MDS - AgeMDS - Age

Morel et al., 1996

3,6729Male

n.s.

3,64

.002

50Female

p

Standard mortality

rate(SMR)

pMedianSurvival

(mo)

Survival (and leukemia

transformation) in MDS dependon transfusiondependancy(packed red

cells/4w)

Survival (and leukemia

transformation) in MDS dependon transfusiondependancy(packed red

cells/4w)

Malcovati et al., 2005n=426

MDS WPSS-Klassifikation (WHO based PSS)MDS WPSS-Klassifikation (WHO based PSS)

λ Five distinct risk groupsλ Significantly different OS

and probability of leukemiaevolution (p

MDS - Individualisierte TherapieMDS - Individualisierte Therapie

SEED (SAAT)ERKRANKUNGKM-BlastenZytogenetikZytopenieSerum LDH etc.

SOIL (SCHOLLE)PATIENTAlterFunktioneller StatusKomorbiditätKognitionQoLSoziale SituationErnährungssituation

ENTSCHEIDUNGTherapie ja/nein ?Wie und wie viel ?

TransfusionsbedarfSerumferritin

Age per se as a risk factor for survival and leukemia transformation in MDS

NRNSNR Advanced age

MDS – Age and AML evolutionMDS – Age and AML evolution

Kuendgen et al., 2006 bei R. Stauder

5-year2-year

12

25

25

22

25

8

0

10≥80

2070-79

1960-69

2040-49

1750-59

830-39

020-29

AML evolution (%)Age

0

5

10

15

20

25

2-year 5-year

20-2930-3940-4950-5960-6970-79≥80

MDS und AlterMDS und Alter

λ Age per se is a risk factor for survival in MDS in all analyses (concerningrisk of leukemia transformation data are controversial)

λ Alter ist vor allem in good risk MDS (low, int-1 IPSS & RA/RARS/RCMD/RCMD-RS ) relevant; bei high risk dominiert die Biologie der Erkrankung

λ In an individual patient age-adjusted life expectancy and standradizedmortality rate have to be considered

λ Nearly all soubgroups of patients loose survival time – diagnostic and therapeutic nihilism are not appropriate

λ a low-risk Gruppe of elderly can be defined which has a life exypectancysimilar to age- und sex- matched group.

MDS und AlterMDS und Alter

λ Das chronologische Alter ist bei MDS ein prognostischer Faktor für das Überleben in allen Analysen uni- & multivariat

λ Zur Leukämietransformation uneinheitliche Datenlage offenbar mitNihilismus bei Älteren

λ Das Alter ist vor allem in good risk MDS (low, int-1 IPSS & RA/RARS/RCMD/RCMD-RS ) relevant; bei high risk dominiert die Biologie der Erkrankung

λ In der individuellen Therapieentscheidung sind die altersbezogene Lebenserwartung und die SMR zu berücksichtigen fast alle Subgruppen von älteren MDS PatientInnen verlieren an

Überlebenszeit→ diagnostischer und therapeutischer Nihilismus (Ageism) sind beim Älteren nicht angebracht

es gibt eine low-risk Gruppe bei Älteren die gegenüber age- und sex-matched nicht verliert.

Lenalidomid

MDS Low-grade und Intermediate I

Anämie, Leukozytopenie, Thrombopenie

Epo ± G-CSF

ATG/CSA

Valproat? Klin. Studie

Del(5q)

Supportive Therapie, Transfusionstherapie ± Eisenchelation

Epo < 500 Epo > 500

Hypoplast.HLADR15

60+

Spender

MDS High-grade und Intermediate II

Allo-SCT

myeloablativoder RIC

IntensiveChemotherapie

ø Spender

RARS with transfusion needNon-RARSRARS with no transfusion need

Epo 60.000 U/week(or DAR 300(150)mcg/w)

At 8 weeksNo response

At 8 weeksResponse

Low-grade MDS Symptomatic Anemia

Epo 60.000 U/week(or DAR 300(150)mcg/w)

+ G-CSF 300mcg/w (100 3 days/week) 16 weeks

Hellström-Lindberg 2003 & 2005; www.nordicmds.org

Response probability: group 1 & 2 (exclude 3, hypocellular MDS, 5q-)

Decreasedose/weekevery 8 w

40-30-20-10-5-0

Add G-CSF300mcg/w

• Control ferritin → iron substitution• G-CSF: Aim a ⇑ neutrophil count to 6-9G/L; if not increase dose of G-CSF• Hb > 12g/dl: Stop; restart with 50% dosiswhen Hb < 12 g/dlAt 16 weeks

No response: Stop

RARS with transfusion needNon-RARSRARS with no transfusion need

Epo 60.000 U/week(or DAR 300(150)mcg/w)

At 8 weeksNo response

At 8 weeksResponse

Low-grade MDS Symptomatic Anemia

Epo 60.000 U/week(or DAR 300(150)mcg/w)

+ G-CSF 300mcg/w (100 3 days/week) 16 weeks

Hellström-Lindberg 2003 & 2005; www.nordicmds.org

Response probability: group 1 & 2 (exclude 3, hypocellular MDS, 5q-)

Decreasedose/weekevery 8 w

40-30-20-10-5-0

Add G-CSF300mcg/w

• Control ferritin → iron substitution• G-CSF: Aim a ⇑ neutrophil count to 6-9G/L; if not increase dose of G-CSF• Hb > 12g/dl: Stop; restart with 50% dosiswhen Hb < 12 g/dlAt 16 weeks

No response: Stop

The relevance of comorbidities in myelodysplastic syndromesImplementation of principles of geriatric oncology in myelodysplastic syndromesDecision making in MDSAge-adjusted life expectancy (years)Standardised mortality rate (SMR)Standardised mortality rate (SMR)Outcome in a given patientMDS - Individualised therapyComorbidity - DefinitionImpact of comorbidity on survival