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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
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