MDS (Myelodysplasticsyndromes)/ MPN ... · Supportive therapy including transfusions & iron‐chelation EPO < 500 U/l and/or low transfusion 2need EPO ≥ 500 U/l and/or high transfusion

MDS (Myelodysplastic syndromes)/MPN (Myeloproliferative neoplasms)

Prognosis and treatment

November 4th 2011, Paris

Reinhard STAUDER MD, MSc, Associate ProfessorDepartment of Internal Medicine V (Hematology & Oncology)

Medical University Innsbruck, Austriareinhard.stauder@i‐med.ac.at

Blood cancer is a typical disease of elderly

Subtype / median age at diagnosis (~yrs)Myelodysplastic syndromes 75 Acute myeloid leukemia 70Multiple myeloma 70Diffuse large B‐cell lymphoma 70 Chronic lymphocytic leukemia 70Myeloproliferative neoplasms(PMF 67, ET 60, CML 50)

SEER Cancer Statistics Review, http://seer.cancer.gov/csr/1975_2008/index.html and Tumor registry Tyrol, www.iet.at

Myeloid neoplasmsWHO‐Classification 2008

Acute myloid leukemia (AML) Myelodysplastic Syndromes (MDS) Myeloproliferative neoplasms (MPN) Myelodysplastic/Myeloproliferative syndromes

Swerdlow et al., 2008

MDS ‐ Characteristics

Dysplastic hamatopoiesis

Ineffective hamatopoiesis cytopenia one or several cell lines

Potential to transform to AML (acute myeloid leukemia)

IPSS GroupIPSS

Total Score

Survival(median; yrs)

25% AML evolution (yrs)

Age at diagnosis Age at diagnosis70yrs >70yrs 70yrs >70yrs

Low 0 9 3,9 >9,4 (NR) >5,8 (NR)Intermediate-1 0,5-1,0 4,4 2,4 5,5 2,2

Intermediate-2 1,5-2 1,3 1,2 1,0 1,4

High ≥2,5 0,4 0,4 0,2 0,4Greenberg et al., 1997

Prognostic variableScore value

0 0,5 1 1,5 2,0

Bone marrow blasts (%) <5 5-10 .... 11-20 21-30

Karyotype 1 Good Intermediate Poor

Cytopenia 2 0/1 2/31 Karyotype: Good: Normal, Y-, 5q-, 20q-; Intermediate: All other; Poor: Chr. 7 aberration and/or ≥3 aberrations.2 Cytopenia: Hb<100 G/l; neutrophil count <1,8 G/l; platelet count < 100 G/l

The risk score IPSS (International prognostic scoring system)

Hematological malignancies in elderly ‐ Items

Demographic analyses & description of “real life” (in registries) beyond euphemistic situation in clinical studies.

Use appropriate statistical methods.

Individualize treatment based on age‐adjusted life expectancy, geriatric assessment & patients´ expectations (biological age).

Develop recommendations & guidelines for elderly. Address renal, cardiac and cognitive impairment and neuropathy.

Perform clinical studies in elderly & in non‐fit.

Propagate the fair treatment for all elderly cancer patients!

EU‐MDS Registry

Prospective European Leukemia Net (ELN) registry of newly diagnosed IPSS low‐risk & Int‐1 risk MDS

14 European countries

Goal > 1000 patients

Several scores are applied to assess performance status, comorbidities and QoL

Median age at diagnosis is ~75yrs

Abstracts: ASH 2009 de Witte et al.EHA 2010 Bowen et al., Stauder et al.ASH 2010 Bowen et al., de Swart et al., Stauder et al.,

020

4060

Freq

uenc

y

20 40 60 80 100Age at Diagnosis (years)EU-MDS Registry

Evaluation of HR‐QoL by EQ‐5D

www.euroqol.org

EQ-5D Descriptive System by Age at Diagnosis

EQ‐5D Dimension n (%)

Age at Diagnosis (Years) Total 18‐29 30‐39 40‐49 50‐59 60‐69 70‐79 80+ Total 1 (0.4) 1 (0.1) 20 (2.3) 74 (8.6) 149 (22.5) 349 (40.5) 220 (25.6) 861 (100)

Mobility Level 1 3 (100) 1 (100) 17 (85.0) 55 (74.3) 133 (85.9) 192 (55.0) 92 (41.9) 493 (57.3)

Level 2 ‐ ‐ 3 (15.0) 19 (25.7) 60 (30.9) 155 (44.4) 127 (57.3) 364 (42.3) χ2=50.8p<0.0001

Level 3 ‐ ‐ ‐ ‐ 1 (0.5) 2 (0.6) 1 (0.5) 4 (0.5)

Self‐Care Level 1 3 (100) 1 (100) 20 (100) 70 (95.6) 184 (94.9) 292 (83.7) 177 (80.5) 747 (86.8)

Level 2 ‐ ‐ ‐ 4 (5.4) 8 (4.1) 53 (15.2) 38 (17.3) 103 (12.0) χ2=30.7p=0.002

Level 3 ‐ ‐ ‐ ‐ 2 (1.0) 4 (1.2) 5 (2.3) 11 (1.3)

Usual Activities Level 1 3 (100) 1 (100) 14 (70.0) 47 (63.5) 150 (77.3) 221 (63.3) 123 (55.9) 559 (64.9)

Level 2 ‐ ‐ 6 (30.0) 22 (29.7) 42(21.7) 106 (30.4) 81 (36.8) 257 (29.9) χ2=28.2p=0.005

Level 3 ‐ ‐ ‐ 5 (6.7) 2 (1.0) 22 (6.3) 16 (7.3) 45 (5.2)

Pain/ Discomfort Level 1 3 (100) 1 (100) 13 (65.0) 43 (58.9) 115 (59.6) 168 (48.0) 83 (37.7) 426 (49.5)

Level 2 ‐ ‐ 6 (30.0) 26 (35.6) 73 (37.8) 166 (47.4) 122 (55.5) 393 (45.7) χ2=30.7p=0.002

Level 3 ‐ ‐ 1 (5.5) 4 (5.5) 5 (2.6) 16 (4.6) 15 (6.8) 41 (4.8)

Anxiety/ Depression Level 1 3 (0.8) 1 (100) 12 (60.0) 41 (55.4) 117 (60.3) 210 (60.2) 133 (60.5) 517 (60.1)

Level 2 ‐ ‐ 8 (40.0) 28 (37.8) 72 (37.1) 123 (35.2) 78 (35.5) 309 (35.9) χ2=6.7p=0.88

Level 3 ‐ ‐ ‐ 5 (6.8) 5 (2.6) 16 (4.6) 9 (4.1) 35 (4.1)








Survival in MDS subgroups

Nösslinger et al., Ann Oncol 2010

Dotted lines represent an age‐ and sex‐matchednon‐MDS population








Age‐adjusted life expectancy

Remaining life years at a given age x

Age x Female Male

0 82.7 77.3

60 24.9 21.0

70 16.4 13.6

80 9.0 7.5

85 6.2 5.4

90 4.2 3.7

100 1.7 1.6

Statistics Austria 2006

Cancer in elderly ‐ individualized therapy

TREATMENT DECISION

SEED DISEASE

BiologyStagingGrading

Risk factor Predictive factor(for response, tolerance) Response parameter

SOIL PATIENT

Age, SexFunctionPerformanceComorbiditiesCognitionSocial supportNutritional statusQoL (Quality of life)

Hematopoietic Cell Transplantation Comorbidity Index (HCT‐CI)COMORBIDITY SCORE

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

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

Heart valve disease (except mitral valve prolapse) 3

Cerebrovascular diesease 1

Mild pulmonary 0

Moderate pulmonary 2

Severe pulmonary 3

Hepatic, mild 1

Hepatic, moderate/severe 3

Moderate/severe renal 2

Prior solid tumour 3

Diabetes 1

Rheumatologic 2

Peptic ulcer 2

Inflammatory bowel disease 1

Obesity 1

Infection 1

Psychiatric disturbance 1

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

Sorror Score of Co‐morbidity

AUCZ

FR

GE

GR

ND

RO

SPSW

UK

0.5

11.

52

2.5

33.

54

Mea

n S

orro

r Sco

re

Mean Score 2.4, median 2, range (0 to 11)(0...low risk; 1-2...intermediate risk; ≥ 3...high risk) EU-MDS Registry

Comorbidity as Prognostic Variable in MDS

ScoreOverall survival (OS)

Event‐free survival (ES)

AML‐freeSurvival(AFS)

HCT‐CIUnivariat P<0.05 P<0.05 n.s.

Multivariat P<0.05 P<0.05 n.s.W. Sperr et al., Ann. Oncology, 2009

Comorbidities arean independentprognostic factorfor OS and EFS in univariate and in multivariate analyses.

Comparative Evaluation of the HCT‐CI and CCI in a Core Data Set of 419 Patients of the Austrian MDS Platform.

Impact of comorbidities in MDS

1708 SEER MDS patients ≥65 yrscm significant in uni‐ and multivariateMost relevant myocardial infarction and COPD

Wang R. et al., Leuk. Research 2009

ACE‐27 MDACC* MDS Score (n=600, retrospective )

Comorbidities %Survival median(months)

None 23 32

Mild 42 17

Moderate 21 15

Severe 14 10

ComorbiditySignificance

for OS

Cardiovascular .0001

Malignancy .0001

Renal .02

Gastrointestinal .05

Endocrine .07

Multivariate model

Parameter Score

Age 2

Comorbiditiesmildmoderatesevere

13

IPSSInt‐2High

23

*MDACC (MD Anderson Cancer Center) Garcia‐Manero et al., # 605; ASH 2010 & JCO 2011

No correlation with leukemia transformation








ESA(Lenalidomid1)

Treatment options in senior low‐risk MDS (IPSS Low‐grade und Intermediate I)

Symptomatic anaemia, granulopenia, thrombopenia

ESA ± G‐CSF (RARS)

CyA (ATG)

Valproic‐acid

Del(5q)

Supportive therapy including transfusions& iron‐chelation

EPO < 500 U/l and/or low

transfusion need 2

EPO ≥ 500 U/land/or high

transfusion need 2

Hypoplastic MDS

HLA‐DR15 3

1 MDS approval so far only by FDA; EMEA approval is pending. Thalidomid?2 Based on predictive model (Nordic score)3 Response more frequent in younger patients, in hypoplastic MDS and in HLADR‐15. 4 5‐Azacytidine EMEA approval for high‐risk MDS & CMML. Might be effective in low risk MDS even in granulopenia and thrombopenia. Is analysed in clinical studies. Has replaced LDARA‐C & LD Melphalan.ATG, anti‐thymocyte globulin; CMML, Chronic myelomonocytic leukemia; ESA, erythropoiesis‐stimulating agent; CyA, Cyclosporin‐A

(5‐Azacytidine4)(Lenalidomid1)

Stauder & Wolf, ESMO Handbook of Cancer in the Senior Patient, 2010

No

Donor

RIC‐HSCT2AML‐like induction/consolidation

or 5‐Azacytidine

Intensive therapy 1

Yes

5‐Azacytidine3or Clinical study

or BSC4

No Donor

1 Depending on age, performance status, comorbidities, feasability, karyotype and patient preference. 2 Upper age limits applied are 50‐55yrs for myeloablative HSCT (hamatopoietic stem‐cell transplantation ) and 65‐70yrs for RIC‐HSCT (reduced intensity conditioning HSCT)3 5‐Azacytidine represents the treatment of choice in elderly patients who are not eligible for intensive therapieslike AML‐induction or HSCT. AZA is effective even in unfavourable karyotype like monosomy 7 or complex aberrations. 4 BSC (best supportive care).

Stauder & Wolf, ESMO Handbook of Cancer in the Senior Patient, 2010

Treatment options in senior high‐risk MDS (IPSS Intermediate II und High grade)








Azacitidine (Vidaza)Phase III, AZA‐001

Fenaux et al., Lancet Oncol, 2009








www.senioren‐krebshilfe.at

Kontaktreinhard.stauder@i‐med.ac.at

Documents

MDS (Myelodysplasticsyndromes)/ MPN ... · Supportive therapy including transfusions & iron‐chelation EPO < 500 U/l and/or low transfusion 2need EPO ≥ 500 U/l and/or high transfusion