Miljø i knoglemarv

MDS

Marianne Bach Treppendahl Læge, PhD

Hæmatologisk Klinik

Rigshospitalet

LT-HSC ST-HSC MPP

CLP CMP

MEP GMP

Erythrocytes Platelets Megakaryocyte

Macrophage

Granulocytes

Monocyte B cell T cell NK cell

Myelodysplastic syndrom (MDS) ~ 250 nye tilfælde per år

Median alder ved diagnose~ 65-70 år

Miljø i knoglemarv

Stintzing et al. 2011, jour of biomedicine and biotechnology

Immunsystemet

Debut tidspunkt

Register Median alder ved diagnose (år)

Dusseldorf

69-73

Pavia

65-71

Spain

74

SW Thames

77 (77-78)

Swedish INCA 2009-2010

75

70% >70 years

Yorkshire Network UK** 75

ELN MDS Registry**

(IPSS Low/INT-1 only)

74 (72.5-75)

1. Germing et al, Leukemia Research, 2000, 24, 983

2. Malcovati et al, Journal of Clinical Oncology, 2005, 23, 7594 3. Sanz et al, ASH 2008,

4. Phekoo et al, Haematologica 2006,91, 1400

**unpublished data

Køns fordeling

Registry Mand / kvinde (%/ratio)

Dusseldorf

56/44 (%)

Pavia

61/39 (%)

SW Thames

1.62 (ratio)

Swedish INCA 56/44 (%)

Yorkshire Network UK** 69/31 (%)

1. Malcovati et al, Journal of Clinical Oncology, 2007, 25, 3503 2. Phekoo et al, Haematologica 2006,91, 1400

**unpublished data

Årsager

• Alderdom

• Mutagen/genotoxic stress

– Tidligere kemoterapi

– Organiske opløsingmidler – Rygning

• Neurofibromatosis

• Kongenital dyskeratosis

• Kongenital neutropeni

– Kostmann

– Schwachman-Diamond

• DNA repair defekter

– Fanconi, Bloom, AT

• Familiær MDS

Erhvervet Arvelige

Symptomer

• Blodmangel (anæmi) – Svimmelhed, hovedpine, hjertebanken, åndenød, træthed.

• Hyppige infektioner

• Blødninger

DIAGNOSEN

MDS diagnose

• Blod prøver

• Udeluk andre årsager til dysplastiske ændringer

– B

mangel

– Folin syre mangel

– Inflammatoriske sygdomme – Cancere

– HIV i

– Parvovirus B19

– Bly and arsenik forgiftning

• Når MDS er diagnosticeret

– Serum erythropoietin

– Vævstype bestemmelse

– Ferritin koncentration

• Knoglemarvsundersøgelse

• Knoglespange

» Imprint og “snit”

• Knoglemarvsaspirat

» Udstryg og koagel

• Perifert blod

» Udstryg

• Markørundersøgelse

• Kromosomundersøgelse

MDS diagnose

Patologi fund

WHO klassifikation 2008

Gruppe Dysplasi Blaster i blod

Blaster

knoglemarv

Ringe

sideroblaster

Cytogenetik 5q−

syndrome

Mest DysE < 1% < 5% < 15% 5q− isoleret RA, RN,

RT, RCUD

DysE, N, T < 1% < 5% < 15% Forskellige

RARS Mest DysE 0 < 5% > 15% Forskellige

RCMD 2−3 linier Rare < 5% < 15% Forskellige

RAEB-1 1−3 linier < 5% 5–9% < 15% Forskellige

RAEB-2 1−3 linier 5–19%

Auer rods  10–19%

Auer rods  < 15% Forskellige

MDS-U 1 linier < 1% < 1% < 15% Forskellige

DysE = dyserythropoiesis; N = neutropenia; RCUD = refractory cytopenia with unilineage dysplasia;

RN = refractory neutropenia; RT = refractory thrombocytopenia; T = thrombocytopenia.

WHO klassifikation

WHO Hyppighed

5q- syndrome RA

RCMD MDS-U

7%

16%

17%

2%

RARS

RCMD-RS

7%

3%

RAEB-1 RAEB-2

13%

15%

Malcovati L, et al. J Clin Oncol. 2005;23:7594-603.

Kromosom undersøgelser

- analyseres mhp. genetiske abnomaliteter

Cytogenetiske afvigelser

Afvigelse Hyppighed (%) de novo MDS (40–70%) -5/del 5q 10–20 (del 5q 5%)

+8 10

-7/del 7q 5–10

-Y 10

17p- 7

del 20q 5

t(11q23) 5–6

Complex ( 3) 10–20 Therpi relateret MDS (95%) -5/del 5q/

-7/del 7q 90

+8 10

t(11q23) 3

Complex 90

Olney HJ, Le Beau MM. Best Pract Res Clin Haematol. 2001;14:479-95.

A C E

B D F

Normal and dysplastic flow cytometric profiling

A-C-E: normal bone marrow; B-D-F: myelodysplastic bone marrow

Adapted from Van de Loosdrecht AA and Westers TM. MDS Foundation News Letter 2013;19:2-4

Markør undersøgelser

- til differentiering mellem celletyperne

Normale KM

MDS KM

PROGNOSE

WHO klassifikation – overlevelse

467 patients

Malcovati L, et al. J Clin Oncol. 2005;23:7594-603.

Overlevelse Leukæmi fri overlevelse

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

RA/RARS

RCMD/RCMD-RS RAEB-1

RAEB-2

Survival time (months)

Cumulative proportion surviving

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

Survival time (months)

Cumulative proportion surviving

RA/RARS

RCMD/RCMD-RS RAEB-1

RAEB-2 AML

IPSS score

Greenberg P, et al. Blood 1997;89:2079-88.

Score

Prognostik variable 0 0.5 1.0 1.5 2.0 Knoglemarv blaster (%) < 5 5–10 — 11–20 21–30

Karyotype Good Int Poor

Cytopenier 0–1 2–3 —

Int = intermediate.

abn = chromosomal abnormalities

Cytogenetics Good Normal: -Y

del 5q 20q- Poor Complex (≥ 3 abn)

-7/del 7q Int Other abn Score

Low 0

Int-1 0.5–1.0 Int-2 1.5–2.0

High ≥ 2.5

Cytopenias Hb < 10 g/dL Neutrophils < 1.8 x 10⁹/L Platelets < 100 x 10⁹/L

Number (%) Median overlevelse (år) 25% AML (år)

Low (0 point) 267 (33) 5.7 9.4

Int-1 (0.5–1.0) 314 (38) 3.5 3.3

Int-2 (1.5–2.0) 176 (22) 1.2 1.1

High ( 2.5) 59 (7) 0.4 0.2

IPSS score

Greenberg P, et al. Blood 1997;89:2079-88.

18

100 90 80 70 60 50 40 30 20 10

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

MDS patients (%)

Time (years)

n = 295 n = 235

n = 171

n = 58

Low Int-1 Int-2 High

n = 314

18

100 90 80 70 60 50 40 30 20 10

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Time (years) n = 179

n = 56

n = 267

MDS patients (%)

AML udvikling Overlevelse

• Lav risiko MDS

– IPSS Low – IPSS Int-1

• Høj risiko MDS

– IPSS Int-2

– IPSS-HR

IPSS-revideret

Blood 2012, Greenberg et al

MDS prognose - IPSS-R

Risk group % of patients Median survial (yr)

Median 25% AML (yr)

Very low 19 8.8 NR

Low 38 5.3 10.0

Intermediate 20 3.0 3.2

High 13 1.6 1.4

Very High 10 0.8 0.73

Greenberg, Blood 2012

MDS prognose - IPSS-R