MDS Marianne Bach Treppendahl Læge, PhD Hæmatologisk Klinik Rigshospitalet
LT-HSC ST-HSC MPP Myelodysplastic syndrom (MDS) ~ 250 nye tilfælde per år Median alder ved diagnose~ 65-70 år CMP CLP MEP GMP Megakaryocyte Monocyte B cell T cell NK cell Granulocytes Erythrocytes Platelets Macrophage
Immunsystemet Miljø i knoglemarv Stintzing et al. 2011, jour of biomedicine and biotechnology
Debut tidspunkt Register Median alder ved diagnose (år) Dusseldorf 1 69-73 Pavia 2 65-71 Spain 3 74 SW Thames 4 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 Phekoo et al, Haematologica 2006,91, 1400 **unpublished data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 1 56/44 (%) Pavia 1 61/39 (%) SW Thames 2 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 Phekoo et al, Haematologica 2006,91, 1400 **unpublished data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 Erhvervet Arvelige 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
Symptomer Blodmangel (anæmi) Svimmelhed, hovedpine, hjertebanken, åndenød, træthed. Hyppige infektioner Blødninger
DIAGNOSEN
MDS diagnose Blod prøver Udeluk andre årsager til dysplastiske ændringer B 12 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
MDS diagnose Knoglemarvsundersøgelse Knoglespange» Imprint og snit Knoglemarvsaspirat» Udstryg og koagel Perifert blod» Udstryg Markørundersøgelse Kromosomundersøgelse
Patologi fund
WHO klassifikation 2008 Gruppe Dysplasi Blaster i blod Blaster knoglemarv Ringe sideroblaster Cytogenetik 5q syndrome RA, RN, RT, RCUD Mest DysE < 1% < 5% < 15% 5q isoleret 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.
Normal and dysplastic flow cytometric profiling Markør undersøgelser A-C-E: normal bone marrow; B-D-F: myelodysplastic bone marrow - til differentiering mellem celletyperne Normale KM A C E B D F MDS KM Adapted from Van de Loosdrecht AA and Westers TM. MDS Foundation News Letter 2013;19:2-4
PROGNOSE
Cumulative proportion surviving Cumulative proportion surviving WHO klassifikation overlevelse 467 patients Leukæmi fri overlevelse Overlevelse 1,0 0,9 0,8 0,7 1,0 0,9 0,8 0,7 RA/RARS RCMD/RCMD-RS RAEB-1 RAEB-2 AML 0,6 0,6 0,5 0,5 0,4 0,4 0,3 0,2 0,1 0,0 RA/RARS RCMD/RCMD-RS RAEB-1 RAEB-2 0 20 40 60 80 100 120 140 0,3 0,2 0,1 0,0 0 20 40 60 80 100 120 140 Survival time (months) Survival time (months) Malcovati L, et al. J Clin Oncol. 2005;23:7594-603.
IPSS score 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 Score Cytogenetics Cytopenias Low 0 Int-1 0.5 1.0 Int-2 1.5 2.0 High 2.5 Good Poor Int Normal: -Y del 5q 20q- Complex ( 3 abn) -7/del 7q Other abn Hb < 10 g/dl Neutrophils < 1.8 x 10 9 /L Platelets < 100 x 10 9 /L Int = intermediate. abn = chromosomal abnormalities Greenberg P, et al. Blood 1997;89:2079-88.
MDS patients (%) MDS patients (%) IPSS score 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 0.2 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 n = 171 n = 58 AML udvikling 4 5 6 7 8 9 101112131415161718 Time (years) n = 235 n = 295 100 90 80 70 60 50 40 30 20 10 0 Low Int-1 Int-2 High 0 1 2 3 n = 179 n = 56 4 5 Overlevelse 6 7 8 n = 267 n = 314 9 101112131415161718 Time (years) Greenberg P, et al. Blood 1997;89:2079-88.
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