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SFH SK kurs MDS 28-30 september 2015 Klinisk presentation, klassifikation, kromosomer och prognos Eva Hellström Lindberg, MD PhD Karolinska Institutet.

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En presentation över ämnet: "SFH SK kurs MDS 28-30 september 2015 Klinisk presentation, klassifikation, kromosomer och prognos Eva Hellström Lindberg, MD PhD Karolinska Institutet."— Presentationens avskrift:

1 SFH SK kurs MDS september 2015 Klinisk presentation, klassifikation, kromosomer och prognos Eva Hellström Lindberg, MD PhD Karolinska Institutet Hematologiskt Centrum Karolinska Universitetssjukhuset Stockholm

2 Innehåll  Klinisk bild  Klassifikationer  Kromosomer  Prognos

3 Man born in 1962  2007  Refered to Hematology, Plt count around 100 x 10 9 /l, no other cytopenia or macrocytosis  46,XY, del(20q) in 22/25 metaphases  2 dysplasias, normal cellularity  MDS, RCMD, IPSS Low,  2008 – 2009  ADD diagnosis  Upper GI tract symptoms  Investigated for interstitial pulmonary changes – sarcoidosis?  Rapidly progressive pulmonary insufficiency  Family history  Father´s mother myocardial infarction at 50 years  Father has type 2 diabetes

4 Man born in 1983  Thrombocytopenia at the age of 7, ”ITP”  2007 Plt 25, Hypoplastic MDS, 46,XY t(1;13) in 3 metaphases  2009 pancytopenia; Hb 100, WBC 2, Plt 20  2010 aplastic anemia – normal cytogenetics  Family history  Fathers mother died of BM hypoplasia age 59  Her father died in pneumonia, age 50  His sister died pneumonia, age 12  Grandmothers 4 full siblings all dead <60 y (cardiac, diabetes)  Grandmothers two younger half brothers became very old  The patient’s mother, father and two younger siblings are healthy  2012 severe symptomatic aplastic anemia

5 Patient 1 Patient 2 Telomere length DNA samples sent to NIH October 2009

6 Mother (?) Patient MO Father (?) Patient TG Patient 2 + his father (and later child born 2010): TERC mutation Pat 2: father Pat 2: mother Patient 1: hTERT mutation

7 Mother (?) Patient MO Father (?) Patient TG Patient 2: died after stem cell transplantation Patient 1: alive and relatively well after pulmonary transplantation

8 The value of a detailed family history  Telomere disease  Dyskeratotis congenita  Other telomere diseases (TERT and TERC mutations)  Familial myelodysplastic syndromes  Familial platelet disorders  Germ-line RUNX1 mutations  Inherited bone marrow failures  Fanconi anemia  Diamond-Blackfan anemia  Inherited sideroblastic anemia Calado & Young, NEJM 2009, Liew & Owen Haematologica 2011, Sakaguchi H Int J Hematol. 2013, Camaschella C, Semin Hematol, 2009

9 42-year-old nurse presenting with severe sideroblastic anemia She used a caraff from the island of Samos, Greece for juice. Lead-containing glaze burnt at suboptimal temperature. Large quantities of lead release into juice, and ingested by patient Hellström Lindberg, Int Arch Occup Environ Health (2): Environmental exposition

10 Vanliga debutsymptom vid MDS  Ibland inga symptom  Ofta smygande start  Trötthet, uttröttbarhet  Andfåddhet, minskad fysisk prestationsförmåga  OBS noggrann anamnes hos äldre  Blåmärken, blödningar  Infektioner

11 Ibland akut presentation  Svår infektion  Blödning  Trombocytopeni  DIC

12 Inflammatoriska symptom  Ses hos ca 10% av MDS  Skala från SR stegring utan symptom till svår generell inflammation  Kan påverka olika organ  Vanligare vid högrisk MDS  ofta dispyt med reumatologer om inflammationen är hönan eller ägget  Behandling  Steroider / immunosuppression  Behandling av MDS klonen Saif, Leukemia & Lymphoma 2002 and Bouali, Rev Med Intern 2005

13 Sweet syndrom - acute neutrophilic dermatosis Buck, Int J Dermatol 2008

14 Sweet syndrom - pyoderma gangrenosum (PG) Buck, Int J Dermatol 2008 Avivi, Leuk Res. 1999

15 Konstitutionella symptom  Ganska vanligt vid CMML och “mixed MDS/MPN, unclassifiable”  Förekommer vid andra typer av MDS  “B-symptom”  Splenomegali (oftast CMML)  Behöver inte alltid vara tecken på högrisk sjukdom Neukirchen, 2900 pts, Eur J Hematol 2009

16 Blödning  Måttligt förhöjt APTT utan symptom är ganska vanligt vid CMML  Allvarlig koagulationsrubbning kan förekomma vid högrisk sjukdom  Blödningsbenägenhet behöver inte vara direkt kopplat till trombocyttal Germing et al, Haematologica 2007

17 MDS (?) responding to IS  Woman born 1963, second opinion in Autoimmune disorders in family  Onset of anemia, high SR, leg pain in 2004  BM TLD, erythroid hyperplasia, cellularity 70%, fibrosis, 46XX. RCMD with fibrosis  Rheumatology work-up – “must be paramalignant”  ATG in 2007 & 2008, normal Hb, decreased inflammation  2009 relapse in anemia - cyclosporin A restarted  2015, slight leg pain, normal blood values, less fibrosis in BM and in full activity  Maintains a low dose CsA

18 Diagnosis of MDS Hematopoietic stem cell Long term Short term Multipotent progenitor CLP CMP B cells T, NK-Tcells NK cells Dendritic cells Pro-B Pro-T Pro-NK GMP MEP Granulocytes Macrophages Platelets Red cells MkP ErP Adapted from Reya et al. Nature (2001) Bone marrow microenvironment Epigenetic alterations Genetic alterations

19 Diagnosis of MDS Hematopoietic stem cell Long term Short term Multipotent progenitor CLP CMP B cells T, NK-Tcells NK cells Dendritic cells Pro-B Pro-T Pro-NK GMP MEP Granulocytes Macrophages Platelets Red cells MkP ErP Adapted from Reya et al. Nature (2001) Bone marrow microenvironment Epigenetic alterations Genetic alterations

20 WHO Classification for MDS 2008  Refractory cytopenia with unilineage dysplasia  Refractory anemia with RS  Refractory cytopenia with multilineage dysplasia +/- RS  Refractory anemia with excess blasts (RAEB-1, 5-9% / RAEB-2 ≥10%)  MDS-unclassified  MDS with isolated del(5q) and BM blasts <5% Cazzola et al., Hematol Clin Oncol North Am 2010

21  Chronic myelomonocytic leukemia (CMML)  Atypical chronic myeloid leukemia, BCR-ABL1 neg  Juvenile myelomonocytic leukemia  MDS/MPN, unclassifiable  RARS associated with marked thrombocytosis  Dysplasia. Ph neg. Monocytes >10 9 /l for >3 months, marrow/blood blasts 0- 20%  Dysplasia. Ph neg. Myeloid non- monocytoid, non-basophil proliferation, marrow/blood blasts 0-20%  0-14 years. Dysplasia. Ph neg. WBC>10, Monocytes >10 9 /l, marrow/blood blasts 0-20%, often monosomy 7  Mix of dysplastic and proliferative features, not fulfilling criteria above  Provisional entity, RARS-T WHO classification of myelodysplastic / myeloproliferative neoplasms

22 Terapirelaterad MDS Fianchi et al, J Hematol Oncol 2012, Klimek, Leuk Res 2012 Quintas-Cardama A, Blood 2011;118(Suppl. 1): Abstract 967.  10% av MDS, internationellt och i INCA registret  Oftast cytostatika (alkylerare, antracycliner, övriga)  Strålbehandling, men ovanligt vid isolerad strålning över begränsade fält  Vanligen 2-7 år efter primärbehandling  Beslut om “tMDS” konsensusbedömning diagnostik- klinik

23 Typfall Fianchi et al, J Hematol Oncol 2012, Klimek, Leuk Res 2012 Quintas-Cardama A, Blood 2011;118(Suppl. 1): Abstract 967.  55-årig man, behandlad pga Hodgkins sjukdom för 3 år sedan, CR. Långsamt sjunkande blodvärden, fr a neutrofiler (0,2) och trc (50). RCMD, 4% blaster, karyotyp 45, XY, -7, +15.  70-årig kvinna med myelom sedan 3 år, tredjelinjens behandling med lenalidomide. Sjuknande blodvärden under 3 månder, nu grav pancytopeni och blödningar. RAEB-2,10% plasmacller i BM, gravt komplex karyotyp inkluderande del(5q), -6, -7, -11, -13, del(17p)  75-årig kvinna behandlad för bröstcancer med op och strålning for 20 år sedan. Macrocytär anemi, RARS, normal karyotyp.

24 Terapirelaterad MDS Fianchi et al, J Hematol Oncol 2012, Klimek, Leuk Res 2012 Quintas-Cardama A, Blood 2011;118(Suppl. 1): Abstract 967.  WHO klassifikationen ganska fyrkantig; tMDS och tAML sammanförs till en kategori  Dock; vanliga riskkriterier lika viktiga vid tMDS som vid de novo MDS.  NMDSG och INCA rekommenerar att klassa enligt de novo MDS men ange “tMDS” som sannolik orsak

25 Riskbedömning vid MDS Fianchi et al, J Hematol Oncol 2012, Klimek, Leuk Res 2012 Quintas-Cardama A, Blood 2011;118(Suppl. 1): Abstract 967.  Förväntad överlevnad  AML transformation  Komplikationer till cytopeni  Sannolikhet att svara på olika behandlingar

26 Kromosomer vid MDS  50-60% av MDS uppvisar kromosomförändringar  40-50% har normal karyotyp  Vanligare hos RARS och CMML  Vanligaste förändringarna isolerad del(5q) > monosomi 7 > trisomi 8  -Y räknas som klonal förändring om klonen är dominant  Komplex karyotyp också vanligt (≥3 aberrationer)  Enligt IPSS-R är ≥4 sämre än ≥3  Enligt IPSS-R ger –Y och del(11q) bättre prognos än normal karyotyp  Stark relation till mutationer

27 Swedish cancer and quality registry Overall survival IPSS Low and INT-1 vs INT-2 and High Lower-risk Higher-risk Ejerblad E, INCA report patients with MDS or MDS/MPN Primary and therapy-related 95% coverage against cancer registry Complete follow-up for survival

28 Swedish cancer and quality registry Overall survival MDS/MPN Ejerblad E, INCA report 2013

29 IPSS for prognosis of untreated MDS Prognostic variable Marrow blasts (%)< Karyotype*Goodintermedpoor Cytopenias0 / 12 / 3 (Hb < 100, plt < 100, ANC < 1.8) * Good: N, 5q-, 20q-, -Y, poor: -7, 7q-, complex, IM: other Score value Risk groupScore valueMedian survival (years) Low05.7 Intermediate Intermediate High≥ Greenberg et al, 1997

30 International Prognostic Scoring System (IPSS) Score % BM blasts <5%5- 10% % % KaryotypegoodINTPoor-- Cytopenia Karyotype: good=normal, -Y, del(5q), del(20q), poor=complex (≥abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities Cytopenias: Hgb <10g/dl, Neutrophils <1.8x10 9 /L, Platelets <100x10 9 /L Greenberg, Blood 1997

31 Anemi och transfusionsbehov ökar risken både för AML och död WPSS scoring system för MDS Prognostic variable0123 WHO categoryRA, RARSRCMD±RSRAEB-1RAEB-2 Karyotype*GoodIntermedPoor- Transfusion requirNoregular-- * Good: N, 5q-, 20q-, -Y, poor: -7, 7q-, complex, IM: other Score value Risk groupScore valueMedian survival (months) Very low0103 Low172 Intermediate 240 High3-421 Very high5-612 Malcovati et al, JCO 2007

32 Greenberg et al, BLOOD, 2012

33 Prognostic variable CytogeneticsVery GoodGoodIntermediatePoorVery Poor BM Blast %≤2%>2-<5%5-10%>10% Hemoglobin g/dl ≥108-<10<8 Platelets≥10050-<100<50 ANC≥0.8<0.8 International Prognostic Scoring System (IPSS- revised) in myelodysplastic syndromes Greenberg, et al., 2012;120: IPSS-revised – new categories

34 Overall survival and AML evolution based on IPSS-R prognostic risk-based categories. Risk groupScore valueMedian survival (years) Very low ≤1,58,8 Low Intermediate 13,5 – 4,53.0 High Very high>60.8 OS AML free survival

35 Mall för IPSS-R calculator/

36 Della Porta, M. G. et al. J Clin Oncol; 27: Prognosis of MDS associated with marrow fibrosis <5% bl OS ≥5% bl LFS ≥5% bl OS <5% bl LFS Fibrosis grade 0-1 Fibrosis grade 2-3 Additional clinical risk factors -Performance status -Ferritin -Mutations

37 Multiprofessionella konferenser  MDS är en klinisk diagnos som kräver input från olika professioner  Anamnes (familjehistoria, exposition, andra orsaker till cytopeni, etc)  Morfologi och histopatologi  Cytogenetik, mutationsanalys  Detta leder till  WHO diagnos  IPSS och IPSS-R score / risk grupp  Information om prognos och behandling  Behandlingsbeslut inklusive expektans, transfusioner och SCT  Registrering I INCA


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