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

Innehåll Klinisk bild Klassifikationer Kromosomer Prognos

Man born in 1962 2007 2008 – 2009 Family history Refered to Hematology, Plt count around 100 x 109/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

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

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

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

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

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

Environmental exposition 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. 2006 (2):165-8.

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

Ibland akut presentation Svår infektion Blödning Trombocytopeni DIC

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

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

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

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

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

MDS (?) responding to IS Woman born 1963, second opinion in 2009. 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

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

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

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

WHO classification of myelodysplastic / myeloproliferative neoplasms 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 >109/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 >109/l, marrow/blood blasts 0-20%, often monosomy 7 Mix of dysplastic and proliferative features, not fulfilling criteria above Provisional entity, RARS-T

Terapirelaterad MDS 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 Fianchi et al, J Hematol Oncol 2012, Klimek, Leuk Res 2012 Quintas-Cardama A, Blood 2011;118(Suppl. 1): Abstract 967.

Typfall 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. Fianchi et al, J Hematol Oncol 2012, Klimek, Leuk Res 2012 Quintas-Cardama A, Blood 2011;118(Suppl. 1): Abstract 967.

Terapirelaterad MDS 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 Fianchi et al, J Hematol Oncol 2012, Klimek, Leuk Res 2012 Quintas-Cardama A, Blood 2011;118(Suppl. 1): Abstract 967.

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

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

Swedish cancer and quality registry 2009-2012 Overall survival IPSS Low and INT-1 vs INT-2 and High 1209 patients with MDS or MDS/MPN Primary and therapy-related 95% coverage against cancer registry Complete follow-up for survival Lower-risk Higher-risk Ejerblad E, INCA report 2013

Swedish cancer and quality registry 2009-2012 Overall survival MDS/MPN Ejerblad E, INCA report 2013

IPSS for prognosis of untreated MDS Score value Prognostic variable 0 0.5 1.0 1.5 2.0 Marrow blasts (%) <5 5-10 --- 11-20 21-30 Karyotype* Good intermed poor Cytopenias 0 / 1 2 / 3 (Hb < 100, plt < 100, ANC < 1.8) * Good: N, 5q-, 20q-, -Y, poor: -7, 7q-, complex, IM: other Risk group Score value Median survival (years) Low 0 5.7 Intermediate 1 0.5-1-0 3.5 Intermediate 2 1.5-2.0 1.2 High ≥2.5 0.4 Greenberg et al, 1997

International Prognostic Scoring System (IPSS) Score 0.5 1 1.5 2 % BM blasts <5% 5-10% - 11-19% 20-30% Karyotype good INT Poor Cytopenia 0-1 2-3 Karyotype: good=normal, -Y, del(5q), del(20q), poor=complex (≥abnormalities) or chromosome 7 anomalies; Intermediate = other abnormalities Cytopenias: Hgb <10g/dl, Neutrophils <1.8x109/L, Platelets <100x109/L Greenberg, Blood 1997

Anemi och transfusionsbehov ökar risken både för AML och död WPSS scoring system för MDS Score value Prognostic variable 0 1 2 3 WHO category RA, RARS RCMD±RS RAEB-1 RAEB-2 Karyotype* Good Intermed Poor - Transfusion requir No regular - - * Good: N, 5q-, 20q-, -Y, poor: -7, 7q-, complex, IM: other Risk group Score value Median survival (months) Very low 0 103 Low 1 72 Intermediate 2 40 High 3-4 21 Very high 5-6 12 Malcovati et al, JCO 2007

Greenberg et al, BLOOD, 2012

IPSS-revised – new categories International Prognostic Scoring System (IPSS-revised) in myelodysplastic syndromes IPSS-revised – new categories Prognostic variable 0.5 1 1.5 2 3 4 Cytogenetics Very Good Good Intermediate Poor Very Poor BM Blast % ≤2% >2-<5% 5-10% >10% Hemoglobin g/dl ≥10 8-<10 <8 Platelets ≥100 50-<100 <50 ANC ≥0.8 <0.8 Greenberg, et al., 2012;120:2454-2465

Overall survival and AML evolution based on IPSS-R prognostic risk-based categories. Risk group Score value Median survival (years) Very low ≤1,5 8,8 Low 2 - 3 5.3 Intermediate 1 3,5 – 4,5 3.0 High 5 - 6 1.6 Very high >6 0.8 OS AML free survival

Mall för IPSS-R http://www.mds-foundation.org/ipss-r-calculator/

Prognosis of MDS associated with marrow fibrosis <5% bl LFS Fibrosis grade 0-1 <5% bl OS ≥5% bl LFS Fibrosis grade 2-3 ≥5% bl OS Additional clinical risk factors Performance status Ferritin Mutations Della Porta, M. G. et al. J Clin Oncol; 27:754-762 2009

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