SINDROMI MIELODISPLASTICHE
• • • • • •
Uomo di 70 aa APR: gastrite cronica, ipertensione arteriosa Sintomi: astenia Hb 9g/dL; MCV 108; GB 2.100 mm3; PLT 83.000; LDH 400; bilirubina ind. 2 Reticolociti bassi Vit B12, folati, bilancio marziale nella norma
• A. midollare: mielodisplasia
• Le mielodisplasie sono patologie clonali caratterizzate dalla displasia midollare che determina emopoiesi inefficace • Midollo ricco displastico • Pancitopenia periferica
• Evoluzione clonale in leucemia acuta
Epidemiology of MDS
• Incidence:
– overall: 5/100.000/year
– ≥65yrs: 20-50/100.000/year • Proportion of people aged >65yrs in Europe: 14%
• Expected new cases of MDS each year in Europe: ~15.000 • Standardized Mortality Ratio (SMR) in MDS is 7.30 with respect to the general population
J Clin Oncol 2005;23:7594-7603
CELLULA STAMINALE TOTIPOTENTE
LINFOPOIESI CELLULA STAMINALE MIELOIDE CFU-GEMM
COLONIE GRANULOCITOMACROFAGICHE CFU-GM LINEA ERITROIDE BFU-E
MEGACARIOCITI CFU-Me
GLOBULI ROSSI
PIASTRINE
CFU-M
MACROFAGI
CFU-G
GRANULOCITI
Morphological score Dyserythropoiesis Megaloblastosis
Pyknosis
Multinuclearity
Nuclear lobulation
Defective Ring sideroblasts hemoglobinisation and cytoplasmic fraying
Leukemia, 2015
Morphological score Dysgranulopoiesis Myeloblast
Auer rod
Abnormal nuclear shape
Hypolobulation
Hypogranulation Leukemia, 2015
Blasts
Agranular
Granular
Auer bodies
Morphological manifestations of dysplasia Dysmegakaryocytopoiesis
Micromegakaryocytes Nuclear hypolobation
Multinucleation
Cause di mielodisplasia • • • • • •
Virus Meccanismi immunologici Fattori tossici ambientali Benzene, sostanze chimiche Radiazioni Chemioterapici ( alchilanti, epipodofilotossine)
CRITERI CLASSIFICATIVI PER LE MIELODISPLASIE
MORFOLOGICI displasia blasti sideroblasti ad anello ANOMALIE CITOGENETICHE ANOMALIE MOLECOLARI
MDS WHO 2016 • MDS with single lineage dysplasia (MDS-SLD)
• MDS-SLD with ring sideroblasts • MDS with multilineage dysplasia –MDS-MLD with ring sideroblasts
• MDS with isolated del(5q) • MDS with excess blasts –MDS-EB1 –MDS-EB2
• MDS, unclassifiable (MDS-U)
Either ≥15% RS or 5% RS and SF3B1 mutation
The lineages manifesting significant morphplogic dysplasia frequently do not correlate with the specific cytopenias in individual MDS cases
BLOOD, 19 MAY 2016 x VOLUME 127, NUMBER 20
Distinct haematological disorder with deletion of long arm of No. 5 chromosome (Van den Berghe H. et al., Nature 1974)
• Female preponderance • 5q- sole karyotypic abnormality
• macrocytic anemia (MCV > 100 fL) • high platelet count • megakaryocytes with monolobulated nuclei • prolonged survival
Insights into the molecular basis of MDS with isolated del(5q)
miRNA-145 miRNA-146a
RPS14
CSNK1A1
P53/Glycophorin
Nature 2008;451:335; Nat Med 2010;16:49; Nat Med 2010;16:59; Cancer Cell. 2014;26:509-20.
Vulnerability of 5q- clone to lenalidomide consequent to gene haploinsufficiency
http://www.cell.com/cancer-cell/abstract/S1535-6108(14)00335-3
WHO 2016
WHO 2008 translation
• MDS with single lineage dysplasia (MDS-SLD)
= RCUD
• MDS-SLD with ring sideroblasts
= RARS
• MDS with multilineage dysplasia –MDS-MLD with ring sideroblasts
= RCMD = RCMD-RS
• MDS with isolated del(5q) • MDS with excess blasts –MDS-EB1 –MDS-EB2
• MDS, unclassifiable (MDS-U)
= RAEB-1 = RAEB-2
QUADRO CLINICO e DI LABORATORIO • • • • • •
ANEMIA MACROCITICA (MCV 105), reticolociti bassi PIASTRINOPENIA NEUTROPENIA IPER FERRITINEMIA SPLENOMEGALIA LDH alte, aumento bilirubina indiretta
LA CITOPENIA E’ DI SEVERITA’ MOLTO VARIABILE E PUO’ COINVOLGERE UNA O PIU’ LINEE CITOPENIA SOSPETTO DIAGNOSTICO MA… MANDATORIO ESCLUDERE ALTRE CAUSE
Proposal for standardized diagnostic procedures in MDS Blood tests • WBC, Hb, PLT count, MCV, reticulocyte, PB smear; • S-folic acid, cobalamin;
• Iron, TIBC, ferritin; • LDH, bilirubin, haptoglobin, Coombs test; • ALT, AST, Albumin, S-protein electrophoresis; • Uric acid, Creatinine, S-erythropoietin; • Thyroid function tests; • Anti-HIV, anti-Parvovirus B19, CMV-test; PNH clone • Exclude thalassemia / hemoglobinopathy.
Diagnosis of Myelodysplastic Syndrome
Bone Marrow Peripheral Blood Morphology
Cytogenetic Analysis
• Bone marrow dysplasia is not specific for MDS • Morphological BM evaluation is dependent form sample quality • Evaluation of dysplasia may be hampered by the presence of hypocellularity or fibrosis (15-20% of MDS cases) • Three months observation
TERAPIA CURATIVA:TMO ALLOGENICO Uomo 30 aa • MDS-EB2 (blasti 18%) • Hb 6; PLT 30.000; GB 1000
• MDS-MLD • Hb9.5; PLT 120.000; GB 900
Uomo 85 aa • MDS-SLD • Hb 7; PLT 200.000; GB 5000
Survival of MDS patients classified according to WHO subgroups Overall survival (P