SINDROMI MIELODISPLASTICHE

SINDROMI MIELODISPLASTICHE • • • • • • Uomo di 70 aa APR: gastrite cronica, ipertensione arteriosa Sintomi: astenia Hb 9g/dL; MCV 108; GB 2.100 mm3...
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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