SINDROMI MIELODISPLASTICHE · • Le mielodisplasie sono patologie clonali caratterizzate dalla...

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

LINEA ERITROIDE MEGACARIOCITI

GLOBULI ROSSI PIASTRINE

BFU-E CFU-Me

COLONIE

GRANULOCITO-

MACROFAGICHE

CFU-GM

CFU-M

MACROFAGI

CFU-G

GRANULOCITI

Morphological score Dyserythropoiesis

Multinuclearity Nuclear lobulation

Megaloblastosis

Pyknosis Defective

hemoglobinisation and

cytoplasmic fraying

Ring sideroblasts

Leukemia, 2015

Morphological score Dysgranulopoiesis

Myeloblast Auer rod Hypolobulation

Abnormal nuclear shape 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

• Female preponderance

• 5q- sole karyotypic abnormality

• macrocytic anemia (MCV > 100 fL)

• high platelet count

• megakaryocytes with monolobulated nuclei

• prolonged survival

Distinct haematological disorder with

deletion of long arm of No. 5 chromosome

(Van den Berghe H. et al., Nature 1974)

miRNA-145

miRNA-146a RPS14

Nature 2008;451:335; Nat Med 2010;16:49; Nat Med 2010;16:59; Cancer Cell. 2014;26:509-20.

P53/Glycophorin

CSNK1A1

Insights into the molecular basis of

MDS with isolated del(5q)

Vulnerability of 5q- clone to lenalidomide

consequent to gene haploinsufficiency

http://www.cell.com/cancer-cell/abstract/S1535-6108(14)00335-3

WHO 2016






–MDS-EB2


WHO 2008 translation

= RCUD

= RARS

= RCMD

= RCMD-RS

= 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

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.

Proposal for standardized diagnostic procedures in MDS

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

J Clin Oncol 2005;23:7594-603

Overall survival (P<.001)

Leukemia-free survival (P <.001)

Variabili indipendenti con valore prognostico

• Citopenie

• Citogenetica

• Blasti

International Prognostic Scoring System (IPSS)

Score

0 0.5 1.0 1.5 2.0

Medullary blasts (%) < 5 5–10 – 11–20 21–30

Karyotype Good* Intermediate† Poor‡ – –

Cytopenia 0/1 2/3 – – –

Low risk 0 points

Intermediate-1 0.5–1.0 points

Intermediate-2 1.5–2.0 points

High risk ≥ 2.5 points

Greenberg P, et al. Blood. 1997;89:2079-88.

*Good: normal, -Y, del(5q), del(20q). †Intermediate: other abnormalities not seen in “good” or “poor”. ‡Poor: complex (≥ 3 abnormalities) or chromosome 7 anomalies.

International Prognostic Scoring System (IPSS)

Punteggio Rischio Sopravvivenza

mediana

0 Basso 5.7 anni

0.5-1.0 Intermedio 1 3.5 anni

1.5-2.0 Intermedio 2 1.2 anni

≥2.5 alto 0.4 anni

Blood 1997;89:2079-2088

International Prognostic Scoring System for MDS

Variable 0 0.5 1 1.5 2

BM blasts % <5 5-10 - 11-20 21-30

Karyotype* Good Intermediate Poor

Cytopenias° 0/1 2/3

*Good: normal, -Y, del(5q), del(20q); Poor: complex,

chromosome 7 anomalies; Intermediate: other

abnormalities.

°Hemoglobin < 10 g/dL, absolute neutrophil count <

1,500/µL, platelet count < 100,000/µL.

Scores for risk groups are as follows: Low, 0; INT-1,

0.5-1.0; INT-2, 1.5-2.0; and High, 2.

Most common cytogenetic abnormalities in MDS

Blood 2007;110:4385–95.

citogenetica

Very good good intermediate poor very poor del (11q) normal -7/7q del(q21) >3 anomalie

-Y del(1;7) +8 del(q26)

del (5q) i(17q) -7/7q et al

del (12p) +19 3 anomalie

del (20q) +21

del (5q) et al ogni doppia

Prognosi Very good 60.8 mesi OS

Good 48.5 mesi

Intermediate 24 mesi

Poor 14 mesi

Very poor 5.7 mesi

Shanz EHA 2010

Revised International Prognostic Scoring System

Blood. 2012;120:2454-65.

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

• Cariotipo complesso

Int-2; survival 1.2aa

Uomo 85 aa

• MDS-SLD

• Hb 7; PLT 200.000; GB 5000

• 46 XY

Low risk; survival 5.7 aa

SOMATIC MUTATION AND PROGNOSIS

Frequency of somatic mutations in MDS

Papaemmanuil et al. Blood. 2013;122:3616-27

SF3B1-SRSF2 splicing

TET2 DNMT3A metilation

Clonal and subclonal driver mutations in MDS

Papaemmanuil et al. Blood. 2013;122:3616-27

CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL

BLOOD, 2 JULY 2015 x VOLUME 126, STEENSMA et al

Relationship between SF3B1 mutation and ring sideroblasts

Quantitative enumeration

of ring sideroblasts

(325 MDS patients)

31% patients

with mutation in SF3B1

97% patients with RS,

3% patients no RS

SF3B1 mutation: positive predictive value for ring sideroblasts 97.7%

Absence of ring sideroblasts: negative predictive value

for SF3B1 mutation 97.8%

P=0.002

RARS, RCMD-RS

35% RA/RCMD/MDSdel(5q)/RAEB

Malcovati et al. Blood 2011;118:6239-46

Prognostic value of SF3B1 mutations

in patients with MDS and RS

Overall Survival

HR .37, P=.003

CI of Disease Progression

HR .31, P=.018

HR .27, P=.007 HR .22, P=.026

RA

RS

/RC

MD

-RS

A

ll W

HO

cate

go

ries

Malcovati et al. Blood. 2015 May 8

Relationship between SF3B1 mutation and ring sideroblasts

Quantitative enumeration

of ring sideroblasts

(325 MDS patients)

31% patients

with mutation in SF3B1

97% patients with RS,

3% patients no RS

SF3B1 mutation: positive predictive value for ring sideroblasts 97.7%

Absence of ring sideroblasts: negative predictive value

for SF3B1 mutation 97.8%

P=0.002

RARS, RCMD-RS

35% RA/RCMD/MDSdel(5q)/RAEB

Malcovati et al. Blood 2011;118:6239-46

MDS WHO 2016






–MDS-EB2


Either ≥15% RS or 5% RS

and SF3B1 mutation

Expected advantages of a molecular

classification

• High accuracy of class prediction (robust biomarkers regardless of morphological criteria).

• Identification of biologically homogeneous entities (more homogeneous prognosis, restricted patterns of clonal evolution).

• Ideal frame for development of targeted therapies and identification of specific mechanisms of resistance to treatment.

COMORBIDITY AND PROGNOSIS

OS secondo rischio MDS-CI nei rischi WPSS basso (A), intermedio (B), alto e molto alto (C-D)

MDS a basso rischio

MDS ad alto rischio

Morirà PER la mielodisplasia o CON la mielodisplasia

TERAPIA

• Eritropoietina 30-40.000 U/sett (epo<500) (IPSS low int-1)

• Supporto trasfusionale

• Ferrochelazione

• 5azacitidina (IPSS-int2 high)

• Lenalidomide (5q-)

• Trapianto allogenico di midollo osseo

• 80 aa

• Cardiopatia ischemica

• Hb 7 g/dl; GB 4700 ANC 2700; PLT 270.00

• MDS-SLD con sideroblasti ad anello

• 46 XY

• IPSS low

TERAPIA



• Ferrochelazione




TERAPIA



• Ferrochelazione (deferoxamina, deferasirox)




• 75 aa

• Hb 8g/dl; GB 800 ANC 100; PLT 40.000

• MDS-EB2

• 46 XX

• IPSS int-2; IPSS-R very high

TERAPIA



• Ferrochelazione

• 5azacitidina (ipometilante) (IPSS-int2 high)



OBIETTIVI DEL TRATTAMENTO IPOMETILANTE MIGLIORARE L’EMATOPOIESI RIDURRE O ANNULLARE IL FABBISOGNO TRASFUSIONALE ALLUNGARE LA SOPRAVVIVENZA GLOBALE

• 50aa

• APR CHT/RT neoplasia mammaria

• Hb 11g/dl; GB 2500 ANC 1100; PLT 110.000

• Cariotipo complesso

• MDS therapy related

TERAPIA



• Ferrochelazione

• 5azacitidina (ipometilante) (IPSS-int2 high)



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