Transcript Myelodysplastic syndromes

Myelodysplastic syndromes
Achievements in understanding and treatment
Myelodysplastic syndromes
• Clonal hematopoietic stem cell disorder characterized by ineffective
hematopoiesis and peripheral cytopenias
• Although a substantial proportion of MDS cases evolve to acute
myeloid leukemia (AML), the natural history of these syndromes
ranges from more indolent forms of the disease spanning years to
those with a rapid evolution to AML
the leukemic disorder in which neoplastic clone that has been
established may or may not fully progress to acute leukemia
Myelodysplastic syndromes
FAB classification system
• Refractory anemia (RA): cytopenia of one PB lineage; normo- or
hypercellular marrow with dysplasias; < 1% PB blasts and <5%
BM blasts
• Refractory anemia with ringed sideroblasts (RARS): cytopenia,
dysplasia and the same % blasts involvement in BM and PB as RA.
Ringed sideroblasts account for > 15% of nucleated cells in
marrow.
• Refractory anemia with excess of blasts (REAEB): Cytopenia or
two or more PB lineages; dysplasia involving all 3 lineages; < 5%
PB blasts and 5-20% BM blasts
• Refractory anemia with excess blasts in transformation: (REAEBt): hematologic features identical to RAEB. >5% blasts in PB or 2130% blasts in BM, or the presence of Auer rods in the blasts
• Chronic myelomonocytic leukemia (CMML):monocytosis in
PB>109/L; < 5% blast in PB and up to 20% BM balsts
Myelodysplastic syndromes
WHO classification system
Myelodysplastic syndromes:
• Refractory anemia (RA)
With ringed sideroblasts (RARS)
Without ringed sideroblasts
• Refractory cytopenia (MDS) with multilineage dysplasia (RCMD)
• Refractory anemia with excess blasts (RAEB)
• 5q- syndrome
Myelodysplastic syndrome, unclassifiable
• Myelodysplastic/Myeloprolipherative diseases
• Chronic myelomonocytic leukemia (CMML)
• Atypic chronic myelogenous leukemia (aCML)
Myelodysplastic syndromes
IPSS risk-based classification system
Marrow blast percentage:
•
•
•
•
<5
5-10
11-20
21-30
0
0.5
1.5
2.0
Cytogentic fetures
• Good prognosis
0
(–Y, 5q- , 20q-)
• Intermediate prognosis
0.5
(+8, miscellaneous singleabnormality, double abnormalities)
• Poor prognosis
1.0
(abnor. 7, complex- >3 abnor.)
Cytopenias
• None or one type
• 2 or 3 type
0
0.5
Myelodysplastic syndromes
Overall IPSS score and survival
Overall score:
low
• 0
Intermediate
• 1 (0.5 or 1)
• 2 (1.5 or 2)
High
• > 2.5
Median survival:
5.7 years
3.5 years
1.2 years
0.4 years
Known molecular abnormalities in
MDS
Gene
Type of anomaly
Incidence
(%)
RAS
(N or K)
Point mutation
(codon 12, 13 or 61)
10-30%
P53
Point mutation or deletion
of other allele
5
FMS
(encodes M-CSF
receptor)
Point mutation
(codon 969 or rarely 301)
5-10
Diagnosis of MDS
• Aplastic anaemia and some disease accompanied
by marrow dysplasia, including wit. B12 and/or
folate deficiency, exposure to haevy metals,
recent cytotoxic therapy and ongoing inflamation
(including HIV and chronic liver disease/alcohol
use) should be ruled out
MDS – clinical findings
• These are non-specific, and are usually the consequences
of cytopenias, including:
- symptoms of anaemia
- infections due to neutropenia, but also to the frequently
associated defect in neutrophil function
- bleeding due to thrombocytopenia (may also occur in
moderately thrombocytopenic patients or even in patients
with normal platelets count, because of
thrombocytopathy)
Myelodysplastic features in MDS
MDS
Dyserythropoiesis
Bone marrow and/or peripheral
blood findings
Bone marrow: multinuclearity,
nuclear fragments,
megaloblastoid changes,
cytoplasmic abnormalities,
ringed sideroblasts
Peripheral blood:
Poikilocytosis, anisocytosis,
nucleated red blood cells
Myelodysplastic features in MDS
MDS
Dysgranulopoiesis
Dysmegakariopoiesis
Bone marrow and/or peripheral
blood findings
Nuclear abnormalities
including: hypolobulation,
ring-shaped nuclei,
hypogranulation
Micromegakariocytes
Large mononuclear forms
Multiple small nuclei
Bone marrow biopsy
• Blood examination and bone marrow aspirate are
sufficient for a diagnosis of MDS
• It is obviously important in cases of difficult
diagnosis , and it could brink additional
prognostic information in some cases
- normal or increased cellularity is seen in 85-90%
od cases
- abnormal localization of immature precusors
(ALIP)
- Fibrosis (significant in 15-20% of cases)
Dysplasia, apoptosis and cytokines in
MDS
• Despite increased proliferation of the marrow, there is an
increased rate of prgrammed cell deathkinetically the
apoptosis prevails over the increased proliferation,
causing the peripheral cytopenia
• Cytokines derived from unselected marrow mononuclear
cells are belived to be extrinsic factors predisposing to
apoptosis (TNF - inhibit normal and MDS colony
growth; INF, IL1, TGF - have also be implicated in
causing apoptosis)
Evidence for an immune – mediated
suppression of the marrow in MDS
• T cells inhibit MDS CFU-E
• CD8+ cells inhibit CFU-GM
• Immunosuppressive agents improve cytopenia in MDS
and eliminate autosuppressive T cells
• T cells are activated in MDS
• T cell are show a skewed T cell receptor V- repertoire
• HLA-DR 15 over representation in MDS and aplastic
anemia