1. Myelodysplastic syndromes
Achievements in understanding and treatment

2. 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

3. 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: (REAEB-t): hematologic features identical to RAEB. >5% blasts in PB or 21-30% 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

4. 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)

5. Myelodysplastic syndromes
IPSS risk-based classification system
Marrow blast percentage:
<
Cytogentic fetures
Good prognosis 0
(–Y, 5q- , 20q-)
Intermediate prognosis 0.5
(+8, miscellaneous singleabnormality, double abnormalities)
Poor prognosis
(abnor. 7, complex- >3 abnor.)
Cytopenias
None or one type
2 or 3 type

6. Myelodysplastic syndromes
Overall IPSS score and survival
Overall score: Median survival:
low
years
Intermediate
1 (0.5 or 1) years
2 (1.5 or 2) years
High
> years

7. 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)
(codon 969 or rarely 301)
5-10

8. 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

9. 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)

10. Myelodysplastic features in MDS
Bone marrow and/or peripheral blood findings
Dyserythropoiesis
Bone marrow: multinuclearity, nuclear fragments, megaloblastoid changes, cytoplasmic abnormalities, ringed sideroblasts
Peripheral blood:
Poikilocytosis, anisocytosis, nucleated red blood cells

11. Myelodysplastic features in MDS
Bone marrow and/or peripheral blood findings
Dysgranulopoiesis
Nuclear abnormalities including: hypolobulation, ring-shaped nuclei, hypogranulation
Dysmegakariopoiesis
Micromegakariocytes
Large mononuclear forms
Multiple small nuclei

12. 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)

13. 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)

14. 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