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Myelodysplastic syndromes

Myelodysplastic syndromes. Achievements in understanding and treatment. Myelodysplastic syndromes. Clonal hematopoietic stem cell disorder ch a racterized by ineffective hematopoiesis and peripheral cytopenias

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Myelodysplastic syndromes

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  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. FAB classification system Myelodysplastic syndromes • 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. WHO classification system Myelodysplastic syndromes 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. IPSS risk-based classification system Myelodysplastic syndromes Marrow blast percentage: • < 5 0 • 5-10 0.5 • 11-20 1.5 • 21-30 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 0 • 2 or 3 type 0.5

  6. Overall IPSS score and survival Myelodysplastic syndromes Overall score: Median survival: low • 0 5.7 years Intermediate • 1 (0.5 or 1) 3.5 years • 2 (1.5 or 2) 1.2 years High • > 2.5 0.4 years

  7. Known molecular abnormalities in MDS

  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

  11. Myelodysplastic features in MDS

  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 MDSand 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

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