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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 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
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
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)
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
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
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)
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 deathkinetically 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 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