Myelodysplastic syndromes Achievements in understanding and treatment

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

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>10 9 /L; < 5% blast in PB and up to 20% BM balsts Myelodysplastic syndromes FAB 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 WHO classification system

Marrow blast percentage: < 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 Myelodysplastic syndromes IPSS risk-based classification system

Overall score: Median survival: low years Intermediate 1 (0.5 or 1) 3.5 years 2 (1.5 or 2) 1.2 years High > years Myelodysplastic syndromes Overall IPSS score and survival

Known molecular abnormalities in MDS GeneType of anomalyIncidence (%) RAS (N or K) Point mutation (codon 12, 13 or 61) 10-30% P53Point 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. B 12 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 MDSBone 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

Myelodysplastic features in MDS MDSBone marrow and/or peripheral blood findings Dysgranulopoiesis Nuclear abnormalities including: hypolobulation, ring-shaped nuclei, hypogranulation DysmegakariopoiesisMicromegakariocytes 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