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>109/L; < 5% blast in PB and up to 20% BM balsts

Myelodysplastic syndromesFAB 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 syndromesWHO classification system

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

Myelodysplastic syndromesIPSS risk-based classification system

Overall score: Median survival:low • 0 5.7 yearsIntermediate • 1 (0.5 or 1) 3.5 years• 2 (1.5 or 2) 1.2 yearsHigh • > 2.5 0.4 years

Myelodysplastic syndromesOverall IPSS score and survival

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 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

Myelodysplastic features in MDS

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

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 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