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Mds csbrp
Myelodysplastic syndromes (MDS) are a group of hematological disorders characterized by ineffective hematopoiesis, dysplasia in the bone marrow, and a high risk of progression to acute myeloid leukemia. The key features of MDS include increased proliferation but failed differentiation of stem cells in the bone marrow, resulting in cytopenias. Many MDS cases progress to acute leukemia. Treatment options are limited and depend on individual risk factors, with median survival ranging from over 5 years in low risk cases to under 2 years in high risk MDS.
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Mds csbrp
- 1.
- 2. The cardinal featuresof MDS are: • Increased marrow proliferation • Failure of stem cells to differentiate & • Increased marrow apoptosis
- 3. • Heterogeneous groupof hematologic disorders • Maturation defects resulting in ineffective hematopoiesis pancytopenia in peripheral blood • “Preleukemia” many progress to overt acute leukemia
- 4. Myelodysplastic SyndromesMyelodysplastic Syndromes •Clonal stem cell disorders • Defective maturation • Ineffective hematopoiesis • Cytopenias and associated complications • High risk for AML
- 5. Myelodysplastic SyndromesMyelodysplastic Syndromes MDSmay be: – Primary (idiopathic) or – Secondary • Genotoxic Drug • Radiation therapy (t-MDS) • t-MDS appears 2 to 8 years after the genotoxic exposure • Transform to AML – More common and the most rapid in t-MDS • Cytogenetic analysis is heplful in diagnosis of MDS – Monosomies 5 and 7 – Deletions of 5q, 7q, and 20q, and – Trisomy 8
- 7. PathogenesisPathogenesis • Poorly understood •Hall mark of MDS: BM progenitors undergo apoptotic cell death at an increased rate > ineffective hemopoiesis • The clone (MDS) proliferate when normal stem cell are damaged (drugs / radiation) • Primary and secondary MDS show similar chromosomal abnormalities – Monosomies 5 and 7 – Deletions of 5q, 7q, and 20q and – Trisomy 8
- 8. Dysplasia, apoptosis andcytokines 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 (TNFα - inhibit normal and MDS colony growth; INFγ, IL1, TGFβ - have also be implicated in causing apoptosis)
- 9. Evidence for animmune – 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-β repertoire • HLA-DR 15 over representation in MDS and aplastic anemia
- 10. FAB classification • Refractoryanemia (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
- 12. Morphological categories WHO classification Myelodysplasticsyndromes: • 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)
- 13. • The WHOproposed changes including reclassification of RAEB-t to AML and adding a subgroup called refractory cytopenias with dysplasia (RCD)
- 14. International Prognostic ScoringSystem (IPSS) • The most practical and validated MDS classification system currently available to clinicians is the IPSS which predicts both survival and risk of transformation to AML based on: – Marrow blast % – Cytogenetics – And number of cytopenias.
- 15. International Prognostic ScoringSystem (IPSS) 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
- 17.
- 18. Morphology • BM ishypercellular • Dysplasia in erythroid, myeloid, megakaryocytic cells • Erythroid – Ringed sideroblasts – Megaloblastic maturation – Nuclear budding • Neutrophils – Pelger-Heut abnomlaity – Hypogranularity – Hypolobation • Megakaryocytes – Pawn ball nuclei – Micro Mkc – Hypolobated nuclei • Myeloblasts <20% in BM and <10% in PBS
- 19.
- 20. 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
- 21. Clinical course • Elderlyage group • Incidental discovery • Weakness, infections, hemorrhages • Survival: – Primary MDS: 9-29months – t-MDS: 4-8months • Progression to AML: 10-40% of cases – More common and rapid in t-MDS • Treatment: – For younger patients – BM transplation – For older patients – Supportive, Thalidomide, DNA methylation inhibitors
- 22. Clinical course • Moderateanaemia is the most common clinical problem in MDS patients, but complete myeloid bone marrow failure also occurs leading to death from bleeding or infection • Approximately half of the patients transform to AML
- 23. Clinical course • Prognosisdepends on the individual’s risk factors, with median survival ranging from 5.7 years in lower-risk group to 1.2 years or less in those with higher-risk MDS • MDS is extremely difficult to treat. Most cases are resistant to current therapies, and the most potent anti-MDS treatments (transplantation and dose intensive chemotherapy) are often too toxic for the majority of patients
- 24.
Editor's Notes
- #5 The term “myelodysplastic syndrome” (MDS) refers to a group of clonal stem cell disorders characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML.
- #6 In MDS the bone marrow is partly or wholly replaced by the clonal progeny of a neoplastic multipotent stem cell that retains the capacity to differentiate but does so in an ineffective and disordered fashion. These abnormal cells stay within the bone marrow and hence the patients have peripheral blood cytopenias.
- #7 MDS may be either primary (idiopathic) or secondary to previous genotoxic drug or radiation therapy (t-MDS). t-MDS usually appears from 2 to 8 years after the genotoxic exposure. All forms of MDS can transform to AML, but transformation occurs with highest frequency and most rapidly in t-MDS. Although characteristic morphologic changes are typically seen in the marrow and the peripheral blood, the diagnosis frequently requires correlation with other laboratory tests. Cytogenetic analysis is particularly helpful, since certain chromosomal aberrations (discussed below) are often observed. ------------------- In genetics, genotoxicity describes a deleterious action on a cell&apos;s genetic material affecting its integrity. This includes both certain chemical compounds and certain types of radiation. Typical genotoxins like aromatic amines are believed to cause mutations because they are nucleophilic and form strong covalent bonds with DNA resulting with the formation of Aromatic Amine-DNA adducts, preventing accurate replication. Genotoxins affecting sperm and eggs can pass genetic changes down to descendants who have never been exposed to the genotoxin.
- #20 Morphology. Although the marrow is usually hypercellular at diagnosis, it is sometimes normocellular or, less commonly, hypocellular. The most characteristic finding is disordered (dysplastic) differentiation affecting the erythroid, granulocytic, monocytic, and megakaryocytic lineages to varying degrees ( Fig. 13-31 ). Within the erythroid series, common abnormalities include ringed sideroblasts, erythroblasts with iron-laden mitochondria visible as perinuclear granules in Prussian blue–stained aspirates or biopsies; megaloblastoid maturation, resembling that seen in vitamin B12 and folate deficiency ( Chapter 14 ); and nuclear budding abnormalities, recognized as nuclei with misshapen, often polyploid, outlines. Neutrophils frequently contain decreased numbers of secondary granules, toxic granulations, and/or Döhle bodies. Pseudo-Pelger-Hüet cells, neutrophils with only two nuclear lobes, are commonly observed, and neutrophils are seen occasionally that completely lack nuclear segmentation. Megakaryocytes with single nuclear lobes or multiple separate nuclei (pawn ball megakaryocytes) are also characteristic. Myeloid blasts may be increased but make up less than 20% of the overall marrow cellularity. The blood often contains pseudo-Pelger-Hüet cells, giant platelets, macrocytes, and poikilocytes, accompanied by a relative or absolute monocytosis. Myeloid blasts usually make up less than 10% of the leukocytes in the blood.
- #21 FIGURE 13-31 Myelodysplasia. Characteristic forms of dysplasia are shown. A, Nucleated red cell progenitors with multilobated or multiple nuclei. B, Ringed sideroblasts, erythroid progenitors with iron-laden mitochondria seen as blue perinuclear granules (Prussian blue stain). C, Pseudo-Pelger-Hüet cells, neutrophils with only two nuclear lobes instead of the normal three to four, are observed at the top and bottom of this field. D, Megakaryocytes with multiple nuclei instead of the normal single multilobated nucleus. (A, B, D, Marrow aspirates; C, peripheral blood smear.)
- #23 Clinical Course. Primary MDS is predominantly a disease of the elderly; the mean age of onset is 70 years. In up to half of the cases, it is discovered incidentally on routine blood testing. When symptomatic, it presents with weakness, infections, and hemorrhages, all due to pancytopenia. Primary MDS is divided into five morphologic categories in the WHO classification,[11] details of which are beyond our scope. Subtypes defined by having a higher proportion of blasts are associated with more severe cytopenias, an increased risk of progression to AML, and a worse prognosis. The presence of multiple clonal chromosomal abnormalities and the severity of peripheral blood cytopenias are independent risk factors also portending a worse outcome. The median survival in primary MDS varies from 9 to 29 months, but some individuals in good prognostic groups may live for 5 years or more. Overall, progression to AML occurs in 10% to 40% of individuals and is usually accompanied by the appearance of additional cytogenetic abnormalities. Patients often succumb to the complications of thrombocytopenia (bleeding) and neutropenia (infection). The outlook is even grimmer in t-MDS, which has a median survival of only 4 to 8 months. In t-MDS, cytopenias tend to be more severe and progression to AML is often rapid. Treatment options are fairly limited. In younger patients, allogeneic bone marrow transplantation offers hope for reconstitution of normal hematopoiesis and long-term survival. Older patients with MDS are treated supportively with antibiotics and blood product transfusions. Thalidomide-like drugs (which appear to alter the interaction of MDS progenitors with bone marrow stromal cells) and DNA methylase inhibitors improve the effectiveness of hematopoiesis and the peripheral blood counts in a subset of patients.[ ------------------------------------- Most attempts to induce haemopoietic cell differentiation have failed. For example, interferon alfa-2 transiently improves platelet counts in some MDS patients. However progression is also possible. Clinical studies with differentiation promoters such as retinoids, Vit D3, butyrates have been disappointing. In contrast, the hypomethylating agent 5-azacytidine has produced significant clinical benefit in patients with MDS
- #24 MDS is primarily a disease of the elderly, with a median age at diagnosis of between 60-80 years. The incidence is approximately double that of AML. The recent increase in MDS incidence may be related to growing awareness, better diagnosis, and an aging population.
- #25 Most attempts to induce haemopoietic cell differentiation have failed. For example, interferon alfa-2 transiently improves platelet counts in some MDS patients. However progression is also possible. Clinical studies with differentiation promoters such as retinoids, Vit D3, butyrates have been disappointing. In contrast, the hypomethylating agent 5-azacytidine has produced significant clinical benefit in patients with MDS Except for a recent trial of azacytidine, none of the other currently available drugs for MDS extends survival, and many are highly toxic. The FTIs are an example of targeted therapy with potential clinical applicability in MDS-modulating an array of tumour signaling cascades via inhibition of farnesyitransferase.