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myelodysplastic syndrome (MDS)

variable group of disorders with clonal proliferation of multipotential hematopoietic stem cells, with dysplasia & ineffective production of one or more cell lines. Classification: - also see classification of myelodysplastic syndrome - refractory cytopenia with unilineage dysplasia (69)* - dysplasia in single cell line - < 5% blasts in bone marrow - refractory anemia with mutilineage dysplasia (33)* - dysplasia in more than 1 cell lineage - +/- ringed sideroblasts - < 5% blasts in bone marrow - refractory anemia with ringed sideroblasts (69)* - erythroid dysplasia - >= 15% ringed sideroblasts - < 5% blasts in bone marrow - MDS with isolated 5q deletion (116)* - increased megakaryocytes with hypolobulated nuclei - < 5% blasts in bone marrow - refractory anemia with excess blasts-1 (18)* - unilineage or multilineage dysplasia - no Auer rods - 5-9% blasts in bone marrow - refractory anemia with excess blasts-2 (10)* - unilineage or multilineage dysplasia - 10-19% blasts in bone marrow - MDS, unclassified - does not fit other categories (?)* - < 5% blasts in bone marrow * median survival in months Etiology: 1) primary idiopathic MDS 2) secondary to chemotherapy with or without radiation [15] - may occur years to decades after chemotherapy [1] 3) inherited defects in DNA repair 4) Down syndrome Epidemiology: 1) 80% of cases > 65 years of age [8] 2) men > women 3) 3.8 cases per 100,000 per year (age-adjusted) [10] Pathology: - clonal disorders of hematopoietic stem cells - hypercellular bone marrow - ineffective maturation of hemapoietic precursurs - pancytopenia (peripheral blood) Genetics: 1) most common: monosomy 7, 5q & 7q deletions 2) ringed sideroblasts & 5q deletion are good prognostic features [27] - possible genes on 5q involved include IRF1, IL5, CDC25C, IL3, CSF2 3) translocations involving chromosome 11 - translocation t(5;11)(q35;p15.5) generating a NUP98-NSD1 fusion product 4) 17p deletion associated with pseudo Pelger-Huet anomaly 5) isolated 20p deletion associated with involvement of erythroid cells & megakaryocytes 6) chromosome 3 abnormalities associated with abnormal megakaryocytes 7) chromosomal translocation t(1;12)(p36.1;p12) MDS2 with ETV6 8) chromosomal translocation t(6;8)(q27;p11) FGFR1OP with FGFR1 9) chromosomal translocation t(11;20)(p15;q11) TOP1 with NUP98 chromosomal translocation t(2;8)(p23;p11.2) MYST3 with ASXL2 (therapy-related MDS) 10) chromosomal translocation t(5;12)(q31;p13) involving ACSL6 with ETV6 (myelodysplastic syndrome with basophilia) 11) chromosomal translocation t(1;3)(p36;q21) involving PRDM16 12) role for MDS1, PURB 13) loss of Y chromosome [1] Clinical manifestations: 1) generally NO splenomegaly 2) clinical course is variable a) incidental mild anemia that may be stable for years b) rapidly evolving acute leukemia Laboratory: 1) complete blood count (CBC) - depression in one or more lines of peripheral blood cells - pancytopenia [1] - MCV generally elevated (macrocytosis)* 2) peripheral smear a) myeloid cell aberrations - immature myeloid cells may be seen - dysplastic neutophils - decreased neutrophil segmentation (Pelger-Huet-like anomaly) - diminished neutrophil granules b) dysplastic erythrocytes - poikilocytosis & macrocytosis, Howell-Jolly bodies c) blasts > 5% associated with progression to AML 3) low reticulocyte count for degree of anemia 4) bone marrow biopsy & aspirate a) cytogenetic analysis 1] normal in aplastic anemia 2] often abnormal in MDS b) generally hypercellular marrow c) 10-15% of patients have hypocellular marrow d) dysplastic erythroid precursors [1] e) iron stain f) > 20% blasts in marrow effectively = AML g) < 2% blasts = low risk [1] h) ringed sideroblasts & 5q deletion are good prognostic features [27] 5) abnormal cytogenetics 6) serum erythropoietin before RBC transfusion [7] 7) iron studies [7] 8) folate in RBC [7]; serum folate, serum vitamin B12 [1] 9) serum vitamin B6 [7] 10) see ARUP consult [12] * antiretroviral drugs can result induce macrocytosis Special laboratory: - an algorithm [29] to diagnose MDS uses: - age, sex - complete blood count - hemoglobin in blood, white blood cell count, platelet count - mean corpuscular volume, neutrophil count, monocyte count - serum glucose - serum creatinine [29] - bone marrow biopsy required for diagnosis [] Complications: 1) bone marrow failure* 2) evolution to acute myelocytic leukemia* - erythroleukemia (AML-M6) 3) neutrophilic dermatosis: Sweet syndrome [1,17] * major causes of death [1] Differential diagnosis: - acute leukemia - myeloproferative disorder - nutritional deficiency - alcoholism - folate deficiency - vitamin B12 deficiency Management: 1) observation for asymptomatic patients with low risk disease [1] 2) supportive care a) RBC transfusions for anemia b) platelet transfusions for thrombocytopenia c) GM-CSF or G-CSF for neutropenia & infectious complications d) erythropoietin first line for symptomatic anemia [30] - benefits 20% of patients with low serum erythropoietin without del(5q) [28] - benefit for patients without del(5q) with high-normal serum erythropoietin who wish to avoid erythrocyte transfusion [30] e) lenalidomide for transfusion-dependent anemia with del(5q) [28] f) erythopoiesis-stimulating agent failure - anti-thymocyte globulin +/- cyclosporine - luspatercept for MDS-RS with ring sideroblasts [28] g) imetelstat (Rytelo) relapsed or refractory myelodysplastic syndrome with transfusion-dependent anemia erythropoiesis-stimulating agent failure [31] 3) bone marrow ablation with allogeneic hematopoietic stem cell transplantation a) only curative treatment b) 50% success rate c) only a minority of patients are candidates 1] eligible patients are < 60 years of age 2] generally, advanced age at diagnosis 3] lack of histocompatible sibling donor d) treatment of choice in eligible patients [1,23] 4) pyrimidine nucleosides (hypomethylating agents) [1] a) may induce complete remission in some patients b) may reduce transfusion dependence & tranformation into acute myeloid leukemia [1] c) 5-azacytidine improves survival relative to: - supportive care - low-dose cytarabine - intensive chemotherapy [1,14] - may take up to 6 months for effect - transfusion support & antibiotics for infections until effect or lack of apparent [1] d) decitabine (associated with appreciable toxicity) 5) thalidomide & analogs a) lenalidomide (Revlimid), FDA-approved 2005 1] may decrease need for transfusion [9] 2] intended specifically for 5q deletion [16] b) thalidomide plus dexamethasone 6) experimental therapies: a) interleukins 3, 6, 11 b) all-trans retinoic acid c) amifostine d) immunosuppressive drugs: - antithymocyte globulin: cases with hypocellular marrow, normal cytogenetics early stage disease, predictors of response include lower platelet count & younger age - cyclosporine: RA subtype e) inhibitors of tumor necrosis factor alpha (etanercept) f) multidrug resistance approaches - quinine - capable of reverting the MDR phenotype (P-glycoprotein) g) resistant AML approaches (high toxicity & risk) 1] topotecan + cytarabine 2] FLAG regimen (fludarabine, cytarabine, G-CSF +/- idarubicin) === Prognosis === - International Scoring System [5] - see international prognostic scoring system for myelodysplastic syndrome - morphologic predictors (median survival): - refractory anemia (4.2 yrs) - refractory anemia with ringed sideroblasts (6.9 yrs) - refractory anemia with excess blasts (1.5 yrs) - refractory anemia with excess blasts in transformation (0.6 yrs) - adverse prognostic factors - complex cytogenetic abnormalities - p53 mutations or LOH: associated with complex karyotypic changes & increased tendency to evolve to AML, reduced response to chemotherapy and shorter survival - CD34 positive staining of bone marrow nucleated cells - increased expression of Wilms tumor gene - increased serum beta-2-microglobulin - comorbidities - congestive heart failure - COPD [13] - 3 years survival 35% [8] - stem cells are resistant to therapy, at least in part due to assuming the G0 phase (in contrast to susceptibility of progenitor cells that remain in cycling phases) [11]

Related

alpha-thalassemia myelodysplasia syndrome classification of myelodysplastic syndrome international prognostic scoring system for myelodysplastic syndrome myeloproliferative disorder

Specific

acute panmyelosis with myelofibrosis chronic myelomonocytic leukemia (CMML) refractory anemia (RA) refractory anemia with excess blasts (RAEB) refractory anemia with excess blasts in transformation (RAEB-T) refractory anemia with ringed sideroblasts (RARS)

General

hematologic neoplasm myeloid disorder

Database Correlations

OMIM correlations

References

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