® HEMATOLOGY BOARD REVIEW MANUAL STATEMENT OF EDITORIAL PURPOSE Myelodysplastic Syndromes The Hospital Physician Hematology Board Review Manual is a study guide for fellows and practicing physicians preparing for board Contributors: examinations in hematology. Each manual Jasleen Randhawa, MD reviews a topic essential to the current prac­ tice of hematology. Mazie Froedtert Willms and Sue Froedtert Cancer Fellow, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI PUBLISHING STAFF PRESIDENT, GROUP PUBLISHER Ehab Atallah, MD Bruce M. White Associate Professor of Medicine, Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI SENIOR EDITOR Robert Litchkofski EXECUTIVE VICE PRESIDENT Barbara T. White EXECUTIVE DIRECtor OF OPERAtions Table of Contents Jean M. Gaul Introduction ................................. 1 Epidemiology, Etiology, and Pathogenesis ........ 1 Clinical Features ........................... 1 Merck is pleased to provide this Classification and Risk Stratification ............ 2 material as a professional service to the medical community. Molecular Basis of MDS ..................... 4 Intermediate-1-Risk MDS ................... 5 5Q-Deletion Syndrome ..................... 8 High-Risk MDS with Del(5q) .................. 9 High-Risk MDS ........................... 10 NOTE FROM THE PUBLISHER: Summary ............................... 11 This publication has been developed with­ out involvement of or review by the Amer­ Board Review Questions .................... 11 ican Board of Internal Medicine. References ................................. 11 Copyright 2014, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. 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Information contained within this publication should not be used as a substitute for clinical judgment. HEMATOLOGY BOARD REVIEW MANUAL Myelodysplastic Syndromes Jasleen Randhawa, MD, and Ehab Atallah, MD INTRODUCTION CLINICAL FEATURES Myelodysplastic syndromes (MDS) are a spectrum Clinically, MDS is usually suspected when a patient of clonal myeloid disorders characterized by ineffec- undergoes evaluation for cytopenias. A bone marrow tive hematopoiesis, cytopenias, qualitative disorders biopsy is essential to establish the diagnosis of MDS, of blood cells, clonal chromosomal abnormalities, which is confirmed by the presence of dysplasia. Biop- and the potential for clonal evolution to acute my- sy also helps to determine the marrow cellularity and eloid leukemia (AML).1 In this review, we discuss architecture, including morphology, and allows for the various pathogenic conditions included in the detailed evaluation of blasts. Cytogenetic evaluation spectrum of MDS and the associated risk stratification of 20 metaphases is required to determine the cytoge- for these conditions. We further discuss the treatment netic patterns. At this time, there is no definitive data recommendations based on the risk status and the showing that flow cytometry or fluorescence in situ expected prognosis. hybridization (FISH) analysis is better at establishing the phenotype than conventional cytogenetics.9 Fatigue and other symptoms secondary to anemia EPIDEMIOLOGY, ETIOLOGY, AND PATHOGENESIS may be seen. The patient may have repeated infections due to severe neutropenia or neutrophil dysfunction In the western population, the onset of MDS usu- and bleeding due to thrombocytopenia or platelet ally occurs after age 50 years, except in cases where dysfunction. Fever may occur as a result of the disease the individual has undergone radiation therapy or itself, irrespective of infection. Hepatomegaly and sple- chemotherapy for a prior malignancy.2,3 The annual nomegaly can occur in 5% to 10% of cases.10 incidence of MDS increases in a logarithmic fash- Less common manifestations of MDS may include ion after the age of 40 years. According to National diabetes. Hypothalamic-posterior pituitary insuffi- Cancer Institute data, the annual incidence of MDS ciency in clonal myeloid states has been associated increases from 2 per 1 million persons at age 40 years with monosomy 7 in the hematopoietic cells, and to more than 40 per 100,000 persons in the septua- these patients experience polyuria, polydipsia, and genarian population. Males are affected 1.5 times as decreased libido.11 Immune or inflammatory syn- often as females.2 dromes have been reported in up to 10% of cases. The etiologic factors that have been associated Some patients may exhibit a syndrome suggestive with increased incidence of MDS are similar to those of systemic lupus erythematosus with fever, pleurisy, that have been associated with increased AML inci- arthritis, and positive plasma antinuclear antibodies dence. These factors include prolonged exposure to preceding progression to AML.12,13 Behçet’s disease, high levels of benzene, alkylating agents, topoisomer- systemic vasculitis, inflammatory bowel disease, sero- ase inhibitors, and radiation.4,5 negative arthritis, and glomerulonephritis have also The major pathogenic mechanism in MDS is been reported with MDS.14–17 ineffective hematopoiesis, causing defective matu- Several laboratory abnormalities can be seen with ration and death of marrow precursors.6 More re- MDS. Iron and ferritin levels may be elevated due cently, significant strides have been made in un- to anemia and transfusions. Lactate dehydrogenase derstanding MDS at a molecular and cytogenetic and uric acid concentrations may be elevated due to level.7,8 Hopefully, this information will help im- a high death ratio of the marrow precursors. Other prove the prognostication of MDS and help indi- abnormalities include monoclonal gammopathy, vidualize therapy to each patient for the best possible hyper-/hypogammaglobulinemia, and increased β2 outcomes. microglobulin levels.18,19 www.hpboardreview.com Hematology Volume 9, Part 3 1 Myelodysplastic Syndromes Table 1. World Health Organization Classification of Myelodysplastic Syndromes Disease Peripheral Blood Findings Bone Marrow Findings Refractory cytopenia with unilineage dys- Single lineage cytopenia, no or rare blasts Unilineage dysplasia (≥10% of the cells in 1 myeloid plasia (RCUD): refractory anemia (RA), (<1%), bicytopenia may be occasionally lineage) <5% blasts, <15% ring sideroblasts within refractory neutropenia (RN), refractory observed erythroid precursors thrombocytopenia (RT) Refractory anemia with ring sideroblasts Anemia, no blasts Erythroid dysplasia only, <5% blasts, ≥15% ringed (RARS) sideroblasts within erythroid precursors Refractory cytopenia with multilineage Cytopenia(s), no or rare blasts (1%), no Dysplasia in ≥10% of cells in 2 or more myeloid cell dysplasia (RCMD) Auer roads, <1x109/L monocytes lineages, <5% blasts, no Auer roads Refractory anemia with excess blasts-1 Cytopenia(s), <5% blasts, no Auer roads, Unilineage or multilineage dysplasia, 5% to 9% (RAEB-1) <1x109/L monocytes (cases with Auer blasts, no Auer roads (cases with Auer rods and rods and <5% blasts in the peripheral <5% blasts in the peripheral blood and <10% blood and <10% blasts in the marrow blasts in the marrow should be classified as should be classified as RAEB-2) RAEB-2) Refractory anemia with excess blasts-2 Cytopenia(s), 5%–19% blasts, occasional Unilineage or multilineage dysplasia, 10%–19% (RAEB-2) Auer roads, <1x109/L monocytes blasts, occasional Auer roads Myelodysplastic syndrome, unclassified Cytopenias, no or rare blasts (≤1%) Unequivocal dysplasia in <10% of cells in 1 or more (MDS-U) myeloid cell lines when accompanied by a cyto- genetic abnormality considered as presumptive evidence for a diagnosis of MDS, <5% blasts *Cases of RCUD with pancytopenia *Cases of RCUD and RCMD with 1% myeloblasts in peripheral blood Myelodysplastic syndrome associated with Anemia, normal to increased platelet Anemia, normal to increased platelet count, no or isolated del(5q) count, no or rare blasts (<1%) rare blasts (<1%) Reprinted with permission from Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114:937–51. Several prognostic systems have been devised for the CLASSIFICATION AND RISK STRATIFICATION risk stratification of patients with MDS. These include the International Prognostic Scoring System (IPSS, The World Health Organization (WHO) has de- Table 2),23 the revised IPSS (R-IPSS, Table 3),24 WHO vised a classification to overcome