Chapter 99 • The myelodysplastic syndromes (MDS) are a group of clonal marrow failure syndromes originating in a hematopoietic progenitor or stem cell. Approximately 25% to 30% of MDS cases progress to acute myeloid leukemia (AML), which is defined by 20% or more marrow blasts. • Approximately 50% of MDS cases are associated with a karyotypic abnormality, usually chromosomal aneuploidy. • Recurrent MDS-associated somatic mutations are now recognized in more than 25 genes. Some of these mutations have prognostic value independent of existing risk stratification tools. • The most important risk factor for MDS is aging. The risk of developing MDS increases greatly after age 65 years. The median age at diagnosis in the United States is approximately 71 years. • Approximately 10% to 15% of MDS cases arise as a consequence of therapeutic or environmental exposure to a DNA damaging agent; these are termed secondary or therapy-related MDS. In patients who had been exposed to ionizing radiation or alkylating agents, abnormalities of chromosomes 5 and 7 are common. Patients treated with topoisomerase II inhibitors may develop rearrangements of the MLL gene at 11q23 or the MECOM (MDS1/EVI1) locus on chromosome 3q21q26. • Patients who develop MDS before age 40 years without a recognized toxin exposure may have a germline DNA repair defect or congenital marrow failure syndrome, such as Fanconi anemia or dyskeratosis congenita. Chromosome breakage analysis and telomere length analysis is appropriate in such patients. • The 2008 World Health Organization (WHO) classification of MDS, refined from the 2001 WHO and 1982 French–American–British (FAB) MDS classifications, defines several subtypes of MDS with varying risk of AML progression or death. The specific diagnosis depends on the proportion of marrow blasts, the number of cell lineages involved by disease, and the presence or absence of ring sideroblasts or chromosome 5q deletion. • Minimal diagnostic criteria for MDS (after exclusion of other causes of cytopenias) include either: 10% or more dysplastic cells in one or more myeloid lineages, increased marrow blasts (≥5%), or the presence of a cytogenetic abnormality or another marker of clonal hematopoiesis. • Not all marrow dysplasia represents MDS. Other causes of cytopenias and abnormal cell morphology must be considered in the initial evaluation of patients, such as nutritional deficiency (e.g., vitamin B12, folate, copper), inflammation, excessive alcohol use, human immunodeficiency virus infection, and non-MDS neoplasms. • In ambiguous cases, the presence of an MDS-associated cytogenetic abnormality, such as deletion of chromosome 5q, can confirm the diagnosis. • Several prognostic tools, including the 2012 Revised International Prognostic Scoring System (IPSS-R), are in widespread use and aid in risk stratification and therapy choice. In general, older patients with higher blast proportion, more severe cytopenias, and higher-risk cytogenetic results have a poorer outlook. • Complications of peripheral blood cytopenias and functional cell defects, including infection and hemorrhage, are the most common causes of death in MDS. Progression to AML following MDS occurs in 25% to 30% of cases and is usually fatal. • In lower-risk cases, supportive care alone may be appropriate. Epoetin or darbepoetin may alleviate MDS-associated anemia. • Anemia of MDS associated with chromosome 5q deletion frequently responds to lenalidomide. Thrombocytopenic patients respond less well.
Myelodysplastic Syndromes
Summary of Key Points
Etiology
Epidemiology
Pathology
Differential Diagnosis
Prognosis
Primary Therapy
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Myelodysplastic Syndromes
