The Myelodysplastic Syndrome

Overview The existence of a hematopoietic disorder characterized by anemia and dyspoiesis preceding the onset of acute myelocytic leukemia (AML) has been recognized since the early part of the twentieth century. Initially designated as preleukemia, the syndrome was ill defined and could only be established with certainty retrospectively. Moreover, the terminology itself conveyed an unwarranted confidence in predicting the outcome that often belied the facts. The more accurately descriptive and appropriate designation as a myelodysplastic syndrome (MDS) was adopted in 1976 by the French–American–British (FAB) study group. The FAB classification permitted the prospective identification of patients within this heterogeneous clonal disorder. MDS, derived from a multipotent hematopoietic stem cell, is characterized clinically by a hyperproliferative bone marrow, reflective of ineffective hematopoiesis, and is accompanied by one or more peripheral blood cytopenias. Bone marrow failure results, leading to death from bleeding and infection in the majority, while transformation to acute leukemia occurs in up to 40% of patients. The evolution of the disease proceeds in accordance with the multistep pathogenesis theory of carcinogenesis and can thus serve as an important model in furthering our understanding of the processes involved in neoplastic transformation. This constellation of findings raises the question of whether MDS represents a frank neoplastic state or is merely a preneoplastic condition in transition. The syndrome appears to represent a spectrum where the initial lesion in the genome, though clinically undetectable, subsequently evolves, with the acquisition of additional genetic and epigenetic lesions, to a state of frank neoplasia. The designation of this disorder as an MDS, rather than preleukemia, permits its distinction from other abnormalities that are known to be associated with the development of acute leukemia. These latter include the classic myeloproliferative syndromes (polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, essential thrombocythemia), aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), as well as Fanconi, Bloom, and Down syndromes. These particular “preleukemic states” are beyond the scope of this chapter. MDS can be further divided into primary and secondary syndromes. The former arise de novo and are of indeterminate etiology, while the latter are induced by identifiable environmental, occupational, or iatrogenic causes. Estimates of the incidence of MDS range from a frequency equal to that of AML or approximately 14,000 new cases per year in the United States to almost twice that of AML. The SEER database now tracks the disease; thus more accurate data will be available in the future. An estimate based on medical insurance claims indicated a total of 107,000 cases in the observation period from 2009 through 2011. The consensus is that the incidence is increasing owing to a number of factors, including greater awareness, greater diagnostic precision, and the aging of the population. Keywords: myelodysplastic syndrome; epigenetics; treatment; hypomethylating agents; azacitidine; decitabine; lenalidomide