Etiology

• Myelodysplastic syndromes (MDSs) are not true dysplastic disorders but rather are clonal disorders of hematopoiesis with site of transformation at a pluripotent stem cell or early myeloid progenitor cell.
• In 50% to 90% of cases associated with chromosomal abnormalities, such abnormalities often are in proximity to oncogenes—partial deletion of the long arm of chromosome 5 (5q-) and the fms gene, monosomy 7 (7-) and the met oncogene—and hematopoietic growth factor genes (5q- and genes for granulocyte macrophage colony stimulating factor [GM-CSF], interleukin-3 [IL-3], IL-5, and macrophage colony stimulating factor [M-CSF] and 7-, and the erythropoietin gene).
• These resultant genetic alterations can manifest by increased apoptosis, which explains the seemingly opposing findings of marrow hypercellularity with peripheral blood cytopenia in patients with MDS. 

• The therapy-related subset of MDS is secondary to previous use of alkylating agents (typically associated with monosomy 7 and 5q-), with an increasing number of cases secondary to previous use of DNA topoisomerase II-targeting agents (epipodophyllotoxins), which typically are associated with translocation involving band 11q23 or band 21q22.
• Chronic exposure to benzene (above the level set by national guidelines) is the most important environmental exposure risk. 

• The new World Health Organization (WHO) classification is a revision of the French-American-British (FAB) system and recognizes the following subtypes: refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS), refractory anemia with excess blasts type I and type II (RAEB I and II), 5 q-syndrome, and unclassified MDS. Refractory anemia with excess blasts in transformation was eliminated from the WHO classification. Chronic myelomonocytic leukemia (CMML) has been reclassified into a new separate category, myelodysplastic/myeloproliferative disorders, along with juvenile myelomonocytic leukemia (JMML) and atypical chronic myelogenous leukemia (aCML). 

• The incidence of MDS is approximately 4 cases per 100,000 population.
• MDS is primarily a disease of the elderly: Among persons older than 70 years of age, the incidence is 20 cases per 100,000, with only 10% to 20% of patients younger than 60, although patients in the therapy-related subset are 10 to 20 years younger. 

• MDS often is a diagnosis of exclusion after other factors and disorders associated with cytopenia and hematopoietic dysplasia are ruled out: vitamin B12 or folate deficiency, recent cytotoxic therapy, heavy metal intoxication, chronic liver disease, and chronic inflammation, which includes human immunodeficiency virus (HIV) infection. 

• Using the International Prognostic Scoring System (IPSS), patients can be categorized into distinctive subgroups with respect to both median survival and the risk for acute leukemic transformation based on four subtype-specific variables: age, percentage of bone marrow blasts, number and type of chromosomal abnormalities, and degree of cytopenia. 

• Usually a “wait and watch” approach is followed, given the poor risk-benefit ratio of intensive (acute myelogenous leukemia [AML]-type) chemotherapy for a majority of patients older than 60 years, although intensive chemotherapy at the time of blast progression is appropriate and may benefit up to one half of the patients, albeit transiently. A minority of patients (those younger than 55 years) may be long-term survivors if they undergo allogeneic bone marrow transplantation. The nonmyeloablative “minitransplant” procedure may increase the upper age limit for transplantation in the future.
• Erythropoietin may reduce requirements for blood transfusion; its efficacy may be augmented by cotreatment with G-CSF. 

• No consistently effective therapies are available, but one fourth to one third of patients respond to agents such as 5-azacytidine, decitabine, thalidomide, amifostine, low-dose ara-C, and topotecan. Novel targeted therapies for MDS are in various phases of clinical trials.