Solving the Mystery of Myelodysplasia

M yelodysplasia (MDS) is a clonal hematopoietic malignancy as stubborn in revealing its pathogenesis as it is in responding to treatment. The disease presents with cytopenia of any or all of the three hematopoietic lineages (red blood cells, platelets, and white blood cells), manifesting clinically as fatigue, bleeding, and infectious disorders. While the disease occurs in only five per 100,000 people, its incidence rises steeply with age, reaching about 20–40 per 100,000 at age 70 years and beyond. Thus, as the population ages, the impact of MDS on the health care system will grow. The natural history of MDS is highly variable. By definition, cases present with low blood counts. Without treatment (and often, despite treatment), patients will embark on one of two paths of disease course, both inevitably fatal. Many will have progressive cytopenias, and eventually succumb to bleeding and infection complications. Other patients progress to acute myeloid leukemia (AML). Unlike " de novo " AML (where the patient presents with leukemia without an antecedent history of a hematopoietic disorder), which can be cured with high-dose combination chemotherapy in about 25% of cases, the " secondary " AML that arises from MDS is incurable by chemotherapy [1]. The diagnosis of MDS requires the bone marrow evidence of dysplasia (abnormal appearing cells) in at least one of the hematopoietic cell lineages. Approximately 50% of cases will have chromosomal abnormalities. The appearance of bone marrow " blasts " (immature progenitor cells) can be normal in many cases, if the blasts represent less than 5% of total bone marrow cells; increasing blasts herald a progression towards AML. Sensitive flow cytometric analysis of cell surface antigens often shows a population of cells displaying an abnormal constellation of antigens, further evidence of disturbed hematopoiesis. Diagnostic and classification schemes are based on the extent of cytopenia, cytogenetic abnormalities, blast percentages, and other morphological features. The older French, American, and British (FAB) diagnostic system divided the disease into refractory anemia (RA), where blast counts were <5%; RA with ringed sideroblasts (RARS); and two classes with increasing blast counts, RA with excessive blasts of >5% (RAEB), and with excessive blasts (>20%) in " transition " to AML (RAEBT). Secondary AML arising from MDS was defined as a marrow blast count of >30% [2]. Recently, the World Health Organization has reclassified MDS, dividing RA into groups with one or several cytopenias, and changing the cutoff of transition to …