The development of new therapeutic strategies for myelodysplastic syndromes (MDS) has gained new momentum fueled by improved characterization of the disease's natural history and biology and by the recent US Food and Drug Administration (FDA) approval of the first agent with an indication for MDS. By integrating morphologic and cytogenetic features with greater discriminatory power, the World Health Organization (WHO) has refined the classification of these stem cell malignancies and enhanced its prognostic utility. Recognition that the malignant phenotype, which characterizes MDS, may arise from mechanistically diverse biological processes has raised new awareness that treatment strategies must be tailored to the pathobiology of the disease. Therapeutics targeting chromatin structure, angiogenesis and the microenvironment that nurtures the MDS phenotype have demonstrated remarkable activity and offer an opportunity to alter the natural history of the disease. This chapter provides an overview of recent developments in the characterization of MDS from the microscope to the laboratory and the translation of these findings into promising therapeutics.In Section I, Dr. James Vardiman reviews the cytogenetic abnormalities that characterize MDS, their clinical and pathologic significance, and the application of the WHO classification. In Section II, Dr. Alan List reviews treatment goals driven by prognostic variables and biological features of the disease that have led to promising small molecule, selective therapeutics. In Section III, Dr. Jean-Pierre Issa provides an overview of epigenetic events regulating gene expression, which may be exploited therapeutically by chromatin remodeling agents. In Section IV, Dr. Theo DeWitte discusses new developments in hematopoietic stem cell transplantation, including reduced-intensity and myeloablative approaches. I. CHARACTERIZATION AND CLASSIFICATION OF MYELODYSPLASTIC SYNDROMES-FROM MORPHOLOGY TO CYTOGENETICS James Vardiman, MD*Although the myelodysplastic syndromes (MDS) were initially considered by many to be synonymous with "preleukemia," this notion has given way to the realization that MDS is a heterogeneous spectrum of stem cell malignancies, with the majority of patients succumbing to complications of bone marrow failure rather than acute leukemia. In 1982 the French-American-British (FAB) cooperative group proposed morphologic guidelines for the diagnosis and classification of MDS that provided a framework against which clinical, biologic and genetic studies could be universally compared.1 Since then nearly 20,000 publications have characterized various features of MDS. Despite such active investigation, a biologic marker that reliably identifies MDS remains elusive. Therefore, morphology remains the cornerstone of diagnosis and an important tool that complements cytogenetic findings for prognostic discrimination. Nevertheless, particularly in "low grade" disease, the morphologic recognition of MDS can be difficult, creating diagnostic indecision. For such cases, app...
This retrospective survey of the EBMT Leukaemia Working Party describes 78 patients with myelodysplasia (MDS) or secondary acute myelogenous leukaemia (sAML) who received an allogeneic bone marrow transplant (BMT). The status of underlying disease at the time of transplantation was prognostic for the 2-year disease-free survival. Thirty-four patients received intensive chemotherapy prior to the conditioning for BMT. The 2-year disease-free survival was 60% for the 16 patients transplanted in complete remission. The results were significantly less favourable for those with more advanced disease who only partially responded to prior intensive chemotherapy (2-year disease-free survival: 18%) while none of those who either relapsed or were resistant to chemotherapy survived BMT for 2 years. Forty-four patients had not received any prior intensive chemotherapy. The disease-free survival at 2 years after BMT was 58 +/- 19% when a patient was transplanted for refractory anaemia (RA(S], 74 +/- 14% for refractory anaemia with excess of blasts (RAEB), 50 +/- 16% for RAEB in transformation (RAEBt), and 18 +/- 11% for secondary AML. Allogeneic BMT can therefore be considered as curative treatment for patients with MDS. Patients with sAML who have a histocompatible donor should be given chemotherapy intensive enough to induce complete remission. If this is achieved these individuals have a prognosis comparable to those with de novo AML in first remission after BMT.
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