Developing a standard treatment algorithm for patients with myelodysplastic syndrome (MDS) is difficult, due to the tremendous heterogeneity of the disease and the limited, variably toxic available therapies. In this chapter, we attempt to place into context the currently available treatment options for patients with MDS, focusing on supportive care and low-intensity therapies. In our summary, we propose a treatment approach to MDS, based on specific clinical presentations.

MDS patients can be classified according to the French-American-British (FAB) classification system,1 the World Health Organization classification system,2 and most recently, the International Prognostic Scoring System (IPSS)3, which integrate a variety of clinical features. These systems do not take into account the biological basis of this set of diseases, which remain ill-defined. The development of targeted therapies for leukemia and related diseases is dependent on identifying genetic lesions that are critical for the growth of the malignant cell or for monoclonal antibody-based therapy, and on identifying cell surface markers that are abundantly expressed on the target cell. No such critical genetic lesions or cell surface markers have been identified for the vast majority of MDS patients; their identification has been hampered by the lack of an animal model of MDS and by difficulties in isolating "MDS-initiating cells" in the laboratory. Thus, other than the use of imatinib for rare chronic myelomonocytic leukemia (CMML) patients with t(5;12), i.e., TEL-PDGFRp-positive CMML, targeted therapies cannot yet be applied to MDS.

The few recurrent genetic abnormalities identified in MDS patients, such as point mutations in the AML1 gene, the t(3;5) that generates the NPM-MLF1 fusion protein, or the t(3;21) (which generates an AML1-EVI-1 fusion), are infrequent. While del(5q), del(7q), del (20q), and trisomy 8 are the most frequent cytogenetic abnormalities found in MDS, the gene(s) affected by these abnormalities have still not been determined. Given the absence of identified genetic abnormalities in MDS hematopoietic cells and the heterogeneity of the disease, studies have also focused on defining the bone marrow milieu that supports or sustains the MDS process. Overactive macrophage function (with increased cytokine secretion), changes in microvessel density, and abnormalities in the maintenance of telomeres have been observed in some MDS patients. Immunologic abnormalities have also been identified in patients with MDS, and these abnormalities (especially those also found in aplastic anemia (AA) patients) have provided the rationale for the testing of immunomodulatory treatments.

Recent discoveries, such as the lack of circulating natural killer T cells in these patients, may provide additional therapeutic options in the future, although some cellular abnormalities may simply represent "down-stream" effects of the impaired hematopoiesis found in MDS, and may not provide insight into new therapies. Similarly, the excess production of inhibitory cytokines by macrophages (and other bone marrow cells) that can suppress hematopoiesis has led to testing of a variety of forms of anticytokine therapy. Though thus far largely unsuccessful, such approaches may be used more effectively in the future. A thorough discussion of the novel therapies being applied to subsets of MDS patients will be covered in Chapter X.

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