Managed Care - July 2008 - (Page H4) (QoL) also are associated with anemia and the other cytopenias. Pathophysiology Ironically, despite the abnormally low blood counts that are the hallmark of MDS, this cluster of disorders often is characterized by an increase in the population of bone marrow precursor cells, or blasts, that give rise to red blood cells (RBCs), white blood cells (WBCs), and platelets. Aberrant stem cells divide rapidly and populate the bone marrow with dysplastic cells — cells that exhibit morphologic changes in the nuclei and cytoplasm, and that lead to significant bone marrow dysfunction. Not only do hematopoietic stem cells fail to differentiate properly in patients with MDS, but an increase in apoptosis, or programmed cell death, among healthy cells also occurs, further contributing to the cytopenias. The initial cause of hematopoietic stem cell injury varies among patients, and may be a result of genetic mutations, cytotoxic chemotherapy, exposure to radiation or other chemicals, and/or viral infections. In some patients, a series of molecular defects, both genetic and environmental, may occur. It is postulated that cumulative mutations are required for the progression to AML (Nimer 2008). tendency to bruise and bleed. Nosebleeds and bleeding of the gums, particularly after dental work, are common symptoms among these patients. The diagnostic evaluation of a patient with MDS requires a detailed clinical history and assessment of clinical status, both of which play a role in placing a patient in the appropriate subcategory for prognosis and treatment. In addition to blood and reticulocyte counts, a peripheral blood smear is obtained to determine the degree of dysplasia exhibited by a patient’s blood cells. A bone marrow examination is used to characterize the cytopenias, rule out differential diagnoses, and obtain a cytogenetic evaluation. Serum levels of erythropoietin (EPO), vitamin B12, ferritin, RBC folate, and iron also are typically obtained during initial evaluation and throughout treatment. The IPSS scoring system For over 25 years, various diagnostic criteria have been analyzed with the goal of developing a classification system useful for diagnosis, prognosis, and treatment implications for patients with MDS. Developed in 1997, the International Prognostic Scoring System (IPSS) has improved upon previous systems with regard to both clinical utility and usefulness in examining clinical trial results. In addition, recent changes in ICD-9 codes for MDS reflect the use of IPSS, and perhaps have helped to further endorse its categories. Greenberg (1997) examined patient databases with the goal of identifying variables that predicted patient outcomes with the greatest degree of reliability. The group zeroed in on cytogenetics (karyotype), percentage of bone marrow blasts, and number of cytopenias as the variables with the greatest prognostic significance; next, they developed a system whereby they could assign points to each of these components based on their clinical impact, with a greater number of points indicating a less favorable prognosis. A patient’s total IPSS score was then used to assign the patient to one of four groups: low risk; intermediate-1 risk; intermediate-2 risk; or high risk. Patients have been further classified as low/intermediate-1 risk or intermediate-2/high risk for treatment purposes, with such approaches for the latter group taking into consideration a greater risk among these patients for the development of acute leukemia. Patient distribution among IPSS risk categories is shown in the Figure. Clinical features and diagnostic evaluation A growing number of patients are diagnosed with MDS while they are still asymptomatic; in these patients, the disease is discovered because abnormal blood counts are found during a routine physical examination. However, in symptomatic patients, clinical features are almost always direct consequences of the cytopenias. Most patients with MDS have varying degrees of anemia, and more than half have significant anemia (hemoglobin <10). If symptomatic, these patients typically complain of fatigue, and may exhibit paleness or shortness of breath. Anemia can exacerbate symptoms associated with a number of comorbidities common among elderly patients, such as coronary artery disease or pulmonary disease, and, in some cases, it is a worsening of the comorbidity that causes the clinician to suspect anemia, and in turn, MDS. Patients with MDS also are at risk for a form of AML that often is refractory to standard treatment. Approximately 40 percent of patients with MDS come to a clinician’s attention because of a low WBC, or neutropenia. Neutropenia elevates the risk of contracting bacterial infections, such as pneumonia and urinary tract infections. In some cases, even patients who have not yet developed neutropenia experience recurrent infections; although WBC counts in these patients are normal, the functioning of these cells is impaired. Another 40 percent of patients with MDS present with a low platelet count, or thrombocytopenia; such patients have an increased Treatment guidelines Transfusion with RBCs and platelets, along with antibiotic supportive care, continues to be the mainstays of treatment for patients with MDS. In addition, erythropoiesis stimulating agents (ESAs) and myeloid growth factors, such as granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF), are now commonly used. More re- 4 MANAGED CARE / SUPPLEMENT
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