Porth's Essentials of Pathophysiology, 4e

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tissue. 20–26 Bone marrow biopsy may be used to deter- mine the molecular characteristics of the leukemia, the degree of bone marrow involvement, and the morphol- ogy and histology of the disease. Cytogenetic studies, which are used to determine chromosomal abnormali- ties, are one of the most powerful prognostic indicators in acute leukemia. In ALL, the staging includes a lumbar puncture to assess CNS involvement. Imaging studies that include computed tomography (CT) of the chest, abdomen, and pelvis may also be obtained to identify additional sites of disease. Several types of treatment may be used for the man- agement of ALL and AML with the primary treatment being chemotherapy. Treatment of ALL in childhood represents one of the great success stories in oncology. During the past decade, advances in ALL therapy have led to 5-year survival rates of greater than 80% in chil- dren. 19 Other age groups tend to do less well, with only about 30% to 40% of adults achieving long-term sur- vival. Chemotherapy leads to remission in over 50% of persons with AML, but the overall survival rate is less than 30%. 4 Bone marrow or stem cell transplanta- tion may be considered for persons with ALL and AML who have failed to respond to other forms of therapy. 17 Because of the risk of complications, bone marrow transplantation is not usually recommended for patients older than 50 to 55 years of age. Chronic Leukemias In contrast to acute leukemias, chronic leukemias are malignancies involving proliferation of more fully dif- ferentiated myeloid and lymphoid cells. 4,7 As with acute leukemia, there are two major types of chronic leuke- mia: chronic lymphocytic leukemia (CLL) and chronic myeloid (myelogenous) leukemia (CML). Chronic lym- phocytic leukemia accounts for about one third of all leukemias and is mainly a disorder of older persons. The average age at time of diagnosis is approximately 72 years. It is rarely seen in people younger than 40 years of age, and is extremely rare in children. 30 Chronic myeloid (myelogenous) leukemia accounts for 10% to 15% of all leukemias. As with CLL, it is predominantly a dis- order of older adults, with an average age of approxi- mately 67 years at the time of diagnosis. Chronic Lymphocytic Leukemia. Chronic lymphocytic leukemia, a clonal malignancy of B lymphocytes, is the most common form of leukemia in adults in the Western world. In the past, CLL was viewed as a homogeneous disease of immature, immune-incompetent, minimally self-renewing B cells, which accumulated because of faulty apoptotic mechanisms. Chronic lymphocytic leu- kemia is now becoming viewed as two related entities based on aggressiveness of the disease. Some persons with CLL survive for many years without therapy and eventually succumb to unrelated diseases, whereas oth- ers have a rapidly fatal disease despite aggressive ther- apy. The two entities are thought to reflect differences in the expression of cell surface CD markers (e.g., CD38) in immunoglobulin variable (V) gene mutations. 30–32

This difference is rarely present in normal B cells but is found in persons with CLL. Persons whose CLL cells have mutated forms of the immunoglobulin gene gener- ally have a more indolent form of the disease; these cells express low levels of the surface antigen. The clinical signs and symptoms of CLL are largely related to the progressive infiltration of the bone marrow and lymphoid tissues by neoplastic lymphocytes and to secondary immunologic defects. Persons with the indo- lent form of CLL are often asymptomatic at the time of diagnosis, and the increase in lymphocytes is noted on a complete blood count obtained for another, unrelated dis- order. As the disease progresses, lymph nodes gradually increase in size and new nodes are involved, sometimes in unusual areas such as the scalp, orbit, pharynx, pleura, gastrointestinal tract, liver, prostate, and gonads. Persons with the aggressive form of CLL experience a more rapid sequence of clinical deterioration characterized by increasing lymphadenopathy, hepatosplenomegaly, fever, abdominal pain, weight loss, progressive anemia, and thrombocytopenia, with a rapid rise in lymphocyte count. Hypogammaglobulinemia is common in CLL, espe- cially in persons with advanced disease. An increased susceptibility to infection reflects an inability to produce specific antibodies and abnormal activation of comple- ment. The most common infectious organisms are those that require opsonization for bacterial killing, such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. The diagnostic hallmark of CLL is isolated increase in lymphocytes. The white blood cell count is usually greater than 20,000/ μ L and may be elevated to several hundred thousand. Usually, 75% to 98% are lympho- cytes. Tests to determine the presence of mutated forms of the immunoglobulin gene (which currently can be detected only in research laboratories) and expression of the CD38 surface antigen may be used to determine whether the leukemia is the indolent or aggressive type. 31 Treatment of CLL usually depends on the presence of prognostic indicators. 31 Persons with the low-risk or indolent form of CLL usually do not require specific treatment for many years after diagnosis and eventually die of apparently unrelated causes. Many persons with intermediate-risk disease may remain stable for many years as well, whereas others may develop complications and need treatment within a few months. Most persons with high-risk CLL require combination chemotherapy at the time of diagnosis. In younger patients with aggres- sive disease, an allogeneic ablative (destruction of bone marrow cells by irradiation or chemotherapy) or non- myeloablative stem cell transplant is a treatment option. Chronic Myelogenous Leukemia. Chronic myeloid (myelogenous) leukemia is a disorder of the pluripo- tent hematopoietic progenitor cell. It is characterized by excessive proliferation of marrow granulocytes, erythroid precursors, and megakaryocytes. 4,7,33–38 The CML cells harbor a distinctive cytogenic abnormality, the previously described Philadelphia chromosome. It is generally believed that CML develops when a single, plu- ripotent hematopoietic stem cell acquires a Philadelphia