Introduction 1.1 Introduction: About 10,500 new cases of acute myelogenous leukemia are diagnosed each year in the United States (Hope et al., 2003). Acute myelogenous leukemia has several names, including acute myelocytic leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia. Before describing the disease and its management, a brief description of Hematopoiesis is provided as a background. 1.1.1 Hematopoiesis The marrow is a spongy tissue where blood cells development takes place. It occupies the central cavity of the bones. All bones have active marrow at birth. By time when a person reaches young adulthood, the bones of the hands, feet, arms and legs no longer have functioning marrow. The back bones (vertebrae), hip and shoulder bones, ribs, breast bone and skull contain marrow that is actively making blood cells in adults. Blood passes through the marrow and picks up formed blood cells for circulation. The process of blood cell formation is called hematopoiesis. A small group of cells, the stem cells, are responsible for making all the blood cells in the marrow. The stem cells eventually transform into the specific blood cells by the differentiation process (Figure 1.1). When the fully developed and functional cells are formed, they leave the marrow and enter in to the blood circulation. In healthy individuals there are sufficient stem cells to keep producing new blood cells continuously (Hope et al., 2003). 1
Blood Cell and Lymphocyte Development Figure 1.1 An abbreviated diagram of the process of hematopoiesis. This process involves the development of functional blood and lymphatic cells from stem cells (Hope et al., 2003). Figure 1.1: Blood Cell and Lymphocyte Development 2
1.1.2 Leukemia: The earliest observations of patients who had marked elevation of their white blood cells by European physicians in the 19th century led to their coining the term "weisses blut" or "white blood" as a designation for the disorder. Later, the term "leukemia", which is derived from the Greek words "leukos" meaning "white" and "haima" meaning "blood", was used to indicate the disease (Lowenberg et al., 1999). Leukemia is a malignant neoplasm of hematopoietic tissue originating in and infiltrating the bone marrow and it is typically categorized as myelogenous or lymphocytic, with each type having an acute or chronic form. The terms "myelogenous" or "lymphocytic" denote the cell type involved. Acute leukemia is a rapidly progressing disease that affects principally cells that are unformed or primitive (not yet fully developed or differentiated). These immature cells cannot carry out their normal functions. Chronic leukemia progresses slowly and permits the growth of greater numbers of more developed cells. In general, these more mature cells can carry out some of their normal functions. Thus, the four major types of leukemia are acute or chronic myelogenous and acute or chronic lymphocytic leukemia. The ability to measure specific features of cells has led to further subclassification of the major categories of leukemia. The categories and subsets allow the physician to decide what treatment works best for the cell type and how quickly the disease may develop (Lowenberg et al., 1999). 1.1.2.1 Acute Myelogenous leukemia (AML): AML is a disorder characterized by excessive clonal proliferation and abnormal differentiation of immature myeloid cells in the bone marrow and peripheral blood, leading to the disruption of normal haematopoiesis. By definition AML has > 30% blast cells in the bone marrow (Lowenberg et al., 1999 and; Bennett 3
et al., 1985). An important distinction is between primary AML which appear to arise de novo and secondly AML which can develop from myelodysplasia and other hematological disease or follow previous treatment with chemotherapy. Both types are associated with distinct genetic markers and have different prognoses. In addition, cytogenetic abnormalities and response to initial treatment have a major influence on prognoses (Hoffbrand et al., 2001). 1.1.2.2 Causes and Risk Factors: In most cases the cause of acute myelogenous leukemia is not evident. Several factors have been associated with an increased risk of disease. These include exposure to very high doses of irradiation, as carefully studied in the Japanese survivors of atomic bomb detonations. Exposure to the chemical benzene, usually in the work place, and also exposure to chemotherapy used to treat cancers such as breast cancer, cancer of the ovary, or the lymphomas. Therapeutic radiation, depending on the dose and the setting, may contribute to the onset of AML. The drug classes known as alkylating agents and topoisomerase inhibitors are most frequently associated with an increased risk of AML among the chemotherapeutic agents. Acute myelogenous leukemia is not contagious. Uncommon genetic disorders such as Fanconi anemia, Schwachman-Diamond syndrome, Down syndrome, and others are associated with an increased risk of AML. Very rarely, families with unexpectedly high frequencies of AML may occur. The affected individuals appeared healthy. It is thought that these families transmit a susceptibility gene(s) to offspring through the germ-line (Hoffbrand et al., 2001). 1.1.2.3 Incidence: About 15 percent of childhood leukemias are cases of acute myelogenous leukemia. Older people are more likely to develop the disease. The risk increases 4
about ten-fold in patients from age 30-34 (about 1 case per 100,000 people) to age 65-69 (about 1 case per 10,000 people); Figure 1.2 (Hoffbrand et al., 2001; Brinker, 1985). 1.1.2.4 Symptoms: The symptoms of AML are caused by replacement of normal bone marrow with leukemic cells, resulting in a drop in red blood cells, platelets, and normal white blood cells. These symptoms include fatigue, shortness of breath, fever, weight loss or loss of appetite, increased risk of infection, enlargement of the spleen, bone pain and joint pain, easy bruising, and bleeding. While a number of risk factors for AML have been elucidated, AML progresses rapidly and is typically fatal in weeks to months if left untreated. (Ronald et al., 2005) 1.1.2.5 Laboratory diagnosis of AML: The diagnosis of acute myeloid leukemia is made based on a compatible clinical history and a confirmatory laboratory investigation. A complete blood count (CBC) is almost always abnormal, with leukemic cells often found in the peripheral circulation. Often, the total white blood cell count is elevated, and the red blood cell count is depressed (anemia) as is the platelet count (thrombocytopenia). A bone marrow examination is almost always required to make the diagnosis of acute myeloid leukemia. The diagnosis of leukemia is confirmed by examination of the cells by microscopy, by the cell surface characteristics of the leukemic cells (based on immunohistochemistry and flow cytometry studies) markers, as well as the presence of certain specific chromosomal abnormalities identified within the leukemic cells. (Yanada et al., 2005) 5
1.1.2.6 Treatment of AML: Leukemia is treated mainly with chemotherapy, although radiotherapy and biological therapy can play a role in certain scenarios. The goals of therapy are to relieve symptoms and put the leukemia into remission and hopefully cure the disease. Active therapy of leukemia is usually divided into two phases: 1. Induction. This is the attempt to attain an initial remission of the leukemia. Standard induction therapy for acute myeloid leukemia includes two drugs: An anthracycline (such as daunorubicin or idarubicin) in combination with the nucleoside analogue, cytosine arabinoside. These drugs are administered intravenously over seven days, in the most common induction regimen. Supportive care (including anti-nauseant medications) is required during the initial hospital stay for induction therapy, which often lasts up to one month. (Pui and Relling, 2000). The chemotherapy drugs will kill normal bone marrow and leukemic cells equally, so the most significant side effects besides nausea and vomiting are a temporary reduction of normal white blood cells, red blood cells, and platelets. The lack of white cells results in lowered immunity and a high likelihood of infections. A low platelet count may result in easy bruisability and spontaneous bleeding, and is treated with routine platelet transfusions. A decrease in the red cell count, termed anemia, may result in fatigue, shortness of breath, and lack of energy. Red cell transfusions are therefore used routinely. (Pui and Relling, 2000). 2. Consolidation. This involves giving repeated cycles of chemotherapy once the patient appears to be in remission. The purpose of consolidation chemotherapy is to eradicate any microscopic amounts of leukemia that are undetectable using standard diagnostic studies. Stem cell transplantation is used instead of consolidative chemotherapy in individuals with adverse prognostic features at the time of leukemic 6
diagnosis. Stem cell transplantation is also used in an attempt to cure acute myeloid leukemia that has recurred after standard chemotherapy treatment. It is also important to consider alternatives to standard therapy for some individuals with acute myeloid leukemia. In the very elderly, the cure rate for acute myeloid leukemia is very low, so consideration of palliative and supportive care is a reasonable option. (Pui and Relling, 2000). 7