Acute Myeloid Leukemia

AML is malignant, clonal disease that involves proliferation of blasts in bone marrow, blood, or other tissue. The blasts most often show myeloid or monocytic differentiation. Almost 80% of patients with AML will demonstrate chromosome abnormalities, usually a mutation resulting from a chromosomal translocation (the transfer of one portion of the chromosome to another).9 The translocation causes abnormal oncogene or tumor suppression gene expression, and this results in unregulated cellular proliferation.10 Genetic syndromes and toxic exposure contribute to the patho-genesis in some patients.

Although the diseases grouped into the acute myelogenous leukemia categories have similar clinical manifestations, the morphology, immunophenotyping, and cytogenetic features are distinct. Cytochemical stains are used along with morphology to help identify the lineage of the blast population. Electron microscopy may also be used to subclassify the various leukemias. When morphology and/or cytochemistry evidence of lineage is absent, flow cytometry is used to specifically tag the myeloid or lymphoid antigens and thus classify the acute leukemias.

Epidemiology

The incidence of AML increases with age, accounting for 80% of acute leukemias in adults and for 15% to 20% of acute leukemias in children. Of note, however, is that when congenital leukemia (occurring during the neonatal period) does rarely occur, it is paradoxically AML rather than ALL and is often monocytic. The rate of AML is somewhat higher in males than females, and there is an increased incidence in developed, more industrialized countries. Eastern European Jews have an increased risk of developing AML, whereas Oriental populations have a decreased risk.11

Table 11.2 lists the conditions that have been documented as predisposing to development of AML. The high incidence of individuals having congenital defects such as Down syndrome and bone marrow failure syndromes such as Fanconi's anemia has demonstrated that these factors are often implicated in the pathogenesis of

162 Part III • White Cell Disorders

Table 11.2 O Conditions and Disorders With Increased Risk for Development of Acute Leukemia

Congenital Defects Acquired Diseases Environmental Factors

Down syndrome

Klinefelter syndrome

Turner syndrome

Monosomy 7 syndrome

Fanconi's anemia

Wiskott-Aldrich syndrome

Neurofibromatosis

Familial aplastic anemia

Fraternal twins and nonidentical siblings

Combined immunodeficiency syndrome

Blackfan-Diamond syndrome

Aplastic anemia Myeloma

Sideroblastic anemia

Acquired genetic changes

Translocations

Inversions

Deletions

Point mutations

Paroxysmal nocturnal hemoglobinuria

Transition from other hematopoietic diseases (myeloproliferative disorders)

Ionizing radiation Alkalating agents Cytotoxic drugs Pesticide exposure Solvents

AML. It has also been well documented that leukemia is associated with exposure to ionizing radiation, as this was most notably reported with the increase in leukemia that occurred following the release of atomic bombs over Hiroshima and Nagasaki in 1945. The fallout from atomic bombs and exposure to nuclear reactor plants has caused much well-founded public apprehension, fear, and concern over the past 50 years.12,13 A wide variety of chemicals and drugs have been linked to AML. In a study involving factories in China, the risk of developing leukemia was five to six times higher in workers with recurrent exposure to benzene than in the general pop-ulation.14 Many drugs, in particular, therapy-related alkylating drugs, are associated with AML emerging after the treatment. All of the chronic myeloproliferative disorders (chronic myelocytic leukemia [CML], idio-pathic myelofibrosis [IMF], polycythemia vera [PV], essential thrombocythemia [ET]) have an increased propensity for terminating in AML, with 60% to 70% of CML cases undergoing a transition to AML.

Clinical Features

All of the signs and symptoms that present so abruptly in patients with AML are caused by the infiltration of the bone marrow with leukemic cells and the resulting failure of normal hematopoiesis. These criminal leukemic cells that invade the bone marrow are dysfunctional, and without the normal hematopoietic elements, the patient is at risk for developing life-threatening complications of anemia, infection due to functional neutropenia, and hemorrhage due to thrombocytopenia (Table 11.3).

Fatigue and weakness are the most common complaints that reflect the development of anemia. Pallor, dyspnea on exertion, heart palpitations, and a general loss of well-being has been described.15 Fever is present is about 15% to 20% of patients and may be the result of bacterial, fungal, and, less frequently, viral infections, or from the leukemic burden of cells on tissues and organs. Easy bruising, petechiae, and mucosal bleeding may be found due to thrombocytopenia. Other more severe symptoms related to decreased platelet counts that occur less commonly are gastrointestinal or genitourinary tract and central nervous system (CNS) bleeding. CNS infiltration with high numbers of leukemic cells has been reported in 5% to 20% of children and approximately 15% of adults with AML.16,17 Headache, blindness, and other neurological complications are indications of meningeal involvement. Leukemic blast cells circulate through the peripheral blood and may invade any tissue. Extramedullary hematopoiesis is common in monocytic or myelomonocytic leukemias. Organs that were active in fetal hematopoiesis may be reactivated to again produce cells when stressed by the poor performance of the overburdened leukemic bone marrow. Hepatosplenomegaly or lymphadenopathy may occur but is not as prominent as that seen in the chronic leukemias. Skin infiltration is very characteristic in monocytic leukemias, particularly gum infiltration, which is termed gingival hyperplasia. When

Table 11.3 O Clinical Findings in Acute Leukemia

Pathogenesis

Signs and Symptoms

Bone Marrow Infiltration

Neutropenia Anemia

Thrombocytopenia

Medullary Infiltration

Marrow

Extramedullary Infiltration

Liver, spleen, lymph nodes, thymus Central nervous system

Gums, mouth Skin

Fever, infection Pallor, dyspnea, lethargy

Bleeding, petechiae, ecchymosis, intracranial hematoma and gastrointestinal or conjunctival hemorrhage (rare)

Bone pain and tenderness, limp, arthralgia

Organomegaly

Neurological complications including dizziness, headache, vomiting, alteration of mental function

Gingival bleeding and hypertrophy

Lesions or granulocytic sarcoma leukemic cells crowd the bone marrow of the long bones, joint pain may be produced.

Laboratory Features

Peripheral Blood and Bone Marrow Findings

The CBC and examination of peripheral blood smear are the first step in the laboratory diagnosis of leukemia. Blood cell counts are variable in patients with AML. The WBC may be normal, increased, or decreased. It is markedly elevated, over 100 X 109/L cells in less than 20% of cases. Conversely, the WBC is less than 5.0 X 109/L with an absolute neutrophil count of less than 1.0 X 109/L in about half the patients at the time of diagnosis.18 Blasts are usually seen on the peripheral smear examination, but in leukopenic patients, the numbers may be few and require a diligent search to uncover. Cytoplasmic inclusions known as Auer rods often present in a small percentage of the myeloblasts, monoblasts, or promyelocytes present in the various subtypes of AML. Auer rods are elliptical, spindle-like inclusions composed of azurophilic granules. Nucleated red blood cells may be present, as well as myelodysplas-tic features, including pseudo-hyposegmentation (pseudo Pelger-Huet cells) or hypersegmentation of the neutrophils, and hypogranulation.

Anemia is a very common feature due to inadequate production of normal red cells. The reticulocyte count is usually normal or decreased. Red cell anisopoikilocytosis is mildly abnormal, with few poi-kilocytes present. Thrombocytopenia, which can be severe, is almost always a feature at diagnosis. Giant platelets and agranular platelets may be seen. Disseminated intravascular coagulation (DIC) is most commonly associated with one of the types of AMLs known as acute promyelocytic leukemia. The DIC is caused by the release of tissue factor-like procoagulants from the azurophilic granules of the neoplastic promyelocytes, which in turn activate coagulation and further consume platelets, leading to dangerous bleeding diathesis.

Before treatment, serum uric acid and lactic dehy-drogenase (LDH) levels often are mild or moderately increased.

The hallmark feature of acute leukemia is always a hypercellular bone marrow, with 20% to 90% leukemic blasts at diagnosis or during relapse. The blast population grows indiscriminately as these cells have only limited differentiation capability and are frozen in the earliest stage of development. The lineage of blasts that predominate depends on the specific type of acute leukemia. The most current classification for hemato-logical and lymphoid tumors published by the World Health Organization (WHO) recommends that the requisite blast percentage for a diagnosis of acute myeloid leukemia be greater than or equal to 20% myeloblasts in the blood or marrow.19 When performing a peripheral blood smear on a patient with a suspected diagnosis of leukemia, at least 200 WBCs should be classified. It is recommended that the blast percentage in the bone marrow be derived from a 500-cell differential count. If the WBC is less than 2.0 X 109/L, buffy coat smears should be prepared for differential counting.

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