Background
Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow.
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. (See Pathophysiology.) Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor. (See Etiology.)
Patients with AML present with symptoms resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells, or both. The time course is variable. (See Clinical.) Workup for AML includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), analysis of genetic abnormalities, and diagnostic imaging. (See Workup.)
Current standard chemotherapy regimens cure only a minority of patients with AML. As a result, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. (See Treatment.) For consolidation chemotherapy or for the management of toxic effects of chemotherapy, readmission is required.
Pathophysiology
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.[1, 2]
This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, the blood, and, frequently, the spleen and liver.
Etiology
Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor.
Antecedent hematologic disorders
The most common risk factor for AML is the presence of an antecedent hematologic disorder, the most common of which is myelodysplastic syndrome (MDS). MDS is a bone marrow disease of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years. Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop AML, whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do.
Other antecedent hematologic disorders that predispose patients to AML include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.
Congenital disorders
Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis. Usually, these patients develop AML during childhood; rarely, some may present in young adulthood.
More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML.[3] Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both.
Likewise, polymorphisms in glutathione S -transferase are associated with secondary AML after chemotherapy for other malignancies.[4]
Familial syndromes
Germline mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for AML, an autosomal dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.[5] Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein alpha, a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by AML.[6]
Taskesen et al evaluated concurrent gene mutations, clinical outcome, and gene expression signatures of CEBPA double versus single mutations in 1182 patients with cytogenetically-normal AML (CN-AML) (aged 16-60 y).[7] Both double-mutated CEBPA and single-mutated CEBPA were associated with favorable outcome compared with wild type CEBPA (5-year overall survival (OS), 63% and 56% versus 39%; P < .0001 and P=.05, respectively). However, in multivariable analysis, only double=mutated CEBPA was a prognostic factor for favorable outcome.
Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.
Environmental exposures
Several studies demonstrate a relationship between radiation exposure and leukemia. Early radiologists (before the use of appropriate shielding) were found to have an increased likelihood of developing leukemia. Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia. Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML.[8] In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.
Previous exposure to chemotherapeutic agents
As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with AML increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.[9]
Patients with previous exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with previous exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors.
Patients with a previous exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase before the development of AML. Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).
Patients with a previous exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).[10]
The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure, but it is only 9-12 months for topoisomerase inhibitors.
Epidemiology
It was estimated that 13,410 new cases of AML (7060 in men; 6350 in women) would occur in the United States in 2007. AML is more commonly diagnosed in developed countries, and it is more common in whites than in other populations.
The prevalence of AML increases with age. The median age of onset is approximately 70 years. However, AML affects all age groups.[11, 12]
AML is more common in men than in women. The difference is even more apparent in older patients. This is likely because MDS is more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of AML in men may be related to occupational exposures (see Etiology).
Prognosis
The prognosis relies on several factors. Increasing age is an adverse factor, because older patients more frequently have a previous antecedent hematologic disorder along with comorbid medical conditions that compromise the ability to give full doses of chemotherapy. A previous antecedent hematologic disorder (most commonly, MDS) is associated with a poor outcome to therapy.
A study by Arellano et al found leukopenia at diagnosis had no prognostic significance in patients with AML.[13]
Findings from cytogenetic analysis of the bone marrow constitute one of the most important prognostic factors. Patients with t(8;21), t(15;17), or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%. Patients with normal cytogenetic findings have an intermediate prognosis and have a long-term survival rate of approximately 25%. Patients with poor-risk cytogenetic findings (especially -7, -5) have a poor prognosis, with a long-term survival rate of less than 10%.
Other cytogenetic abnormalities, including +8, 11q23, and miscellaneous, have been reported to be intermediate risk in some series and poor risk in others.
The presence of an FLT3 mutation is associated with a poorer prognosis. Mutations in CEBPA are associated with a longer remission duration and longer overall survival. Mutations in NPM are associated with an increased response to chemotherapy.
A study by Metzeler et al determined that TET2 mutations had an adverse prognostic impact in an otherwise favorable-risk patient subset using the European LeukemiaNet (ELN) molecular-risk classification of patients with primary cytogenetically normal AML.[14]
In 2007, an estimated 8990 deaths from AML occurred in the United States. Of these, 5020 occurred in men and 3970 occurred in women.
In adults, treatment results are generally analyzed separately for younger (18-60 y) patients with AML and for older patients (>60 y). With current standard chemotherapy regimens, approximately 30-35% of adults younger than 60 years survive longer than 5 years and are considered cured. Results in older patients are more disappointing, with fewer than 10% of surviving over the long term.
A study by Kayser et al found that therapy-related AML (t-AML) was an adverse prognostic factor for death in complete remission but not relapse and overall survival in younger intensively treated patients.[15] It was also an adverse prognostic factor for relapse but not death in complete remission in older, less intensively treated patients.
A study by Varadarajan et al found that having ever smoked decreased overall survival in patients with AML.[16]
Patient Education
Patients with AML should be instructed to call their healthcare providers immediately if they are febrile or have signs of bleeding.
For patient education resources, see the Blood and Lymphatic System Center and the Skin, Hair, and Nails Center, as well as Leukemia and Bruises.
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| Marker | Lineage |
| CD13 | Myeloid |
| CD33 | Myeloid |
| CD34 | Early precursor |
| HLA-DR | Positive in most AML, negative in APL |
| CD11b | Mature monocytes |
| CD14 | Monocytes |
| CD41 | Platelet glycoprotein IIb/IIIa complex |
| CD42a | Platelet glycoprotein IX |
| CD42b | Platelet glycoprotein Ib |
| CD61 | Platelet glycoprotein IIIa |
| Glycophorin A | Erythroid |
| TdT | Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1 |
| CD11c | Myeloid |
| CD117 (c-kit) | Myeloid/stem cell |
| Abnormality | Genes Involved | Morphology | Response |
| t(8;21)(q22;q22) | AML/ETO | M2 | Good |
| inv(16)(p13;q22) | CBFb/MYH11 | M4eo | Good |
| Normal | Multiple | Varies | Intermediate |
| -7 | Multiple | Varies | Poor |
| -5 | Multiple | Varies | Poor |
| +8 | Multiple | Varies | Intermediate-poor |
| 11q23 | MLL | Varies | Intermediate-poor |
| Miscellaneous | Multiple | Varies | Intermediate-poor |
| Multiple complex* | Multiple | Varies | Poor |
| * Refers to 3-5 different cytogenetic abnormalities, depending on the classification used. | |||
| Translocation | Genes Involved | All-Trans-Retinoic Acid Response |
| t(15;17)(q21;q11) | PML/RARa | Yes |
| t(11;17)(q23;q11) | PLZF/RARa | No |
| t(11;17)(q13;q11) | NuMA/RARa | Yes |
| t(5;17)(q31;q11) | NPM/RARa | Yes |
| t(17;17) | stat5b/RARa | Unknown |
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