Practice Essentials
Acute myeloid leukemia (AML) is a malignant disease characterized by the abnormal proliferation and differentiation of myeloid precursors in the bone marrow. AML is the most common form of leukemia in adults, with most cases occurring in individuals over the age of 60 years. [1]
AML is a genetically complex disease that includes numerous subtypes with heterogeneous molecular profiles. [2] Traditionally, most AML subtypes have been distinguished from myelodysplastic syndrome (MDS) by the presence of at least 20% blasts in the bone marrow or peripheral blood; however, current classification recognizes MDS/AML in patients with 10-19% blasts. [3, 4]
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. [1] (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 Presentation.) The workup for AML includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), and analysis of genetic abnormalities. (See Workup.)
Current standard chemotherapy regimens cure only a minority of patients with AML, and an expanding array of molecularly targeted agents is becoming available. Consequently, 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.) Readmission is frequently required for the management of toxic effects of chemotherapy.
Go to Oncology Decision Point for expert commentary on AML treatment decisions and related guidelines.
Pathophysiology
The underlying pathophysiology in AML consists of clonal expansion and arrested maturation of hematopoietic stem cells and progenitor cells. The initial mutations result in the development of leukemia stem cells, which have the ability for self-renewal and are multipotent and highly proliferative. This allows for the acquisition of additional mutations. [1] A genomic study in 1540 patients with AML identified 5234 driver mutations across 76 genes or genomic regions; driver mutations were found in 96% of the patients, and 86% had two more driver mutations. [5] These researchers' proposed genomic classification included subgroups with the following genomic anomalies [5] :
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NPM1 mutation
-
Mutated chromatin and/or RNA-splicing genes
-
TP53 mutations and/or chromosomal aneuploidy
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Inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MY11
-
t(15;17)(q22;q12); PML–RARA
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t(8;21)(q22;q22); RUNX1–RUNX1T1
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MLL fusion genes; t(x;11)(x;q23)
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inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2, MECOM(EVI1)
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IDH2R172 mutations
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t(6;9)(p23;q34); DEK–NUP214
The changes in the bone marrow result in two 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 the abnormal myeloblasts, 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, MDS with ringed sideroblasts) generally do not develop AML, whereas patients with high-risk MDS (eg, MDS with excess blasts) frequently do.
Other antecedent hematologic disorders that predispose patients to AML include aplastic anemia and myeloproliferative disorders, especially myelofibrosis.
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, they 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. [6] 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. [7]
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. [8] 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. [9]
Holme et al studied 27 families with familial MDS/AML. All of the families were screened for RUNX1, CEBPA, TERC, TERT, GATA2, TET2, and NPM1 mutations. Five of the 27 families had telomerase mutations (3 TERT, 2 TERC), one had a RUNX1 mutation, and four had heterozygous GATA2 mutations. [10]
Gao et al reviewed GATA2 mutations associated with familial AML-MDS. [11] GATA2 is a transcription factor crucial for hematopoietic differentiation and lymphatic formation. Germline GATA2 mutations are involved in a rare group of complex syndromes with overlapping clinical features of immune deficiency, lymphedema, and propensity to AML or MDS.
With the routine use of expanded next-generation genetic panels on bone marrow, and with confirmation on nonhematopoietic tissues, many more patients are being diagnosed with germline mutations that predisposed them to AML. Among these genes are DDX41, SRP72, ANKRD26, and ETV6. [12] The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia now includes a subtype "Myeloid neoplasms with germ line predisposition". [13] Thus, to properly classify patients with AML, these genes must be included in nextgen panels.
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 tobacco have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML. [14] 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 have the erythroleukemia subtype of AML (AML-M6). Exposure to soot, creosote, inks, dyes, and tanning solutions and coal dust have also been associated with AML. [15]
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. [16]
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. 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.
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, these patients develop leukemia with other balanced translocations, such as inversion 16 or t(15;17). [17]
Epidemiology
The American Cancer Society (ACS) estimates that 20,800 new cases of AML (11,600 in men, 9200 in women) will occur in the United States in 2024. [18] 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.
AML is more common in men than in women, especially 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 higher prevalence of AML in men may be related to occupational exposures (see Etiology).
The ACS estimates that in 2024, 11,220 deaths from AML will occur in the United States. Of those, 6290 are expected to occur in men and 4930 in women. [18]
Prognosis
The prognosis depends on several factors. Increasing age is an adverse factor, because older patients more frequently have a previous antecedent hematologic disorder and/or poor-risk cytogenetic and molecular markers that make the leukemia resistant to chemotherapy. Older patients also frequently have comorbid medical conditions that compromise the ability to tolerate full doses of chemotherapy. A previous antecedent hematologic disorder (most commonly, MDS) is associated with a poor outcome of therapy.
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 35%. Patients with poor-risk cytogenetic findings (especially -7, -5, or monosomal karyotype) have a poor prognosis, with a long-term survival rate of less than 10%. [19]
Other cytogenetic abnormalities, including +8, 11q23, and miscellaneous, have been reported to confer intermediate risk in some series and poor risk in others.
The presence of an FLT3 mutation is associated with a poorer prognosis. Biallelic mutations in CEBPA are associated with a longer remission duration and longer overall survival. [20] Mutations in NPM are associated with an increased response to chemotherapy. Patients with TP53 mutations have a particularly poor prognosis. [21]
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. [22]
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 40-45% 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% surviving over the long term. Overall, cure rates for younger patients have improved over the past few decades, but little progress has been made in improving the survival of older patients. [23]
The prognosis of therapy-related AML is particularly poor, with 5-year survivals of approximately 10%. The prognosis is better for the subset of patients with therapy-related AML who have favorable cytogenetic abnormalities. [24, 25]
A study by Varadarajan et al found that having ever smoked decreased overall survival in patients with AML. [26] Crysandt and colleagues found that in younger patients with de novo AML, overweight and obesity were risk factors for an impaired response to induction therapy and shorter disease-free and overall survival. [27]
Death in patients with AML may result from uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.
Patient Education
Patients with AML should be instructed to call their healthcare providers immediately if they develop a fever 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.
Tables
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 |
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 |
Risk Group |
Cytogenetic Abnormality |
Favorable |
t(8;21)(q22;q22.2); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1q22); CBFB-MYH11 Biallelic mutated CEBPA Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow |
Intermediate Risk |
Mutated NPM1 and FLT3-ITDhigh Wild-type NPM1 without FLT3-ITD or with FLT3- ITDlow (without adverse risk genetic lesions) t(9;11)(p21.3;q23.3); MLLT3-KMT2A Cytogenetic abnormalities not classified as favorable or adverse |
Poor Risk |
t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23.3); KMT2A rearranged t(9;22)(q34.1;q11.2); BCR-ABL1 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM (EVI1) -5 or del(5q); -7; -17/abn(17p) Complex karyotype, monosomal karyotype Wild type NPM1 and FLT3- ITDhigh Mutated RUNX1 Mutated ASXL1 Mutated TP53 |
