Acute Myelogenous Leukemia Workup
- Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD more...
Approach Considerations
Workup for acute myelogenous leukemia (AML) includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), analysis of genetic abnormalities, and diagnostic imaging.
Blood Studies
Complete blood count
A complete blood count (CBC) with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with AML can have high, normal, or low white blood cell (WBC) counts.
Coagulation studies
The most common abnormality is disseminated intravascular coagulation (DIC), which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products. Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC.
Peripheral blood smear
Review of the peripheral blood smear confirms the findings from the CBC count. Circulating blasts are usually seen. Schistocytes are occasionally seen if DIC is present.
Blood chemistry profile
Most patients with AML have an elevated lactate dehydrogenase (LDH) level and, frequently, an elevated uric acid level. Liver function tests and blood urea nitrogen (BUN)/creatinine level tests are necessary before the initiation of therapy.
Blood culture
Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.
Human Leukocyte Antigen or DNA Typing
Perform human leukocyte antigen (HLA) or DNA typing in patients who are potential candidates for allogeneic transplantation.
Bone Marrow Aspiration and Biopsy
Bone marrow aspiration and biopsy are the definitive diagnostic tests for AML.
Bone marrow aspiration
A blast count can be performed with bone marrow aspiration. Historically, according to the French-American-British (FAB) classification, AML was defined by the presence of more than 30% blasts in the bone marrow. In the newer World Health Organization (WHO) classification, AML is defined as the presence of greater than 20% blasts in the marrow.[1] (See Histologic Findings.) The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell lines.
Aspiration slides are stained for morphology with either Wright or Giemsa stain. To determine the FAB type of the leukemia, slides are also stained with myeloperoxidase (or Sudan black), terminal deoxynucleotidyl transferase (TdT) (unless performed by another method [eg, flow cytometry]), and double esterase.
Bone marrow biopsy
Bone marrow biopsy is useful for assessing cellularity. Biopsy is most important in patients in whom an aspirate cannot be obtained (dry tap). Bone marrow samples should also be sent for cytogenetics testing and flow cytometry.
Flow Cytometry (Immunophenotyping)
Flow cytometry (immunophenotyping) can be used to help distinguish AML from acute lymphocytic leukemia (ALL and further classify the subtype of AML (see the table below). The immunophenotype correlates with prognosis in some instances.
Table 1. Immunophenotyping of AML Cells (Open Table in a new window)
| 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 |
Cytogenetic Analysis
Cytogenetic studies performed on bone marrow provide important prognostic information (see the tables below). They are useful for confirming a diagnosis of APL, which bears the t(15;17) chromosome abnormality and is treated differently.
Table 2. Common Cytogenetic Abnormalities in AML (Open Table in a new window)
| 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. | |||
Table 3. Cytogenetic Abnormalities in APL (Open Table in a new window)
| 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 |
Fluorescence in situ hybridization (FISH) studies can be used to get a faster overview of cytogenetic abnormalities than traditional cytogenetic studies. FISH does not replace cytogenetics.
Molecular Marrow Evaluation
Several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. The bone marrow should be evaluated at least for the commercially available tests. Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement. When possible, the bone marrow should be evaluated for Fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations.
FLT3 is the most commonly mutated gene in persons with AML and is constitutively activated in one third of AML cases.[17] Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3 ITDs have a poor prognosis. Analysis of FLT3 is commercially available.
Mutations in NPM1 are associated with increased response to chemotherapy in patients with a normal karyotype.[18] Thiede et al studied FLT3 and NPM1 in 1485 patients with AML.[19] The analysis of the clinical impact in 4 groups (NPM1 and FLT3 -ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation (without a FLT3 -ITD) had a significantly better overall and disease-free survival and a lower cumulative incidence of relapse.[19] Analysis of NPM1 is commercially available.
Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings and are associated with a longer remission duration and longer overall survival.[20] ERG overexpression is an adverse predictor in cytogenetically normal AML.
A study by the Cancer and Leukemia Group B (CALGB) found that high BAALC expression was associated with FLT3-ITD, wild-type NPM1, mutated CEBPA, MLL-PTD, absent FLT3-TKD and high ERG expression. In a multivariate analysis, high BAALC expression independently predicted lower complete remission rates when ERG expression and age were adjusted for and shorter survival when FLT3-ITD, NPM1, CEBPA and WBC count were adjusted for.
The clinical impact of MLL partial tandem duplication (MLL-PTD) was evaluated in 238 adults aged 18 to 59 years with cytogenetically normal de novo acute myeloid leukemia who were treated by CALGB. Of the patients with MLL-PTD, 92% achieved complete remission compared with 83% of patients without MLL-PTD.
Ley et al identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the cells of a patient with AML and a normal karyotype.[21] The authors sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile but were absent in all 79 patients with a favorable-risk cytogenetic profile. The median OS among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 mo vs. 41.1 mo, P < 0.001).
Schwind et al measured miR-181a expression in pretreatment marrows in 187 adults (< 60 y) with CN-AML. Higher miR-181a expression was associated with a higher complete remission (CR) rate (P =.04), longer OS (P =.01) and a trend for longer disease-free survival (P =.09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-internal tandem duplication (FLT3-ITD) and/or NPM1 wild-type, where higher miR-181a expression associated with a higher CR rate (P =.009) and longer disease-free survival (P < .001) and OS (P < .001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (≥60 y) patients with CN-AML.[22]
Gene-expression profiling is a research tool that allows a comprehensive classification of acute myelogenous leukemia (AML) based on the expression pattern of thousands of genes.
Other Tests
Gene-expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.[23]
Chest radiographs help assess for pneumonia and signs of cardiac disease in individuals with AML.
Multiple gated acquisition (MUGA) scanning is needed once the diagnosis of AML is confirmed because many chemotherapeutic agents used in treatment are cardiotoxic.
Electrocardiography should be performed before treatment of AML.
Histologic Findings
The traditional FAB classification of AML is as follows:
- M0 - Undifferentiated leukemia
- M1 - Myeloblastic without differentiation
- M2 - Myeloblastic with differentiation
- M3 - Promyelocytic
- M4 – Myelomonocytic; M4eo - Myelomonocytic with eosinophilia
- M5 - Monoblastic leukemia; M5a - Monoblastic without differentiation; M5b - Monocytic with differentiation
- M6 - Erythroleukemia
- M7 - Megakaryoblastic leukemia
The newer WHO classification is as follows[1] :
- AML with recurrent genetic abnormalities - AML with t(8;21)(q22;q22), (AML1/ETO); AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)(q22), (CBFB/MYH11); APL with t(15;17)(q22;q12), (PML/RARa) and variants; AML with 11q23 (MLL) abnormalities
- AML with multilineage dysplasia - Following myelodysplastic syndrome (MDS) or MDS/myeloproliferative disease (MPD); without antecedent MDS or MDS/MPD but with dysplasia in at least 50% of cells in 2 or more lineages
- AML and MDS, therapy related - Alkylating agent or radiation-related type; topoisomerase II inhibitor type; others
- AML, not otherwise classified - AML, minimally differentiated; AML, without maturation; AML, with maturation; acute myelomonocytic leukemia; acute monoblastic or monocytic leukemia; acute erythroid leukemia; acute megakaryoblastic leukemia; acute basophilic leukemia; acute panmyelosis and myelofibrosis; myeloid sarcoma
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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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