Sections

Workup

Approach Considerations

The workup for acute myeloid leukemia (AML) includes the following:

Blood tests
Bone marrow aspiration and biopsy (the definitive diagnostic tests)
Analysis of genetic abnormalities
Diagnostic imaging

Immunophenotyping by flow cytometry of bone marrow or peripheral blood samples can be used to help distinguish AML from acute lymphocytic leukemia (ALL) and further classify the subtype of AML. Cytogenetic studies performed on bone marrow provide important prognostic information and can guide treatment by confirming a diagnosis of acute promyelocytic leukemia (APL).

Perform human leukocyte antigen (HLA) or DNA typing in patients who are potential candidates for allogeneic transplantation.

In patients with signs or symptoms suggesting central nervous system (CNS) involvement, computed tomography (CT) or magnetic resonance imaging (MRI) should be performed. Lumbar puncture is indicated in those patients if no CNS mass or lesion is detected on CT or MRI.^[25]

Chest radiographs help assess for pneumonia and signs of cardiac disease in individuals with AML.

Evaluation of myocardial function is needed once the diagnosis of AML is confirmed because many of the chemotherapeutic agents used in treatment are cardiotoxic. Echocardiography or multiple gated acquisition (MUGA) scanning is particularly important for patients who have a history or symptoms of heart disease or risk factors for iatrogenic cardiotoxicity (ie, exposure to cardiotoxic drugs or thoracic radiotherapy).^[25]All patients should have a baseline electrocardiogram before starting treatment for AML.

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. Patients with acute monocytic leukemia also have a high incidence of clinically significant 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. Elevation of those test results indicates possible tumor lysis syndrome, which should be treated expeditiously. Liver function tests and blood urea nitrogen (BUN)/creatinine tests are necessary before the initiation of therapy.

Blood culture

Appropriate cultures should be obtained in patients with fever, or with signs of infection even in the absence of fever.

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. Common Antigens for 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. Guidelines from an international expert panel, on behalf of the European LeukemiaNet (ELN), recommend risk stratification for patients with AML on the basis of genetic abnormalities. The ENL identifies three levels of risk: favorable, intermediate, and adverse.^[26]

Genetic abnormalities that convey favorable risk are as follows:

t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22) ; CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with low allelic ratio (< 0.5) FLT3-ITD
Biallelic mutated CEBPA

Genetic abnormalities that convey intermediate risk are as follows:

Mutated NPM1 and high allelic ratio (≥0.5) FLT3-ITD
Wild-type NPM1 without FLT3-ITD or with low allelic ratio FLT3-ITD (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2A
Cytogenetic abnormalities not classified as either favorable or adverse

Genetic abnormalities that convey adverse risk are as follows:

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 or monosomal karyotype
Wild-type NPM1 and high allelic ratio FLT3-ITD
Mutated RUNX1
Mutated ASXL1
Mutated TP53

Note that neither mutated RUNX or mutated ASXL1 should be used as an adverse prognostic marker if it occurs together with favorable-risk AML subtypes.^[26]

Cytogenetic studies are also useful for confirming a diagnosis of APL, which bears the t(15;17) chromosome abnormality and is treated differently. See Table 2, below.

Table 2. 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 an overview of cytogenetic abnormalities more quickly than can be done with traditional cytogenetic studies. However, FISH does not replace cytogenetics.

Although it has been known for some time that patients with multiple cytogenetic abnormalities have a poor prognosis, Breems et al demonstrated that a monosomal karyotype (defined as two or more distinct autosomal monosomies or one single autosomal monosomy in the presence of structural abnormalities) confers a particularly poor prognosis.^[27]Several other groups have since confirmed this finding.^{[28, 29]}

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 with 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 cases of AML and is constitutively activated in one third of AML cases.^[30]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.^[31]In a study by Thiede et al of FLT3 and NPM1 in 1485 patients with AML, 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.^[32]Analysis of NPM1 is commercially available.

Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings. Biallelic mutations are associated with a longer remission duration and longer overall survival.^[33] 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.^[34]

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 AML 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.^[35]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 overall survival (OS) of patients with DNMT3A mutations was significantly shorter than that of patients without such mutations (12.3 vs. 41.1 mo, respectively; 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 =0.04), longer OS (P =0.01) and a trend for longer disease-free survival (P =0.09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-ITD and/or NPM1 wild-type, where higher miR-181a expression was associated with a higher CR rate (P =0.009) and longer disease-free survival (P< 0.001) and OS (P< 0.001). 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.^[36]

Gene expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.^[37]Marcucci used next-generation sequencing analysis of methylated DNA to identify differentially methylated regions associated with prognosis in older patients with AML. Seven genes were associated with prognosis: CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8. The fewer the genes with high expression, the better the prognosis.^[38]

Several groups have demonstrated that mutations in IDH1 and IDH2 have an adverse effects on prognosis in AML. Next-generation sequencing can detect these abnormalities and can identify patients who are candidates for therapies targeting these mutations.^[39]

Other Tests

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 French–American–British (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 PML/RARa; AML with t(9;11)(p21.3;q23.3), (MLLT3-KMT2A); AML with t(6;9)(p23;q34.1), (DEK-NUP214); AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2), (GATA2, MECOM); AML (megakaryoblastic) with t(1;22)(p13.3q133), (RBM15-MKL1), AML with BCR-ABL1; AML with mutated NPM1; AML with biallelic mutations of CEBPA. AML with mutated RUNX1
AML with myelodysplasia-related changes (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)
Therapy-related myeloid neoplasms. AML and MDS, therapy related - Alkylating agent or radiation-related type; topoisomerase II inhibitor type; others
AML, not otherwise classified - AML, with minimal differentiation; AML, without maturation; AML, with maturation; acute myelomonocytic leukemia; acute monoblastic or monocytic leukemia; pure erythroid leukemia; acute megakaryoblastic leukemia; acute basophilic leukemia; acute panmyelosis and myelofibrosis; myeloid sarcoma

The International Consensus Classification (ICC) of AML, updated in 2022, is as follows^[40]:

Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2)/ PML::RARA; ≥ 10% blasts required for diagnosis
APL with other RARA rearrangements; ≥ 10% blasts required for diagnosis
AML with t(8;21)(q22;q22.1)/ RUNX1::RUNX1T1; ≥ 10% blasts required for diagnosis
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/ CBFB::MYH11; ≥ 10% blasts required for diagnosis
AML with t(9;11)(p21.3;q23.3)/ MLLT3::KMT2A; ≥ 10% blasts required for diagnosis
AML with other KMT2A rearrangements; ≥ 10% blasts required for diagnosis
AML with t(6;9)(p22.3;q34.1)/ DEK::NUP214; ≥ 10% blasts required for diagnosis
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1); ≥ 10% blasts required for diagnosis
AML with other MECOM rearrangements; ≥ 10% blasts required for diagnosis
AML with other rare recurring translocations; ≥ 10% blasts required for diagnosis
AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 ≥ 20% blasts required for diagnosis
AML with mutated NPM1 ≥ 10% blasts required for diagnosis
AML with in-frame bZIP CEBPA mutations ≥ 10% blasts required for diagnosis
AML and MDS/AML with mutated TP53; 10-19% MDS/AML) and ≥ 20% (AML) blasts required for diagnosis
AML and MDS/AML with myelodysplasia-related gene mutations; 10-19% blasts required for diagnosis of MDS/AML and ≥ 20% required for diagnosis of AML; defined by mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2
AML with myelodysplasia-related cytogenetic abnormalities; 10-19% blasts required for diagnosis of MDS/AML and ≥ 20% required for diagnosis of AML; defined by detecting a complex karyotype (≥ 3 unrelated clonal chromosomal abnormalities in the absence of other class-defining recurring genetic abnormalities), del(5q)/t(5q)/add(5q), −7/del(7q), +8, del(12p)/t(12p)/add(12p), i(17q), −17/add(17p) or del(17p), del(20q), and/or idic(X)(q13) clonal abnormalities
AML not otherwise specified (NOS); 10-19% blasts required for diagnosis of MDS/AML and ≥ 20% required for diagnosis of AML
Myeloid sarcoma

In addition, the ICC recommends using the following diagnostic qualifiers following a specific MDS, AML (or MDS/AML) diagnosis^[40]:

Therapy-related – Prior chemotherapy, radiotherapy, immune interventions
Progressing from MDS – MDS should be confirmed by standard diagnostics
Progressing from MDS/MPN (specify) – MDS/MPN should be confirmed by standard diagnostics
Germline predisposition

Treatment & Management

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Table 1. Common Antigens for Immunophenotyping of AML Cells

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

Table 2. Cytogenetic Abnormalities in APL

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

Table 3 AML Cytogenetic Risk Factors

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-ITD^low
Intermediate Risk	Mutated NPM1 and FLT3-ITD^high Wild-type NPM1 without FLT3-ITD or with FLT3- ITD^low (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- ITD^high Mutated RUNX1 Mutated ASXL1 Mutated TP53

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Author

Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Clarence Sarkodee Adoo, MD, FACP Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Clarence Sarkodee Adoo, MD, FACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Acute Myeloid Leukemia (AML) Workup

Approach Considerations