Key Points
Disease summary:
Acute myeloid leukemia (AML) is a malignant disease originating from a hematopoietic cell that has acquired self-renewal properties. Hundreds of genetic aberrations have been described in AML cells, and recent evidence suggests that on average 13 genetic aberrations are present in AML cells.
Patients usually present with signs of anemia, infection, or bleeding.
The diagnosis is made if greater than or equal to 20 myeloid blasts are present in peripheral blood or bone marrow.
Conventional cytogenetics and molecular screening for fusion proteins PML-RARα, RUNX1-RUNX1T1, CBFB-MYH11, and for mutations of NPM1, CEBPA, and FLT3 should be obtained at diagnosis.
Intensive chemotherapy should be given to all eligible patients consisting of cytarabine and an anthracycline.
Consolidation treatment consists of high-dose cytarabine or allogeneic hematopoietic stem cell transplantation depending on prognostic factors.
Acute promyelocytic leukemia (APL) is treated differently than other AML patients (including all-trans retinoic acid [ATRA] and an anthracycline) and has a good prognosis.
Differential diagnosis:
Includes myelodysplastic syndromes (MDSs), aplastic anemia, other leukemias, or myeloproliferative neoplasms.
Monogenic forms:
No monogenic form of AML is known. However, AML can be recapitulated in the xenotransplant model by overexpression of the fusion gene MLL-AF9 and MLL-ENL in human cord blood cells.
Family history:
AML is considered as an acquired disease with no increased risk for family members. However, there are rare familial cases of AML in whom germline mutations in RUNX1, CEBPA, and GATA2 have been found; 20% to 60% of carriers of these mutations develop myeloid malignancies.
Twin studies:
Twin studies showed a high rate of concordance of AML between identical twins. However, the risk to develop AML for the twin of an AML patient is similar as in the normal population after the age of 6.
Environmental factors:
Exposure to benzene, radiation, and chemotherapy (topoisomerase II inhibitors, alkylating agents) are known risk factors for AML.
Genome-wide associations:
Three single-nucleotide polymorphisms (SNPs) have been identified to confer susceptibility to therapy-related AML (rs1394384, rs1381392, and rs1199098). They have not been prospectively tested to guide management of patients treated with chemotherapy.
Pharmacogenomics:
SNPs in activating and inactivating enzymes of cytarabine have been shown to affect treatment toxicity and outcome, but are not routinely evaluated. Cytarabine dose is currently not adapted to the genotype of its metabolizing enzymes.
Diagnostic Criteria and Clinical Characteristics
Diagnostic evaluation should include.
Differential blood count.
Wright-Giemsa stained blood or bone marrow smears evaluated by light microscopy to verify the presence of greater than or equal to 20% myeloid blasts.
Myeloid lineage of blast cells is confirmed by cytochemical stains such as myeloperoxidase, Sudan black B (myeloid) or nonspecific esterase (monocytic), and/or by immunophenotyping for hematopoietic progenitor cells (CD34, HLA-DR, CD117), myeloid (MPO, CD13, CD33), monocytic (CD14, CD64), erythroid (CD71, glycophorin A), or megakaryoblastic (CD41, CD61) cell surface antigens.
Conventional cytogenetic analysis of bone marrow cells using chromosome banding techniques is required for correct classification of AML according to the 2008 WHO classification.
Reverse transcriptase-polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH) are recommended for some recurrent translocations t(8;21)(q22;q22); inv(16)(p13q22) or t(16;16)(p13;q22); t(15;17)(q22;q12) and gene mutations (NPM1, CEBPA, FLT3) due to their impact on treatment decisions.
Human lymphocyte antigen (HLA) typing of patients less than 70 to 75 years of age depending on the results of cytogenetic and molecular analyses.
Patients present with symptoms related to anemia, infection, and bleeding like fatigue, weakness, dyspnea on exertion, fever, abscess, mucosal bleeding or petechiae, and signs of extramedullary cell masses like gingival hyperplasia or skin lumps. About 5% of cases are asymptomatic and are diagnosed based on differential blood counts. Severe anemia or thrombocytopenia may require blood transfusions and infections require antibiotic treatment. Patients with APL characterized by t(15;17)(q22;q12) may develop disseminated intravascular coagulation requiring treatment in the ICU. Historical data suggest that the median survival of untreated patients is 6 months.
Screening and Counseling
The vast majority of AML cases are acquired during a lifetime, and no markers for early detection or for screening of family members have been established. For rare familial cases of AML, predisposing mutations in RUNX1 (like in familial platelet disorder where constitutional microdeletions involving chromosomal region 21q22.12 leads to a deletion in RUNX1), CEBPA, or GATA2 have been identified. Currently, screening for RUNX1, CEBPA, or GATA2 mutations should only be offered to family members if a family member of the patient has been diagnosed with AML and also harbors a mutation in RUNX1, CEBPA, or GATA2.
Several genetic syndromes are associated with an increased risk to develop AML (eg, Fanconi anemia, congenital neutropenia). There are also several predisposing conditions for AML like myelodysplastic syndromes, myeloproliferative neoplasms, aplastic anemia, and paroxysmal nocturnal hemoglobinuria. AML may also develop secondary to chemotherapy. However, AML cases are genetically very heterogeneous and thus no genetic markers exist to date that could be used for screening for secondary AMLs. In AML patients in whom allogeneic hematopoietic stem cell transplantation (alloHSCT) is anticipated, siblings and in some cases also parents are screened for their HLA type to identify potential donors.
Familial AML is very uncommon. Familial platelet disorder is an autosomal dominant disease associated with RUNX1 mutations. A myeloid malignancy like myelodysplastic syndrome (MDS) or AML develops in 20% to 60% of patients (median 35%). In patients with chromosome 21q22 deletions AML developed in 25% (3 of 12 patients). Nearly all family members tested positive for CEBPA mutations developed AML. In family members with proven GATA2 mutations MDS or AML developed in 53%.
As family members of AML patients may become stem cell donors, information on the risks of stem cell harvest will be required. Bone marrow hematopoietic stem cells are harvested from anesthesized patients by multiple punctures of both iliac crests. Alternatively, hematopoietic stem cells may be mobilized to the peripheral blood by subcutaneous administration of granulocyte colony-stimulating factor (G-CSF). These stem cells can then be harvested by leukapheresis. G-CSF administration in breast cancer patients treated with chemotherapy increased the risk to develop MDS or AML by threefold. However, registry data from the United States and Europe have not identified any increased risk of AML or MDS when G-CSF was administered to over 100,000 healthy individuals who donated peripheral blood stem cells, however, the median follow-up of these studies is less than 5 years.
Management and Treatment
AML is a heterogeneous group of diseases that are classified according to the World Health Organization (WHO) classification from 2008. Two-thirds of the patients can be classified according to cytogenetic or molecular aberrations. Patients should be offered the opportunity to participate in clinical trials. Some study groups have implemented a rapid molecular screening (within 48 hours) for patients with suspected AML to identify predictive markers that will guide the subsequent treatment. These aberrations include t(8;21)(q22;q22); inv(16)(p13q22) or t(16;16)(p13;q22); t(15;17)(q22;q12) and mutations of NPM1 and FLT3. All patients should receive intensive induction and consolidation chemotherapy, however, as the median age at diagnosis is 70 years, several patients are not eligible for intensive chemotherapy.
Cytarabine in combination with daunorubicin or idarubicin is the standard treatment for induction chemotherapy. The first treatment cycle may be repeated after 3 to 4 weeks. About 70% to 80% of patients 60 years or younger and approximately 50% of patients older than 60 years achieve a complete remission (<5% blasts in bone marrow and normalized blood counts) after induction chemotherapy. Mortality during induction chemotherapy ranges from 5% to 10%. High remission rates are achieved in molecular subtypes with t(8;21)(q22;q22), inv(16)(p13q22) or t(16;16)(p13;q22), and mutations of NPM1 independent of patient’s age supporting the application of intensive chemotherapy also in elderly patients with these aberrations.
Current options include high-dose cytarabine (3g/m2
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