Acute Myeloid Leukemia

Chapter: Acute Myeloid Leukemia
McMaster Section Editor(s): Mark Crowther
Section Editor(s) in Interna Szczeklika: Andrzej Hellmann, Bogdan Ochrem
McMaster Author(s): Mark Crowther
Author(s) in Interna Szczeklika: Jerzy Hołowiecki
Additional Information

Definition, Etiology, PathogenesisTop

Acute myeloid leukemia (AML) is a malignant blood disease characterized by the presence of a clone of transformed myeloid cells originating at early stages of myelopoiesis. The cells predominate in bone marrow and peripheral blood and infiltrate various organs, affecting their function.

The etiology of AML is unknown, although documented risk factors include exposure to ionizing radiation, benzene, and cytotoxic agents (alkylating drugs, topoisomerase inhibitors).

Clinical Features And Natural HistoryTop

1. General symptoms: Fever, fatigue, bone and joint pain.

2. Manifestations of anemia.

3. Manifestations of immunodeficiency: Stomatitis (painful aphthous or ulcerative lesions, reactivation of herpesvirus infection, severe tonsillitis, periodontal lesions); increased susceptibility to infection, including bacterial sepsis and fungal infections.

4. Hemorrhagic manifestations: Most frequently gingival bleeding, epistaxis, cutaneous and mucosal purpura, urogenital and/or gastrointestinal bleeding.

5. Manifestations of leukostasis (~5% of patients develop abnormalities of microcirculation associated with white blood cell [WBC] counts >100,000 cells/microL): Altered mental status, headache, visual disturbances, features of hypoxemia caused by impaired pulmonary perfusion, priapism.

6. Manifestations of leukemic infiltrates in various tissues and organs: Flat cutaneous lesions or nodules, gingival infiltrates, splenomegaly and/or hepatomegaly (in ~30% of patients), lymphadenopathy (in patients with monocytic leukemias), impaired visual acuity, signs of otitis media and/or otitis externa, various respiratory manifestations (up to severe respiratory failure), heart failure, hematuria, bone and joint pain, osteonecrosis, peripheral and central neurologic signs and symptoms.

7. Abdominal pain and signs of peritonitis caused by infection, petechiae in the gastrointestinal mucosa, or intestinal obstruction caused by leukemic infiltrates.

8. The clinical course is severe: patients who do not receive appropriate treatment die within a few weeks due to complications of leukemia.


Diagnostic Tests

1. Complete blood count: Leukopenia predominating in most countries with easy access to blood cell analysis; leukocytosis possible in selected patients who have not sought medical attention at the time of early symptoms; anemia; thrombocytopenia. Peripheral blood smear usually shows leukopenia without circulating blasts; if blasts are present, they are accompanied by few mature granulocytes (intermediate forms observed in reactive leukocytosis or myeloproliferative neoplasms are absent).

2. Bone marrow examination (aspiration): Morphology, cytochemistry, immunophenotyping, cytogenetic analysis, molecular studies. Bone marrow biopsy is performed when aspiration fails to provide a bone marrow sample sufficient for the assessment of cellularity and stromal abnormalities.

3. Other laboratory studies: Abnormal coagulation parameters, increased serum lactate dehydrogenase levels, hyperuricemia and hyperkalemia caused by the lysis of leukemic cells. Patients with high WBC counts may develop artifactual hyperkalemia, hypoxemia, and hypoglycemia due to the effects of leukemic cells after the samples are drawn.

Diagnostic Criteria

The diagnosis of AML is established in patients with ≥20% blasts (including myeloblasts and their equivalents: monoblasts, promonocytes, and megakaryoblasts) in bone marrow or peripheral blood (patients with 6%-19% blasts are diagnosed with myelodysplastic syndrome [MDS]). In patients with specific cytogenetic abnormalities—t(15;17), inv(16), or t(8;21)—or with a myeloid sarcoma, the diagnosis of AML can be made regardless of the percentage of blasts.

AML is classified into types and subtypes on the basis of morphology, cytochemistry, immunophenotype, cytogenetics, and molecular studies. The presence of Auer rods on bone marrow examination is pathognomonic of AML.

Classification of risk groups (according to the European LeukemiaNet) based on the results of cytogenetic and molecular studies: Table 7.8-1.

The adverse-risk group also includes secondary AML in patients after radiotherapy and/or chemotherapy, AML preceded by MDS, and AML with primary treatment resistance.

Differential Diagnosis

Infectious mononucleosis, acute lymphoblastic leukemia, some non-Hodgkin lymphomas, MDS and myeloproliferative neoplasms with high blast counts, recovering marrow (particularly in patients with recently treated B12 deficiency).


An optimal treatment regimen offering the highest chance for cure at the lowest possible risk of adverse effects should be planned after the baseline assessment of prognostic factors. Patients with all subtypes of AML except for acute promyelocytic leukemia (APL) (see below) receive the same remission induction and consolidation therapy but their subsequent treatment depends on risk factors, age, and comorbidities. Generally, in low-risk patients and patients with poor performance status treatment is less aggressive, while in high-risk patients with good performance status it is more radical and may include bone marrow transplantation. Treatment of patients with potentially curable disease should be conducted in health-care facilities with access to state-of-the-art cytogenetic and molecular diagnostics, providing intensive hematologic/oncologic therapy.

1. Remission induction consists of combination chemotherapy that is aimed at reducing the leukemic cell burden to a level below the limit of detection by standard hematologic studies as well as restoring normal hematopoiesis. The standard regimens include an anthracycline (daunorubicin, idarubicin, or mitoxantrone) and cytarabine. Additional agents, such as cladribine, may be added but it is unclear if any specific therapy has improved efficacy compared with combination therapy with an anthracycline and cytarabine. Tumor lysis syndrome can occur and appropriate measures should be provided to prevent this complication in all patients. In patients achieving remission, bone marrow function is restored.

Criteria of complete remission (CR) are as follows:

1) No extramedullary leukemia.

2) Peripheral blood: No blasts, granulocytes >1000/microL, platelets >100,000/microL.

3) Independence of red blood cell transfusions.

4) Bone marrow: Blasts <5%.

2. Remission consolidation: Postremission treatment is aimed at eradicating residual disease, including minimal residual disease (MRD) (presence of leukemic cells at a level producing no clinical manifestations and detectable only using sensitive methods [flow cytometry, molecular studies]). Regimens include high-dose cytarabine, sometimes combined with mitoxantrone, usually administered in 2 to 4 cycles, and in some patients combined with prophylactic treatment of central nervous system disease (intrathecal methotrexate and cytarabine).

3. Maintenance treatment is aimed at maintaining remission and preventing relapses of leukemia.

1) Patients in the adverse-risk or intermediate-risk group who have good performance status and have both access to a bone marrow transplant center and a donor available:

a) Allogeneic hematopoietic stem cell transplant (HSCT) results in 4-year disease-free survival (DFS) rates of 40% to 50% (with transplantation-related mortality of up to 15%). In patients who are elderly or have poor performance status, allogeneic HSCT with reduced conditioning can be used.

b) Autologous HSCT (transplantation-related mortality <5%) results in 4-year DFS rates of 30% to 45%. This is performed in patients for whom no donor is available or who have other contraindications.

2) In favorable-risk patients, various strategies may be employed after achieving CR. One such strategy is 4 cycles of consolidation therapy with high-dose cytarabine followed by careful monitoring of remission at the MRD level. An alternative therapy is autologous HSCT after 1 to 2 consolidation cycles.

4. Treatment of patients with resistance to first-line treatment or with relapse: In patients with late relapses (>6 months), standard induction therapy is repeated. In other patients, second-line treatment is used (agents with no cross-resistance with the first-line drugs, new combinations of drugs, or use of experimental agents in the clinical trial setting, eg, clofarabine); at the same time, patients may be considered for HSCT, and if this is not feasible, for other experimental treatment modalities (eg, targeted therapies, immunoconjugates). Consideration of early referral to palliative care should be considered, given the evidence of a beneficial outcome on quality of life and survival.

5. Supportive treatment is essential for effective antineoplastic therapy and patient survival. This includes:

1) Prevention of infection: Prophylactic treatment may be considered in selected at-risk patients (fluoroquinolones, antifungal agents; acyclovir [INN aciclovir] in patients with positive anti-herpes simplex virus antibodies).

2) Treatment of infection: Early empiric (or targeted, if possible) antimicrobial treatment including coverage of opportunistic pathogens (see Febrile Neutropenia).

3) Management of hyperleukocytosis (>100,000/microL): Hydroxyurea (INN hydroxycarbamide) 50 to 60 mg/kg/d until WBC counts decrease to 10,000 to 20,000/microL, fluids.

4) Treatment of anemia and thrombocytopenia: Transfusions of packed red blood cells (in patients with symptomatic anemia) and platelet concentrates (if platelet counts are <10,000/microL [prophylactic treatment] or in patients with higher platelet counts when accompanied by bleeding, fever, infection, coagulopathy, or severe mucositis).

5) Prevention of tumor lysis syndrome.

6) Administration of recombinant growth factors to stimulate hematopoiesis may be considered in selected patients.

7) Appropriate nutritional management, either enteral or parenteral.

8) Psychologic counseling.

9) Prevention and treatment of nausea and vomiting.

6. APL, associated with a specific promyelocyte morphology and pathognomonic chromosomal translocation t(15;17), is a subtype of AML that is uniquely responsive to retinoic acid therapy or therapy with arsenic compounds. Long-term DFS is routinely achieved. Patients with this potentially curable AML variant should be cared for in an expert center familiar with the current “best practices” in treatment.


1. Tumor lysis syndrome.

2. Febrile neutropenia.

3. Bleeding, mainly due to thrombocytopenia or less frequently caused by coagulopathy, disseminated intravascular coagulation, or increased fibrinolysis.


Perform follow-up clinical examination and a complete blood count with differential blood count every 1 to 3 months for the first 2 years after the end of therapy (the highest risk of relapse), then every 3 to 6 months for another 3 years. Recurrent disease can be confirmed by bone marrow aspiration or peripheral blood flow cytometric analysis.


Cure rates are highest in patients aged <60 years with favorable cytogenetic features (Table 7.8-1) and no unfavorable molecular features who achieve rapid CR during induction therapy. Combination chemotherapy alone may achieve cure in some favorable-risk patients with AML (50%). In other patients, who constitute the majority of the patient population, cure rates are 10% to 15%. In selected low-risk adult patients, highly intensive chemotherapy regimens may produce 5-year survival rates of 40%, while HSCT is associated with >60% cure rates in eligible patients who survive to transplant and who do not die as a result of the transplant.


Table 7.8-1. Classification of risk groups according to the European LeukemiaNet based on the results of cytogenetic and molecular studies

Genetic group





inv(16) or t(16;16)

Normal karyotype and biallelic CEBPA mutation

Normal karyotype and mutated NPM1 without FLT3-ITD

Intermediate I

All acute myelogenous leukemias with normal karyotype except for those included in the favorable risk group

Intermediate II


Cytogenetic abnormalities not classified as favorable or adverse


inv(3) or t(3;3)




-5 or del(5)


Complex karyotype (≥3 abnormalities)

Source: Blood. 2010;115(3):453-74.

FLT3, fms-related tyrosine kinase 3; ITD, internal tandem duplication.

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