History and exam
Key diagnostic factors
common
pallor
Common finding on physical examination due to anaemia.
ecchymoses or petechiae
Common finding on physical examination due to thrombocytopenia.
Other diagnostic factors
common
fatigue
Many patients have fatigue. Caused by bone marrow infiltration, anaemia, or the action of associated systemic inflammatory cytokines.
dizziness
Many patients have dizziness. Caused by bone marrow infiltration, anaemia, or the action of associated systemic inflammatory cytokines.
palpitations
Many patients have palpitations. Caused by bone marrow infiltration, anaemia, or the action of associated systemic inflammatory cytokines.
dyspnoea
Many patients have dyspnoea. Caused by bone marrow infiltration, anaemia, pulmonary infection, or the action of associated systemic inflammatory cytokines.
fever and infections
lymphadenopathy
Common finding on physical examination due to extramedullary leukaemic infiltration.
Enlarged lymph nodes are frequently the initial cause for seeking medical attention by the patient.
hepatosplenomegaly
Common finding on physical examination due to extramedullary leukaemic infiltration.
mucosal bleeding
Bleeding from the gums or nose or menorrhagia in females may be due to associated thrombocytopenia.
uncommon
skin and/or testicular mass
May be present due to extramedullary leukaemic infiltration.
skin infiltration
Leukaemia cutis may be present.
The presence of cutaneous ulcers (e.g., Sweet's syndrome or pyoderma gangrenosum) may indicate underlying malignancy.
Sweet's syndrome is characterised by fever, leukocytosis (symptomatic hyperleukocytosis; symptoms include respiratory distress and altered mental status), and tender, erythematous, well-demarcated papules and plaques on skin, which show dense neutrophilic infiltrates.
Pyoderma gangrenosum is characterised by presence of ulcers on leg, or less commonly the hands. Develops as a consequence of immune dysfunction and may be associated with AML.
gingival enlargement
Consequence of leukaemic infiltration; gingivae bleed easily due to associated thrombocytopenia.
bone pain
Related to bone marrow infiltration by blast cells.
skin chloromas
May be present due to extramedullary leukaemic infiltration.
abdominal pain
Severe abdominal pain may be present due to leukaemic infiltration or infection.
Acute abdomen is rarely noted on physical examination.
neurological symptoms (e.g., headache, confusion)
May be present due to meningeal leukaemic infiltration.
Risk factors
strong
age over 65 years
AML is more common in older adults.[5][6] In the US, approximately 61% of cases are diagnosed in people aged 65 years or over (2017-2021 data).[5] The median age at diagnosis is 69 years in the US.[5]
In the UK, approximately 66% of cases are diagnosed in people aged 65 years or over (2017 to 2018 data).[6]
previous treatment with chemotherapy
Alkylating agents (e.g., cyclophosphamide, melphalan, mechlorethamine) predispose to AML (latency of 5-10 years), with associated chromosome 5 and 7 abnormalities.[7][8][11]
Topoisomerase II inhibitors (e.g., etoposide, teniposide, and anthracyclines such as doxorubicin) predispose to AML (latency of 1-5 years), with associated chromosome 11q23 (KMT2A gene) abnormalities.[7][8][11][12] Other cytogenetic abnormalities associated with these agents include t(15;17)(q22;q12), which results in acute promyelocytic leukaemia (APL, a subtype of AML), and t(8;21).
previous haematological disorders
The incidence of AML is increased in patients with previous haematological disorders, including: aplastic anaemia (particularly in the presence of monosomy 7); paroxysmal nocturnal haemoglobinuria; myelodysplastic syndrome (which evolves to AML in approximately 30% of patients); chronic myeloid leukaemia (may progress to myeloid blast crisis); chronic myelomonocytic leukaemia; and myeloproliferative neoplasms (polycythaemia vera, essential thrombocythaemia, primary myelofibrosis).[13][14][15][16][17]
inherited genetic conditions
Inherited chromosomal fragility disorders and bone marrow failure syndromes are associated with an increased risk for AML.[18][19][20]
These include Bloom's syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, Kostmann's syndrome, Fanconi's anaemia, dyskeratosis congenita, Shwachman-Diamond syndrome, severe congenital neutropenia, and Diamond-Blackfan anaemia.[1][2][18][19][20][21][22][23][24]
Familial AML may be due to germline mutations of the tumour suppressor gene TP53 (Li-Fraumeni syndrome) or deletion at the carboxy terminus of CEBPA, which encodes a granulocytic differentiation factor.[43][44]
Neurofibromatosis due to abnormalities of the tumour suppressor gene NF1 at chromosome 17q11.2 predisposes to AML, usually in the second decade of life.[45]
constitutional chromosomal abnormalities
Down's syndrome (trisomy 21), Klinefelter's syndrome (XXY), and Patau's syndrome (trisomy 13) are associated with increased risk of AML.[25][26][27]
In those with Down's syndrome who develop AML, additional unbalanced chromosomal abnormalities such as dup(1q), del(6q), del(7p), dup(7q), +8, +11, and del(16q) are distinctive and may contribute to the pathogenesis.[28]
radiation exposure
Historically, survivors of the atomic bombing of Hiroshima and Nagasaki had an increased incidence of myelodysplastic syndromes and AML.[9] This incidence was highest in those under 20 years of age at the time of exposure.[46]
Radiotherapy, particularly in combination with alkylating agents (e.g., cyclophosphamide, melphalan), also predisposes to AML.[7][8][47]
benzene exposure
A 2- to 10-fold increase in leukaemia, predominantly AML, occurs in painters, printers, petroleum refinery workers, and chemical, rubber, and shoe manufacturing workers exposed to benzene.[48]
Additional benzene exposure occurs due to smoking or from unleaded petrol vapours.[49] The risk of leukaemogenesis is proportionate to the level of exposure.[50]
Benzene exposure is associated with a depletion of CD4+ lymphocytes.[51]
weak
environmental exposures
Smoking has been found to be associated with the development of AML.[29][30]
Use of hair dyes and alcohol consumption has also been linked with AML, but the evidence is weak and inconsistent.[31][32][33][34]
A 1.1- to 1.4-fold increased risk of AML occurs in agricultural workers. This has been attributed to pesticides, diesel fuel, fertilisers, and infectious agents.[35] Abattoir workers, veterinarians, and meat packagers also have an increased risk.[36][37]
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