Acute myeloid leukaemia

The exact underlying cause of acute myeloid leukaemia (AML) is unknown. However, a number of risk factors have been identified.

Exposure to ionising radiation

Risk of AML is increased in those exposed to ionising radiation (e.g., radiotherapy as part of myeloablative conditioning before stem cell transplantation).[7][8]

Cytogenetic abnormalities involving chromosomes 5 and 7 are associated with exposure to radiation.[9][10]

Previous treatment with chemotherapy

AML can develop in those previously treated with topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin) or alkylating agents (e.g., cyclophosphamide, melphalan, chlormethine), usually after a latency period of 1-5 years or 5-10 years, respectively.[11][12][13][14]

Loss of chromosome 5 and/or 7 is a common cytogenetic feature in patients treated with alkylating agents.[11][12][15] Cytogenetic abnormalities involving chromosome 11q23 (KMT2A gene) are associated with topoisomerase II inhibitors.[11][12] Other cytogenetic abnormalities associated with these agents include chromosomal rearrangements such as t(15;17)(q22;q12), which results in acute promyelocytic leukaemia (APL, a subtype of AML), and t(8;21).

Previous haematological disorders

Risk 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 (MDS), chronic myeloid leukaemia, chronic myelomonocytic leukaemia, and myeloproliferative neoplasms (polycythaemia vera, essential thrombocythaemia, primary myelofibrosis).[16][17][18][19][20]

Inherited genetic disorders

Risk of AML is increased in those with inherited chromosomal fragility disorders (e.g., Bloom's syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, Kostmann's syndrome), Li-Fraumeni syndrome, neurofibromatosis, and inherited bone marrow failure syndromes (e.g., Fanconi's anaemia, dyskeratosis congenita, Shwachman-Diamond syndrome, severe congenital neutropenia, and Diamond-Blackfan anaemia).[1][2][21][22][23][24][25][26][27]

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.[28][29][30] 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.[31]

Exposure to benzene

Risk of AML is increased in workers exposed to benzene (e.g., painters, printers, petroleum refinery workers, and chemical, rubber, and shoe manufacturing workers).[32]

Benzene exposure may also occur through smoking or gasoline vapour inhalation.[33] The risk of leukaemogenesis is proportionate to the level of exposure.[34]

Environmental exposures

Smoking has been found to be associated with the development of AML.[35][36]

Use of hair dyes and alcohol consumption has also been linked with AML, but the evidence is weak and inconsistent.[37][38][39][40]

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.[41] Abattoir workers, veterinarians, and meat packagers also have an increased risk.[42][43]

Cytogenetic abnormalities

Patients with AML may have a normal karyotype, or cytogenetic abnormalities that are either unbalanced (e.g., due to loss or gain of chromosomes or parts of a chromosome such as 5q, 7q, 11q, 13q, 12p, 17p) or balanced (e.g., due to chromosomal rearrangements affecting genes such as KMT2A at 11q23, RUNX1 at 21q22, RARA at 17q21, CBF-beta at 16q22).[1][2][27] Normal karyotype is frequent in de novo AML or MDS.[12]

APL (a subtype of AML) is characterised by a t(15;17)(q22;q12) balanced chromosomal rearrangement, which results in the PML::RARA fusion gene.[27][44]

Genetic mutations

Patients with AML may have genetic mutations, including TP53, KIT, FLT3 (ITD and TKD), CEBPA (basic leucine zipper [bZIP] domain), IDH1, IDH2, NPM1, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2.[27][45]

Genetic abnormalities have been incorporated into classification systems to define specific subtypes of AML, and some have prognostic implications that can guide risk stratification (e.g., TP53 mutation is an adverse-risk genetic abnormality).

See Classification and Criteria.

In AML, genetic abnormalities in haematopoietic precursor cells result in uncontrolled proliferation and clonal expansion of myeloid blasts that are unable to differentiate into mature neutrophils, red blood cells, or platelets. This can lead to bone marrow failure (manifest as anaemia, neutropenia, and/or thrombocytopenia), the most common cause of death in AML. As there is little correlation between blast percentage and cytopenias, secretion of inhibitory substances such as chemokines (rather than physical replacement of normal blood cells in the bone marrow by the myeloid blasts) is thought to lead to suppression of normal haematopoiesis.[46]

Anaemia may lead to pallor, fatigue, dizziness, palpitations, and dyspnea.

Neutropenia may lead to severe infections by endogenous aerobic gram-positive and gram-negative bacteria, and Candida and Aspergillus species.[47] Increasing neutrophil counts is a useful predictor of treatment response in AML.

Thrombocytopenia may lead to mucosal bleeding, bruising, ecchymoses, and petechiae.

Leukaemic infiltration of the lungs, spleen, liver, lymph nodes, gums, skin, testicles, or central nervous system (CNS) may occur, usually when the white blood cell (WBC) count is >50 × 10⁹/L (>50,000/microlitre), and blasts are monocytic or express CD56 antigen on their surface.[48][49]

Leukostasis (symptomatic hyperleukocytosis), a life-threatening complication of AML, may occur if WBC count is extremely elevated (>100 × 10⁹/L [>100,000/microlitre]). Symptoms of leukostasis include respiratory distress and altered mental status, caused by leukaemia cells impairing microvascular perfusion in pulmonary and CNS tissue, respectively.

The 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms[1]

The WHO classification classifies acute myeloid leukaemia (AML) based on the presence of AML-defining genetic abnormalities, and by differentiation (i.e., for AML cases lacking defining genetic abnormalities).

AML with defining genetic abnormalities*

Acute promyelocytic leukaemia (APL) with PML::RARA fusion
AML with RUNX1::RUNX1T1 fusion
AML with CBFB::MYH11 fusion
AML with DEK::NUP214 fusion
AML with RBM15::MRTFA fusion
AML with BCR::ABL1 fusion
AML with KMT2A rearrangement
AML with MECOM rearrangement
AML with NUP98 rearrangement
AML with NPM1 mutation
AML with CEBPA mutation
AML myelodysplasia-related (defined by cytogenetic abnormalities or somatic mutations**)
AML with other defined genetic alterations.

*A blast threshold is not required except for ‘AML with BCR::ABL1 fusion’ and ‘AML with CEBPA mutation’, which require ≥20% blasts for diagnosis.

**The presence of 1 or more ‘AML myelodysplasia-related’ defining cytogenetic abnormalities or somatic mutations, and/or a history of myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasms (MPNs; e.g., chronic myelomonocytic leukaemia), is required for diagnosing ‘AML myelodysplasia-related’. Defining cytogenetic abnormalities include: complex karyotype (≥3 abnormalities); 5q deletion or loss of 5q due to unbalanced translocation; monosomy 7, 7q deletion, or loss of 7q due to unbalanced translocation; 11q deletion; 12p deletion or loss of 12p due to unbalanced translocation; monosomy 13 or 13q deletion; 17p deletion or loss of 17p due to unbalanced translocation; isochromosome 17q; and idic(X)(q13). Defining somatic mutations include: ASXL1; BCOR; EZH2; SF3B1; SRSF2; STAG2; U2AF1; and ZRSR2.

AML defined by differentiation

AML with minimal differentiation
AML without maturation
AML with maturation
Acute basophilic leukaemia
Acute myelomonocytic leukaemia
Acute monocytic leukaemia
Acute erythroid leukaemia
Acute megakaryoblastic leukaemia.

International Consensus Classification (ICC) of myeloid neoplasms and acute leukaemias[2]

The ICC classification of acute myeloid leukaemia (AML) is hierarchical, whereby AML-defining recurrent genetic abnormalities are prioritised. Diagnostic qualifiers (including prior therapy, antecedent myeloid neoplasms, and germline predisposition) are appended to diagnostic classifications for specific diagnosis.

AML hierarchical classification

Acute promyelocytic leukaemia (APL) with t(15;17)(q24.1;q21.2)/PML::RARA (≥10% blasts required)
APL with other RARA rearrangements (e.g., IRF2BP2::RARA; NPM1::RARA; ZBTB16::RARA; STAT5B::RARA; STAT3::RARA) (≥10% blasts required)
AML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 (≥10% blasts required)
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11 (≥10% blasts required)
AML with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A (≥10% blasts required)
AML with other KMT2A rearrangements (e.g., AFF1::KMT2A; AFDN::KMT2A; MLLT10::KMT2A; TET1::KMT2A; KMT2A::ELL; KMT2A::MLLT1) (≥10% blasts required)
AML with t(6;9)(p22.3;q34.1)/DEK::NUP214 (≥10% blasts required)
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1) (≥10% blasts required)
AML with other MECOM rearrangements (e.g., MECOM::MYC; ETV6::MECOM; MECOM::RUNX1) (≥10% blasts required)
AML with other rare recurring translocations (≥10% blasts required)
AML with t(9;22)(q34.1;q11.2)/BCR::ABL1 (≥20% blasts required)
AML with mutated NPM1 (≥10% blasts required)
AML with in-frame basic leucine zipper (bZIP) CEBPA mutations (≥10% blasts required)
AML and myelodysplastic syndrome (MDS)/AML with mutated TP53 (variant allele fraction of ≥10%) (10% to 19% blasts required for MDS/AML; ≥20% blasts required for AML)
AML and MDS/AML with myelodysplasia-related gene mutations* (10% to 19% blasts required for MDS/AML; ≥20% blasts required for AML)
AML with myelodysplasia-related cytogenetic abnormalities** (10% to 19% blasts required for MDS/AML; ≥20% blasts required for AML)
AML not otherwise specified (NOS) (10% to 19% blasts required for MDS/AML; ≥20% blasts required for AML).

*Defined by gene mutations including: ASXL1; BCOR; EZH2; RUNX1; SF3B1; SRSF2; STAG2; U2AF1; and ZRSR2.

**Defined by cytogenetic abnormalities including: 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)/del(17p); del(20q); and idic(X)(q13) clonal abnormalities.

Diagnostic qualifiers for specific AML or MDS/AML diagnosis

Therapy-related (prior chemotherapy, radiotherapy, immune interventions)
Progressing from MDS (MDS should be confirmed by standard diagnostics)
Progressing from MDS/myeloproliferative neoplasms (MPN) (MDS/MPN should be confirmed by standard diagnostics)
Germline predisposition.

Aetiology

Pathophysiology

Classification