Synonyms: acute myelogenous leukaemia, acute myeloblastic leukaemia
See also the separate Childhood Leukaemias article.
Acute myeloid leukaemia (AML) is a malignant disease of the bone marrow in which precursors of blood cells are arrested in an early stage of development. Most AML subtypes show more than 30% blasts of a myeloid lineage in the blood, bone marrow, or both. There is maturational arrest of bone marrow cells in the first stages of development. The mechanism involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities. This reduces the number of normal blood cells. In addition, failure of apoptosis leads to accumulation in various organs, especially the liver and the spleen.
Advances in genomics technologies have identified AML as a genetically heterogeneous disease; many patients can now be categorised into clinicopathological subgroups based on their underlying molecular genetic defects.
Although historically classified by the largely descriptive French-American-British (FAB) criteria, myeloid neoplasms including AMLs are now classified according to the World Health Organization (WHO) classification from 2001, revised in 2008.
|WHO classification of AML|
|AML with characteristic genetic abnormalities||Includes: |
In general, these patients have a higher rate of remission and a better prognosis compared with other types of AML.
|AML with multilineage dysplasia||Includes patients who have had a prior myelodysplastic syndrome (MDS) or myeloproliferative disease that transforms into AML. This occurs most often in elderly patients and often has a worse prognosis.|
|AML and MDS, therapy-related||Includes patients who have had prior chemotherapy and/or radiation and subsequently develop AML or MDS. These may have specific chromosomal abnormalities and often carry a worse prognosis.|
|AML not otherwise categorised||Includes other subtypes of AML that do not fit into the above categories.|
The French-American-British (FAB) classification system divides AML into eight subtypes:
- M0: acute myeloblastic leukaemia, minimally differentiated.
- M1: acute myeloblastic leukaemia, without maturation.
- M2: acute myeloblastic leukaemia, with granulocytic maturation.
- M3: promyelocytic, or acute promyelocytic leukaemia.
- M4: acute myelomonocytic leukaemia.
- M4eo: myelomonocytic together with bone marrow eosinophilia.
- M5a: acute monoblastic leukaemia.
- M5b: acute monocytic leukaemia.
- M6a: acute erythroid leukaemias, including erythroleukaemia.
- M6b: pure erythroid leukaemia.
- M7: acute megakaryoblastic leukaemia.
- AML is the most common acute leukaemia in adults. The incidence of the AMLs in European adults is 5-8 cases per 100,000.
- AML can occur at any age but the incidence increases with age and the median age of onset is 67.
- Its significance has grown with an ageing population: of the 2,000 cases of AML diagnosed annually in the UK, 1,400 will be in the over-60s.
A number of predisposing factors have been postulated but most cases arise without apparent cause.
- Antecedent haematological disorders include MDSs. Other conditions that predispose patients to AML include:
- Aplastic anaemia.
- Paroxysmal nocturnal haemoglobinuria.
- Polycythaemia rubra vera.
- Most patients with chronic myeloid leukaemia - a myeloproliferative disorder - eventually develop a blast phase indistinguishable from AML.
- Radiation is certainly a risk factor for chronic lymphocytic leukaemia but other studies linking leukaemia with radiation give conflicting results and sometimes methodology is poor. Survivors of the Japanese atomic bombs were more likely to develop leukaemia, as were scientists who were exposed to excessive radiation. Those with ankylosing spondylitis who have received radiotherapy are also more likely to develop leukaemia.
- Some congenital disorders predispose to the disease, usually in childhood but occasionally in early adulthood. These include:
- Bloom's syndrome
- Down's syndrome
- Congenital neutropenia
- Fanconi's anaemia
- Rare families have been described where AML seems to have a genetic component, inherited as an autosomal dominant condition. They tend to present in the sixth or seventh decade.
- Exposure to benzene can produce aplastic anaemia and pancytopenia. This can progress to AML, usually of the M6 variant.
- Patients who have survived cancer chemotherapy are at risk. Those who have had alkylating agents, with or without radiation, often have a myelodysplastic condition that can progress to AML with specific cytogenetic abnormalities. Patients who have received topoisomerase II inhibitors do not have a myelodysplastic phase prior to developing AML but also have cytogenetic abnormalities. Alkylating agents tend to give two to five years between exposure and the development of leukaemia but, for topoisomerase II inhibitors, latency is only three to six months.
The presentation may be related to bone marrow failure (causing anaemia, neutropenia and thrombocytopenia) or due to organ infiltration.
- Children or young adults may present with acute symptoms over a few days to a few weeks.
- Older people may present with fatigue over weeks or months.
- Dizziness and shortness of breath on exertion may present in older people and, if there is coronary heart disease, it may present with angina or myocardial infarction.
- Although white blood cell (WBC) counts are very high, neutrophils are low and fever is a common presenting sign. There may be failure to respond to antibiotics.
- Bleeding may be caused by thrombocytopenia, coagulopathy resulting from disseminated intravascular coagulation (DIC), or both.
- Haemorrhage in the lungs, the gastrointestinal tract and the central nervous system can be life-threatening.
- Splenomegaly can cause fullness in the left upper quadrant and early satiety.
- If WBC count is extremely high (>100 x 109/L), it can cause leukostasis with respiratory distress and altered mental status. Leukostasis is a medical emergency that requires immediate intervention.
- There can also be bone pain.
- The most common sites for infiltration are the liver, spleen and gums.
- Pallor may be obvious.
- Signs of infection can be nonspecific. Fever or pneumonia may present.
- Thrombocytopenia often causes petechiae on the lower limbs. DIC may aggravate the situation and cause larger lesions. Petechiae are small dots, purpura is larger and ecchymoses are larger bruises.
- Hepatomegaly and splenomegaly may be found. Lymphadenopathy is less common.
- Leukaemia cutis is an uncommon condition due to infiltration of the skin.
- Gingivitis is common, with swollen, bleeding gums. This may lead to initial presentation at the dentist.
The diagnosis of AMLs requires the examination of peripheral blood and bone marrow specimens, using morphology, cytochemistry, immunophenotyping, cytogenetics and molecular genetics.
- FBC will often show a variable degree of anaemia and thrombocytopenia. Total WBC count may be normal, high or low, and sometimes extremely high, but neutrophils are usually depleted and blast cells are seen in their place.
- Clotting screen - DIC is common, especially in M3, with prolonged prothrombin time, low levels of fibrinogen and fibrin degradation products (FDPs) present.
- Lactate dehydrogenase levels are usually raised and rapid cell turnover may raise uric acid.
- Liver and renal function must be checked before initiating chemotherapy.
- The variants with acute monocytic leukaemia (M5) and acute myelomonocytic leukaemia (M4) can reduce potassium, calcium and magnesium.
- If fever is present, appropriate steps should be taken to identify and to treat infection.
Specialist diagnostic tests
- Bone marrow aspiration is the diagnostic procedure. The WHO classification requires more than 20% blasts in the peripheral blood, to make a diagnosis of AML.
- Patients potentially suitable for allogeneic stem cell transplantation (alloSCT) should be HLA typed at diagnosis, as should their available first-degree family members. In high-risk disease (eg, poor karyotype), early matched unrelated donor allogeneic transplantation must be considered, and a donor search should be performed as early as possible.
- Cytochemical stains allow classification into seven of the subtypes M1 to M7. These stains may not be useful for M0 (acute undifferentiated leukaemia) or M7 (acute megakaryocytic leukaemia) and so flow cytometry is used.
- Cytogenetic studies are also performed to provide important information about prognosis. They are also useful to confirm acute promyelocytic leukaemia (APL), which shows the t(15;17) and is treated differently. Chromosomal analyses are performed on children with AML to identify subgroups for prognostic assessment and to tailor therapy. Techniques such as gene expression profiling are increasingly used.
- CXR may show pneumonia or signs of heart disease.
- Multiple-gated acquisition (MUGA) scan is required because many chemotherapeutic agents used in treatment are cardiotoxic. ECG is also necessary.
The usually accepted criteria of response in AMLs are blast clearance in the bone marrow to <5% of all nucleated cells, morphologically normal haematopoiesis and return of peripheral blood cell counts to normal levels. For detailed discussion of current AML treatments, see references.
- Treatment is co-ordinated in specialised centres and is frequently trial-based. Different regimes tend to be used for younger and older patients. It is delivered in two phases:
- Induction (to attain remission). The standard combination for induction is cytarabine and daunorubicin.
- Post-remission consolidation (intensification).
- A number of chemotherapeutic agents are used, including daunorubicin, mitoxantrone and arabinosylcytosine.
- Stem cell transplantation (SCT):
- A recent meta-analysis suggests that alloSCT has significant relapse-free and overall survival benefit for intermediate- and high-risk AML but not for low-risk AML in first complete remission.
- Patients with AML in intermediate- and poor-risk groups are candidates for alloSCT. Patients in these risk groups without a family donor may qualify for alloSCT with an HLA-matched unrelated donor identified through an international donor registry.
- APL subtype is treated rather differently to the rest of AML. The use of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO), usually in combination with other chemotherapy agents, has transformed the treatment of the disease. Supportive treatment, in particular the management of DIC, commonly associated with APL, and the avoidance of invasive procedures wherever possible, are important.
Other aspects of care include blood product replacement, antibiotics for infection and allopurinol to reduce uric acid levels. Patients with excessive leukocytosis at presentation may require emergency leukophoresis before commencing chemotherapy. Reverse barrier nursing may be necessary in the neutropenic phases of treatment.
- Prognosis is dependent upon age, cell type and the burden of the disease.
- The prognosis is also worse with increasing socio-economic deprivation.
- About 13% of people with AML develop secondary malignancies.
- Around 80% achieve remission following induction.
- Survival rates have increased over the past few decades to about 70%.
- Children aged 0–2 years with AML have traditionally been considered to have a relatively poor prognosis but the prognosis for this group has also improved.
- Bone marrow transplant may be offered where there is a suitable donor and 60-70% will have long-term remission or cure.
- AML associated with Down's syndrome has a good prognosis.
- In younger patients, complete remission rates of at least 80% may be reached, with five-year overall survival about 40%.
- Patients failing to respond to one or two cycles of induction treatment are considered refractory and are at very high risk of ultimate treatment failure.
- Cytogenetic analysis informs prognosis: patients with t(8;21), t(15;17) or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%, whilst those with normal cytogenetic findings have an intermediate prognosis and have a long-term survival rate of approximately 25%. AMLs with complex karyotype abnormalities and/or chromosomal monosomies have the poorest prognosis.
- Remission is less likely in AML following myelodysplasia or previous cytotoxic chemotherapy.
- Older patients tend to have a worse prognosis - in the over-60s, remission rates are about 60%, but remissions are usually transient, with median survival being 5-10 months and probability of remaining in remission five years after diagnosis being less than 10% (compared with 30-35% of adults <60 years old).This is in part due to a higher incidence of less favourable cytogenic markers in AML in this age group, increased resistance to chemotherapy, poorer initial performance status and other medical comorbidities limiting the use of intensive chemotherapy.
- Pre-existing medical conditions such as diabetes, coronary heart disease or chronic obstructive pulmonary disease are also associated with a poorer prognosis.
- In the APL subgroup, remission is achieved in 70-90%, although the risk of haemorrhagic complications is higher during induction.
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