Acute Myeloid Leukaemia (AML) is a malignancy arising from the myeloid lineage of haematopoietic stem cells. Strictly speaking this includes all cells that are not lymphocytes i.e. granulocytes, erythrocytes, megakaryocytes. However, usually it is neutrophil and other granulocyte stem cells that are affected.
It is the most common type of acute leukemia in adults and the incidence increases with age. However, it is a relatively rare cancer with an incidence of 3 per 100,000 annually. The disease develops very rapidly, with death occurring months after diagnosis if left untreated.
The aetiology of AML is unclear but the following are generally considered risk factors:
In addition certain diseases can increase the likelyhood of getting AML, these are:
AML, like all haematological malignancies, is classifeid under the WHO 2008 classification. The details of this are convoluted and go beyond the scope of this article, however they are based upon molecular advances in haematology and reflect the diverse range of genetically different malignancies.
An older classification system, which is still a valuable tool for learning about AML is the French American British Classificaiton (FAB). This has eight main categories that differentiate AML on the basis of maturity of blast cells and the lineage they have taken.
In this classification, morphology and immunophenotyping is used to recognise the origin of the different cells. This is performed on bone marrow samples.
Normally haemopoietic stem cells in the bone marrow develop into mature blood cells. These stem cells may either become a myeloid or lymphoid blast cells. The lymphoblasts mature into B-cells and T-cells while the myeloblasts develop into red blood cells, white blood cells and platelets. In AML it is thought that genetic damage results in uncontrolled proliferation, decreased apoptosis and prevents differentiation of the myeloblasts into mature blood cells. As the cells have not matured they are unable to function properly and the accumulation results in bone marrow failure.
As AML is an acute leukaemia, the turnover of blasts is high, which is why more than 20% blasts are detected in the marrow, allowing it to be classsified as an acute leukaemia. The high cell turnover also means that intracellular enzymes such as LDH will be raised. Cellular debris can also provoke disseminated intravascular coagulation, a potentially devestating consumptive coagulopathy. This is a particular feature of acute promyelocytic leukaemia.
The main signs and symptoms are:
Tissue infiltration of leukaemic cells may also occur. An important example of this is in acute promyelocytic leukaemia, in which gum hypertrophy is present.
The full blood count should be the initial investigation, which usually shows a low haemoglobin, low platelets and a high white cell count but low neutrophils. Most modern full blood count machines will be able to detect abnormal blasts and 'red flag' these to lab staff.
After this point a blood film is made to see if there are any blasts visible. A bone marrow aspirate and trephine is then necessary, to demonstrate the presence of more than 20% myeloblasts, which is consistent with AML.
Further genetic and chromosomal studies can be used to inform prognosis, there are many different translocations and mutations that are studied in specialist tertiary centres.
Treatment consists of two phases:
Induction of remission aims to achieve complete remission which means a morphologically normal bone marow and peripheral blood count. Induction therapy has severe toxic side effects, including anaemia, low white cell count and low platelet count. Complete remission is achieved when there are no morphologically detectable leukaemic cells in the blood or bone marrow and the blood count has returned to normal. However, there may still be some leukaemic cells present and this can lead to relapse. Consolidation therapy aims to eliminate any residual disease and can consist of further chemotherapy, allogeneic or autologous stem cell transplantation. As with most haematological malignancies, allopurinol to prevent tumour lysis syndrome should be used. Radiotherapy is not usually a feature of AML treatment.
It is worth mentioning that acute promyelocytic leukaemia has a unique translocation between chromosomes 15 and 17 that results in a fusion protein known as PML-RARA. The agent all trans retinoic acid (ATRA) is a drug that overcomes this translocation and induces differentiation of the blast cells. This makes them less likely to rapidly turnover and cause DIC.
An important factor in predicting prognosis of AML is the genetic make-up of the leukaemic cells. For example, FLT3 gene mutations confer a poor prognosis.
In addition, patient related factors play a strong role in prognosis, patients over the age of 60 are unlikely to tolerate the toxicity of chemotherapy or bone marrow transplantation, so more conservative measures may be necessary. Failing to achieve a complete response in the first cycle of chemotherapy increases the possibility that relapses to treatment will occur in the future.
Patients under 60 can expect a 70-80% chance of complete response, however with high risk phenotypes, the five year relapse rate can be as high as 90%. For patients over 60, 50-60% achieve a complete remission, however relapse rates are much higher.
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