Introduction
Acute myeloid leukaemia (AML) is a type of cancer of the part of the bone marrow that normally makes ‘myeloid’ cells. These include red cells (transport oxygen), platelets (control bleeding), and neutrophils (fight infection). Cancerous cells called ‘blasts’ accumulate in the bone marrow, reducing the normal production of blood cells as well as infiltrating and disrupting other organs around the body. AML typically develops acutely over a period of days to weeks and without treatment patients will deteriorate rapidly.
Cause
People of all ages can get AML and the average age at presentation is 65 years. The genetic systems that control the development of bone marrow stem cells are damaged at multiple sites, leading to the rapid and uncontrollable growth of myeloid cells, as well as a block in their normal maturation. In the vast majority of cases, the cause for this is not known. There are a handful of rare families where a predisposition to AML appears to be inherited. Exposure to significant radiation, heavy metals, or chemicals, such benzene, are known to increase the risk of developing AML. Chemotherapy treatment for other cancers can also increase the chances of developing secondary AML and some bone marrow problems (such as myelodysplasia) carry an increased risk of transformation to secondary AML.
Symptoms and signs
Most patients will have symptoms or signs relating to a reduction in the number of normal blood cells, e.g.
| • | Fatigue or breathlessness because of reduced red cells (anaemia). | ||||
| • | Fever, increased infections, or mouth ulcers because of reduced white cells (neutropenia). | ||||
| • | Pinpoint skin bruising (petechiae) or mucosal bleeding (nosebleeds, gum bleeding, and heavy periods) due to reduced platelets (thrombocytopenia) or abnormalities in blood clotting. | ||||
Other problems may include gum swelling, bone pain, swollen lymph glands, enlarged liver/spleen, skin deposits, or neurological symptoms. If the white blood cell count is very high, the blood becomes very thick (‘leucostasis’) and can cause breathlessness, headache, or visual problems.
Tests
| • | Confirm diagnosis | ||||
| • | Full blood count (FBC) and blood film | ||||
| • | Bone marrow examination with specialist diagnostics | ||||
| • | Look for complications of disease
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| • | Prepare for treatment
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AML is often easy to diagnose from examining the patient's blood film and bone marrow under the microscope. There are many different types of leukaemia and treatment varies, so to confirm the diagnosis, specialist diagnostic tests are performed. These include immunophenotyping, cytochemistry, and genetic analysis.
Cytogenetic and molecular genetic analysis additionally allows categorization of the AML into ‘good’, ‘standard’, and ‘poor’ risk disease, which affects the type of treatment offered.
Treatment options
Without treatment, AML is a rapidly fatal disease; however, with appropriate treatment, many patients can be cured. Treatment aims can range from a curative intention or alternatively to control (palliate) the leukaemia for a period of time to maximize the quality of life. Which one is chosen will depend on the age and general health of the patient, which AML risk group the patient is in, and whether they are at initial diagnosis or at relapse. All the patients should be encouraged to take part in clinical trials where available.
| • | Supportive care – antibiotics, red cell, and platelet transfusion. | ||||
| • | Palliative chemotherapy to reduce blood count, e.g. hydroxycarbamide, 6MP. | ||||
| • | Non-intensive chemotherapy, e.g. low-dose cytarabine, azacitidine. | ||||
| • | Intensive chemotherapy, e.g. DA 3+10, 3+7, DAT, ADE, HiDAC, MACE/MiDAC. | ||||
| • | Bone marrow transplantation.
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Intensive chemotherapy
In fit patients under 65, intensive chemotherapy will typically be recommended. This involves up to four ‘blocks’ of chemotherapy administered intravenously and each requiring a 4-week stay in hospital. A tunnelled line is usually inserted to provide easy access to the blood stream for tests and the administration of chemotherapy. The chemotherapy aims to eradicate the abnormal leukaemic cells, but wipes out healthy dividing cells too, which results in hair loss, possible infertility, gut toxicity (nausea, sore mouth, and diarrhoea), and bone marrow suppression (low blood counts). The chemotherapy drugs we use today have changed very little over the past 20–30 years; however, we are better at supporting these patients through intensive treatment with widely available blood products and broad-spectrum antibiotics. The first block is given with the aim of achieving a complete remission. This means that the leukaemia cannot be seen visually in the bone marrow, however, is often there at levels below detection (minimal residual disease – (MRD)). Subsequent blocks are given to improve the depth of the remission and so reduce the chances of the AML returning.
Allogeneic stem cell transplantation (ASCT) may be recommended in patients who are identified as poor risk, where the risk of relapse following chemotherapy alone is unacceptably high. ASCT offers the best chance of preventing relapse, but carries significant risks, so needs to be carefully considered. An ASCT involves more chemotherapy followed by a stem cell infusion from a matched donor. Siblings are usually tested in the first instance, and if no sibling match is identified an unrelated donor can be searched for.
Non-intensive chemotherapy
Intensive chemotherapy is potentially curative but brings significant toxicity and so is not always appropriate in patients who are older or less fit. This group may be offered less intensive chemotherapy, such as subcutaneous cytarabine or azacitidine. The chance of being cured with this approach is significantly less but it may control the leukaemia for a period of time without significant treatment-related toxicity. Those, who are felt to be too frail for any kind of chemotherapy, can be supported with blood transfusions, antibiotics, and tablets to try and suppress (although not remove) the leukaemia.
Outlook
A small proportion of patients will not respond to chemotherapy (refractory) or will succumb to treatment-related toxicity. Around 80% of patients will go into remission. However, a significant number will relapse leading to an overall cure rate of 30–40% for younger patients. Prognosis is affected by age, gender, patient fitness, initial response to treatment, origins of the disease (de novo vs. secondary), and the increasingly complex genetics now being revealed inside the leukaemia cells. Current trials are looking at the role of a range of new drugs, the ideal number of courses of intensive treatment, detecting MRD positive patients to better tailor therapy, and the wider use of ASCT in older patients as well as a range of laboratory work trying to understand how AML develops and how we can better risk stratify patients and develop new treatment approaches.
Summary
| • | AML is a serious form of bone marrow cancer. | ||||
| • | The median age is ∼65 years. | ||||
| • | The cause is unknown in the majority of cases. | ||||
| • | It is rapidly fatal if untreated. | ||||
| • | Curative therapy requires multiple cycles of intensive inpatient chemotherapy. | ||||
| • | Genetic risk stratification allows tailored treatment and use of ASCT. | ||||
| • | All the patients should be encouraged to take part in clinical trials where available. | ||||
Resources
There are many resources online but those that are most worth a visit are: Macmillan Cancer Support (http://www.macmillan.org.uk), Leukaemia and Lymphoma Research (http://www.leukaemialymphomaresearch.org.uk), Leukaemia Care (http://www.leukaemiacare.org.uk). The latest UK consensus guidance on diagnosis and treatment can be found in the British Journal of Haematology, volume 135, pages 450–474 (2006).