An average of 2,400 new cases of acute leukaemia are diagnosed every year in England and Wales. Acute leukaemia develops due to a maturation arrest related to genetic damage in the early stages of blood cell development. This leads to an accumulation of immature, undifferentiated 'blast' cells.
Broadly speaking, there are two types of acute leukaemia; acute lymphoblastic leukaemia (ALL), mainly affecting young children, and acute myeloblastic leukaemia (AML), which commonly affects older adults.
However, the presenting symptoms are often identical and both diseases do occur at all ages.
About 85 per cent of cases of ALL occur in children under 15, with a peak in cases between two and five years of age.
Approximately one in every 2,000 children will develop ALL.
In some cases an initial genetic mutation has been shown to be present at birth predisposing the child to developing overt ALL later in life.
For example, the 'TEL-AML1' mutation is present in around 1 per cent of newborns but less than 1 per cent of those born with this mutation will go on to develop leukaemia.
The triggers for developing ALL are multifactorial. In addition to infective triggers, research has shown that possible late exposure to some antigens or exposure to new antigens increases the likelihood of developing ALL.
Extensive research has not yet found a causal link with environmental factors, such as living near to nuclear powerstations or mobile phone masts.
AML is more common in older people, with most cases occurring in people over 50, reaching an incidence of one in 10,000 at age 80.
Many progress from myelodysplasia, a condition where there is stem cell damage similar to leukaemia but there is still some residual but dysfunctional maturation of blood cells producing cytopenias with atypical morphological features.
Classification of AML subtypes has helped identify prognostic factors and response to different types of chemotherapy.
Initially the auer rod (an abnormal, needle-shaped inclusion found in some myeloblasts) helped to differentiate AML from ALL on morphology alone but acute leukaemia classification has progressed steadily.
The WHO classification is presently used and relies on morphology, cell markers and genetic analysis, which helps identify which early cell type has undergone maturation arrest and at what stage.
Presenting signs and symptoms are often non-specific. Bone marrow failure due to accumulation of blasts leads to signs and symptoms of anaemia (weakness and fatigue), neutropenia (multiple or recurrent infections) and thrombocytopenia (easy bruising and bleeding).
Splenomegaly is sometimes detected but rarely hepatomegaly. Non-tender lymphadenopathy would suggest ALL. Specific signs, such as gum hypertrophy are seen in acute monoblastic leukaemia, which is a subtype of AML.
Differential diagnosis in children includes immune thrombocytopenia, which can present with bleeding and bruising or, very rarely, aplastic anaemia where pancytopenia occurs due to bone marrow failure.
Viral infections, such as cytomegalovirus and Epstein-Barr can produce severe malaise, lymphadenopathy and blast- like cells on the blood film.
In adults, haematinic deficiencies can lead to marrow failure as can alcohol abuse and bone marrow infiltration from metastatic carcinoma.
Almost all cases are identified with laboratory analysis of a FBC. The laboratory would then contact the patient's GP if the patient is not in hospital. Transfer to hospital is required.
Bone marrow examination is the definitive investigation as clinical examination is not usually helpful in management.
Specialised tests are sent to central laboratories to prove clonality of the blast cells and detect any associated chromosomal aberration.
Treatment depends on the age and fitness of the patient. Patients less than 60 years are treated with intensive chemotherapy. They require a Hickman line for chemotherapy administration.
Patients will need frequent blood product support and severe infection is a risk so antibiotics are needed. Three to four courses of chemotherapy are given over five months. A small number of patients will require bone marrow transplantation due to poor prognostic features, such as inadequate response to chemotherapy or the presence of adverse cytogenetics.
Patients who are deemed unsuitable for intensive chemotherapy are treated with blood products alone or low-intensity chemotherapy, with an emphasis on quality of life.
Patients with ALL will also require intrathecal chemotherapy, with possible cranio-spinal radiotherapy to prevent occult disease in the cerebrospinal fluid causing relapse at a later stage. All ALL patients receive 18 months of maintenance therapy of mainly oral chemotherapy as an outpatient as this improves the eventual cure rate.
A general rule is that prognosis can be estimated as normal life expectancy (85) minus age (so a child of 10 has a 75 per cent survival whereas an adult of 75 has a 10 per cent chance).
However, there is variation due to a number of subtypes of ALL and AML with differing prognosis. Younger patients present with good risk features, while older patients present with poor prognostic features, such as multiple chromosomal aberrations in AML and the 9;22 translocation in ALL.
Children who survive leukaemia tend to have a good outlook although they can suffer late effects of treatment, such as growth retardation, reduced fertility, obesity, avascular necrosis of femoral heads and cardiac fibrosis.
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1. How is it thought that acute lymphoblastic leukaemia develops?
2. What are the presenting signs and symptoms of acute leukaemia?
3. What is the mainstay of treatment for acute leukaemia?
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- Dr Bareford is a consultant haematologist and Dr Francis is a specialist registrar, Russells Hall Hospital, Dudley, West Midlands
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