What are the main types of leukaemia?
Leukaemia targets the myeloid cells, which fight bacterial and parasitic infection and prevent the spread of tissue damage, or lymphocytes, specifically B- and T-lymphocytes that are the linchpin of the immune system. Both types of leukaemia may be acute or chronic.
What are the symptoms?
Symptoms of leukaemia are related to bone marrow failure and the effects of organ infiltration. Individual symptoms will vary depending on the type of leukaemia and how advanced it is. In many cases, symptoms prove vague and non-specific, with similarities to common influenza. A final diagnosis can only be confirmed by a conclusive blood test and biopsy results. Patients displaying hallmarks – especially swollen lymph glands – should be referred to their GP.
Leukaemia is a cancer of the bone marrow and blood characterised by the uncontrolled growth and accumulation of immature white blood cells (blasts). Unable to function like mature healthy leukocytes, these abnormal cells instead fill and flood the bone marrow, blocking normal haematopoiesis. The resulting disruption to the carefully controlled balance of white cells, red cells and platelets seriously compromises the body’s infection-fighting, oxygen-carrying and blood-clotting capabilities. Blasts can also infiltrate the organs and build up in the lymphatic system.
Leukaemia is the 13th most common cancer in the UK and accounts for approximately 2.5 per cent of all British cancer cases.1 Overall, around 7,400 people in the UK are diagnosed with leukaemia each year, equivalent to 20 people every day.1 Despite being the most common form of childhood cancer, over 90 per cent of cases are actually diagnosed in adults.1
The incidence of leukaemia in the UK had been increasing slowly over time up until the end of 1990s, fuelled partly by better diagnosis and recording. However, the last few years have seen a shift in this trend, with a slight fall in incidence rates since the start of the new millennium. Today, the lifetime risk of developing leukaemia is estimated at one in 76 for men and one in 108 for women in the UK.1
Types
There are four key kinds of leukaemia, classified according to the type of white blood cell affected and the speed at which the cancer develops:
– acute myeloid leukaemia (AML)
– acute lymphoblastic leukaemia (ALL)
– chronic myeloid leukaemia (CML)
– chronic lymphocytic leukaemia (CLL).
Myeloid leukaemia targets the myeloid cells (principally monocytes and granulocytes) that fight bacterial and parasitic infection and prevent the spread of tissue damage.2
Lymphoblastic leukaemia affects the lymphocytes, specifically B- and T-lymphocytes, which are the linchpin of the immune system.
Leukaemia can develop slowly, with a gradual onset of symptoms and protracted progression over a number of years requiring no immediate treatment. This is chronic leukaemia. In contrast, acute leukaemia advances rapidly and aggressively. Symptoms can become life-threatening quickly and immediate intervention is imperative.
Around 2,200 cases of AML are diagnosed each year in the UK – mostly in patients aged over 65 years.1 In contrast, ALL is rare in adults but is the most common type of childhood leukaemia. Of the 600 ALL cases diagnosed each year, half are in adults and half in children.1
CLL is the most common type of chronic leukaemia, with 2,300 patients diagnosed each year.1 It is more prevalent in the over 60s and very unusual in patients under 40 years old. In comparison, CML is rare – with only 600 cases occurring per year, equivalent to one in every 500 cancers diagnosed in the UK.1
Signs and symptoms
Symptoms of leukaemia are related to bone marrow failure and the effects of organ infiltration. Generally these include:
– tiredness and lack of energy
– breathlessness
– pale skin
– mild fever or night sweats
– slow healing of cuts
– abnormal bruising or bleeding
– petechial rash (small red or purple spots under the skin)
– bone and joint pain (caused by pressure from cells building up in the marrow)
– swollen lymph nodes
– left side abdominal pain (indicative of an enlarged spleen)
– repeated infections
– loss of appetite
– weight loss
– itchy skin.
Individual symptoms vary depending on the type of leukaemia and how advanced it is. In many cases, symptoms are vague and non-specific, with similarities to common influenza. In chronic leukaemia, there may be a total absence of symptoms.
The majority of CML patients present during the chronic phase of the disease and around half of these will be asymptomatic, with the cancer diagnosed by chance following a routine blood test for another condition.3
Diagnosis
The key diagnostic tests for leukaemia are a full blood count and bone marrow biopsy.
Blood tests indicate whether white cell levels are low or high, reveal any abnormal leukaemic cells in the blood and identify deficiencies in platelet or red cell count. Bone marrow biopsy is a confirmatory tool to verify the presence of cancerous cells and check the type of leukaemia.
Further investigations may also be carried out to shed light on the progress and extent of the leukaemia and offer insights into the best treatment strategy. These include:2
– cytogenic testing to analyse the genetic make-up of the cancerous cells and assess sensitivity to treatment
– immunophenotyping to identify antigens present on leukaemic cells
– lymph node biopsy to assess how far the leukaemia has spread
– scans (CT, MRI, x-ray or ultrasound) to establish the health of other organs and check for lymph node or spleen enlargement.
Differential diagnosis
Leukaemia presents with a diffuse set of symptoms potentially attributable to a whole host of different, and considerably more common, conditions. Differential diagnosis based on symptoms alone is therefore extremely challenging.
In clinical practice, although symptoms may raise the index of suspicion, a final diagnosis of leukaemia can only be confirmed by conclusive blood test and biopsy results. Patients displaying any of the hallmarks potentially indicative of leukaemia – particularly swollen lymph nodes – should be referred to their GP for rule-out blood tests. In these cases it is important to offer reassurances that, in the vast majority of patients, the symptoms are extremely unlikely to be caused by leukaemia.
Cause
Leukaemia is a complex disease involving intricate, interwoven cellular pathways with no clearly-defined cause. In some types of leukaemia, a genetic component is obvious. Between 90 and 95 per cent of patients with CML carry a chromosomal abnormality known as the Philadelphia (Ph) chromosome, where genetic material is translocated between chromosomes 9 and 22.3,4 The resulting Ph chromosome contains the bcr-abl oncogene, which expresses a tyrosine kinase enzyme with increased proliferative activity, key to the development of chronic phase CML.3,4
In childhood acute leukaemia, there is considerable support for a ‘two-hit’ hypothesis. According to this theory, children born with a pre-existing vulnerability to acute leukaemia (such as a genetic mutation) remain healthy unless exposed to an environmental trigger (the second hit) that initiates disease development.2
Risk factors for leukaemia development1,2
– Immunosuppression
Patients with HIV/AIDS or organ transplant recipients on long-term immunosuppressives have double or triple the normal risk of leukaemia.
– Age
The risk of AML, CML and CLL increases with age.
– Gender
ALL and CML are more common in men than women.
– Genetic disorders
ALL occurs with 20- to 30-fold higher frequency in patients with Down’s syndrome.
– Autoimmune conditions
Patients with rheumatoid arthritis, autoimmune haemolytic anaemia and ulcerative colitis have between three to eight times the normal risk of developing AML.
This may be due to the autoimmune disorder itself or because of the pharmacotherapy used to treat it.
– Benzene exposure
– Other blood disorders – eg aplastic anaemia
– Smoking
Smoking doubles the risk of AML and may account for as many as 17 per cent of all myeloid leukaemia cases.
– Family history
The risk of CLL is six- to nine-fold higher for first-degree relatives of a CLL patient.
– Radiation exposure
Radiotherapy treatment for other types of cancer confers an increased risk of acute leukaemia.
Diagnostic X-rays during pregnancy have been linked to an increased risk of leukaemia in the child.
– Past chemotherapy
Chlorambucil, melphalan or cyclophosphamide for Hodgkin’s lymphoma or breast cancer carry a small increase in the risk of blood changes that may lead to AML.
Etoposide, mitoxantrone, amsacrine and idarubicin are associated with a slightly raised risk of ALL.
Survivors of childhood cancer have 10 times the normal risk of developing leukaemia 10 years post-treatment.
– Alcohol during pregnancy
One study found the risk of AML in the first 18 months of life was more than doubled if the mother consumed alcohol during pregnancy.
– Weight
A BMI >30 is associated with a slightly increased risk of AML and a 25 per cent higher risk of developing CML.
– Occupation
Certain occupations have been linked to increased risk of developing chronic leukaemia – likely due to inherent chemical or pesticide exposure. These occupational risks extend to: agricultural workers, rubber or plastics manufacturers, tailors and dressmakers, cleaners, builders and labourers.
Pathophysiology
Leukaemia begins with DNA mutations in the bone marrow stem cells. The term lymphoblastic denotes the fact that cancerous changes occur in a type of marrow cell that forms lymphocytes, while myeloid indicates that the cell changes take place in the type of marrow cell that normally goes on to form red blood cells, some types of white cell and platelets.5
AML can develop from either myeloid stem cells or myeloid blasts. The result is an overproduction of immature granulocytes or monocytes. In CML, the myeloid stem cells or bone marrow stem cells themselves can become leukaemic, resulting in cancerous granulocyte white blood cells. As a result, CML is sometimes referred to as chronic granulocytic leukaemia (CGL). ALL and CLL both affect the lymphoid lineage; ALL develops from lymphoid blast cells, whereas CLL affects B-lymphocytes.
In acute leukaemia, normal bone marrow is completely displaced by a malignant clone of immature blasts.6 Chronic leukaemias, on the other hand, have few or no blast cells.5 White cells are almost fully grown when leaving the bone marrow so can function (albeit suboptimally); however, counts are high and continue to rise too rapidly, with loss of infection-fighting properties over time.
CML has three distinct phases – chronic, accelerated and blastic. The chronic phase can last anywhere from three months to 22 years, with periods of disease dormancy extended since the discovery of new oral therapies. Progression, which is triggered by further rumblings of genomic instability, usually starts with the accelerated phase.4 After six to 12 months, this progresses to the blastic phase – also known as blast crisis – which behaves similarly to AML and is typically fatal within six months.3
Prognosis
The prognosis for patients with leukaemia is continuing to improve. In the last 30 years, five-year survival rates have more than tripled, with around 40 per cent of patients now surviving the disease for at least five years after diagnosis.1 Nevertheless, leukaemia still accounts for over 4,000 deaths each year in the UK.1 The majority of these mortalities (80 per cent) occur in patients aged over 60 years.1
Helen Boreham is a freelance medical writer with an MSci in medicinal chemistry
Reflect
Which type of leukaemia is most commonly seen in children? What chromosomal abnormality are patients with CML likely to have? Which occupations have been linked to an increased risk of chronic leukaemia?
Plan
This article describes the four main types of leukaemia: acute myeloid leukaemia, acute lymphoblastic leukaemia, chronic myeloid leukaemia and chronic lymphocytic leukaemia. It includes information about signs and symptoms, diagnosis, causes, risk factors and the pathophysiology of the disease.
Act
– Find out more about the types of leukaemia from the Merck online manual at http://tinyurl.com/leukaemia01.
– Revise your knowledge of blood cell types and learn more about the tests used in leukaemia diagnosis and the Philadelphia chromosome from the American National Cancer Institute website at http://tinyurl.com/leukaemia02.
– The Leukaemia and Lymphoma Research website has detailed booklets about each of the leukaemia types containing information that may be useful for your patients at http://tinyurl.com/leukaemia07, http://tiny
url.com/leukaemia09, http://tinyurl.com/leukaemia10, http://tinyurl.com/leukaemia11.
Evaluate
Are you now familiar with the different types of leukaemia? Could you recognise the symptoms? Are you confident in your knowledge of the causes, risk factors and pathophysiology of this disease?
References
1. Cancer Research UK www.cancerresearchuk.org
2. NHS Choices www.nhs.uk
3. Duncan N. Adult myeloid leukaemias: pathogenesis, clinical features and classification. Clinical Pharmacist 2010; 2: 117-121
4. Smith V. Chronic leukaemia – characteristics and treatment. Hospital Pharmacist 2003;10:110-16
5. Leukemia & Lymphoma Society www.leukemia-lymphoma.org
6. Nijjar R. Acute leukaemia – characteristics
and treatment. Hospital Pharmacist 2003;
10: 99-107