 |  |  | | | Leukaemia and Related Diseases | | | | |
| | Acute lymphoblastic leukaemia
Acute myeloid leukaemia
Chronic lymphocytic leukaemia
Chronic myeloid leukaemia
Hodgkins disease
Non-Hodgkins lymphoma
| Other Lymphoid Malignancies |
Multiple myeloma
Solitary plasmacytoma
Plasma cell leukaemia
Monoclonal gammopathy of unknown significance
Waldenstroms macroglobulinaemia
| Other Myeloid Malignancies |
The Myelodysplastic Syndromes
Refractory anaemia
Refractory anaemia with ring sideroblasts
Refractory anaemia with excess blasts
Refractory anaemia with excess blasts in transformation
Chronic myelomonocytic leukaemia
| The Myeloproliferative Disorders |
Essential thrombocythaemia
Polycythaemia vera
Myelofibrosis
Leukaemia and related disorders are cancers of the blood. This handbook provides information about
 | Blood, bone marrow and the lymphoid system (in health) |
| The signs and symptoms of blood cancers |
| The diagnostic tests used for blood cancer |
| The main forms of treatment |
For the most current information available you are advised to visit Leukaemia Research Fund website at www.lrf.org.uk. Our website is regularly reviewed and updated.
Specialised publications on the individual diseases can be obtained from Leukaemia Research Fund.
 | The blood in health |
"Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path...." William Harvey (1578-1657)
Blood consists of a fluid (plasma) which contains three main types of cells - red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (thrombocytes). The numbers of each type of blood cell vary between people and at different ages but these values are quite stable for healthy individuals. Each type of blood cell has different functions.
Red cells contain a pigment called haemoglobin, which can bind oxygen and carry it from the lungs to the tissues where it is released to fuel the body's chemistry. White cells are vital components of the body's immune system - its defence against invading organisms. The immune system consists of the white cells in our blood and a number of sites including lymph nodes, which are spread throughout the body, the spleen, tonsils, adenoids and other organs. The key components of these organs, called the lymphoid tissues, are large numbers of white cells called lymphocytes.There are several different types of white blood cell. Platelets form the first line of response to tissue injury, they stick together at the site of damage and stop the bleeding. They also release substances which trigger the formation of a firm clot, a scar and healing.
Production of blood cells
| Blood cell production |
All types of blood cell are made in the bone marrow which is a spongy tissue in the middle of bones. Blood cells are produced from very primitive cells called stem cells. Less than 1 in 5,000 of the marrow cells is a stem cell. The stem cells give rise to a progressively maturing series of different cell types which eventually lead to all the functional blood cells found in the circulation.
Growth and development of normal cells in the bone marrow is carefully controlled to produce the correct number of each type of cell to keep the body healthy. This is extremely demanding with about 3 million red cells and 120,000 white cells produced every second. All blood cells grow old and die when they are no longer needed. The life span of blood cells varies widely. Red blood cells live for about four months after they leave the bone marrow, the most frequent white cell, the neutrophil has a life time of just a few hours and platelets of a few days. It is because white cells and platelets have such short life spans that they cannot easily be replaced by transfusions, although some specialised lymphocytes live for many years. To maintain the proper numbers of each type of blood cell it is important that cells die off and are cleared from the blood at the end of their useful life span. A blood cancer results either from a failure of cells to grow old and die or an excessive, uncontrolled production of cells, or more commonly, a combination of both factors.
Both the production of blood cells, and maintenance of the correct numbers of each type of blood cell, are controlled by chemicals called growth factors. These will be mentioned again under treatment as some types of growth factor have been produced in the laboratory and are now used in treatment. It is also known that abnormal levels of growth factors are involved in the actual disease process in some cases, for example patients with myeloma have abnormal levels of a growth factor called Il-6 in the blood and bone marrow.
| The conditions |
"Whatever State of the human Body doth disorder the vital, the natural, or even the animal functions of the same, is called a Disease." Hermann Boerhaave (1715).
It is important to recognise that each patient is unique and their experience of their disease is equally unique. Any printed information is inevitably generalised. The only person who can offer reliable advice to a patient on how their disease might progress and how it might respond to treatment is their own doctor. Patients are entitled to ask for a second opinion (and many consultants recognise this and welcome such a suggestion) especially if the condition is a rare one or has presented in an unusual way. It should be emphasised that requesting a second opinion does not imply that a patient lacks confidence in their specialist. When someone has a serious, possibly life-threatening, illness it is natural that they wish to ensure they have sought all the advice available.
The word leukaemia comes from a Greek word which means literally “white blood”. Leukaemia is often referred to as cancer of the blood. The term refers to a group of closely related malignant conditions affecting the immature blood-forming cells in the bone marrow.
In leukaemia normal control mechanisms break down and the marrow starts to produce large numbers of abnormal white blood cells of an identical type
This disrupts the normal production of blood cells leading to anaemia and a low platelet count. Often in leukaemia the spleen and liver will become enlarged and this may cause abdominal discomfort. Also, in some cases, the lymph glands (described below) are enlarged. The large numbers of white cells being produced in leukaemia are all abnormal which means that patients may have frequent, severe infections because the diseased white cells are being produced in place of normal, infection-fighting cells.
Leukaemia can be classified as lymphoid or myeloid and as either acute or chronic. Lymphoid and myeloid refer to the type of white cell affected. If this is a lymphocyte or lymphocyte-like cell, the condition is called lymphocytic or lymphoblastic leukaemia. Myeloid leukaemias affect any of the other types of white blood cells or the red cell or platelet producing cells (called megakaryocytes). The terms acute and chronic are often misunderstood. They refer only to the speed at which the disease progresses if it is left untreated, not to the severity of the disease. Acute leukaemia comes on quickly and, if not effectively treated, will rapidly progress. Chronic leukaemia is slow to develop and slow to progress, even when not treated.
Lymphomas are cancers of the lymphatic tissues.
The lymphatic system is a series of fine vessels similar to blood vessels. It drains fluid away from the tissues and returns it to the bloodstream. Throughout the system there are small organs called lymph nodes (sometimes called lymph glands). There are clusters of nodes in the armpits, groins, neck and in the pelvis, abdomen and chest. In response to an infection the lymph nodes may become swollen. For example, the swollen glands that many people associate with a throat infection are really lymph nodes. They are packed with specialised white cells called lymphocytes. Lymphocytes also make up a significant proportion of the circulating white blood cells. Lymphocytes can be classified by special laboratory tests into B cells, T cells and null cells. These categories reflect their function; B cells are mainly responsible for production of antibodies, T cells control the behaviour of other lymphocytes and may be capable of killing some infectious organisms, especially viruses. One important group of null cells are the natural killer cells, which can kill infecting organisms and parasites directly.
The different types of lymphocytes are grouped within the lymph node in a very specific way according to their function. The spleen (an organ in the upper abdomen which helps fight infection and removes worn-out blood cells), the thymus (an organ under the breastbone) and the tonsils and adenoids (in the throat) are also part of the lymphatic system. There are localised areas of lymphoid tissue within the skin and in the gut wall. These can give rise to specific types of lymphoma. There are many different types of lymphoma but historically two main groups have been recognised. One group is called Hodgkin's lymphoma and the other is known as non-Hodgkin's lymphoma.
Multiple myeloma is a form of cancer that affects a specialised type of lymphocyte called a plasma cell. Plasma cells are a specialised form of B-lymphocyte that normally produce antibodies. Multiple myeloma is the commonest of the plasma cell malignancies. Occasionally myeloma presents in just one site (plasmacytoma) or as a leukaemia-like illness (plasma cell leukaemia).
Multiple myeloma is overwhelmingly a disease of later life. It is rare in young adults and unknown in children. The condition is called multiple myeloma because most patients have evidence of disease at a number of different bony sites in the body. The disease is accompanied by a breakdown in the structure of the bones. This is due to increased activity of cells in the marrow which continually break down and reform bone. In myeloma the destruction exceeds replacement and "holes" in the bones result. This also releases large amounts of calcium into the blood which may lead to kidney damage. There are several stages of multiple myeloma. A high proportion of patients with myeloma will, at some stage during their treatment, become free of symptoms and require no active treatment. This occurs even though the disease has not been eliminated. This is known as plateau-phase and may last for several years.
| Myelodysplastic syndromes |
The myelodysplastic syndromes (MDS) are a group of diseases in which the production of blood cells is severely disrupted. These are called:
| Refractory anaemia (RA) |
| Refractory anaemia with ring sideroblasts (RAS) |
| Refractory anaemia with excess blasts (RAEB) |
| Refractory anaemia with excess blasts in transformation (RAEBt) |
| Chronic myelomonocytic leukaemia (CMML) |
Myelodysplasia is a potentially confusing term that may be used either to describe certain abnormal features seen in the bone marrow or to refer to the specific condition MDS. If there is any doubt about which is meant, it is important for the patient to clarify with the specialist how the term is being used. In contrast to leukaemia, in which just one type of blood cell is produced in excessively large numbers, the production of any one and sometimes all types of blood cells may be affected in myelodysplastic syndrome. The poor quality of the blood cells produced means that a significant proportion of them are destroyed before they leave the bone marrow. This means that the levels of red cells, white cells and platelets in the blood may be abnormally low. When the levels of all types of blood cells are low the condition is called pancytopaenia.
Myelodysplastic syndrome is mainly seen in people over the age of 50 years and in this age group it is more common in men. In younger patients the numbers of men and women are about equal. Treatment of myelodysplastic syndrome is not usually aimed at affecting the progress of the underlying disease but at improving quality of life by reducing and controlling symptoms of anaemia (due to lack of haemoglobin), infections (due to lack of white cells) or spontaneous bleeding (due to lack of platelets). This is known as supportive treatment.
| The myeloproliferative disorders |
The myeloproliferative disorders are a group of conditions in which there is
overproduction of one or more type of blood cell. Polycythaemia rubra vera (PRV) mainly affects red blood cells, essential thrombocythaemia (ET) mainly affects platelets while in myelofibrosis there is excessive production of the fibrous tissue which normally acts as a support for the bone marrow.
Patients with aplastic anaemia have a failure of production of all types of blood cells. The bone marrow contains large numbers of fat cells instead of the blood producing cells which would normally be present. This is called marrow hypoplasia or aplasia. The disease in most cases is acquired, that is it is not inherited and is not present from birth. Marrow hypoplasia is an inevitable consequence of the use of high doses of drugs and radiotherapy in the treatment of cancer. However, this type of bone marrow failure differs from acquired aplastic anaemia in that prompt recovery is expected when the drug or radiation treatment is stopped. There is a rare inherited form of the disease called Fanconi anaemia.
The disease may affect people of any age but it is seen most often in young adults and in people over the age of 60 years.
| Causes of leukaemia and related diseases |
"The predisposing Causes of Cancer are three,...viz., age, parts, and hereditary disposition; perhaps climate..." John Hunter (1728-1793).
Like all cancers, leukaemias and the related diseases arise as a result of changes in, or damage to, the genes which control cell growth, development and division. In most cases, no specific cause can be identified. There are certain factors known to increase the risk of developing leukaemia or one of the related diseases. Very occasionally, there is a clear cause as in the cases of leukaemia and myeloma seen in atomic bomb survivors.
Inheritance
There is no evidence that any form of blood cancer can be inherited. Even in the very rare cases of blood cancer being present at birth, the disease has developed as a result of cell damage which happened in the womb. Recent research has demonstrated that in many cases of childhood leukaemia the initial genetic damage (which will eventually lead to leukaemia) occurs before birth. The factors in the mother's environment which lead to this are not known although there is clear evidence that smoking and/or heavy drinking during pregnancy increase the risk ofchildhood leukaemia.
In the majority of cases of leukaemia and other forms of cancer, there is no evidence that relatives of the patient are at greater risk than anyone else, though there are some inherited conditions in which the risk of developing cancer is increased. These conditions account for only a very small number of cases of blood cancer. If the same form of leukaemia occurs in more than one member of a family, it may be appropriate to consult a genetics counsellor. It should be possible to arrange this through your specialist.
It is thought that possibly 10% of cases of chronic lymphocytic leukaemia may be familial – there is a web site discussing this topic at www.icr.ac.uk/haemcyto/fcll/index.html. A small percentage of acute myeloid leukaemia cases may be familial – this is very uncommon.
Down's syndrome is associated with an increased risk of developing leukaemia. Children with Down's syndrome often have a leukaemia-like blood picture which becomes normal without treatment. This suggests that one or more genes on chromosome 21 may play important roles in the normal development of blood cell production.
Age
In general, the risk of developing leukaemia or a related condition increases with age. With over three million new blood cells being produced every second, it is inevitable that some cells will accumulate damage to genes over the years. The only reason that cancer is not even more common with increasing age is that all cells in our body have quite sophisticated defences against harmful mutations. Usually, when cells undergo changes to their genetic material these are detected and the cell undergoes a form of suicide, called apoptosis or programmed cell death. There are a few types of blood cancer, however, which occur more commonly in childhood than in adults. One of these is acute lymphoblastic leukaemia, which is more common between the ages of two and five years than at any other age. This is known as the childhood peak of leukaemia. Some diseases, such as myeloma and chronic lymphocytic leukaemia, are extremely rare in young people.
Infections
Leukaemia is not a condition that can be acquired by contact with a person who has the disease. It is however possible that some viral infections may act as triggers or as co-factors. The pattern of exposure to infection may explain the childhood peak of acute lymphoblastic leukaemia. As the level of childhood infectious disease has declined in developed nations and families have become smaller, it has become less common for children to be exposed to infection(s) in the first year of life. Rarely, a delayed first stress on the immune system may lead to the development of leukaemia. Evidence to support this includes a reduction in risk for leukaemia seen following some types of immunisation and in children who attend crèches or similar groups during the first year of life.
The population mixing that occurs when a new town is built or large numbers of workers move into a new area has also been suggested as a significant cause of childhood leukaemia. In this case the stress is less on the timing of exposure and more on the novel nature of the infectious agent. This theory and the timing of infection theory are not exclusive; it is likely that both factors influence the risk of developing leukaemia.
There is only one virus definitely known to cause leukaemia or lymphoma in humans. This virus is called HTLV-1 (human T cell leukaemia/lymphoma virus). It is only common in Japan and to a lesser extent in the Caribbean. It takes decades from the time of infection for the leukaemia or lymphoma to develop. This virus causes very few cases of leukaemia or lymphoma seen in the UK.
A virus called the Epstein-Barr virus (EBV) is associated with some cases of a type of lymphoma called Hodgkin's lymphoma in children and older adults. It is clear that EBV by itself is not enough to cause the disease because infection with the virus is very common in the general population whereas Hodgkin's lymphoma is fairly rare.
There are no other definitely identified links between a virus and leukaemia or lymphoma but some experts believe that other forms of the disease(s) may be caused by an abnormal reaction to an immune stimulus, possibly from a virus.
Aplastic anaemia, which is a rare disease, may occur as a complication of viral hepatitis or of other viral infections. Viral infections are, however, probably the cause of only a very small number of cases.
Chemicals
The commonest chemical exposure linked to leukaemia is almost certainly cigarette smoking; which has been shown to be a significant risk factor for acute myeloid leukaemia. It has been estimated that as many as a quarter of all cases may be caused by smoking. Benzene in high concentrations is known to cause leukaemia and it is possible that other similar chemicals may increase the risk of leukaemia and related diseases. The major source of benzene exposure in the UK population is cigarette smoke. Some people are exposed to benzene in the course of their work. There are very strict regulations governing the use of benzene in the workplace and it is very unlikely that anyone in Britain would be exposed to dangerous levels of benzene because of their occupation. There are very small amounts of benzene present in unleaded petrol but this is not considered high enough to be a leukaemia risk.
In some groups of workers, for example farmers and agricultural workers, there appears to be an increased risk of certain conditions, such as myeloma and lymphoma. This may be related to chemical exposures but there are many other features of an agricultural lifestyle which might be responsible including chronic exposure to pollen and other biological material which might stimulate the immune system.
Radiation
Ionizing radiation
Ionizing radiation is the term used for the kind of radiation given off by X-ray
machines or by radioactive materials. High doses of radiation can definitely increase the risk of leukaemia and related diseases. This has been shown in the atomic bomb survivors and by the experience of other people accidentally exposed to high levels of radiation. Most experts believe it is extremely unlikely that very low levels of radiation can cause leukaemia or related diseases. Very few, if any, people in Britain are likely to be exposed to the high levels of radiation which are known to cause leukaemia.
Some years ago it was reported that children who had been exposed to medical X-rays before birth were more likely to develop leukaemia. The introduction of ultrasound has virtually eliminated the need to use X-rays during pregnancy. Special care is taken by hospital staff to avoid X-raying women who might be pregnant. Modern X-ray machines deliver a much smaller dose of radiation. On the very rare occasions when a pregnant woman needs to be X-rayed, special precautions are taken to reduce the risk even further.
Non-ionizing radiation
Some studies have suggested that there appears to be an increased risk of leukaemia in children who live near electrical power-lines or other electrical facilities. It is suggested that electromagnetic fields (EMF) may be capable of either causing leukaemia or accelerating the development of the condition. These studies have relied on very small numbers of cases and on estimates of the strength of exposure to electromagnetic fields. The majority of published reports have concluded that it is very unlikely that there is any increase in the risk of leukaemia as a result of exposure to electromagnetic fields. The use of electricity has increased enormously over the last 20 to 30 years whilst the rate of childhood leukaemia has remained relatively constant. The peak in the number of childhood cases between two and five years of age cannot be explained by this theory.
A consortium of UK cancer charities has funded the largest ever study of possible causes of childhood cancer. One aspect of this study has been to consider the possibility that proximity to overhead power lines or other electrical facilities might increase the risk of childhood leukaemia. The results of this study have shown no evidence in the UK of any relationship between proximity to power lines and the risk of childhood leukaemia. The majority of large studies in other countries have confirmed similar negative results.
A recent report indicated that there may be an association between very high magnetic fields (more than 0.4 micro Tesla) and a slight increase in risk of childhood leukaemia. The report stressed, however, that this association did not prove that exposure to powerlines caused leukaemia. Importantly, the report emphasised that only about 0.5 % of children in the UK would be exposed to such high intensity fields.
Secondary leukaemia
Some forms of leukaemia and related diseases are seen more often than is usual in patients who have received intensive therapy with anti-cancer drugs. This is known as secondary leukaemia. The most common conditions seen in this group of patients are acute myeloid leukaemia and myelodysplastic syndrome. It is important to understand that only a very small percentage of cancer patients go on to develop leukaemia or a related condition as a result of their treatment. Unfortunately, these secondary malignancies are often more resistant to drug treatment and may be very difficult to treat.
There are two major types of treatment-related AML. One type, which follows treatment with alkylating agents, tends to come on within five to ten years after treatment, often is preceded by MDS and is associated with characteristic chromosome changes. The other type results from treatment with a class of drugs called topoisomerase II inhibitors – there is usually only a short delay after treatment, the condition presents as myelomonocytic or monocytic leukaemia (rather than MDS) and the chromosome changes are different.
| Diagnosis |
"Observe, record, tabulate, communicate. Use your five senses. It is much
more important to know what sort of a patient has a disease than to know
what sort of a disease a patient has." William Osler (1849-1919)
In leukaemia and related diseases the signs and symptoms of illness are non-specific. The features may be different in the different types of leukaemia. These signs and symptoms can all occur in more common, non-cancerous conditions. For example, most patients with brain tumours will have headaches at some time but very few headaches are caused by brain tumours. Patients may show any combination of symptoms. Some may be more obvious than others. Initial symptoms may appear to be nothing worse than a bout of flu. Anyone who develops persistent symptoms should see their doctor promptly.
The symptoms which are seen most often in leukaemia and related diseases are:
| Fatigue and limited capacity for exercise |
| Breathlessness on exertion |
| | Paleness, tiredness, weakness, or fatigue and breathlessness are caused by anaemia (low haemoglobin levels which reduces the ability of the blood to carry oxygen) |
| Excessive bruising, often spontaneous |
| Bleeding from mucous membranes (gums, etc.) and from the gut; pre-menopausal women may have heavy menstrual bleeding |
| | These symptoms are caused by a low number of platelets. |
| Persistent infections |
| Fever, which is often present even in the absence of clear indications of infection |
| Night sweats |
| | These are caused by low numbers of normal white blood cells and by a high metabolic rate. Infections are a problem because there are few normal white cells present. Fever may occur even in the absence of infection, probably as a result of a general speeding up of body metabolism because of the high rate of tumour cell production. This may also explain the night sweats that are typically a feature of lymphoma and some forms of leukaemia. |
| Abdominal discomfort |
| Feeling of fullness when eating |
| | These may be a problem in those conditions where there is swelling of the spleen, the liver or both. |
| Enlarged lymph nodes |
| | Swollen lymph nodes are a particular feature of lymphoma but they may also be present in chronic lymphocytic leukaemia or acute lymphoblastic leukaemia. |
In patients with multiple myeloma there are additional signs and symptoms.
| Pathological fractures |
| Pain in bones |
| | These are caused by bone lesions. Abnormal blood cell production in the bone marrow or damage to the bone in myeloma may cause the pain and lead to pathological fractures, that is broken bones resulting from very slight injuries. |
In most cases of leukaemia or related diseases the initial diagnosis is made at a local (District General) hospital. It is often necessary, depending on the exact diagnosis, for patients to be referred to specialist centres for treatment.
Once initial treatment is complete many patients continue their treatment under the care of their local hospital; this is known as shared care.
Initial tests
These are carried out at the time of diagnosis or shortly afterwards.
Full blood count
This is a test which measures the different types of blood cell and the haemoglobin level. The full blood count is done on a machine. When a patient has leukaemia or a related condition this is usually clear from the initial results. These results may even indicate the most likely specific diagnosis. If the blood count shows clear abnormalities suggesting the possibility of leukaemia or a related condition, the general practitioner will be contacted urgently by the laboratory where the test has been done. A repeat blood count will be done (to confirm the result) and further tests will be arranged. A patient with leukaemia is likely to have a low red cell and platelet count and be anaemic. The total white cell count is usually much higher than usual. Most of these white cells, however, are immature and are incapable of fighting infections. This means that patients are prone to infection. In the acute leukaemias the white count may occasionally be lower than normal values.
Polycythaemia rubra vera will cause a very high haemoglobin level, red cell count and a high packed cell volume (PCV). The PCV is a measure of what proportion of the total blood volume is made up by the red blood cells. Patients with essential thrombocythaemia have very high platelet counts. The white cell count may be normal or reduced.
In patients with aplastic anaemia all the types of blood cell i.e. red cells, white cells and platelets, will be reduced.
Blood film report
If the results of a full blood count are abnormal, a blood film will be examined under the microscope. The appearance of leukaemia and many of the related diseases on a blood film is quite distinctive and the diagnosis is often clear by this stage. The blood count and blood film reports are of less significance in lymphoma and multiple myeloma, in which they often appear normal. In some cases of acute leukaemia, especially in children, the blood count and film may be normal or even show reduced numbers of cells.
Additional tests
These are carried out to confirm the diagnosis and may be repeated
throughout the treatment and afterwards in order to monitor progress.
Bone marrow aspirate/biopsy
A bone marrow sample is necessary in almost all patients with leukaemia or a related disease. This involves obtaining a small amount of marrow from inside the bone with a needle, and usually a sample from the bone itself to show the structure of the bone marrow cavity. The first is known as a bone marrow aspirate, the second is a bone marrow trephine. The samples are usually obtained from the back of the hipbone, although rarely the sternum (breastbone) may be used instead for bone marrow aspirates (but not for trephines). The procedure causes some discomfort but does not take very long. The procedure is carried out with a local anaesthetic and in some cases sedation. In children, it is quite common for a general anaesthetic to be given.
Elderly patients with chronic lymphocytic leukaemia who are well at the time of diagnosis often need no treatment initially and they may not need to have a bone marrow biopsy. If treatment is required later, a biopsy will often be taken before treatment begins.
Chromosome analysis (karyotype)
This may be done on cells from the blood, the bone marrow or both. In leukaemia and related diseases there are changes to the chromosomes of the affected cells compared to normal cells from the same patient. The exact pattern of these changes may be important in diagnosing the exact type of leukaemia and in predicting the likely response to treatment. In some conditions, these changes may also allow the use of very sensitive tests to determine how well the disease is responding to treatment.
Diagnostic imaging
This may be carried out at various stages. Some patients will have none of the
following tests were as some may have them done repeatedly.
| X-ray or radiograph |
| | Most patients with leukaemia will require X-rays even if these are only chest X-rays to screen for infection. Some patients will require frequent X-rays. Patients may worry about this because they associate radiation with cancer but this should not be a concern. Modern diagnostic X-ray equipment gives very low doses of radiation and the benefit to the patient heavily outweighs any possible risk. |
| CAT scan or CT scan |
| | This is a special form of X-ray examination. A series of X-ray pictures are taken very rapidly by a machine. A sophisticated computer then builds up the information into a 3-D picture of the internal organs that can be examined “slice-by-slice”. This overcomes the problem with conventional X-rays of difficulty in seeing soft tissues within the body. This is of particular importance when soft tissues would normally be obscured by shadows from bones. |
| MRI scan |
| | MRI scans do not use X-rays. This form of imaging uses very strong magnets and reveals much more detail of soft tissues such as the brain and can detect infiltration by tumour. MRI scanning is very accurate in picking up multiple myeloma and lymphoma. |
| Classification, staging and prognostic stratification |
"The urge to classify is a fundamental human instinct; like a predisposition to sin, it accompanies us into the world at birth and stays with us to the end." Hopwood, A. T.; Proceedings of the Linnaean Society of London (1957)
The value of classification of the diseases is that in virtually all the main forms of blood cancer there appear to be biologically different subtypes of disease. These subtypes probably have different causes and in many cases respond differently to treatment. In some instances, the information used to classify the diseases is also important in predicting the likely response to treatment and prognosis. There are a number of systems for classifying the leukaemias and related diseases. These are based on morphology (the appearance of cells/tissues) and immunological and cytogenetic investigations.
In all forms of leukaemia, lymphoma and related diseases the initial diagnosis and classification is based on the morphology of the tumour cells as seen under the microscope. In the acute leukaemia and myelodysplastic syndromes morphological classification is based on a convention called the FAB system. This is described after the group of French, American and British haematologists who designed the scheme.
There are separate FAB classifications for acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and some conditions related to leukaemia. The ALL FAB classification is not widely used in clinical practice.
Management of L1 and L2 ALL is essentially the same and the L3 type is so
different that it is treated more like a lymphoma than like other types of ALL.
There are eight subtypes of AML in the FAB system. The most important of
these in relation to treatment and outlook are listed below.
|
| M3 | Also known as acute promyelocytic leukaemia. This form of the disease is usually very responsive to vitamin A derived drugs |
| M6 | This is also called erythroleukaemia because many of the leukaemia cells appear to be immature red cells rather than white cells |
| M7 | This form of AML affects the cells which make platelets |
The FAB classification of the myelodysplastic syndromes is:
| Refractory anaemia |
| Refractory anaemia with ring sideroblasts |
| Refractory anaemia with excess blasts |
| Refractory anaemia with excess blasts in transformation |
| Chronic myelomonocytic leukaemia |
Immunological classification is mainly applicable to lymphoid malignancies; it is based on the type of lymphocyte affected, i.e. the B cell or the T cell. The immunological classification, together with the level of development in the T or B cell series, and the characterisation of chromosome abnormalities is extremely useful in predicting the response to treatment.
Lymphomas are classified according to a number of features including the appearance of the affected tissues under the microscope, the results of immunological tests and various specialised staining methods. In the past, a number of different classification systems have been in use. This caused great difficulty for clinicians and researchers in this field. As a result a classification called the Revised European American Lymphoma (REAL), which is more clinically and practically useful, was introduced. The REAL classification has now been adopted, with minor modifications, by the World Health Organization. This is called the REAL/WHO classification.
Occasionally patients are reclassified from a diagnosis of leukaemia to lymphoma or the other way around. This may seem alarming, implying uncertainty on the part of the doctors. In fact, lymphoma and lymphoid leukaemias represent extremes of a spectrum. In cases in the middle of this spectrum the diagnosis may depend on the specialist's opinion. This should not be a cause for alarm because in these borderline instances the treatment is the same however the condition is classified.
Staging is a system of estimating how extensively a disease has progressed from its starting point and whether the patient is showing significant symptoms. It is not used for acute leukaemia because the disease is usually widespread throughout the body and patients typically have symptoms of their illness when they are diagnosed.
In chronic lymphocytic leukaemia many patients are diagnosed by chance at a time when they feel perfectly well. The staging system for this disease is based on whether the lymph glands and spleen are enlarged as well as on the results of laboratory tests.
The staging system for lymphoma depends on the extent of spread of the disease and on what signs and symptoms the patient may have. For myeloma it depends not on the extent of spread but on the results of various tests which, taken together, indicate the severity of the disease.
In most other conditions related to leukaemia decisions on prognosis and on treatment are based on the classification of the subtype rather than on a staging system. In some diseases there are accepted methods for predicting which patients are likely to have good or less good outcomes.
These predictions are based mainly on the results of laboratory tests, although age and general health also have to be considered. This process is known as prognostic stratification. The exact number of categories and the way in which patients are assigned to categories vary widely between the different diseases.
| Treatment |
"“Do not waste time and annoy the patient by doctoring a symptom; attack
the disease" Charles Warrington Earle (1891)
The different types and subtypes of leukaemia and related diseases vary greatly in their response to different forms of treatment. Some forms of the diseases are chemosensitive which means they are easily treated with chemotherapy (anti-cancer drugs). Similarly, forms of the diseases that are very responsive to radiotherapy are known as radiosensitive. If a patient has no response to treatment, their condition is described as refractory or resistant.
The primary objective of treatment is to eliminate all detectable tumour cells. This is called a remission. A complete remission occurs when the patient is symptom-free and laboratory tests show no evidence of malignant cells. Sometimes this will mean that the disease has been completely eliminated and the patient is cured. However even the most sophisticated tests cannot detect very small numbers of tumour cells and patients who are in complete remission, according to all available tests, may still have tumour cells present. Frequently a patient responds to treatment but there is still evidence of the disease; this is called a partial remission or partial response. If a patient has achieved either a partial or a complete remission but the disease later returns this is called a relapse. In some cases relapse occurs while the patient is still receiving active treatment. This is a relapse “on-treatment” and often indicates that the alignant cells are resistant to the drugs or other treatment being used. This is often very difficult to treat although it may respond to the use of new drugs, particularly when these attack the malignant cells in a different way to those already used. In other cases the condition relapses after all the active treatment has been completed. This is a relapse “off-treatment”. Relapses off-treatment may occur because not all of the malignant cells have been killed when treatment is stopped. When this happens further treatment using the same drugs that were used to achieve the original remission may be successful.
Some patients may have very few symptoms and very slowly progressing disease, for example some older patients with chronic lymphocytic leukaemia. If this is so, the advice will often be that no treatment is necessary. However, the patient should have regular check-ups so that treatment can commence if the disease becomes more active. In other cases, such as some forms of myelodysplastic syndrome, the patient may be anaemic and have symptoms but there may be no treatments available which affect the course of the disease. In this situation treatment can be offered to control the symptoms and this may be referred to as supportive treatment or palliative therapy.
The mainstay of treatment for leukaemia and related conditions is the use of anti-cancer drugs (chemotherapy). Most anti-cancer drugs act by killing all dividing cells. Although this is effective against the cancer it also causes side-effects by damaging dividing cells, e.g. in the hair roots, skin and gut. There are some drugs that are more specific in killing the tumour cells and these tend to have fewer side-effects. For some types of leukaemia it is usual to use combinations of drugs to reduce possible problems of resistance that may otherwise develop. A specialised form of chemotherapy called biological therapy uses versions of natural substances such as interferon or growth factors which are produced in the laboratory. A new generation of drugs is emerging which are designed to target particular characteristics of the leukaemia cell. An example is Glivec (imatinib), which is now recommended as the standard choice for first-line treatment of chronic myeloid leukaemia.
Radiotherapy uses high energy X-rays to kill tumour cells. It is not normally used in leukaemia because the tumour cells are spread throughout the body and radiotherapy would give an unacceptably high dose of X-rays to healthy cells. It has been used in the past to kill acute lymphoblastic leukaemia cells in the fluid around the brain and spinal cord (where drugs cannot easily penetrate), but this use is becoming infrequent in children. Reduction in use of radiotherapy to the central nervous system (CNS) has been achieved by finding better ways to use existing drugs. Radiotherapy is mainly used in the treatment of lymphoma and in some of the plasma cell malignancies such as multiple myeloma and solitary plasmacytomas. It was thought that radiotherapy worked mainly by directly killing cells. It is now known that radiotherapy causes severe damage to the dividing cells without killing them. Such damaged cells normally self-destruct in a process called programmed cell death or apoptosis. The degree of radio-sensitivity of a particular type of blood cancer depends on whether the cells are still liable to die off if damaged. In some cancer cells damage to the genes that cause injured cells to self-destruct makes them resistant to radiation. Radiotherapy is just as non-selective as chemotherapy but, because it is possible to aim the radiation beam accurately, the side-effects tend to be more localised. Total body irradiation may be used in bone marrow/stem cell transplantation to prevent the recipient's immune system from rejecting the donor's stem cells.
| Stem cell transplantation |
Stem cells from the bone marrow or blood are necessary to restore normal blood cell production when the bone marrow no longer functions. Sometimes damage to the bone marrow is the result of intensive treatment for leukaemia or a related cancer of the blood, in which case the patient requires a stem cell transplant. The most common reason for a transplant is treatment of leukaemia or other blood cancers, when these have a poor chance of being cured with conventional treatment. The most important aspect of the stem cell transplant is to provide enough of the stem cells that produce all the blood cells. It is also important to avoid complications of this treatment such as infection and rejection of the transplant.
Sources of stem cells
Stem cells may be obtained either from the bone marrow or by using a special machine to separate them out from the circulating blood. A transplant using stem cells obtained from the blood is called a peripheral blood stem cell transplant. In either case the stem cells may be those of the patient or from a donor.
An exciting development in the field of paediatric haematology is the use of stem cells from the umbilical cord blood of a newborn infant. It is hoped that tissue matching will be less of a problem using cord blood stem cells. These cells can be frozen and stored which offers the possibility of “off-the-shelf” transplants. There is very little experience in the use of cord blood stem cells for adult recipients. The major problem is the comparatively low number of stem cells available in cord blood donations.
Types of donor
Transplants may be performed using the patient's own stem cells. This is called an autograft. Any form of transplant from a donor is called an allograft. If a family member of the patient provides stem cells they are known as a related donor. The best match in terms of tissue typing is an identical twin. This is called a syngeneic transplant. However, an identical twin may not be the ideal donor because there may be a higher risk of the original cancer returning. The most common related donor is a tissue matching brother or sister of the patient, but occasionally a parent or child of the patient may be suitable. This form of transplant is only feasible for about one in three patients who have a sibling or, rarely, a parent with a matching tissue type. Less closely related kin are rarely a match so they are not usually tested. If no related donor is available, it may be necessary to seek a matched unrelated donor.
There are over nine million registered potential bone marrow donors worldwide. An increasing number of bone marrow transplants involve unrelated donors. The chance of finding a suitable matched unrelated donor is between one in 10,000 to 20,000. Patients who are not of Caucasian origin may experience greater difficulty in finding an unrelated donor. This is because tissue types vary in their frequency between different ethnic groups and the overwhelming majority of potential volunteer donors are Caucasians. For this reason donor registries are particularly anxious to recruit more volunteers from the ethnic minority communities.
Eligibility for transplantation
All transplants, whether donor or autologous, carry certain risks and the general physical condition of a patient is a key factor in determining whether they are eligible. The general health criteria are more strict for a matched donor transplant than for an autologous transplant. Until very recently this was reflected in a lower maximum age limit for donor transplants. A new technique, called a mini-transplant or non-myeloablative transplant, has extended the range of availability of donor transplants. The key factor in the new technique is that it uses less intensive preparation with drugs and radiation.
A splenectomy may be performed in any form of blood cancer in which a very enlarged spleen is causing symptoms. The benefits of removing the spleen (splenectomy) vary depending on the degree of enlargement of the spleen and the exact nature of the disease. Splenectomy will, at the least, relieve the discomfort resulting from an enlarged spleen. In patients who have had their spleen removed there is a higher risk of certain types of serious infection. The risk is not so great that patients need to change their lifestyle but they should see a doctor immediately if they become ill and they must inform the doctor that they have had a splenectomy. They will be immunised against certain infections and take penicillin for life to reduce the risk of infection.
A newly diagnosed patient is very likely to be invited to take part in a clinical trial. Clinical trials are carefully supervised comparisons of treatments to determine the best possible options. The starting point for a clinical trial is the best currently available treatment. The most common aims of a trial are to find out whether a new drug or a new way of using existing drugs might give improved results.
Clinical trials are an absolute requirement for the advancement of treatment for the blood cancers. The best available treatment can only be replaced by one that is compared against it and shown to be superior. There are three types of trial to evaluate either a new drug or clinical target for an already licensed drug. Phase I trials primarily focus on safety to establish how much of a new drug can be given to patients without causing serious adverse effects. Phase II trials involve small groups of patients to establish the best response to different doses and frequency of administration of a drug or combination of drugs. Phase III trials compare the effectiveness of the new drug (or combination with existing drugs) with the best available treatment to date
Most phase III trials are called randomised controlled trials because patients are allocated at random to one of the treatment arms. Any patient invited to join a trial will have a clear explanation from their doctor of what is involved. Any patient can refuse to enter a trial or withdraw at any time without any prejudice to the quality of their care. Most drug treatment (chemotherapy) is given according to treatment plans called protocols. Protocols stipulate which drugs should be used, the range of dosage and the timing of the drugs. If a patient is taking part in a clinical trial then they will definitely be treated according to a set protocol. Protocols are usually known by names derived from the initials of the drugs included. An example is CHOP which may be used in the treatment of lymphoma. The initials stand for cyclophosphamide, hydroxydaunorubicin, Oncovin (which is another name for vincristine) and prednisolone.
| Types of drugs used in the treatment of leukaemia and related diseases |
All anti-cancer drugs must be used with extreme caution, if at all, in patients who are pregnant or breastfeeding. Men and women who are on treatment are advised to take contraceptive precautions. Your specialist will give advice on how long these must continue after completion of treatment. Some forms of anti-cancer treatment may impair fertility. Patients who are hoping to have children after treatment must discuss the options to preserve fertility or store semen with their specialist.
Side-effects of medication often depend on the dosage being administered and on what other medical conditions a patient may have. It is preferable that advice on side-effects is given by a patient's specialist. Information on specific drugs can be obtained from the Electronic Medicines Compendium website, which can be accessed at http://emc.medicines.org.uk .
There is no evidence that any special diet can influence the progress of leukaemia or any related condition. Patients should seek to ensure that they have a healthy balanced diet. If patients have no appetite, or are having difficulty eating, the hospital dietician may be able to offer advice. There are no foods which must always be avoided, unless a doctor advises otherwise. Alcohol, in moderation, is usually permitted except where it may interact with certain drugs. Some patients with lymphoma find that they become intolerant of alcohol by either becoming very sensitive to small quantities or even experiencing unpleasant reactions when they drink.
Vitamin supplements have not been shown to have any effect on the disease in normal amounts. Laboratory experiments have shown that some cancer cells grow better in the presence of very large amounts of Vitamin C. It is probably unwise to take very large dosages of any vitamin or other dietary supplement unless advised by your doctor to do so.
| Alternative and complementary therapies |
Alternative therapies in this context mean treatments used in place of conventional treatment and complementary therapies mean treatments used alongside conventional treatment.
There are many extravagant claims made for alternative therapies, none of these has ever been substantiated and many patients have lost their lives as a result of rejecting conventional treatment. Anecdotal claims for cures in cases where patients have also received conventional treatment should be regarded with particular caution. Most treatments do not have their maximum effect immediately and it is common for patients to credit the most recent therapy with any improvement. Warning signs of “quackery” include claims that a given treatment will cure many different diseases (with widely differing causes and natures), claims that a treatment cures all forms of cancer and claims that a treatment will cure cancer and AIDS.
Complementary therapies, such as aromatherapy and other massage therapies may offer significant quality of life benefits. There is no evidence that they affect the underlying disease process. Massage therapies should be undertaken with care by patients with lymphoma. Although it may be perfectly safe there is a theoretical risk that massage might force tumour cells into the circulation. Patients should check with their doctors before undertaking complementary therapies. The Bristol Cancer Help Centre (0845 123 2310) can offer information and advice on complementary therapies for cancer patients.
| Summary |
All of the conditions discussed in this booklet affect the bone marrow or the lymphoid system. The behaviour of the diseases is very different. Some of the conditions would be rapidly fatal if not treated whereas others are compatible with a long survival even without treatment. The severity of symptoms is very variable. Some patients, for example those with chronic lymphocytic leukaemia, may have no symptoms at the time of diagnosis. When symptoms are present they may resemble a bout of flu or other minor illness.
In most cases the cells affected are part of the immune system which means that patients are very susceptible to infection. Other symptoms depend on how badly the bone marrow is involved and on the direct involvement of other organs or tissues. If the spleen or liver are swollen this may cause abdominal pain. If the bone is affected, particularly in myeloma, then there may be quite severe bone pain.
The only person who can offer reliable advice to a patient on how their disease might progress and how it might respond to treatment is their own doctor. Patients are entitled to ask for a second opinion and many consultants recognise this and welcome such a suggestion, especially if the condition is a rare one or has presented in an unusual way.
It is important to emphasise that requesting a second opinion does not imply that a patient lacks confidence in their specialist. When someone has a serious, possibly life-threatening, illness it is natural that they wish to ensure they have sought all the advice available.
It may be helpful for patients or relatives to seek information from other patient support organisations. Reading textbooks is not recommended, particularly when these are found in public libraries and therefore very likely to be out of date. Even the most recent textbook will have been written a year or more before it reaches publication and parts will almost certainly be out of date. Clinicians supplement the information in textbooks by reading specialist medical journals and by attending conferences and meetings. A great deal of information can now be found on the Internet and especially on the World Wide Web. It is important to remember that anyone can place material on the Web and much of this is inaccurate and sometimes even dangerous. Leukaemia Research’s website, www.lrf.org.uk, has links to many other sources of information on leukaemia and related diseases. Although we cannot guarantee the content of other websites we have selected those which seem likely to be the most reliable. It is usually best to start with a trustworthy organisation and follow links from that site rather than rely on typing a disease name into a search engine.
In seeking information it is important to always remember that the only person who can offer reliable advice is a doctor with the appropriate expertise and access to the patient's full notes. In particular it is important to be aware that each individual will respond differently to treatment and, even in those diseases which have less promising outlooks, many patients will do better than average.
|
|
|
|
