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Updated 25 August 2014

Leukaemia

Leukaemia is a cancer of the blood forming cells. It starts from a single immature cell that becomes abnormal. Over time, several changes take place in that cell before

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Summary

  • Each year, 35 people in every million learn that they have leukaemia of whom five will be children.
  • Leukaemia is a cancer of the blood forming cells.
  • It starts from a single immature cell that becomes abnormal and starts to divide in an uncontrolled fashion.
  • Leukaemia is grouped according to the speed at which the disease develops and the type of cell that becomes abnormal.
  • Treatment for leukaemia is complex, varies with the type of leukaemia and is not the same for all patients.

Definition

Leukaemia is a cancer of the blood forming cells. It starts from a single immature cell that becomes abnormal. Over time, several changes take place in that cell before it becomes malignant. Once it is malignant, the cell keeps producing large numbers of malignant daughter cells, some of which mature, and some of which remain as immature as the original abnormal cell.

To understand leukaemia, it is helpful to know a little about how blood is made, what the different types of blood cells are, and about what happens when leukaemia develops:

  • Normal Blood Cells: The blood is made up of a fluid called plasma and three types of cells. Each type has special functions.
  • White blood cells (also called WBCs or leukocytes) help the body fight infections and other diseases. There are several different types of leukocytes, each with different functions. Neutrophils and monocytes are the most important cells to fight acute infections such as those caused by bacteriae. Monocytes also play an important role in chronic infection where they are joined by lymphocytes that control and produce antibodies to germs. Two other cell types occur in the blood and these are eosinophils, that play an important role in allergies and parasitic infections and basophils.
  • Red blood cells (also called RBCs or erythrocytes) carry oxygen from the lungs to the body's tissues and take carbon dioxide from the tissues back to the lungs. The haemoglobin in the red cell gives them their characteristic red colour.
  • Platelets are like tiny plugs that block holes in blood vessels and help form blood clots that control bleeding.
  • Blood cells are formed in the bone marrow, the soft, reddish-brown spongy centre of bones. New (immature) blood cells are called blasts. Blasts mature to form white blood cells, red blood cells or platelets. Normally, blood cells are produced in an orderly controlled way, as the body needs them.
  • Leukemic cells: When leukaemia develops, a single cell changes and starts producing large numbers of blasts in an uncontrolled way. Depending on the type of leukaemia, these blasts either do not mature at all, or mature into poorly functioning versions of their normal counterparts.

Different types

Leukaemia is grouped according to the speed at which the disease develops. Acute leukaemias develop fast, while chronic leukaemias develop more slowly. This corresponds with how well the leukaemia cells mature. Acute leukaemia cells are mostly stuck at the blast stage while most chronic leukaemia cells develop into almost normal mature leukocytes.

Leukaemia is then further divided according to what type of cells the leukaemia cells are trying to become. This is either lymphoid (also known as lymphocytic), for cells trying to be lymphocytes, or myeloid (also known as myelogenous or non-lymphocytic), for all the other cell types.

This gives us four main groups of leukaemia:

  • Acute lymphocytic leukaemia (ALL) is the commonest leukaemia in children, although it also affects adults.
  • Acute myeloid leukaemia (AML) occurs in both adults and children. This type of leukaemia is sometimes called acute non-lymphocytic leukaemia (ANLL). AML is further divided according to which type of myeloid cell the blasts show features of trying to become, according to the proportion of mature cells and according to whether or not certain specific abnormalities of chromosomes are present. Of these, acute promyelocytic leukaemia is the only one where the treatment is appreciably different.
  • Chronic lymphocytic leukaemia (CLL) mostly affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children.
  • Chronic myeloid leukaemia (CML) occurs mainly in adults. A very small number of children also develop this disease. This was the first leukaemia ever recognised, and gave leukaemia its name, from the Greek, "leuk-" (meaning "white") and "-aemia" (meaning "blood"). Literally "white blood", from the thick white layer of leukocytes that can be seen in CML if blood in a tube is allowed to stand.

There are several other uncommon types of chronic leukaemia (also referred to as chronic lymphoproliferative conditions) such as hairy cell leukaemia, prolymphocytic leukaemia, adult T-cell leukaemia/lymphoma, Sezary syndrome, chronic myelomonocytic leukaemia, large granular lymphocyte leukaemia, plasma cell leukaemia and mast cell leukaemia. These are not specifically discussed here, although many of the principles will be same.

Cause

The cause of leukaemia is unknown for the majority of patients. There are however a few known causes.

These are:

  • exposure to radiation as was seen at Chernobyl, Hiroshima and Nagasaki. Patients who receive large doses of radiotherapy for other cancers also have a higher chance of getting leukaemia.
  • some chemotherapy drugs may increase the risk of getting AML.
  • some viruses increase the risk. Epstein-Barr virus is associated with a subtype of ALL but only a very small proportion of people who get infected by the virus develop leukaemia.
  • previous blood disorders such as myelodysplasia and aplastic anaemia.
  • benzene exposure is associated with CML.
  • hereditary risk factors. Having Down's syndrome increases the chance of developing AML.

For most of these causes, a large number of people are exposed but very few actually develop leukaemia. This is linked to the "multi-hit" theory of the development of cancers, where a cell has to be damaged ("hit") in a number of different ways over time before it becomes cancerous.

Symptoms

When leukaemia develops, the leukaemia cells take over the bone marrow and prevent the normal formation of the different blood cells.

They affect the normal three cell lines and their functions:

  • Leukaemia cells are abnormal cells that cannot do what normal blood cells do. They cannot help the body fight infections. For this reason, people with leukaemia often get infections and have fevers.
  • They crowd out the normal blood-forming cells. As a result there are not enough red blood cells to carry oxygen, so patients become tired and pale (called anaemia), and there are not enough platelets to stop bleeding and bruising.

In acute leukaemia, symptoms develop quickly. In chronic leukaemia, symptoms may not appear for a long time; when symptoms do appear, they are generally mild at first and get worse gradually. Doctors often find chronic leukaemia during a routine checkup.

Some of the common symptoms of leukaemia are:

  • Fever, chills, sore throat and other flu-like symptoms
  • Weakness and fatigue
  • Frequent infections
  • Loss of appetite and/or weight
  • Swollen or tender lymph nodes, liver or spleen
  • Easy bleeding or bruising
  • Tiny red spots (called petechiae) under the skin
  • Swollen or bleeding gums
  • Sweating, especially at night
  • Bone or joint pain

In acute leukaemia, the abnormal cells may collect around the brain or spinal cord. The result may be headaches, vomiting, confusion, loss of muscle control, and epilepsy-like fits (called seizures). Leukaemia cells also form solid swellings in various parts of the body. The testicles are an important place where this may happen. In chronic leukaemia, the abnormal blood cells may gradually collect in various parts of the body including the liver, spleen, central nervous system, testicles and skin.

If the number of white blood cells is extremely high, the blood becomes thick and syrup-like. This leads to less oxygen being delivered to the body's organs, including the brain. Patients with such high numbers of white cells become forgetful, confused, drowsy, and may even suffer a stroke. Treating patients with this problem is an emergency.

When to see a doctor

Because the symptoms of leukaemia are often vague, people may think they just have a bad case of the 'flu that won't go away.

It is a good idea to see a doctor if:

  • a sore throat persists for more than a week or two
  • unexplained bleeding develops (gums, bowels, urine, skin, eyes, nose)
  • repeated infections, unexplained fevers or sweating start happening
  • lymph nodes don't settle within a fortnight
  • unusual tiredness or lack of energy sets in
  • there has been unusual or unexpected weight loss

Most patients who have these problems do not have leukaemia. But if leukaemia is present and is not thought of, its vague manner of showing itself would lead to the diagnosis being missed for a while longer.

Diagnosis

Any diagnosis relies on a good medical history (the story of how the illness developed), a physical examination and special tests guided by the history and examination. The physical examination in leukaemia will pay close attention to signs of bleeding and petechiae, enlarged lymph nodes (in the neck, under the arms, in the groin), how pale the tongue and eyes are and the size of the liver and spleen. The doctor may also check for signs of any swelling of the testicles and any change in the blood vessels at the back of the eye (the only place in the body where the blood vessels can be seen without looking through skin).

Blood tests are important in the diagnosis of leukaemia. A sample of blood is examined under a microscope to see what the cells look like and to determine the number of mature cells and blasts. Although blood tests may reveal that a patient has leukaemia, they may not show what type of leukaemia it is.

To check further for leukaemia cells or to tell what type of leukaemia a patient has, a haematologist, oncologist, or pathologist performs a bone marrow biopsy. The doctor withdraws the sample by inserting a needle into a large bone (usually the hip) and removing a small amount of liquid bone marrow. This procedure is called bone marrow aspiration. A bone marrow biopsy is performed with a larger needle, and a small piece of bone and bone marrow is removed. This is usually done under local anaesthetic, often with sedation.

The marrow is then examined under the microscope, usually by a pathologist. If leukaemia is found in the bone marrow sample, further tests are done on the marrow to determine the type of leukaemia. The patient's doctor also orders other tests to find out the extent of the disease. A spinal tap (also known as a lumbar puncture) checks for leukaemia cells in the fluid that fills the spaces in and around the brain and spinal cord (the cerebrospinal fluid). Chest X-rays can reveal signs of disease in the chest.

Treatment

Treatment for leukaemia is complex, varies with the type of leukaemia and is not the same for all patients. The treatment is tailored to fit each patient's needs and the goals of treatment. It also depends on the patient's age, symptoms, and general health.

Whenever possible, patients should be treated at a medical centre that has doctors who have experience in treating leukaemia. In South Africa, these doctors can be found at some of the Medical Schools (Bloemfontein, Cape Town, Durban, Johannesburg, Pretoria) as well as at some private hospitals in Cape Town and Johannesburg. If this is not possible, the patient's doctor should discuss the treatment plan with a specialist at such a centre.

Acute leukaemia needs to be treated right away. The goal of treatment is to bring about a remission. To make sure the leukaemia does not relapse, more therapy may be given. Many people with acute leukaemia can be cured. However curative treatment is very intensive and may be physically and psychologically demanding. For some patients, particularly the elderly for whom the chance of a cure is somewhat lower, palliative treatment is an option that may provide many months of good quality of life.

Some chronic leukaemia patients may not require immediate treatment. However, they should have the leukaemia monitored frequently to determine when treatment needs to start. Treatment is usually done on an outpatient basis, and may be as mild as a couple of tablets a day. Treatment is usually used to control rather than cure the leukaemia. A bone marrow transplant is usually needed to cure a chronic leukaemia, but for a variety of reasons, few patients are suitable for this.

A diagnosis of leukaemia usually comes as a big shock to a patient. It is important then to involve family and friends who can support the patient through this difficult time. The doctors and nurses are usually very happy to answer questions and to provide information for family and friends. It often helps to make a list of questions, as people tend to forget the questions they wanted to ask once they see the doctor. Similarly, people seldom remember everything they are told the first time. The doctors know this and will repeat information if necessary. Taking notes, reading booklets and searching the Internet may be helpful in learning more about the disease.

Methods of treatment
Leukaemia is usually treated with chemotherapy, sometimes with radiotherapy and sometimes with biological therapy. Bone marrow transplantation is usually used only after there has been a good response to initial therapy. Chemotherapy is the use of drugs to kill cancer cells. There are many different types of chemotherapy for the very many different types of cancers, and their side effects are also very different. Chemotherapy can be very mild, from capsules that cause very few side effects, to injections and drips that run over several days. What kind of chemotherapy is used depends on the type of leukaemia and the patient.

For patients who need repeated courses of intravenous chemotherapy, the doctors may suggest placing a semi-permanent catheter into a vein (sometimes known as a Hickman or J line). This is a thin plastic tube that goes under the skin on the chest into a vein in the neck or chest. Although it is painful immediately after it has been put in, the pain settles quickly and the patient can then have all injections, blood tests and blood transfusions through the catheter. This avoids having repeated injections and drips in the arms.

For acute leukaemias, it is often important to get chemotherapy into the fluid (called CSF) around the brain and spinal cord. Intravenous and oral chemotherapy do not get into this fluid because of a specialised barrier the body has to protect the brain, called the blood-brain barrier. To treat leukaemia in the CSF, doctors inject intra-thecal chemotherapy through a lumbar puncture. Because it would be too toxic to give all the chemotherapy at once, doctors give the chemotherapy in cycles or courses, followed by time for the patient to recover from any side effects and for the immune system to recover. Sometimes the patient will need to stay in hospital.

Radiotherapy (also called radiation therapy) uses high-energy rays like X-rays to stop cancer cells from growing and multiplying. This may be directed to a specific part of the body like the spleen, or to the whole body, usually as preparation for a bone marrow transplant.

Biological therapy (also called immunotherapy) involves treatment with substances that affect the immune system's ability to destroy cancer cells. The two available types of biological therapy are Interferon, which stimulates the immune system to kill cancer cells, and monoclonal antibodies, which stick to cancer cells to draw the immune system's attention to them. These are usually used in the chronic rather than the acute leukaemias.

Bone marrow transplantation is a way of allowing doctors to use very large doses of chemotherapy and radiotherapy to kill the cancerous cells. It is currently preferred in some centres to use peripheral blood stem cells from the donor. A second option is the Graft-versus-Leukaemia effect, where the cells from the new marrow recognise the leukaemia cells as cancerous and kill them. A few days before the transplant, the patient's marrow is destroyed with the treatment and a new bone marrow given back to the patient. The new healthy marrow is given in a bag through a drip, much like a blood transfusion. This new marrow finds its way through the blood back to the bones, and starts growing straight away. But it takes a few weeks before the new marrow is able to produce enough cells to fight off infections and prevent bleeding. During that time, the patient has to stay in hospital and be protected from and treated for any infections or signs of bleeding that may develop.

The healthy bone marrow may come from a donor, or it may be marrow that has been removed from the patient and stored before the high-dose treatment. If the marrow comes from a donor, this is usually a brother or sister, but the donation can also be from a bone marrow registry.

Donating bone marrow
Up until a few years ago, donating bone marrow meant having multiple bone marrow aspirates under a general anaesthetic. Today, doctors give a colony-stimulating factor by daily injection just under the skin, much like an insulin injection, for a few days at home. The doctor or nurse usually teaches the donors how to give the injections to themselves. The injections stimulate the release of the very youngest cells (peripheral blood stem cells) from the marrow into the blood.

A needle is put into a vein in the arm and a small amount of blood drawn from the arm into a machine. This machine separates the plasma and the different types of cells in the blood from each other. The young cells are stored separately and everything else, the plasma and most of the cells, are returned to the donor, either through the same needle or through another needle in the other arm. This procedure is done many times and lasts several hours. At the end of it, the donor is able to go home and feels no worse than a blood donor would.

The donor's marrow has an enormous amount of reserve capacity and functions quite normally after the donation. Because the marrow has to match the patient's marrow, not just anyone can be a donor. There is only a 25 percent chance that a brother or sister will match. For patients who do not have a matching family member, bone marrow registries may be able to find someone who is a match.

Bone marrow registries are lists of members of the public who have volunteered to be a marrow donor if someone should need to match their marrow. Only a tube of blood is needed for typing the white blood cells for a person to be put onto the list. The chances of a member of the public matching a patient's marrow are about 1 in 100 000 in South Africa. This is because the country is such a diverse mix of different populations. The South African Bone Marrow Registry (Tel: 021-4046445) is based in Cape Town but the three South African blood transfusion services (SABTS, NBTS, WPBTS) also accept blood from people who want to be added to the registry.

Supportive care
Because leukaemia patients get infections very easily, they may receive antibiotics and other drugs to help protect them. They are often advised to stay out of crowds and away from people with colds and other infectious diseases. If an infection develops, it can be serious and should be treated promptly. Patients may need to stay in hospital for the infection to be treated.

Anaemia and bleeding are often seen in patients with leukaemia, and may be treated with red blood cell or platelet transfusions.

Side effects of treatment
Because leukaemia cells originally come from normal cells, they share many of the same workings as normal cells. This makes it difficult to kill leukaemia cells without injuring normal cells. Doctors, and the companies that make the drugs, work hard to minimise these side effects as well as to provide other medication to control the side effects. Not everyone will experience the same side effects or the same severity of side effects, but it is not possible to eliminate all side effects from all patients.

Chemotherapy typically works by killing rapidly multiplying cells, because cancer cells generally multiply rapidly. Unfortunately the body has some normally rapidly multiplying cells – like the lining of the mouth and gut, the sperm-producing cells in the testicles, cells in the hair roots and the normal bone marrow cells. Exactly which normal cells may be affected depends mainly on which drugs are used and how big the doses are. The side effects will then correspond to how badly the normal cells are affected. For instance, if the chemotherapy affects the hair root cells, there may be hair loss. Not all chemotherapy does this. Many chemotherapy drugs affect the lining of the gut, causing nausea, loss of appetite or even vomiting.

Most side effects settle during the recovery period. Some chemotherapy makes the skin unusually sensitive to sunlight and this may last longer than the usual recovery period. Patients should ask their doctors about this before going into the sun.

When chemotherapy affects the testicles, men may stop producing sperm. This may be permanent but, as some surprised fathers have discovered, the testicles may recover. Because this effect is somewhat unpredictable, men often choose to store sperm in a sperm bank, should they want to father children later.

The ovaries may also be affected, causing changes much like menopause, with hot flushes and irregular periods. This can be treated with hormone replacement therapy (HRT), temporarily or even permanently if the ovaries do not recover. Most children treated for leukaemia do not have problems with fertility when they grow up but, again, this depends on the drugs, the doses and whether radiotherapy is used.

Patients receiving radiotherapy often lose their hair. The scalp or the skin in the treated area may become red, dry, tender and itchy. This may be made worse by some lotions and creams, so patients should check with their radiotherapists before applying anything to the affected area.

Radiotherapy may also cause nausea, vomiting and loss of appetite, but this can be treated or even prevented with modern very powerful anti-nausea drugs. Patients also often feel very tired after radiotherapy, and should try to rest more than before they became ill. But it is also important to exercise to keep the muscle and general body tone in good condition. Some of radiotherapy's side effects may be permanent or take a very long time to resolve.

Children (especially young ones) who receive radiotherapy to the brain may develop problems with learning and coordination. For this reason, doctors use the lowest possible doses of radiation, and they give this treatment only to children who cannot be treated successfully with chemotherapy alone. Also, radiation to the testicles is likely to affect both fertility and hormone production. Most boys who have this form of treatment are not able to have children later on. Some may need to take hormones to help them grow and develop normally.

Patients who have a bone marrow transplant usually have more side effects than they may have had up till then. This is because the treatment is so much more intense. In addition, they may develop Graft-Versus-Host Disease (GVHD), especially if the transplanted marrow is from a donor. In GVHD, the donated marrow's immune system reacts against the patient's tissues (most often the liver, the skin, and the digestive tract).

GVHD can be mild or very severe. It can occur any time after the transplant (even years later). New drugs reduce the risk of GVHD and treat the problem if it occurs.

Nutrition
Some cancer patients find it hard to eat well and they may lose their appetite. In addition, the common side effects of therapy such as nausea, vomiting, or mouth sores, can make eating difficult. For some patients, foods taste different. Also, people may not feel like eating when they are uncomfortable or tired.

Eating well means getting enough calories and protein to help prevent weight loss and regain strength. Patients who eat well during cancer treatment often feel better and have more energy. In addition, they may be better able to handle the side effects of treatment. Doctors, nurses, and dietitians can offer advice for healthy eating during cancer treatment.

Follow-up care
Regular follow-up visits to the doctor are very important after treatment for leukaemia. Sometimes, because there are only a few centres in South Africa treating leukaemia, you may have to move to that city for several months or more.

The checkups are important to make sure the patient is recovering well after the chemotherapy, and that the leukaemia is controlled or has not returned. Checkups usually include blood tests and from time to time, bone marrow biopsies and possibly lumbar punctures.

Cancer treatment may cause side effects many years later. For this reason, patients should continue to have regular checkups and should also report health changes or problems to their doctor as soon as they appear.

Psychological support
As mentioned before, being given a diagnosis of leukaemia is a big shock to most patients. Not only does it make patients face their fear of dying, but it also may cause worries about employment, paying the bills, looking after people at home and all the many responsibilities of daily life.

Parents of children with leukaemia may worry about whether their children will be able to take part in normal school or social activities, and the children themselves may be upset about not being able to join in activities with their friends.

Worries about tests, treatments, hospital stays, and medical bills are also common. Doctors, nurses, and other members of the team can help with answers to questions and suggest other people who may be able to help with specific problems.

Many of the leukaemia treatment centres have a social worker or counsellor as part of the team who can help patients work through their feelings and cope with problems, as well as help with financial aid and transport.

Friends, relatives and members of the clergy can also be very helpful at this time. Patients often want to talk about their feelings, especially about dying – friends and family should be open to this. This is also a time of enormous stress for partners and families, and support from friends for the family as a whole is often very valuable.

Reviewed by: Dr Mike du Toit, Clinical haematologist: Constantiaberg Medi-Clinic, Cape Town, March 2010

 
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