APLASTIC ANAEMIA

What is aplastic anaemia?

Patients with aplastic anaemia have a complete failure of production of all types of blood cells. As a result 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. There is a rare inherited form of the disease called Fanconi Anaemia. There is a separate Leukaemia Research Fund leaflet on this condition.

Aplastic anaemia is an inevitable consequence of use of high dose drugs and radiotherapy in treatment of cancer but 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.

The disease may affect people of any age but there are peaks of incidence in young adults and in people over the age of 60 years.

Causes

It is thought that in most cases of acquired aplastic anaemia the damage to bone marrow stem cells is caused by an auto-immune reaction. This happens when the body's immune cells become confused and start to attack body tissues. In about three quarters of all cases of aplastic anaemia this autoimmune reaction has no clear underlying cause. This is called idiopathic aplastic anaemia.

In the remaining cases there is evidence of exposure to some factor which is known to cause damage to bone marrow stem cells. Examples include drug treatment, some chemicals and certain diseases and infections. Some factors such as benzene and drugs may damage the stem cells directly, others such as infections probably trigger off auto-immune damage. Aplastic anaemia may occur in pregnancy, but this is extremely rare. These cases usually resolve with the end of the pregnancy.

Drugs which may, rarely, cause aplastic anaemia include:

• anti-cancer drugs
• immunosuppressants
• drugs used to treat rheumatoid arthritis
• some antibiotics.

Whenever a patient is given drugs known to carry a risk of aplastic anaemia they must have regular blood counts.

Certain diseases may, rarely, lead to aplastic anaemia. These include:

• viral hepatitis
• other viral infections
• disorders of the immune system

Occasionally a patient who has a disease of the bone marrow may develop complete marrow failure and their diagnosis will then become aplastic anaemia.

Signs and symptoms

The symptoms and signs seen most often in aplastic anaemia are:

• fatigue
• paleness
• shortness of breath on exertion
• rapid heart rate
• infections
• rash
• easy bruising
• nose bleeds
• bleeding gums
• prolonged bleeding

Tiredness and weakness are caused by anaemia (too few red cells); bruising and/or bleeding problems result from a low platelet count. Infections are a problem despite the apparent high white cell count because there are very few healthy white cells.

Patients may show any combination of these symptoms. Some may be more obvious than others. Initial symptoms may appear to be nothing worse than excessive tiredness or a bout of flu.

Anyone who develops any of the following signs or symptoms should see a doctor:

• fever which persists more than a few days
• weakness or persistent tiredness
• swelling in the abdomen
• bleeding problems e.g. heavy periods, blood in the stool, bleeding gums when cleaning teeth
• unexplained or widespread bruising
• bone pain

Diagnosis

A general practitioner who sees a patient with aplastic anaemia may suspect the possibility of leukaemia. The diagnosis of aplastic anaemia cannot be made clinically or based on the blood count alone. Many conditions can lead to a reduced blood count and similar signs and symptoms.

The initial diagnosis, based on the appearance of the blood film and before the bone marrow has been examined, may be leukaemia.

Although the clinical appearance of aplastic anaemia may be similar to other bone marrow and blood diseases the diagnosis is normally very clear once the full results of laboratory tests are available.

Full blood count
This is a test which measures the different types of blood cell and the haemoglobin level.

A patient with aplastic anaemia will have a low red count and so be anaemic. The white count and platelet count are usually also low.

The full blood count is done on a machine and the results give a strong indication that the patient has marrow failure although it cannot show the cause of the condition.

The general practitioner may take a blood sample and send it to the pathology laboratory or the patient may be sent to the laboratory to have blood taken. In either case, if the blood count suggests aplastic anaemia or leukaemia the patient or the family doctor will be urgently contacted by the hospital. A repeat count will be done (to confirm the result) and further tests will be arranged.

Blood film report
When the results of a full blood count are abnormal a blood film will be examined. The appearance of aplastic anaemia on a blood film is very distinctive. The striking feature of aplastic anaemia is the absence of abnormalities which would explain the low numbers of blood cells present.

Bone marrow biopsy
In all patients with aplastic anaemia a bone marrow sample will be required. This involves obtaining a small amount of marrow from inside the bone with a needle and a sample from the bone itself showing the structure of the bone marrow cavity. The first is known as a bone marrow aspirate, the second as a bone marrow trephine. The samples are usually obtained from the back of the hip bone, although the sternum (breast bone) 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 usually carried out with sedation as well as local anaesthetic. It may be necessary to sample more than one site in aplastic anaemia to confirm that there is no other bone marrow disease present.

The main bone marrow finding which defines aplastic anaemia is that the few blood producing cells which are present appear normal. The cells in aplastic anaemia do not show chromosome abnormalities.

In conditions, such as leukaemia and myeloma, which may also lead to very low blood counts, the bone marrow contains very large numbers of abnormal cells. The cells in these conditions nearly always have very typical chromosome abnormalities.

In the diseases of the bone marrow which most resemble aplastic anaemia such as myelodysplasia or myelofibrosis the numbers of blood producing cells are considerably reduced. The cells which are present in the bone marrow in these diseases are very abnormal under the microscope.

Chromosome analysis
This may be done on the cells from the blood, the bone marrow or both. In conditions which may resemble aplastic anaemia there are changes to the chromosomes in the marrow cells. In aplastic anaemia these types of changes are not seen, except in Fanconi anaemia when the chromosomes show multiple breaks.

The initial diagnosis will probably be done at a local hospital but the patient may well be referred to a specialist centre for treatment.

Treatment

Aplastic anaemia can be classified as mild or severe based on the results of the laboratory tests. The condition is classed as severe if two out of three of the following are present:

• absolute neutrophil count less than 500 x 109/l
• platelet count less than 20 x 109/l
• reticulocytes (immature red cells) less than 1%
• and the patient has a bone marrow with markedly reduced numbers of blood-producing cells

Very severe disease is considered to be present in those who have neutrophils less than 200 x 109/l.

Severe aplastic anaemia is a life-threatening condition. Studies have shown that mortality one year after diagnosis is more than 80% for patients with severe disease which is not treated aggressively. Non-severe disease has a better prognosis.

The outlook in aplastic anaemia has been greatly improved because of the introduction of better support measures, the appropriate use of bone marrow transplantation and the introduction of immunosuppressive therapy.

Supportive therapy
Recovery from aplastic anaemia may take many months or even years and during this time the patient needs to be supported with transfusions of red blood cells and platelets. Patients with severe disease need to be shown precautions to take against acquiring infections and in all patients infections have to be treated promptly with antibiotics.

Red blood cell transfusions are usually required about one a month, the frequency of platelet transfusions depends upon the presence or absence of bleeding symptoms and signs. Patients are usually transfused with blood products from which the white blood cells have been removed so that the patient does not become sensitised to transfusions. In general, it is advisable to keep to a minimum transfusions for patients who are going to have bone marrow transplantation.

Immunosuppressive therapy
Drugs which suppress the immune system are used in patients with severe aplastic anaemia who are not able to have a bone marrow transplant. This is effective in those cases where the damage to the marrow stem cells has been caused by the immune system. Special antibodies called ATG (anti-thymocyte globulin) and ALG (anti-lymphocyte globulin) are used in treatment of aplastic anaemia. These antibodies reduce the activity of the lymphocytes which are attacking bone marrow stem cells.

A drug called cyclosporin may be used instead of, or alongside, ATG or ALG. This drug affects T-lymphocytes quite specifically. Common side-effects of cyclosporin include high blood pressure, swelling of the gums and tremors. Rarer but more serious side-effects are seizures, renal failure and infection. The serious side-effects are avoided by careful monitoring of the chemistry of the blood and by the use of appropriate antibiotics. Cyclosporin can be used for many years without serious complications.

Immunosuppressive treatments, by their very nature, increase the risk of infection in people already susceptible to it. For this reason, ATG and ALG are always given to patients in an isolation environment where infection can be excluded. Cyclosporin is less harmful in this respect.

Treatment, other than a bone marrow transplant, will not restore lost and destroyed stem cells. It will allow recovery of the remaining stem cells so that the blood count improves to a level which renders the patient free of the need for transfusions, or at least minimises this need. Several courses of treatment may be necessary.

Bone marrow transplantation
The successful replacement of the stem cells with healthy marrow from a tissue matched donor may cure aplastic anaemia.

Bone marrow transplantation is a risky procedure but success rates as high as 80% have been reported when the donor is a closely matched brother or sister. Given the very high mortality rate in severe aplastic anaemia the indication for transplantation is strong.

Patients with aplastic anaemia should be transplanted without the use of irradiation. Rejection of the graft is prevented by using a drug called cyclophosphamide often together with antibodies including antilymphocyte globulin which immunosuppress the recipient. The risk of graft failure, that is rejection of the bone marrow transplant, is greater for patients with aplastic anaemia than for patients with leukaemia. There are many reports of spontaneous recovery following the immunosuppressive effects of cyclophosphamide in patients who have not received radiation. Second transplants have been successfully given to patients who have had graft rejection.

Bone marrow transplantation vs Immunosuppression
There are some clear recommendations for treatment choices. Children, adolescents and young adults with sibling donors should be transplanted. Patients who have no sibling donor should be treated with immunosuppressive drugs. High risk patients, who have very low neutrophil counts, should receive intensive supportive treatment.

For older patients who have sibling donors opinion is more divided. Some specialists recommend transplantation for any patient below the age of 50 years. Other experts have recommended an initial trial of immunosuppressive drugs followed by a bone marrow transplant if the immunosuppressive drugs fail to work or if myelodysplasia or leukaemia later develop. Patients who fall into this group should discuss the choices carefully with their specialist before arriving at a decision on treatment.

Other treatment options
The only treatments which have been shown to offer clear benefit in treating severe aplastic anaemia are stem cell transplantation and immunosuppression. In both cases delaying treatment is often harmful. For this reason it is not currently recommended that other treatments should be tried first.

Blood forming growth factors such as G-CSF, may have a role to play in the treatment of of aplastic anaemia. For example they may accelerate recovery following immunosuppressive treatment. However, there is also concern that if used for a prolonged period of time, they may stimulate the proliferation of more malignant cells in the aplastic marrow. Their use is under constant review and assessment in clinical trials.

Androgens, which are male hormones, have sometimes been found to produce a response but they have not improved survival in any trial. The benefits of using androgens along with immunosuppression have not been determined. A trial of androgens may be appropriate in patients who do not respond to immunosuppression or in less severe cases of aplastic anaemia.

Corticosteroids in standard doses may ease the side-effects of ALG treatment but they do not have any effect on the aplastic anaemia. Very large doses of corticosteroids may restore blood cell production but they have much more severe side-effects than ATG or ALG and so they are not recommended.

Patients with aplastic anaemia are particularly vulnerable to damage to large joints which may result from steroid treatment. There is no clinical or laboratory evidence to support the use of low-dose corticosteroids.

Pregnancy-associated aplastic anaemia
In most cases of pregnancy-associated aplastic anaemia the only treatment needed is support with blood and platelet transfusions as needed and antibiotics when required. About one third of cases show improved blood counts once the pregnancy ends, but for the remaining two thirds the disease persists and may indeed become worse. Patients who have had aplastic anaemia which has responded to immunosuppression may relapse if they become pregnant and will require careful consideration with specialists to discuss the risks of becoming pregnant.

Long-term follow up
Patients treated with immunosuppressive drugs or in whom there is a spontaneous recovery of bone marrow function continue to have an underlying abnormality in the bone marrow. A minority of patients may relapse, sometimes in response to additional environmental stress such as pregnancy or virus infections. The disease may evolve, particularly with the emergence of blood cells which survive less well than normal. This is called paroxysmal nocturnal haemoglobinuria (PNH). There is a separate Leukaemia Research Fund leaflet on PNH. A very small minority of patients will develop more malignant changes in the recovered bone marrow. For these reasons it is necessary to continue the follow up of patients who have had aplastic anaemia for many years, though checks on the blood count only need to be carried out six-monthly or yearly.