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Primary Immunodeficiency Assocation (PIA) Archive

Bone Marrow Transplantation for primary immundodeficiency

Foreward
Why consider bone marrow transplantation (BMT)?
How does BMT work?
What are the pros and cons of BMT?
Which patients and why?
Before for Bone Marrow Transplantion
Preparing for the transplant
Transplant day
Patients' stories
After the transplant: restoration and recovery
Fertility and cryo-presernvation of ovarian and testicular tissue

Foreward

By Fiona Sandford

Since 1968, bone marrow transplants (BMTs) have been an important treatment for primary immunodeficiencies. Until relatively recently, BMTs were limited to babies with Severe Combined Immunodeficiency (SCID). More recently, as the nature of different immunodeficiencies has become better understood, and as techniques in bone marrow transplants have improved and so lessened the risks, families with conditions such as Wiskott-Aldrich, Hyper IgM and other combined immunodeficiencies are being offered the choice of a bone marrow transplant.This booklet is designed to help families facing BMTs. I wrote about my family's experience of our son Kit's transplant for the PiA's newsletter Insight. The response to that article was overwhelming and clearly indicated that there was a lack of written information on the subject. In this booklet, Dr Andrew Cant gives the medical background to bone marrow transplants and immunodeficiencies, Judith Armstrong, theBMT nurse co-ordinator at Great Ormond Street Hospital, gives some practical advice on preparing for transplant, and Rebekah Lwin, Clinical Psychologist also at Great Ormond Street Hospital, discusses the aftermath and recovery period. In addition, five families who have recently lived through BMTs tell of their experiences. These families have children of different ages, with different conditions and different types of transplant. They have written candidly about this most difficult period, and the PiA is very grateful to them for having the courage to share their experiences. One of the side effects of the drugsused in transplant that greatly concerns families is the possible effects on future fertility. Recent developments have allowed some families to take steps to try to minimise this risk, and this is discussed in the article by Dr Alison Leiper and Rebekah Lwin. Each bone marrow transplant is different. BMT centres have different physical facilities, and therefore different practices. Children react differently to the drugs used, and experience different side effects. For some families the period before transplant is the hardest, for some the time in hospital is most difficult and for some the recovery period causes the most problems.

Questions on bone marrow transplantation for primary immundodeficiency

By Dr Andrew Cant, a member of PiA's Medical Advisory Panel, senior lecturer in child health, consultant paediatric immunologist and director of the Primary Immunodeficiency Unit at Newcastle General Hospital

Why consider bone marrow transplantation (BMT)?

To answer this question we need to remember the immune system's origins. White blood cells are the key players in our body's immune system and arise from a population of self-perpetuating bone marrow cells called stem cells. As these divide and multiply some of the daughter cells become new stem cells whilst the others develop into different blood cells - red cells, platelets, neutrophils, monocytes or lymphocytes. The most severe forms of Primary Immunodeficiency, particularly those seen in childhood, are due to genetic faults which prevent the proper development or function of one of these groups of cells, and exciting research in the last few years has pinpointed these defects. In X-linked agammaglobulinaemia (Bruton's Disease) a fault in the gene, or blueprint for a messenger molecule called Bruton's Tyrosine kinase, prevents B-lymphocytes developing from progenitor cells in the bone marrow, so patients cannot make antibodies. Patients with the B-positive Severe Combined Immunodeficiency (SCID) cannot make a special molecule on the surface of lymphocytes and so cannot receive the signals necessary for growth and development of those cells. Such children lack T-lymphocytes and have Blymphocytes that cannot produce antibodies. The loss of these two major parts of the immune system means that even trivial infections are fatal. The best treatments for primary immunodeficiency are those which fully correct the particular deficiency. When B-cells fail to develop, infusions of antibody in the form of intravenous immunoglobulins (IVIg) completely correct the problem.

In SCID, however, although IVIg will replace antibodies the B-lymphocytes cannot make, it cannot restore T-lymphocyte function and children still die of infections with viruses which only T-cells can eliminate. The only way to treat severe T-cell defects is to replace the faulty self-perpetuating stem cells with ones without the genetic faults and so allow the development of normal T-cells. Because stem cells are self-perpetuating, as long as this new bone marrow remains viable, the patient is cured. SCID was first successfully treated by bone marrow transplantation in 1968, using the patient's brother as a donor. The patient is still alive and well, and her brother's bone marrow stem cells are still dividing, replicating and giving rise to a fully functioning immune system.

How does BMT work?

Bone marrow cells carry distinct identification tags on their surface, known as tissue types. We inherit half our tissue types from one parent and half from the other. Tissue types are extremely important as they enable us to recognise and destroy foreign cells. Without them we could not deal with invading bacteria and viruses, as happens in Bare Lymphocyte syndrome, where tissue types are not made.

However, if bone marrow from a person from one set of tissue types is given to a person with a different set, the two systems recognise each other as foreign and fight! If the recipient's immune system gains the upper hand the donor's bone marrow is rejected; if the donor's system wins, then the patient develops a severe inflammation in the skin, liver and gut, known as Graft-vs-Host Disease (GvHD) which can be fatal. Because brothers and sisters each inherit tissue types from the same parents, there is a one-in-four chance that a brother and/or sister will have inherited the same tissue types. When using bone marrow from such a brother/sister, the risks of graft rejection or GvHD are low and such transplants are the most successful.

Although unrelated people carry different tissue types, the number of types is not endless, and by chance, two out of 18,000 people will share more or less the same tissue types. Because of good will, it has been possible to set up registries of several hundred thousand people across the world who are willing to donate bone marrow. In this way patients can be matched with unrelated donors whose tissue types are almost as exactly matched as brothers and sisters who share the same tissue types.

In the last fifteen years it has also proved possible to use bone marrow of different tissue types - so called mismatched transplants. This has really only been successful in SCID and even then it is a difficult technique, as the T-lymphocytes (which are mainly responsible for GvHD) must be removed from the donor's bone marrow before the marrow is infused into the patient. Although this largely prevents GvHD, it increases the chances that the marrow will be rejected, and also greatly increases the delay before the new immune system functions, so increasing the risk of infection. Nevertheless, with meticulous painstaking care, such BMTs are often successful, particularly for infants with SCID who cannot easily reject marrow.

What are the pros and cons of BMT?

Having identified a suitable donor, the patient must be carefully assessed. It is important to detect infections that may have already damaged the lungs or liver, as problems here reduce the chances of a successful transplant. The patient is then admitted to a sterile environment and their own marrow destroyed with powerful drugs, usually used for treating cancer, or sometimes a mixture of these drugs and radiotherapy. By wiping out the patient's immune system the risk of rejection is largely prevented, but infection becomes a risk. After ten days of this treatment, marrow is taken from the donor under a general anaesthetic by pushing a needle into the donor's pelvic bones and collecting some marrow. The donor may feel a little uncomfortable for a few days, but quickly makes up for the marrow that has been taken, and providing the donor is in good health, this procedure carries only a tiny risk. Marrow is infused into the patient like blood into a vein and we then wait whilst the donor marrow cells find their way to the patient's bone marrow cavity, start multiplying and after two to three weeks, begin to appear in the blood. During this time the patient produces no blood cells and needs infusions of the platelets.

A very careful watch is kept for signs of infection which is treated very promptly and thoroughly. Sometimes there is a degree of GvHD when the new marrow cells start to appear, or 'take'. This may require treatment with immunosuppressant drugs. Occasionally the marrow is rejected and the patient's own marrow reappears, and both rejection and GvHD increase the risk of infection. About six weeks after the graft takes, the patient's new immune system starts to develop, and a little later they can go home, although antibiotics and IVIg are often needed for up to a year whilst the new immune system fully matures. Successful bone marrow transplantation is usually curative and it is very exciting to see poorly, sick patients transformed into normal healthy children. However, when unsuccessful, usually because of rejection or Graft-vs-Host Disease, patients often die from infection.

A few patients remain unwell after a BMT because the graft has only partially taken, or because of ongoing GvHD, but by and large BMT is either fully successful or not successful at all. When a baby has SCID, which untreated is always fatal within a few weeks or months, decision-making is not difficult and doctors and parents wish a BMT to be attempted, unless the child is so severely ill with infection that the chances of success are negligible.

In other immunodeficiencies where patients can remain relatively well for a number of years if given IVIg and antibiotics, decision-making can be more difficult.

Which patients and why?

Bone marrow transplantation is the only way to give new T-cells or phagocytes and so T-cells and phagocyte immunodeficiencies are the main indication for BMT. When T-cells do not work at all (as in SCID) BMT is essential. In otherT-cell immunodeficiencies with partial T-cell function, matters must be considered more carefully. At present Wiskott-Aldrich syndrome and the Hyper IgM syndrome (CD40 Ligand deficiency) as well as some types of combined immunodeficiency (many of which we now know to be minor forms of SCID) are the main indications for BMT. If there is a brother or sister who shares the same tissue types, or an unrelated donor who is well matched, then many of these patients will benefit from BMT. Patients with Chronic Granulomatous Disorder (CGD) and a tissue type identical brother or sister, are also now being considered. When asking the question: "Is bone marrow transplantation the right treatment for patients with immunodeficiency? "it is helpful to ask the following questions:-

• Does the patient have a T-lymphocyte or phagocyte deficiency?
• Is the patient already receiving the best possible other forms of treatment? (For example, IVIg and preventative antibiotics)
• What is the likely future course of the patient's condition? What will their future health be like? How disabled will they be and what life expectancy do they have?
• Is there a suitable donor? (If there is a tissue type identical brother or sister, or a well-matched unrelated donor, BMT will be less risky.)
• Has there already been serious infective damage to the patient's lungs or liver which would make transplantation more risky?
• What do the patient, parents, doctors and nurses ogether feel is the best course of action?

Our understanding of primary immunodeficiency diseases and our expertise in bone marrow transplantation are rapidly improving, so the answers to these questions are changing! Careful follow-up of patients and pooling of data between treatment centres - a successful example of European collaboration - has taught us a great deal about the longer term outlook for T-cell immunodeficiencies such as Hyper IgM syndrome (CD40 Ligand deficiency) andWiskott-Aldrich syndrome. We now know that the long-term risks of liver disease in Hyper IgM and cancer of the white blood cells in Wiskott-Aldrich syndrome seem greater than was thought. At the same time, BMT from a matched brother /sister or unrelated donor is proving successful in over 80% of cases, and younger patients without serious liver or lung damage do best. In CGD there is concern that although patients can remain healthy in childhood, serious problems may arise in early adult life, so BMT is being advocated if there is a matched brother/sister donor.

The government funds a national programme for the assessment and treatment of children with severe forms of primary immunodeficiency, centred around units in London and Newcastle. Once referred, each patient is carefully assessed in the light of the most recent scientific information and matters are fully discussed with all concerned. In this way the best treatment is worked out on an individual basis, balancing the risks and benefits of BMT against the risks and benefits of continuing with the best possible supportive care. The more severe the immunodeficiency, the younger the patient, the less severe the damage to lungs and liver from any infection, and the better the match of any potential donor, then the more there is in favour of carrying out BMT.

Advice is changing and we realise that this can be unsettling for families who had previously not considered BMT, or had been told that BMT was not the best treatment for their child. We also very much recognise the dilemma of considering a BMT for a child who is currently very well, but who may become unwell in three, five, ten or fifteen year's time. This dilemma is made all the more difficult because BMT is most likely to be successful in such a well child, whereas if one waits until serious infection has set in, this makes BMT a much more risky undertaking. Although decision-making can be hard, successful results are so encouraging and it is remarkable how much better children can be when they have been given a new immune system.

Before for Bone Marrow Transplantion

By Judith Armstrong, the Bone Marrow Transplant Nurse Co-ordinator at Great Ormon Street Hospital.

The following information explores bone marrow transplantation, and many of the questions frequently asked by families and children who are considering this as a possible treatment.

The decision to transplant

Bone marrow transplantation is a complex, high-risk treatment which makes huge demands on the patient and their carers. The decision to go ahead with a transplant must be made with the knowledge that it offers the best possibility of a cure but also that the treatment can fail and even be fatal. Your doctors will explain to you the side effects and potential risks of treatment as well as the potential benefit in order to help you make a well informed decision for your child. The transplant centre will also want to meet your child, to ensure that he/she has an age appropriate understanding of what the treatment will involve, and also to include her/him in the decision making process. At a later stage, a clinical nurse specialist, social worker, psychologist, doctor or counselor will arrange to meet with you and tell you more about bone marrow transplants. These sessions are good opportunities for you to ask more questions and to discuss particular concerns. As part of your child and family's preparation for bone marrow transplantation, written information, audio tapes or videos, some of which should be age appropriate for your child should also be available from your transplant centre.

Finding a donor

The best donor for bone marrow transplantation, is a matched sibling (brother of sister) or other family member. This is because such an individual has inherited an identical tissue type to the patient, which allows the bone marrow to be transplanted with a lower risk of any reaction occurring between the recipient and the donor. In the absence of a matched family member, it is usually possible to find an unrelated donor from one of the worldwide panels.

Who should be tissue typed?

At most centres, the patient and the immediate family are tissue typed first. Each child will randomly inherit one of four possible tissue type combinations from the same parents. In searching for a potential bone marrow donor, each full sibling (brother or sister) has a 25% chance of being compatible with another.

What does tissue typing involve?

Tissue typing involves taking a blood sample from the patient and any potential donor. From the blood, it is possible to identify if the potential donor's bone marrow is the same as your child's. This is a complex test which may take a week or more before you are given results. Your transplant centre will be able to advise you regarding the length of time which you will have to wait.

Is it possible that a parent will match?

This is possible, however it is unlikely. Both parents would have to share similar tissue types in order for their child to inherit an identical tissue type to either parent. This can occur if both parents share a tissue type which may be common within the general
population, or if there is consanguinity within the family, e.g. the parents are cousins or both families are related in some other way.

Could there be a potential match within the extended family?

An extended family search looks among other relatives and may be carried out if a suitable sibling donor is not available. Your transplant centre may ask you questions about your family tree and will give advice as to whether an extended family search is appropriate. To carry out an extended family search randomly without a proven indication can be fruitless and can give false hope of finding a donor. Each transplant centre has its own policy with regards to searches of this nature, however, the following points may be useful indications for carrying out an extended family search:

• If both parents share similar tissue types

• If there is known consanguinity within the family e.g. both parents/families are related

• If the family originates from a country with a small non-immigrant population

What happens if a suitable potential donor is not identified within my family?

Your transplant centre will search for an unrelated volunteer donor whose bone marrow is compatible with your child's. Within the UK, there is an organisation called the Anthony Nolan Bone Marrow Trust, which is a charity-based organisation that has a registry of tissue types from volunteers within the general population. There are additional registries in the UK, based in Bristol and Wales and many others overseas, with the total number of donors now in excess of four million. Additionally, there are cord blood banks situated within the UK and overseas which are searched as donated umbilical cord blood is an alternative source of stem cells.

Your child's tissue type is sent to each registry. On identification of a volunteer who may match your child, additional blood is requested from the potential donor to confirm their tissue type. Identifying a potential compatible bone marrow donor for your child may take time which can cause anxiety, particularly if an unrelated donor search is necessary. Your transplant centre understands this and will endeavour to keep you informed as to what progress has been made and will do their best to identify a donor as quickly as possible.

Is an unrelated volunteer donor always found?

It is usually possible to find a donor for Caucasian patients. Children from ethnic minorities within the UK e.g. Mediterranean, Eastern Europe, African, African-Caribbean, Asian, Chinese or from a mixed ethnic background, may have difficulty in finding a compatible, unrelated donor. The donor panel registries are based mainly in UK, Europe, USA Canada and Australia, with smaller registries developing in other countries. Due to the location of these registries recruitment of Caucasian volunteer donors outnumbers those from ethnic minority groups. In this situation some families appeal for volunteers from their own ethnic background to come forward to be tissue typed. This is hard work with no assurance of success. It is unlikely that your hospital will be able fund or organise this but they can advise you as to where you can find help.

What does donation of bone marrow involve for the donor?

On identifying a suitable donor, he/she will undergo a medical examination. This is carried out to ensure that the volunteer is fit to donate and also to ensure that their donation causes no harm to your child. The donor undergoes the same stringent tests as a blood donor, including screening for infectious viruses such as hepatitis and H1V.

How is the bone marrow removed?

The donor will be admitted to hospital, generally for one night. He or she will receive a general anaesthetic and the bone marrow which looks like blood, is withdrawn from the hip bones using a syringe and needle. The marrow taken will replace itself naturally very quickly. As the donor will receive a general anaesthetic, no pain will occur during the actual procedure. However, the donor may experience some tenderness around the lower where the marrow has been taken from. General weakness and tiredness is expected for a few days afterwards. Adult donors are advised to take a week off work and children some time off school.

What are the risks for the donor?

Because the donor requires a general anaesthetic, there is a small risk, as there would be with any other procedure involving anaesthesia. It is a minor operation and the donor will receive a hill medical examination before the procedure to ensure that they are fit to undergo a general anaesthetic.

Sibling (brother or sister) donors

If a brother or sister is found to be a potential bone marrow donor, there are sensitive issues that you may find useful to discuss with your transplant centre. Care needs to be taken when discussing tissue typing results with your children Many siblings, if found to have compatible bone marrow, take great pride and pleasure in being able to help their brother or sister in this very special way Others may feel extremely alarmed at the prospect, but sense an expectation of what is required by their family The remaining siblings in your family may feel disappointed at having lost out on their opportunity to donate bone marrow. Before the bloods are taken for tissue typing, or the results are known it may be useful to discuss with each of your children how they might feel if asked to give bone marrow to their brother or sister. This will encourage questions and could be a good opportunity to identify any fears or worries at an early stage. It is important that everyone is included in the preparations and discussions prior to admission for bone marrow donation and transplant, both at home and in hospital. It can also help, if each child is given his/her own specific role which contributes towards caring for their brother or sister. A common fear is that, if the transplant is unsuccessful, the bone marrow donor may blame themselves. There needs to be an understanding and belief that giving bone marrow is one component of a large, complex process. The donor is not responsible for the outcome of his brother or sister's treatment. Age appropriate, honest information should be given in a sensitive manner and your transplant centre can assist you with this. Picture stories, books about hospitalisation, time to listen and answer questions, visits to the transplant centre are all useful in helping your child who is to be the donor, and other siblings understand the process.

Unrelated donors

If an unrelated donor is chosen, great care is taken to protect you and your child's anonymity as well as the donor’s. Some recipients and donors do meet at a much later stage upon request of the recipient and their family and also at the discretion of the transplant centre and the donor panel. Anonymous cards or a small gift can be sent to the donor via your transplant centre. This gesture is often greatly appreciated by the donor.

Preparing for the transplant

How will my child receive chemotherapy, blood products and the bone marrow?

Your child will have a central venous line, often referred to as a Hickman line, which is inserted into a large vein under a general anaesthetic. Chemotherapy blood products, drugs including antibiotics, nutrition, hydration, and even the actual bone marrow are all given through this line which is also used for blood sampling. This means that your child will no longer have to cope with needles. The central line is a thin, light silicone tube which exits onto the chest once it has been threaded through a large vein. Following insertion, the area around the line may feel slightly sensitive but this soon wears off. The line will not affect your child's mobility nor restrict the types of clothing he/she can wear. A dressing covers the line to protect and keep it secure. Baths are allowed, but your child will be discouraged from getting the line wet. Most children return home with the central line as often it is still useful at the time of discharge from hospital. Generally families cope well at home, looking after a child who has a central line. You will be given the necessary training and information to help you manage. The line is removed under a general anaesthetic once it is no longer needed. This may be any time from approximately 4-12 months after the transplant.

Chemotherapy

Once your child is in hospital, prior to receiving new bone marrow he/she will be given cytotoxic chemotherapy drugs.

Chemotherapy is a necessary part of the process in preparing the body to accept new bone marrow. The function of chemotherapy is to destroy the defective bone marrow, including the stem cells. The combination and amount of chemotherapy drugs that your child will receive, will depend on his/her initial diagnosis and the type of bone marrow transplant which he/she is to receive. Your child may receive chemotherapy for up to 12 days before receiving the new bone marrow.

Unfortunately there are a number of side effects which cannot be avoided and which may cause your child to become extremely unwell.

What are the common problems in association with chemotherapy?

Nausea and vomiting
Nausea and vomiting are frequent problems which are worst during the initial phase of chemotherapy. This may continue at intervals throughout the transplant period due to antibiotics or infection. Anti sickness drugs will be given regularly to your child in order to reduce this symptom as much as possible.

Stomatitis and Mucositis
Stomatitis is ulceration of the oral mucosa (lining of the mouth) and is a direct side effect of chemotherapy. A sore mouth can be extremely painful, resulting in your child not wanting to eat, drink, swallow or speak.
The mucous membrane also lines the entire gastro intestinal tract where ulceration can also occur, referred to as Mucositis. This can result in abdominal cramps and diarrhoea. Not all children suffer from the above side effects and the severity of symptoms varies considerably.

If your child experiences these symptoms, he/she will lose their appetite and may lose weight. Pain relief will be given as well as necessary intravenous nutrients and fluids. As the mouth and gut heals, your child's appetite will improve and gradually they will be encouraged to eat or drink again. Chemotherapy may also cause altered taste but this problem will slowly resolve.

Bruising and bleeding
When platelets are low, symptoms such as nose bleeds are common and your child will also bruise easily. To minimise these symptoms, it will be necessary to give platelet transfusions intravenously until the new bone marrow starts to produce its own platelets. Early on, this may be as often as every two days and even when your child returns home, they may still require platelet transfusions at your local hospital. Eventually, this will become unnecessary as the new marrow will produce an adequate number of platelets.

Anaemia
Until the new bone marrow starts to produce its own red blood cells, your child will receive regular blood transfusions, to prevent anaemia.

Hair loss
Hair loss gradually occurs about seven to ten days after the last dose of chemotherapy over a period of three to seven days, and it can be irritating if it gets into the eyes and mouth. If your child has long hair, suggest having it gradually cut shorter before coming into hospital. This may help your child adjust to his/her hair loss and it may also help to minimise any discomfort. It is important to warn your child that they will lose their hair and also to reassure them that following the transplant, hair does grow back.

Occasionally, it will return a slightly different texture or colour. If your child wishes, your transplant centre can organise a wig, although most children choose to wear a variety of hats or baseball caps

Infection
Once the chemotherapy has destroyed the unhealthy bone marrow, your child will become extremely susceptible to infection until the stem cells in the new bone marrow produce new white blood cells. This can take between three to five weeks to happen. During this period, your child will be protected from infection, but any sign of infection will be immediately treated with intravenous antibiotics.

How will my child be monitored and protected from infection?

Specially trained nursing staff on the transplant unit will generally observe your child, including taking his/her temperature and blood pressure throughout the day and night. Nose and throat swabs will also be regularly carried out as well as collecting blood, urine and stool samples in an attempt to identify any infection which needs treatment. This constant around the clock surveillance may feel intrusive and disruptive to you and your child, especially during the night. However, it is a crucial measure as any infection in an immuno-compromised child can lead to a critical situation if undetected and left untreated.

Protection from infection

To help protect and prevent your child from acquiring infections, specific antibiotics and anti fungal medicines will be given to your child at the start of chemotherapy. These medicines are referred to as prophylactic drugs and your child will continue on these for a period of time once home, following the transplant.

During the period of time when your child is at their most prone to infection, he/she will be transferred into their own room to minimise contact with people other than those crucial to his/her care. Restricting social contact helps to minimise the risk of infection being spread to your child from other people. Many centres refer to this as the 'isolation period' and to your child's room as an 'isolation room'. These terms are slightly misleading, but please do not be alarmed. The following section aims to explore what the 'isolation period' will involve for you, your child and family.

What is an isolation room?

This is an every day room within the transplant unit which may have filtered air. The room is not sterile, but will have been thoroughly cleaned, especially for your child. When your child is at their most susceptible to infection, towards the end stage of the course of chemotherapy, he/she will be transferred to this room and will remain there for up to three to five weeks, or until the new bone marrow starts to produce white blood cells which will protect him/her from infection.

Who is allowed into the isolation room?

Most transplant centres will restrict your child's daily contact with persons other than parents, guardians, hospital staff and carers. Visitors are also restricted, including children.

Will I have to wear special clothing?

Different transplant centres will give different recommendations. Most centres will provide you with plastic aprons or cotton gowns to wear over your own clean clothes. Some centres may also ask you not to wear hand or wrist jewellery which can be difficult to clean. The most important and simple precaution is thorough and frequent hand washing whilst looking after your child.

What happens if I become unwell during the isolation period?

During isolation, your child is susceptible to infections which could make them unwell. Anyone who has been in contact with chicken pox, shingles or measles and has not had any of these diseases themselves should not come into contact with your child. Anyone with signs of illness, such as high temperature, coughs, colds, diarrhoea, vomiting, conjunctivitis (red sore eyes), or a cold sore should also not have contact with your child. As your child's carer, it is very important that you eat properly, take breaks, get sleep and fresh air in order to stay as fit and well as possible. If you do suspect that you are becoming unwell, please let staff know on the unit as soon as possible and they will advise you as to the most appropriate action.

What can I take into the isolation room?

Again, each centre differs slightly, but will advise you before your child's admission as to what is allowed. Generally, most items are allowed into the room as long as they have had minimal handling, are new or washable.
Despite some restrictions, the room will become you and your child's home for several weeks, therefore it is important to bring some familiar items e.g. photographs, pictures, books, which will help to make it 'your own'.

Will I be able to stay with my child?

Children's hospitals do not have restricted visiting hours. Your transplant centre will actively encourage you to stay with your child and to be involved in their care. However, it is important that you take frequent breaks. Most hospitals only have enough facilities for one parent to stay overnight, but you may wish to discuss alternating this arrangement with your partner or a relative or friend that your child is comfortable with.

How involved will I be in caring for my child?

You and your child will need the expertise, information and advice of the transplant centre. However, as a primary carer, your child will need you. Staff on the transplant unit will support and advise you regarding how to meet the basic needs of your child and will help you to continue to parent your child. Your role will be vital.

Transplant Day

Your child will receive the new bone marrow after all the chemotherapy has been given. The bone marrow is given intravenously, into the central line, over approximately two hours and is similar to receiving a blood transfusion. Whilst receiving the bone marrow, your child will be monitored for any reactions but normally the procedure is straightforward and uneventful. Whilst the transfusion is in progress, your child may want to play games, read, watch TV or just sleep. Some families like to take photographs or even video the event, particular if a brother or sister has been the donor.

How will I know when the new bone marrow is working?

Following the transplant, blood samples will be taken from your child daily, to show the number of red blood cells, platelets and neutrophils being produced by the stem cells in the new bone marrow. During the first two to three weeks following the transplant, these cells will remain extremely low. As the new bone marrow begins to grow and function and produce blood cells of its own, the levels of red blood cells, platelets and white blood cells in the blood will increase. At this stage, a blood test is carried out to confirm that the new blood cells are being produced by the donor bone marrow. This test is referred to as 'engraftment studies' and will indicate that the new bone marrow is has begun to function.

When will my child be better?

It may take one to two years for full immunity to return. Each child is different and your transplant centre will continue to monitor your child's immunity once you have returned home. Depending on the type of transplant that your child has received, within three to four months after the transplant has taken place, he/she may have adequate immunity to allow infection precautions to relax. At six to eight months post-transplant, your child may have returned to school and the acute stage of treatment for most children and their carers is behind them.

Patients' stories

See separate page here.

After the transplant: restoration and recovery

by Rebekah Lwin, Clinical Psychologist attached to the BMT unit at Great Ormond Street
Hospital.

In making the decision to proceed with bone marrow transplant (BMT) concerns are often Focused, understandably, on preparations for the hospital admission and the transplant itself. These are seen as the areas that need the most immediate and critical attention and the greatest family adjustment. As a consequence, the personal, social and professional resources that may be required after BMT may often be overlooked, yet this too can be a difficult and psychologically stressful period which can benefit from early consideration and preparation.

It can be helpful to think about BMT as a process of discrete stages, each raising different concerns and drawing on different personal resources and coping skills:

Stage 1: Pre-bone marrow transplant - decision making and preparation
Stage 2: Hospital admission - separation, isolation and the BMT
Stage 3: Discharge - leaving hospital, early recovery and family re-adjustment
Stage 4: Long term adaptation

In our experience most families generally cope and cope well with the hospital admission period. It is difficult, tiring, distressing, demanding but the schedule is well structured and time limited. This stage is planned in careful detail by hospital and family and is usually well supported by extended family, friends and employers. Discharge from hospital comes after a hospital period of six to eight weeks, or longer for some children, and news of the discharge date is greeted with relief excitement, a flurry of domestic activity (generally cleaning and adding the finishing touches to recent home improvements) but also some anxiety, especially about leaving the protective environment of the hospital and the vigilance and availability of ward staff.

This stage of the BMT process places different demands on the BMT child and family for although the critical event is over the recovery is far from complete. Medication, weekly clinic visits, blood tests are all a continuing requirement. Children may feel tired and unwell, may object to continued restrictions and resist taking medication. Difficulties with Eating and persistent nausea and vomiting are common for a while after going home. The risk of infection is still high and the maximisation of a germ-free environment and continued isolation from children and large public groups remain necessary.

Chemotherapy will have resulted in the loss of hair and the use of steroids may result in further changes in appearance which can be very distressing, particularly for the older child. Parental and sibling roles and tasks which were reorganised to accommodate the hospital admission may need to change again, although not yet back to what they used to be. Siblings may protest and voice their needs now that the family is back together. Friends may not understand, perceiving the critical event as being over. Local health and education services may not respond with the speed or degree of service that is desired. Hospital re-admissions may be necessary and this possibility should be prepared for, both practically and psychologically In fact, family life rarely gets back to normal immediately but rather undergoes yet another reorganisation and presents a new order to adjust to.

Comments from parents two to three months after returning home highlight how difficult this time can be for some families.

‘It wasn't quite as hard as we expected while in hospital, but the adjustment to being back home was much harder than expected,'

‘Probably not prepared enough for how it hits you once you're at home - all soexhausted, lots of drugs, weekly hospital visits etc. It's not normal at all.’

‘The energy levels just went... mentally and emotionally we were drained. You don't sleep properly or eat properly in hospital; parents must be really run down at the end of the hospital stay.’

For the BMT child and siblings, these first few months after returning home can be a frustrating time. The belief that the purpose for the BMT was to improve health and quality of life may be stretched to the limit and psychological responses to the illness, treatment, separation and isolation may emerge. The nature of these responses may depend on the age of the child and their role in the BMT process and should not be confused with normal developmental changes in behaviour or concerns about issues unrelated to BMT. Younger children may behave uncharacteristically, seeking attention and constant reassurance or reverting to younger behaviours. Older children may experience and display changes of mood or become temperamentally difficult at times.

Problems may develop with schoolwork or with friendships. These reactions are likely to be normal, though perhaps alarming for child and parent, and will require patience and the opportunity to discuss concerns both for the future and from the past. Behavioural or emotional reactions four to twelve months after BMT may reflect delayed responses to the hospital period and illness in general but may too reflect concern about reaching significant milestones that clearly mark progress but can also raise fears and anxieties such as, removing a central line, stopping medications, returning to school or changing medical teams. Trusting in being cured, adjusting to a new confidence of ‘wellness’ from a fear of 'illness' can, for some, be a wobbly bridge to cross.

In general, it takes most families six months to a year after BMT to fully recover and adapt to the enormity of what they have been through. Awareness that recovery includes a psychological process as well as a physical one and that the ups and downs are an expected and commonly experienced part of the process may minimise disappointment and difficulties. Getting 'back to normal' can take time, but that is not abnormal.

Practical points to consider

• On returning home, do not expect too much of or from yourself, rest as much as possible and try to carve out some individual time for each child, your partner and yourself as well as family time.

• Prepare the BMT child and siblings for the certainties as well as the possibility for uncertainties that may follow the immediate discharge from hospital.

• Prepare the BMT child (and yourself) for the fact that he/she will probably receive less one-to-one attention from you and gently remind him/her of the needs of any brothers or sisters in the family.

• Do not be alarmed by swings in mood, poor concentration, poor sleep patterns or the development of inexplicable fears, in yourself or your children. Such responses are not uncommon and are usually short-lived. Do however talk these through with someone from the BMT team who can reassure you and advise you further.

• Well-meaning friends often continue to exaggerate attention on the BMT child and sibling donor (where there is one). Try to encourage an even distribution of attention: research evidence shows that, of all children, it is the non- donor sibling who is particularly vulnerable.

• Ensure that friends and family who have been supporting and helping you know that coming home does not necessarily mean that everything is better, they should not expect you to get your life back to normal immediately. Be clear about the help and support that you now need.

• Prepare the BMT child for going back to school by encouraging contact with friends (one as this is permitted. Home tuition should also be arranged for the months before the child returns to school, and schools should be made aware of what BMT involves and how your child has responded.

• Each family is different: you may or may not experience any problems post-transplant. Be prepared for them but do not expect them.

Fertility and cryo-presernvation of ovarian and testicular tissue

The effect of the drugs used in transplant on future fertility often greatly concernsfamilies. This article, by Dr Alison Leiper and Rebekah Lwin of Great Ormond Street Hospital looks at recent developments.

Fertility is affected in children who have undergone bone marrow transplantation using Busulphan and Cyclophosphamide as conditioning chemotherapy prior to the bone marrow infusion (if total body irradiation is used during the conditioning regimen then puberty may also be affected). The combination of these drugs acts on the ovaries in girls and testes in boys resulting in compromised fertility for almost all children, although there have been instances of spontaneous recovery of fertility some years after BMT.
There is evidence that the child's age and gender and the dose of chemotherapy may all influence the likelihood of permanent infertility. Of all the possible long term effects of bone marrow transplant the probability of infertility often raises the greatest concern for parents and children.

What can be done?

At present, little can be done with any certainty of success. If the child is male and has already progressed through puberty (adolescence), then a sperm sample can be collected by masturbation and stored in the frozen state (cryo-preserved) until it is required in adulthood.

Another approach is to collect the sperm, if they are present, from the urine of a child who is near to puberty, and store these in the same way. In the young pre-pubertal boy sperm are not present and semen cannot be collected.

Other ways of preserving male fertility in this age group, are being sought. For females of any age the situation is not simple. Although eggs (oocytes) taken directly from the ovary prior to transplant can be cryo-preserved, there is a very high risk of genetic damage during the thawing procedure, which would lead to abnormality in the offspring. This, therefore, is not an option for preservation of female fertility. Currently the only feasible option is either adoption or donation of fresh oocytes from another healthy women, at the time pregnancy is desired by the patient. This has led scientists to look for other ways of maintaining female fertility.

It is possible to obtain a wedge of ovarian or testicular tissue, containing immature eggs or sperm, by an operation under general anaesthetic, prior to bone marrow transplantation. This tissue can be successfully cryo-preserved and may eventually be the method of choice for preserving fertility. Much research is directed at trying to develop the immature eggs and sperm into mature 'gametes' capable of initiating a pregnancy Attempts are also being made at putting sperm back into the patient's testes after BMT. However, at the present time this is only experimental and no results have been achieved in humans. Research is mainly carried out on adults who are able to give consent for this operation themselves, and where the hospital has sought permission of its Ethical Committee.

Options for the pre-pubertal child

The options for pre-pubertal children are limited but are currently under discussion nationally by paediatric oncologists (children's cancer specialists) and bone marrow transplant specialists, who work within United Kingdom Children's Cancer Study Group centres. These specialists are working towards the cryo-preservation of testicular and ovarian tissue (described above) within an ethical, acceptable, safe and legal framework, and in close discussion with the Human Fertilisation and Embryology Authority (HFEA). The HFEA govern the use of mature human oocytes and sperm (gametes) but as yet have no legislation for the use of immature gametes.

Within these discussions, the safety of the child is paramount, and following recognition that children's rights need to be respected, under the Children Act 1989, a case has been put forward that the child's fully informed consent is required. This of course is not possible with a very young child and here difficulties arise. In the older child who is pre-pubertal, it is possible to ensure that the child has understood the information provided, by careful counselling and feedback, and in this setting it may be possible to store tissue. Experimentation is not allowed on the tissue unless Ethical Committee approval has been gained. Storage of the tissue has to take place at recognised HFEA approved centres. However, there are still many issues to be resolved such as the ownership of the tissue (e.g. does it belong to the child, the child's family the hospital?), and what happens to the tissue if the child were to die.

Great care should be taken when discussing these issues with children; that they do not confuse fertility with sexual ability or sexual identity and to offer reassurance that even though they may be infertile, they will still be able to lead an active sexual life in adulthood. Similar consideration and reassurance should also be given to boys who attempt to produce a sample of sperm themselves for storage but, for whatever reason, are unable to do so.

Risks to the child of cryo-preservation of tissue

Operative risks

• The operative risks of haemorrhage, infection and general anaesthetic are greater in the female than in the male, as an abdominal operation is required.
• In both sexes the operation to remove a wedge of tissue takes place pre-BMT. This procedure exposes the child to increased risk from infection and bleeding.
• Loss of a testicle can occur through haemorrhage which may compromise a child's pubertal development.

Potential risks to the offspring

• The length of storage may be very long e.g. 20 years and it is not fully known how this length of storage will affect the immature sperm or eggs and hence the offspring.
• BMT in females is associated with pre-maturity, low birth weight and a higher perinatal mortality rate in their offspring than in the normal population.
• The gene causing the immunodeficiency may be passed on to offspring who could then be carriers of the condition, or have the condition themselves in the rare cases of dominant inheritance.

Conclusions

Although cryo-preservation of ovarian and testicular tissue prior to BMT is technically feasible and possible, research for development of immature eggs and sperms into mature gametes capable of producing pregnancy has not yet led to success in humans.

The approach to older pubertal children is different from that of the younger child, because the ethical requirements are that the child should be fully informed and the information understood, before the parents can give consent. This is particularly pertinent when there is no guarantee of preservation of fertility, and the risks of operation may therefore outweigh the benefits.

The different approach required for children is not always appreciated at centres dealing with adults, because of issues concerning informed and Ethical Committee Approval, where more thought needs to be given to the child's consent and Ethical Committee approval.

The Human Fertilisation and Embryology Authority may eventually bring in legislation to govern this issue.

The increasing success of BMT has meant that it is only recently that children with severe immunodeficiencies can confidently think in terms of long-term survival and the opportunity for starting their own families. As a result, very little is known about children's attitudes towards infertility and their psychological responses to these new techniques being offered. We need more information about the experiences of children, their parents and subsequent partners in order to understand better and inform more fully.