What is bone marrow?
Bone Marrow is the organ or 'factory' responsible for the production of blood cells. It is located in the core of long bones and the spongy centre of flat bones such as the hip bones, ribs and skull. The earliest, most immature cells are called stem cells. Stem cells can divide to produce more stem cells or differentiate to produce red cells (RBC), white blood cells (WBC), or platelets. RBC carry oxygen around the body, delivering it to all tissues. WBC are the body's main defence against infection. Platelets are small sticky cells which prevent and stop bleeding.
Once they are released from the marrow into the blood, platelets and WBC cells have only a short life span. RBC live for about 3 months. Due to their limited life span all blood cells must be constantly renewed from the stem cell pool. Because of their ability to produce all types of blood cells on an ongoing basis, stem cells are the most important cells in bone marrow transplantation.
What is a bone marrow transplant?
A bone marrow transplant (BMT) is a procedure carried out to replace defective bone marrow stem cells with healthy cells. Stem cells may fail either because of an underlying disease or due to the effects of chemotherapy or radiotherapy. Chemotherapy and/or radiotherapy, if given in high enough doses will completely destroy bone marrow cells. As a result patients receiving such treatment will die of anaemia, infection, or bleeding, if healthy new marrow is not transplanted. Thus BMT's not only cure diseases in which the marrow is defective, but also allow higher doses of chemotherapy and radiotherapy to be used, than would otherwise be possible. A BMT therefore offers hope of cure to patients with leukaemia and other cancers who do not respond to conventional doses of treatment.
Types of bone marrow transplants
There are three types of BMT. These are named according to the relationship between the patient (recipient) and the person from whom the stem cells are obtained (donor).
Autologous BMT involve the collection of the patient's own stem cells, either by harvesting bone marrow or peripheral blood stem cells (PBSC's). These cells are then frozen and stored. When required, the cells are reinfused (given back) to the patient after high doses of chemotherapy. The cells which are frozen at the time the chemotherapy is administered are not affected by the drugs given. When the frozen cells are given back to the patient they will rapidly regrow and replace those cells affected by the drugs. Because the marrow is that of the patient, there are fewer complications than after a transplant using bone marrow from another individual.
An Autologous BMT is most commonly used to allow bigger doses of chemotherapy or radiotherapy to be given to treat an advanced cancer or to treat some types of leukaemia after a remission (absence of disease) has been achieved. At the Royal Children's Hospital, Melbourne the most common disorders treated by autologous BMT are acute myeloid leukaemia, advanced neuroblastoma, and other solid tumours either after a relapse or for those that are very advanced at diagnosis.
Autologous BMT are not applicable to diseases where the bone marrow stem cells are defective. Examples of such disorders are aplastic anaemia (a serious disorder in which the stem cells are severely reduced in number) and inherited disorders of the immune system in which the lymphocytes are absent or non functional and patients develop severe infection.
Syngeneic BMT are transplants from one identical twin to the other. Such a transplant is effectively the same as an autologous transplant because the donor's bone marrow is identical to the patient's. Syngeneic BMT may be used to treat diseases such as aplastic anaemia, leukaemia and other cancers, but not to treat inherited diseases such as immune deficiencies.
Allogeneic BMT are transplants from a donor other than an identical twin. The most common and most suitable donor used is a brother or sister (sibling) of the patient. HLA antigens, the tissue typing groups important in establishing compatibility between donor and recipient, are inherited half from each parent. This means any brother / sister pair have a 1:4 chance of being HLA identical and therefore suitable as a donor / recipient pair for a BMT.
Unless parents are related ie. cousins, they are rarely suitable as donors for their children. Sometimes however, a search in the extended family may identify a suitable relative (parent, grandparent, aunt or uncle ) who is fully matched or only mismatched at one of the 6 major HLA antigens. A relative who matches at 5:6 of the HLA antigens is a suitable donor for a transplant but more complications are expected than if a fully matched brother or sister is the donor.
Patients who do not have a suitable donor in the family, may find an unrelated donor on one of the world wide Volunteer Bone Marrow Donor registries. Searching these registries and identifying a suitable donor is a time consuming and expensive exercise. Although a donor will not be identified for all patients, many who otherwise could not have a BMT are now able to benefit from the good will of these volunteers. As with a family mismatched donor, the risks associated with a matched unrelated donor BMT (MUD) are greater than with a sibling transplant. Should your child require a MUD BMT the consultant will provide you with more detailed information.
The blood which is left in the placenta after the delivery of a baby contains quite large numbers of stem cells. Large banks of stored, donated cord bloods are now avaliable for searching around the world and may provide suitable stem cells even when no bone marrow donor is available. Cord blood is being used increasingly as a source of stem cells for transplantation instead of bone marrow.
Allogeneic BMT is usually recommended as the best available treatment for the following conditions:
• Severe Aplastic Anaemia,
• Acute lymphoblastic leukaemia (ALL) if a relapse has occurred while the child is still on chemotherapy, or within a year of stopping therapy,
• Some types of ALL in 1st remission, if there are features at diagnosis which suggest a very high risk of relapse,
• Acute myeloid leukaemia, either in 1st remission or following a relapse after a previous autologous BMT,
• Chronic myeloid leukaemia while still in a stable phase of disease, usually in the first year after diagnosis,
• Congenital immunodeficiency diseases such as ;
• Severe combined immunodeficiency (SCID)
• Wiscott Aldrich Syndrome (WAS)
• Bare lymphocyte Syndrome
Waiting for a bone marrow transplant
What happens in the time period leading up to a decision to proceed with a BMT will depend on the condition your child has. If you have an infant who has a severe immunodeficiency, or your child has recently been diagnosed as having aplastic anaemia, your child will be receiving supportive care (antibiotics, blood products, gammaglobulin) and a BMT is usually scheduled as soon as a donor can be identified.
If your child has recently suffered a relapse of leukaemia, the important first step will be to get him/her back into remission with a change in chemotherapy. A BMT has a much greater chance of being successful if done while your child is in remission and is well. The urgency for a BMT will vary from child to child. Every attempt is made to transplant those children at high risk of recurrence as soon as possible after a donor is found. For others transplantation is less urgent, and the BMT can be scheduled electively. Unfortunately some children will relapse, either while still searching for a donor or while on the transplant waiting list.
Pre transplant conditioning
The initial phase of the actual BMT procedure involves the administration of high doses of chemotherapy and possibly total body irradiation (TBI). This 'conditioning' treatment has two important goals;
• to destroy your child's lymphocytes, (the cells which may recognise the new bone marrow as foreign) so that they do not attack and reject the donor marrow, and
• to kill any surviving leukaemia cells which could otherwise cause a relapse.
Many children with congenital immune defects are unable to reject a graft and will not require conditioning. Patients having a BMT from an identical twin for a non cancerous condition, also require no conditioning.
The combination of drugs used and whether your child receives TBI, will depend on the reason for your child's BMT, the treatment he/she has previously received and your child's age.
Commonly used combinations for conditioning are;
• Busulphan and cyclophosphamide,
• Busulphan, VP-16 and cyclophosphamide,
• TBI, thiotepa and cyclophosphamide, or
• TBI and VP-16.
Patients receiving BMT's from mismatched family donors or from unrelated donors usually receive ATG (Antithymocyte globulin) in addition to one of these conditioning protocols. The conditioning regimen felt to be most appropriate for your child will be discussed with you by the consultant. Expected side effects of the particular regimen will also be discussed. You are encouraged to ask questions about anything that is unclear to you. Written information about conditioning will be provided when discussion around transplant and obtaining consent takes place.
The transplant day
The day of the BMT is counted as day '0'. The days over which the conditioning is given are numbered backward from this day ie. D-3, D-2, D-1 D0. Days after the transplant are then numbered D+1, D+2, etc. The actual BMT is usually performed two to three days after the last dose of chemotherapy, to ensure that the drugs have been eliminated from the body.
The Bone marrow donation
Bone marrow is harvested from the hip bones of the donor, in the operating theatre, under a general anaesthetic. The marrow is sucked out using a needle and syringe in the same way as when bone marrow tests are done. No cuts or stitches are needed. The amount of marrow taken depends on the weight of the patient having the transplant.
The side effects of donating bone marrow are minimal. Some pain at the harvest sites is to be expected for a few days however this is usually relieved with oral pain killers such as paracetamol. If the bone marrow harvest occurs in the morning, young donors are often able to go home that evening. Older donors may need to rest in hospital for a day following the procedure. Rarely, if the donor is much smaller than the patient, a blood transfusion may be required. In general an oral iron supplement is sufficient to ensure that the donor's blood count rapidly returns to normal.
The bone marrow that has been harvested from the donor is returned to the patient after it has been filtered to remove fat and tiny bone particles. If the RBC groups of the donor and recipient are different it may also be necessary to remove the RBC from the marrow, to prevent a reaction. The bone marrow is given in the same way as a blood transfusion, via the HICKMAN® catheter. The bone marrow cells find their way to the marrow spaces which have been emptied by the conditioning treatment.
The weeks after the transplant
Once the bone marrow has been given to the patient, there is a period of two to four weeks before the marrow cells divide sufficiently and the blood count starts to improve. During this time the blood count is very low and most patients develop a fever, requiring intravenous antibiotics. The germs which are present on the skin and in the nose and gut of all patients are often responsible for these infections, entering the blood stream through breaks in the skin or through mouth or gut ulcers. Careful skin and mouth care are most important in reducing this infection risk to the minimum.
Graft versus host disease
Once the bone marrow has taken (engraftment) and the blood count improves, the lymphocytes of the donor may recognise that the cells of the recipient are different from those of the donor, and try to reject the tissues of the recipient. The tissues which are particularly targeted for attack are the skin, the gut and the liver, causing rash, diarrhoea, and jaundice (yellow skin). This reaction is called acute graft versus host disease (AGVHD) and occurs early after the transplant. AGVHD may settle with treatment but may persist or recur, requiring treatment over many months (chronic GVHD).
Skin affected by chronic GVHD may become thickened or very thin and develop colour changes with the skin being lighter or darker in different areas. The mouth and eyes may become dry. Difficulty in absorbing food may result in the need for a special diet. Chronic liver problems may lead to scarring of the liver and gradual deterioration of liver function. Stiffening of joints occasionally occurs. Treatment of CGVHD delays recovery of immune function and increases the susceptibility of the patient to infection.
Veno occlusive disease
During the first 30 days post BMT your child is also at risk of a condition called veno-occlusive disease of the liver (VOD). This is due to a toxic effect of the chemotherapy and radiotherapy on the small blood vessels in the liver, causing a blockage of these vessels, interfering with the flow of blood through the liver. Patients who have had previous liver damage from drugs or infection (hepatitis) are at increased risk of VOD. The liver swells and is tender, and fluid builds up in the abdomen. A drug called Heparin is given to all patients to reduce the risk of VOD.
It is during the period of conditioning, the pre-engraftment period of neutropaenia and infection and the risk period for VOD and AGVHD that your child requires the specialised care of the BMT unit. Once the blood count has recovered sufficiently to bring infection under control, AGVHD is responding to treatment and your child is beginning to eat, he/she will be discharged either to home or to Ronald McDonald House. Platelet transfusions may still be necessary as an outpatient and your child's progress will be reviewed regularly.
Making the decision
Making the decision for your child to undergo a BMT can be difficult. Your child's consultant will discuss in detail with you the reasons why a BMT is being considered for your child, as well as the expected results and possible complications. The following factors need to be considered in each individual case;
• the expected outcome of the disease with conventional treatment,
• the probability of curing the disease with a bone marrow transplant,
• the risks of a serious complication after the transplant,
• the general health of your child, including his/her emotional ability to cope with a BMT, and
• the availability of a donor.
A BMT is a difficult procedure, which has an impact not only on your child undergoing the BMT, but the whole family. It is important that all members of the family are informed about the BMT to a level appropriate to their understanding.
Once the decision is made to proceed with a BMT, the timing will depend on your child's condition, the availability of a donor, and the number of children on the waiting list. When your child comes to transplantation a positive, hopeful attitude on your part will help him/her. Please remember that caring for your child is a team effort and that you are important members of that team. If you do not understand something please ask!