|  |  |  | | | | Bone marrow and stem cell transplantation | | | | |
| | The booklets in this series are intended to provide general information about the diseases they describe.
In many cases the treatment of individual patients will differ from that described in the booklets.
At all times patients should rely on the advice of their specialist who is the only person with full information about their diagnosis and medical history.
 | Bone marrow and blood cells |
What is bone marrow?
Bone marrow is a spongy tissue found within bones. All blood cells are produced within the bone marrow. To sustain the necessary levels of blood cells the bone marrow of an adult must produce about 3 million red cells and 120,000 white cells every second. All these cells originate from a small population of stem cells. Less than one in 5000 of the marrow cells is a stem cell. As well as producing mature blood cells stem cells have the remarkable ability to reproduce themselves. This maintains the pool of blood forming stem cells throughout life.
Normal marrow produces three types of blood cell – red cells, platelets and white cells. Red blood cells contain a protein, called haemoglobin, which carries oxygen to the body tissues. A lack of haemoglobin is called anaemia which will cause fatigue after gentle exercise, general weakness and shortness of breath. Red blood cells survive for about four months (from the time they are produced in the bone marrow).
Platelets circulate in the blood and are important following an injury, because they are involved in forming a blood clots to prevent continued bleeding. A shortage of platelets can cause bruising and bleeding from minor wounds and from the gut, mouth and other sites. Platelets live for about eight days (in the blood circulation).
There are several different types of white blood cell, which co-operate to protect the body against infection with bacteria, viruses, fungi and parasites. One of the most important of these for general defence against infection, is the neutrophil.
Lymphocytes are another specific type of white blood cell. They are responsible for the production of antibodies and other important functions within the immune system. Some specialized lymphocytes may live for many years, unlike other white cells which live for hours or days. Lymphocytes are able to recognise cells foreign to the body and trigger a response by the immune system to eliminate them. This process may also be triggered by a stem cell transplant and without careful matching may lead to serious complications.
Both the production of blood cells and maintenance of the correct numbers are controlled by chemicals called growth factors. Several types of growth factor have been produced in the laboratory and can be used in treatment and to assist in collection of stem cells for transplantation.
The bone marrow cannot carry out its normal function if it is affected by cancers of the blood (e.g. leukaemias or myeloma) or invasion by cancerous cells from tumours elsewhere in the body. Radiation therapy and most drugs used to treat cancer will also damage the marrow. The bone marrow stem cells are particularly sensitive to the effects of cancer treatment because of the enormous rate of blood cell production. If the marrow is irreversibly damaged by disease or treatment the only curative option is a stem cell transplant.
| Stem cell transplants and the immune system |
The immune system has evolved to protect the body against foreign invaders. These may be bacteria, parasites, fungi or viruses. Unfortunately, the immune system cannot recognise transplanted stem cells from a donor as beneficial and there is a need to minimise the patient's reaction against the incoming bone marrow graft. However, at the same time, the incoming immune system may act beneficially in helping to destroy residual leukaemia cells in the patient.
The main cells of the immune system are lymphocytes, which can be classed into several types, and monocytes. The major types of lymphocyte are:
 | B cells, which mature into plasma cells that secrete antibodies, the proteins that recognise and attach to foreign substances known as antigens. Each type of B cell makes one specific antibody, which recognises one specific antigen. |
| T cells which directly attack infected, foreign, or cancerous cells. T cells also regulate the immune response and work primarily by producing proteins called lymphokines. |
| Natural killer cells (NK cells) produce powerful chemical substances that bind to and kill any foreign invader. They attack without first having to recognise a specific antigen. |
| What is a stem cell transplant? |
Stem cell transplantation (SCT) is the term now used in preference to bone marrow transplantation(BMT).
When a patient’s bone marrow fails to produce new blood cells, for whatever reason, they will develop anaemia, be prone to frequent, persistent infections and may develop serious bleeding problems. The anaemia can be treated reasonably effectively by blood transfusions. However, white cells cannot be effectively transfused and the short life-span of platelets limits the effectiveness of platelet transfusions. If normal blood cell production cannot be restored, and the marrow failure is very severe patients will inevitably die of infection or of bleeding.
In order to restore blood cell production a patient may be given healthy stem cells. These may be the patient’s own stem cells which were collected prior to the disease or intensive treatment. This is known as an autologous transplant or an autograft. If healthy stem cells cannot be obtained from the patient they be from a donor (e.g. from a brother or sister or an unrelated person). This is particularly powerful in eliminating malignant disease from the marrow. A relatively new source of stem cells is the blood from the umbilical cord and placenta of a new born infant. However the number of stem cells obtained will be less than that obtained from an adult donor. At present this form of transplant is only suitable for children.
Any form of transplant from a donor is called an allograft or an allogeneic transplant. The best match in terms of tissue typing (see later) is an identical twin. This is called a syngeneic transplant. If a family member of the patient provides stem cells they are known as a related donor. The most common donor is a brother or sister of the patient, but occasionally a parent or child of the patient may be suitable. This form of transplant is only feasible for about one in three patients who have a sibling or, rarely, a parent with a matching tissue type. Less closely related kin are rarely a match so they are not usually tested. If no related donor is available, it is necessary to search for a matched unrelated donor.
A major limitation on stem cell transplantation is the ability of the patient to withstand the high doses of drugs and radiation typically given before the transplant. Unfortunately, many of the conditions for which a donor stem cell transplant is the only curative option mainly affect older patients. An autologous transplant is generally considered to be less dangerous than an allogeneic transplant, and therefore the upper age limit at most centres is about 55 years for the latter and between 60 and 70 years for an autologous transplant.
Apart from age, the patients general health will be considered in order to decide their eligibility for a transplant. If a patient has other illnesses, for example heart disease, it is unlikely that they will withstand the intensive chemotherapy and radiotherapy (also called conditioning treatment) that is needed to prepare the patient for the transplant. Therefore such patients may not be eligible for a transplant regardless of thier age.
| Why are stem cell transplants needed? |
There are three situations in which a patient may require a stem cell transplant. Two of these relate to failure of the bone marrow to produce blood cells while the third offers an opportunity to cure an otherwise incurable inherited disease.
Stem cell transplants are predominantly used as part of the treatment for certain types of malignant diseases, mainly leukaemia, lymphoma or myeloma which involve the bone marrow.Of almost 18,500 stem cell transplants carried out in Europe in 1998 13,750 (75%) were for leukaemia or one of the related blood cancers. Over 95% of all donor transplants were carried out in patients with leukaemia, lymphoma, or aplastic anaemia.
Almost all cancer drugs and all but very localised radiotherapy will damage normal tissues as well as cancer cells. This damage particularly affects cells lining the gut, the skin, hair follicles and the bone marrow stem cells. Most affected tissues can recover completely given time. The bone marrow stem cell is particularly vulnerable and may be irreparably damaged by high dose treatment or radiotherapy. The availability of a stem cell transplant will allow a patient to receive intensive treatment for their disease even though this will destroy normal marrow function. The transplanted donor marrow also helps to eliminate the leukaemia. This is called graft versus leukaemia (GvL) or graft versus tumour effect. Transplants can be performed to allow intensive therapy of other forms of cancer.
A less common indication for a stem cell transplant is failure of the bone marrow without obvious cause; a condition called aplastic anaemia. Although this condition can be treated with drugs which suppress the activity of the immune system this approach does not restore the bone marrow to function completely normally. A donor stem cell transplant is the only curative treatment for this condition and is recommended for young patients who have a well matched family donor. A stem cell transplant may also be the only curative option for patients with certain inherited conditions, particularly severe forms of thalassaemia and immune deficiencies.
| Source of stem cells |
Until recently, bone marrow was the only source of stem cells for transplantation. The procedure for obtaining bone marrow is known as harvesting and is normally carried out under general anaesthetic. The risk for this procedure is very small and the procedure has been carried out on a very large number of volunteer donors with no serious side-effects.
About one litre of marrow is collected from the bones of the pelvis by inserting a special needle a number of times and drawing off marrow. This represents a small proportion of the donor's marrow and it is replaced very quickly. It is common practice to take a unit of blood from the donor a week before the donation and to transfuse this after the donation to replace lost blood volume. Using the donor's own blood completely eliminates any slight risk of transfusion-borne infection. The donor is able to leave hospital the day after making a donation. There is usually some soreness but most people are able to resume work within a few days and are completely back to normal in a week or two.
In the case of an autologous bone marrow transplant, patients act as their own donors and the procedure is identical to that outlined above. The marrow can be frozen and stored for months or even years. This is often done with marrow collected from a patient with chronic phase of chronic myeloid leukaemia or with indolent lymphoma. Both of these diseases may undergo transformation to a more aggressive form. An autograft at this stage using the stored stem cells may be capable of reversing this transformation. In acute leukaemia harvesting marrow during remission (that is when the disease has responded to treatment) offers the possiblity of an autograft shoud the disease return.
| Peripheral blood stem cells |
There are small numbers of stem cells in the circulating blood in normal health. These are known as peripheral blood stem cells (PBSC). Normally there are insufficient numbers of these to harvest them from the blood. The use of PBSC for transplantation became practical when it was found that it was possible to mobilise stem cells from the bone marrow into the peripheral blood. There are a number of ways in which this can be achieved. Growth factors, which are natural substances which control production of blood cells, can increase the numbers of stem cells in the blood. For healthy donors growth factors may be given alone as an injection under the skin. Donors may experience a degree of bone pain as a side-effect. This is usually easily controlled with non-prescription painkillers. For patients receiving treatment for cancer growth factors can be given together with a small dose of chemotherapy.
Stem cells are obtained from the circulation by passing the donor's blood through a machine and then returning it to the donor. The machine will collect the blood cell population that contains the stem cells. The remainder of the blood is returned to the patient or donor. This process is called leukapheresis. It usually requires about two sessions of two to three hours on successive days and is less invasive than bone marrow harvesting. No anaesthetic is needed which means that leukapheresis can be done as an outpatient procedure. Any potential donor will be given a detailed briefing on the procedure and on related risks by the transplant team.
Leukapheresis is much less inconvenient for the donor than a bone marrow donation. To avoid the risk of infection all the sections of the machine which come into contact with the donor's blood, are disposed of after use.
Most patients who receive peripheral blood stem cell transplants spend a shorter time in hospital, compared to those who recieve a bone marrow transplant, and are at less risk of complications because both their white blood cell and platelet counts return to normal more rapidly.
Normally, after a baby has been delivered the placenta and the umbilical cord are examined for any abnormality and then discarded. Blood vessels in the umbilical cord contain only blood from the baby because the mother’s blood cells do not cross the placenta. It should be emphasized that the cells are not collected from the baby but from the cord and the placenta, materials which are normally discarded. Careful studies have shown that the procedure carries no risk of harm to the baby or the mother.
The harvesting of cord blood stem cells provides a valuable clinical resource which is otherwise wasted. For this reason banks of frozen cord blood donations have been established in a number of countries including the UK. The reduced number of stem cells in a single donation has largely limited the use of cord blood transplants to children. In most cases these have been from a brother or sister of the patient. At the moment there is very limited banking of cord blood cells in Britain.
A special case arises where a pregnant woman has an existing child who is affected by a condition which may require treatment with a stem cell transplant (e.g. leukaemia or aplastic anaemia). In this case the obstetrician and the specialist treating the affected child should be involved in discussions whether special arrangements should be made for collection of cord blood stem cells from the present pregnancy.
There are several commercial organizations which offer to harvest and store cord blood stem cells on a long-term basis. Most experts do not recommend this as an option. The probability of a child requiring the use of their own stored stem cells is extremely low. For a child with leukaemia it may be undesirable to use their own stored stem cells. This is because there is evidence that their cord blood may contain stem cells with the same genetic lesions which originally contributed to the development of their leukaemia.
| Type of transplant |
Autologous transplant
For some patients it may be possible to use their own bone marrow or peripheral blood stem cells. This is known as an autologous transplant (autologous means related to self). This form of transplant can be used for many types of patients. These include patients with chronic leukaemia, lymphoma and myeloma. Trials are still continuing for other condiditons such as acute leukaemia and solid tumours.
One of the benefits of autologous transplantation is that there is no need to search for a related or unrelated donor. Family size and the pattern of inheritance of tissue types mean that only about 30% of patients have a perfect match from an immediate relative. Of the remaining 70%, many will not be able to find a matched donor in the unrelated volunteer donor panels. In cases where a donor is found the process may take many months during which time their disease mayprogress.
Stem cells collected for an autologous transplant may be contaminated with tumour cells that may cause a relapse (return of the disease) after treatment. This is particularly likely when the transplant is being performed for leukaemia, lymphoma or myeloma. It may be possible to remove, or to reduce the number of malignant cells by special techniques prior to the transplant. This is called purging and is done in one of two ways. The first is by isolating the stem cells and giving this enriched population to the patient. This is called positive selection. The other approach is to use selective treatments to remove the malignant cells from the marrow harvest before the stem cells are returned to the patient. This is called negative selection.
The two methods can be used on the same marrow or stem cell harvest. Development of very sensitive tests for the detection of minimal numbers of malignant cells has improved the ability to assess the success of purging techniques. It remains to be proven whether or not removing contaminating tumour cells reduces the risk of relapse after treatment. A significant limitation to the use of positive or negative selection is that both approaches reduce the number of stem cells available for transplant. If a stem cell collection contains small numbers of stem cells it may not be feasible to carry out purging.
The risks directly associated with the transplant procedure (infection, graft failure) are lower for an autologous transplant but the risk of the original disease returning (relapse) is greater. The greater risk of relapse is almost certainly due to the absence of a Graft versus Leukaemia effect which is described below. The greater relapse rate can also be due to residual tumour cells which were not removed by purging.
| Allogeneic (donor) transplant |
Any transplant in which the marrow comes from a donor is called an allogeneic transplant. It is necessary for the stem cells to be collected from a donor whose tissue type closely matches that of the patient. Even in this situation, the tissue types are unlikely to be identical because there are other minor tissue type markers which influence the immune reaction between donor and patient.
The body can distinguish between tissues which are self (not to be attacked) and foreign or non-self cells (which are to be attacked and destroyed). This is done by detecting specific markers on the surface of cells. The most important of these markers are called Human Leukocyte Antigens (HLA). There are six major markers, three inherited from each parent. The three markers are inherited from each parent as a “packet” of markers called a haplotype. In the diagram ABC, DEF, 123 and 456 each represents a haplotype. A child receives one haplotype from each parent as shown. Because the HLA markers are inherited in this way, for any one sibling (brother or sister) there is about a 25% chance of a full tissue match, a 25% chance that they will share no markers and a 50% chance that they will share half their markers. This assumes that the parents do not have any haplotypes in common. If they do the chance of a match will be higher.
It is necessary to have a good tissue match in order to minimise the risk of graft rejection. The match will never be perfect except in the case of identical twins. Because of the way in which the tissue types are inherited a non-identical sibling who matches for the six main markers is also likely to match on most of the minor tissue type markers. This makes a matched sibling donor a better choice than an unrelated donor who matches on all six main markers.
An allogeneic transplant contains immune cells from the donor. These will recognize the cells of the recipient as “foreign” and will attack them. This causes a condition called Graft versus Host Disease (GvHD), which may be severe and may even be life threatening. There is a beneficial aspect to this immune response by the donor cells – the same process will destroy residual leukaemia cells very effectively. This is known as the Graft versus Leukaemia effect (GvL). Many clinical trials are seeking to achieve the maximum GvL-effect with the minimum of GvHD.
GvHD can be a serious complication of stem cell transplantation. Attempts have been made to prevent GvHD but this was found to lead to an increased rate of relapse (return of the original disease). This was shown to be due to the loss of the GvL effect and confirmed the importance of GvL in a successful stem cell transplant.
A procedure called donor lymphocyte infusion exploits the Graft versus Leukaemia effect for treatment of patients who have relapsed following an allogeneic transplant. Lymphocytes are harvested from the original donor and transfused into the patient. DLI has become the treatment of choice for patients who relapse following allogeneic transplantation. This technique has proved to be most effective in treating relapses in patients with chronic leukaemia, especially chronic myeloid leukaemia. DLI is less effective in other conditions but may still be of benefit.
HLA identical
A transplant between identical twins is called a syngeneic transplant. Such transplants are extremely rare. Because the donor and recipient are genetically identical there is minimal risk of graft rejection. There is no graft versus host disease and therefore likely to be little or no graft versus tumour effect.
The usual type of related donor is a matched sibling (brother or sister). Where a sibling is completely matched they are known as an HLA identical donor. The average family size means that about one third of patients will be fortunate enough to have a well-matched brother or sister to act as a donor.
Haplotype identical
It is possible that patients without a matched sibling available it may be possible to use a half-matched family member. This is known as a haplotype identical match. In general, haplotype identical transplants are between partly matched brothers and sisters or a parent and their child. The number of stem cells available it is more common for the parent to be the donor. Whether a haplotype identical donor is acceptable depends largely on how well the remaining markers are matched. Some mismatches are more significant than others.
Occasionally, particularly in ethnic groups in which cousin/cousin marriages are common, there may be a good tissue match with an aunt, uncle or cousin.
Volunteer Donor
For patients who lack a related donor it may be necessary to look for a Matched Unrelated Donor (MUD), also known as a volunteer unrelated donor (VUD). The probability of finding a suitable donor depends on a number of factors including the rarity of the patient’s tissue type. There are now several million volunteers around the world who have been tissue-typed as potential bone marrow donors and in theory this should help up to 70% of patients to find a suitable donor. Unfortunately practical problems such as tracing donors, their availability for marrow donation and the donor's age and their own health status mean that only about 10% of searches result in a transplant.
In all bone marrow registers the majority of potential donors are from the Caucasian population. This means that there are particular difficulties in finding donors for patients from non-Caucasian ethnic groups because some tissue types are rare within the Caucasian population. Ethnic minorities are under-represented on donor registers which makes it difficult to find suitable donors for patients within certain ethnic groups.
The closeness of a match needed for a good result depends on which particular tissue markers are identical or non-identical. For some markers, it may be possible to accept a degree of mismatch and so improve the chances of finding an acceptable donor. The older the patient the greater the need for close matching since graft versus host disease tends to be more common and severe with increasing age.
Cord Blood
There are now cord blood banks in many countries. There are over 75,000 units of cord blood stem cells available worldwide and to date over 1500 transplants have been carried out using cells from these banks. The results of these transplants confirm the theoretical prediction that cord blood stem cells need not be as closely matched as bone marrow or peripheral blood stem cells to ensure a successful outcome. However, the low number of stem cells in a single donation compared to an adult stem cell donation has largely restricted these transplants to children. Research is being directed towards overcoming this restriction in order to extend this option to adult patients.
| The transplant procedure |
Prior to a transplant patients will receive a conditioning regimen of drugs and/or radiation, in order to destroy the bone marrow cells. This is called myeloablation. In the case of a donor transplant this is necessary to prevent rejection of the donor cells. This stage cannot be omitted even in patients with aplastic anaemia in whom the marrow has already failed or there is a high risk of graft rejection. Conditioning for an allogeneic transplant is typically either with busulphan and cyclophosphamide or cyclophosphamide with total body irradiation.
For many patients who are older or have other illnesses this procedure is too stressful and they are unable to receive a donor transplant. A non-myeloablative stem cell transplant is a recent innovation. This is sometimes known as a mini-transplant or as transplant-lite. It uses lower doses of drugs and radiation to suppress the patient’s immune response sufficiently to allow donor cells to become established. There is usually a stage during which the patient has a mixture of their own and donor marrow cells. This is called mixed chimaerism. This can be followed by full chimaerism which means the complete replacement of patient marrow with donor marrow.
Despite the reduced intensity of pre-transplant treatment, the toxicity of this procedure remains relatively high compared to chemotherapy alone. Non-myeloablative transplants extend the possibility of allogeneic transplantation to a wider patient population but will not be appropriate for all patients.
For autologous transplants the problem of rejection does not arise but conditioning regimens are still used to eliminate any residual diseased marrow. A regimen called BEAM is frequently used. This is a combination of several drugs given over a period of five days. For myeloma patients, the drug melphalan is frequently used, with or without total body irradiation.
| Receiving the conditioning regimen |
Often high-dose chemotherapy used, is given intravenously. For this reason a tube called a central line is placed under the skin of the chest and into a vein. This is often done in the operating theatre where an X-ray machine can be used to ensure it is correctly inserted. Local painkillers and a sedative are given as necessary to ensure that the procedure is not painful. The central line removes the need for the patient to have repeated injections during the course of treatment. The line remains in place until the treatment is finished. It is possible to wash and shower as normal. One effect of the chemotherapy drugs is nausea but with current anti-sickness drugs this is nom rarely severe.
This is not necessary for all patients but may offer a treatment advantage for some. It is important to calculate the dose accurately and this is done by a specialist radiologist. There is a number of side effects associated with radiotherapy. These will vary depending on the exact type of treatment and will be discussed in detail by the specialist. In order to reduce these side effects radiotherapy is given in divided doses or fractions. The exact number of fractions given depends on the procedures practised in the treatment centre but often a fraction is delivered in the morning and another in the evening for several days. The treatment is not painful at the time it is administered. It is necessary to lie still in front of the beam of radiation. A special support is prepared to help the patient remain in exactly the right position.
The bone marrow or blood stem cell transplant is given very simply in the same way as a blood transfusion into a vein in the arm or into the central line. Once the blood-producing stem cells are in the circulation, they find their own way to the sites in the bone where the new marrow will establish itself. Regular post-transplant blood counts will indicate when new white blood cells are starting to be produced. This confirms that the transplant has been successful. For peripheral blood stem cell transplants it normally takes about two weeks for the blood count to improve to the point where the recipient can go home. This process takes about twice as long following autologous and allogeneic bone marrow transplants. It takes up to two years for bone marrow function to fully recover.
A natural substance called G-CSF is produced in the body to control the production of white blood cells. G-CSF can now be produced in the laboratory and can be given by injection to stimulate blood cell production or to mobilise stem cells into the blood. G-CSF accelerates the recovery of the bone marrow and stimulates the production of normal granulocytes and monocytes after a transplant. It may also help to reduce the risk of infection.
| Risks of transplantation |
Graft versus Host Disease (GvHD)
With improved tissue-typing methods (which have reduced the risk of graft failure or rejection) and better supportive care for patients with infections; graft versus host disease has become the major life-threatening risk following an allogeneic transplant. Graft versus host disease occurs when the donor’s immune system attacks the patient’s body. It mainly affects the tissues of the skin, the liver and the gut. A distinction is made between acute and chronic graft versus host disease which is, to some extent, arbitrary and based on a timepoint at 100 days post transplant. There are significant differences in the behaviour of acute and chronic GvHD and the division is clinically useful. For example, the lungs may also be affected in chronic graft versus host disease.
Acute Graft versus Host Disease
When GvHD occurs within the first 100 days after transplant it is termed acute GvHD. This form typically causes a severe rash and may also attack cells in the liver and gut leading to nausea and vomiting and jaundice. Factors known to increase the risk of acute GvHD include:
| increasing age of the recipient |
| a donor who has had a pregnancy |
| any donor who has received a blood transfusion |
| reduced doses of immunosuppressive drugs post-transplant and; |
| less exact tissue match between donor and recipient |
Acute GvHD can be graded as Grade I to Grade IV on the extent and severity of the condition. Grade I may require no treatment, although some centres recommend treatment if the transplant is from an unrelated donor. Grade II or higher is considered moderate to severe and always requires treatment. Moderate to severe acute GvHD is a serious and potentially life-threatening complication of allogeneic stem cell transplantation.
Acute GvHD can be prevented by giving more intensive treatment to suppress the immune reaction post-transplant but this increases the risk of serious infections. Removal of a particular type of lymphocyte from the graft has also been shown to reduce the risk of acute GvHD but this increases the risk of graft rejection, serious infections and of relapse (return of the original disease).
Once moderate to severe acute GvHD has been diagnosed the first choice of treatment is usually steroids (prednisolone) to increase the level of immunosuppression. If this is unsuccessful then a drug called Atgam (anti-thymocyte globulin) may be used to reduce the numbers of T-lymphocytes which play a key role in causing and sustaining graft versus host disease.
Chronic Graft versus Host Disease
Chronic GvHD can present in many different ways. In the majority of cases it affects the skin. It can also affect the lungs, liver and immune system. It may resemble certain auto-immune diseases, which may confuse the diagnosis.
Chronic GvHD may present in patients in the absence of acute GvHD (de novo onset”), in patients who had acute GvHD which resolved fully (“quiescent onset”), or following persistent acute GvHD (“progressive onset”). It may develop at any time from three months post-transplant to six months after the end of immunosuppressive treatment. Known risk factors are:
| increasing age of the recipient |
| prior acute GvHD |
| donor lymphocyte infusion (DLI) and; |
| infection with the HSV virus (cause of chickenpox and shingles) |
The treatment of choice for most patients with chronic GvHD is high dose steroid (prednisolone). If the patient has poor risk features such as progressive onset chronic GvHD, low platelets, or jaundice then cyclosporine or a drug called tacrolimus may be used alongside prednisolone. Limited (skin, liver or both) chronic GvHD has a good prognosis. If the condition is more widespread then the long-term outlook is poorer. The commonest cause of death related to chronic GvHD is infection and patents will usually receive multi-drug antibiotic therapy in an attempt to prevent this complication.
Once pre-transplant conditioning has finished, any nausea will soon clear up. Almost all patients develop a sore mouth and it can be difficult to swallow. This is controlled with mouthwashes or injections of painkillers. It is important for the patient to have painkillers when the mouth starts to get sore in order to make mouthcare more tolerable. Candida infections of the mouth are also common and are prevented or treated with mouthwashes and tablets. Diarrhoea is a frequent side effect of the conditioning regimen but may also be associated with graft versus host disease. Invariably patients develop temperatures that are associated with infections and need early treatment. Patients may become short of breath. If this happens the doctor must be informed so that chest X-rays can be arranged.
Infections are frequent in the immediate post-transplant period. These may be bacterial, viral or fungal infections. In all cases where infections develop they are difficult to treat because the patient is not producing white cells, particularly neutrophils which guard against bacterial infections. Strict anti-infection precautions are taken. These may include keeping the patient in special isolation units, giving antibiotics by mouth, specially treating the patient's food and sterilising everything that comes in contact with the patient. During this period visitors may be restricted in the amount of time they can spend in the patient’s room. The use of growth factors to speed up the grafting process has reduced the length of time such precautions are necessary.
The much earlier recovery of the neutrophil count in patients receiving peripheral blood stem cell transplants greatly reduces the risks from infection and, in some centres, these patients do not require isolation nursing and are cared for on the open ward.
If an infection does happen it will be treated very promptly with the most suitable antibiotics or anti-fungal drugs. The majority of patients who develop an infection can be successfully treated.
Cyomegalovirus (CMV) is a particularly important cause of illness after allogeneic transplants. It can inhibit bone marrow activity and most importantly cause a widespread pneumonia, which can be fatal. Antiviral drugs, especially ganciclovir are given.
There is a risk from internal bleeding during the period before the platelet count recovers. This can be guarded against with platelet transfusions. The introduction of peripheral blood stem cell transplants has greatly reduced the length of time the platelet count takes to recover to normal and so lessened the risk from bleeding. A growth factor to stimulate platelet production has been developed but results from clinical trials have not been promising and this is not in routine use.
Inevitably, during the transplant procedure, the patient will fail to produce enough red cells and will therefore become anaemic. This is monitored by regular blood counts and is treated by blood transfusions.
A serious complication of transplantation is failure of the stem cells to repopulate the bone marrow cavities. This means that new blood cells are not produced in sufficient numbers. This failure of engraftment can affect the platelets, white cells and red cells to varying degrees. Rarely, there is total failure of engraftment with none of these cells being formed at all. Total failure to engraft will lead to the death of the patient, unless a further transplant is possible.
Graft failure may result from immune rejection which is most likely when there is a poor match between the tissue types of the donor and the recipient. Although most cases of graft failure appear to be caused by an adverse immune reaction, it is clear that this is not the only cause. There are rare instances of an autograft failing in which there is no possibility of a tissue-type mismatch.
It is recognized that the number of stem cells in the graft strongly affects the risk of graft failure. The number of stem cells can be assessed before the conditioning regimen begins and provided this is done the risk of graft failure for this reason is very small.
A frequent serious complication is a lung condition called interstitial pneumonitis. This can occur both as an early and as a late complication. It may be the result of chest infections particularly caused by cytomegalovirus or Pneumocystis carinii. In many instances there is no obvious cause. Quite a high proportion of cases of lung damage will respond to steroid treatment.
Many patients, even without Graft versus Host Disease, develop a lung condition called interstitial fibrosis which may cause abnormal lung function tests but has little or no impact on day-to-day activities. Patients should not assume that an abnormal result of lung function indicates that they have serious lung problems. If concerned, they should discuss the situation with their specialist.
High-dose chemotherapy and/or radiation, which are given during the conditioning phase of a stem cell transplant, may cause a liver complication known as veno-occlusive disease. Veno-occlusive disease happens when blood vessels within the liver become clogged and swollen. The liver's ability to carry out its normal functions of breaking down toxic substances, drugs and waste products is impaired. The liver may swell as a consequence and kidney function may be affected leading to water retention. In severe cases of veno-occlusive disease fluid may enter the abdominal cavity (ascites) or the lungs may be affected. Liver damage resulting from mild or moderate veno-occlusive disease is usually reversible. Severe veno-occlusive disease is potentially fatal.
One of the major long-term complications of receiving radiotherapy is the risk of developing cataracts in the lens of the eye. Patients will be monitored for this and if cataracts develop the patient will be referred to an ophthalmologist for treatment.
| Impaired reproductive ability |
Virtually all patients who undergo allogeneic stem cell transplant will be permanently sterile. This is particularly if total body irradiation is used. In children, growth and sexual development may also be affected.
| Autologous transplantation |
The risks are less than those associated with an allogeneic transplant. The introduction of peripheral blood stem cell transplants has reduced the risk of side effects even further. Infections are still a problem after autografts but the precautions that are taken do not need to be as stringent as for an allogeneic bone marrow transplant. However, the patients are still kept in isolation for a short period of time.
There is a very small risk of failure of engraftment. It is recognized that the number of stem cells in the graft strongly affects the risk of graft failure. The number of stem cells can be assessed before the conditioning regimen begins and provided this is done the risk of graft failure for this reason is very small.
Discharge from hospital is usually possible about three weeks after the transplant. It can take up to three months before the patient feels completely well.
| Outcome of treatment |
The likelihood of success for a bone marrow or stem cell transplant depends on the type of disease being treated, the source of the stem cells and the general fitness of the patient before the procedure.
In some conditions such as chronic myeloid leukaemia, myelodysplasia or severe aplastic anaemia it may be the only treatment that offers the prospect of cure. In others, like childhood acute leukaemia, it is reserved for a minority of patients with a less than average chance of responding well to conventional treatment.
| Supportive care |
Various aspects of the management of the patient having a bone marrow transplant are not standard for other hospital patients.
These mainly apply to the critical period between the destruction of the diseased marrow and the restoration of normal blood cell production by the new marrow. During this period patients are at particular risk of infection. Details of supportive care may differ from hospital to hospital. Patients will normally be provided with detailed advice on diet and precautions against infection.
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