Bone marrow transplantation
Bone marrow (or stem cell) transplantation (BMT) is a cure for many primary immunodeficiency (PID) conditions. In the last 20 years there have been huge advances in success and survival rates, in the range of conditions and the upper age limit of patients that can be treated by BMT.
What is bone marrow?
Bone marrow is the soft, spongy tissue found in the centre of bones. It is responsible for producing the three main types of blood cells: red blood cells, white blood cells (cells of the immune system) and platelets. All of these start off as immature cells called ‘stem cells’. These cells mature in the bone marrow and are then slowly released into the bloodstream. A bone marrow or stem cell transplant involves collecting healthy cells from a matched donor and introducing them into the person with PID. These new healthy stem cells then start to make fully functional white blood cells that function as a normal immune system and are capable of fighting infection. For most patients undergoing a BMT for PID a genetic mistake will have been identified, which affects the function of their bone marrow stem cells (therefore preventing the development of a normal immune system).
What is involved?
The person with PID receives bone marrow or stem cells (sometimes stem cells are collected from the umbilical cord blood of babies) from a donor who shares the same ‘tissue type’ as them and is therefore called a ‘match’. Two types of match are normally considered: a perfectly matched related donor (this is usually a brother or a sister) or a well-matched unrelated donor. Occasionally, a less well matched (mis-matched or half match ‘Haplo’) donor may be considered.
To allow for these new cells to grow and develop the patient must undergo ‘conditioning’. This involves giving several powerful medicines called chemotherapy, which work in two ways:
to kill off the patient’s own bone marrow stem cells and make space for the new healthy stem cells
to suppress the patient’s immune system to encourage acceptance of the new cells.
In some forms of SCID, transplant can be undertaken without conditioning.
How long does it take?
Having a BMT involves a long stay in hospital (on average 6–8 weeks, although it may be longer), during which time the patient is looked after in an isolation room on a transplant ward. This ward may have more restrictions on visiting, diet and hygiene than a general ward. This is because during a transplant the patient’s immune system is extremely low and a few extra precautions are necessary to protect them from infection.
Over the last few years there has been slow and steady, but significant, progress in BMT techniques, and recent results for PIDs are extremely good. Survival and cure are now equivalent with either a matched sibling or a well-matched unrelated donor and reach 85–95 per cent in specialist centres designated to transplant PID patients.
Whilst transplantation is generally best tolerated in childhood, successful outcomes are now possible in young people and adults using new transplantation techniques. However, BMT is not without risk.
What are the risks?
The main risks are infection and graft-versus-host disease (GvHD). In GvHD the new bone marrow from the donor may recognise the patient’s cells as ‘foreign’ and react against them. GvHD can cause problems with the skin, liver and bowels. Also, immediately after the BMT, the patient remains very immunodeficient and susceptible to infection. It may take up to 6 months for the new immune system to grow and function properly and during that time, prophylactic antibiotics and immunoglobulin will need to be taken.
Doctors have made some general recommendations about BMT for PIDs. These are:
BMT should start to be considered soon after a diagnosis of a PID. This is because better outcomes are usually achieved if those affected do not have a history of serious infections, inflammatory or autoimmune problems. This means that doctors will want to test siblings or other family members to see if they are a tissue match. If siblings are not a tissue match, then doctors can start to find a well-matched unrelated donor. The doctors are also then able to give appropriate counselling over a period of time to help people make this important decision once a suitable donor is found.
BMT should be done in a specialist centre that has experience of transplanting people with a PID. This is because the doctors will know about the specific PID and be able to give good-quality up-to-date advice about risks and benefits.
You should discuss the suitability and individual risk factors for you and your family with doctors and nurses involved in your care.
Finally, it is important to remember that although a person’s PID may be cured by BMT, the inheritance issues of passing their condition to future offspring remain.
Conditions that can be treated by BMT
Here is a list of the types of PID that could be treated by BMT. The list includes the most common indications but is by no means exhaustive and other specific PIDs may be suitable for transplantation.
Severe combined immunodeficiency (SCID) syndromes
- IL2RG (Common Gamma Chain, X-linked; IL-2R deficiency)
- IL-2 receptor alpha chain (CD25) deficiency
- ADA-SCID
- JAK3 deficiency
- IL7R alpha deficiency
- CD45 deficiency
- CD3 antigen delta subunit deficiency (CD3D)
- CD3 antigen epsilon subunit deficiency (CD3E)
- CD3 antigen zeta subunit deficiency (CD3 Z)
- Coronin 1A deficiency
- RAG1 and RAG2 deficiency
- Artemis
- DNA-PKcs deficiency
- AK2 deficiency
Combined immunodeficiency conditions
- Combined immunodeficiency (CID)
- Omenn syndrome
- Cernunnos deficiency
- DNA ligase 1 and 4 deficiency
- CD8 antigen deficiency
- ZAP70 deficiency
- Foxp3 deficiency
- PNP deficiency
- ORAI 1 deficiency
- STIM1 deficiency
- CD8 antigen deficiency
- ITK deficiency
- CD40 deficiency
- CD40 ligand deficiency (CD154)
Diseases of immune dysregulation
- Familial hemophagocytic lymphohistiocytosis syndrome (FHLH)
- Perforin 1 deficiency (PRF-1)
- Munc 13.4 deficiency (UNC 13D)
- Syntaxin 11 deficiency
- Munc 18.2 deficiency (STXBP2)
- X-linked lymphoproliferative syndrome
- APDS
Other well-defined primary immunodeficiencies
- Wiskott–Aldrich syndrome (WAS)
- Chediak–Higashi syndrome
- Griscelli syndrome
- Chronic mucocutaneous candidiasis (CMC)
- Congenital dyskeratosis (some forms)
- Schimke disease
- CD25 deficiency
- HLA class I and HLA class II deficiency
- DOCK8 deficiency
- STAT5b deficiency
- IL-10 receptor deficiency
- Hyper IgE syndrome – autosomal dominant (STAT 3 deficiency)
- Hyper IgE syndrome – autosomal recessive
- Severe congenital neutropenia
- Leukocyte adhesion deficiency (LAD)
- Shwachman–Diamond syndrome
- Chronic granulomatous disease (CGD)
Frequently asked questions
Once doctors have exhausted the possibility of finding a related donor within the family then they will begin the search of a match on national registries such as the Anthony Nolan Registry and cord stem cell banks. Searches can also be made worldwide through international registries. Umbilical cord blood may be used, and haploidentical transplants are on the increase as above if no suitable matched donor is available. Finally, for some patients with no matched donor, gene therapy is an option and the number of indications where this is possible has increased over the last few years.
BMT works best when there is a 100% or 90% match of important markers on cells between the donor and the person having the BMT. A brother or sister has a 25% chance of being a perfect match and are often used as donors. A parent is usually only a 50% match so traditionally not always seen as being ideal donors, although by chance some parents may be a better match. Newer BMT techniques mean that “haplo” BMTs are being increasingly performed when no other suitable donor can be found. Haploidentical means half-identical, and these are 50% matches, usually a parent. The stem cells or bone marrow for a haplo-BMT need special treatment to remove cells that would attack the patient and the time for the immune system to get up and working again is considerably longer, but it does provide an alternative where none used to exist.
Usually adults who are being considered for BMT have had chronic problems such as lung and gut disease over a long period of time. The accumulation of tissue damage from these chronic problems and infections often make BMT more difficult. Also because of the risks of BMT, the choices of whether a BMT is the right thing to do is more difficult especially since adults may have dependent relationships, the risk of financial hardship with time off work etc.
No over the past few years, more adults have started to be treated by BMT but the numbers are still low. One recent major advance has been the development of what is known as ‘reduced-intensity conditioning’; this is a milder form of chemotherapy used to prepare the patient for the donor’s bone marrow. This has been used successfully in BMT for some adults with PID. It is likely that more adults with PID will be treated by BMT in the next few years.
This depends on the type of CVID, its genetic basis and the health problems, past and present that the person may have. CVID is probably a collection of multiple genetic disorders with sufficient common features for them to be given the same umbrella diagnostic label. From our current understanding, some immune deficiency is caused by genetic changes that only affect the immune system, but in other disorders, the driver behind many of the symptoms of the disease may be in non-immune cells with the same genetic abnormality. When the disorder is restricted to the immune system and the symptoms are severe enough, it may be appropriate to consider BMT. When the disorder affects cells in other tissues and organs and more widely, or we just don’t know, the risks of the BMT may not be met with an improvement in the overall clinical condition. Except for very severe cases, more like combined immune deficiency (CID) or where a patient has one or more lymphomas and has CVID, at present the approach in general is to pursue a genetic diagnosis, and when there isn’t one, to consider non-BMT options.
This all depends on the type of SCID and how tissue type compatible the donor cells are. For some children with SCID with a perfect tissue match from their brother or sister conditioning using chemotherapy may not be necessary at all if the transplant is undertaken early enough in life.
Sometimes a BMT doesn’t “take” because the graft is rejected. In that situation, it may be possible to consider doing another transplant. However, this is dependent on whether the original donor is suitable or whether another suitable donor can be found. The medical condition of the patient considered for subsequent transplant has to be good enough for it to be attempted. There can also be a build-up of toxicity in the body from the chemicals used to prepare the body for transplant during chemotherapy which can complicate further attempts at BMT. Second transplants have been done successfully for a number of PID patients but as mentioned above, a number of different factors need to be taken into account.
This page was reviewed by Professor Emma Morris, Professor of Clinical Cell and Gene Therapy, Division of Infection & Immunity, University College London. December 2023.
