Why is stem cell transplantation used?
Haemopoietic stem cell transplantation (HSCT) is broadly used in two categories of disease: Firstly, in malignant haematology / oncology when standard dose intravenous chemotherapy alone is not considered sufficient to cure the disease [1], Secondly, in non-malignant haematology and metabolic-endocrine conditions to replace a patient’s bone marrow, when it is not producing all the blood cells or necessary enzymes required for healthy life. This informsation is concerned with the first category – malignant haematology / oncology in children and young people.
After conventional chemotherapy a person’s bone marrow will normally recover and start to produce sufficient blood cells within 2-3 weeks. However, the chemotherapy given in stem cell transplant (SCT) is so strong it renders the bone marrow incapable of recovering in time to keep the person well. Depending on the disease being treated, the chemotherapy given is sometimes termed ablative, meaning it is so strong that it renders the bone marrow incapable of ever recovering. Such intensive chemotherapy can only be used if fresh or cryopreserved (previously harvested and stored) stem cells are available to give back to the patient to replace his/her destroyed marrow and allow recovery of bone marrow function.
What are haematopoietic stem cells?
Haematopoietic stem cells are immature cells made in the bone marrow. They are not normally found in large numbers in the blood stream, as the body instructs them to differentiate into committed platelets or red or white cells before leaving the marrow. Stem cells can be collected from the bone marrow, peripheral blood and umbilical cord blood.
Different types of Stem Cell Transplants (SCT)
- Autologous – “auto” means “self / own” and in an autologous transplant the patient receives his/her own stem cells.
- Allogeneic – “allo” means “other” and in an allogeneic transplant the patient receives stem cells from an HLA compatible donor, who may be related (sibling or family member) or unrelated (identified from one of the donor registries). Human leukocyte antigen (HLA) is a protein found on most cells in the body. The protein is used to match the patient and the donor for stem cell transplant. The best transplant outcome happens when a patient's HLA and the donor's HLA closely match.
Autologous transplants
Autologous transplants are used for a child or young person with an oncological malignant tumour or lymphoma who requires very high dose therapy followed by stem cells to allow bone marrow recovery.
Allogeneic transplants
Allogeneic transplants are used for a child or young person with a malignant haematological disorder. The patient receives stem cells from a donor. Initially any siblings will be tissue typed to try to identify an HLA compatible donor.
- There is a 1 in 4 chance that a sibling will be HLA compatible and be an acceptable donor. [2]
- In some specific circumstances a parent may be an acceptable mis-match transplant. It is very unusual for a parent to be a perfect HLA match with their child, as the child receives 50% of their tissue type from the mother and 50% from their father.
Unrelated donors
Around 70% of patients requiring transplant will not have a suitable donor within their family, therefore a suitable donor will need to be found.[7] This is done by searching United Kingdom (UK) registries first, then expanding to international registries if no UK donors are found. Donors will be sourced from 2 main categories: adult (bone marrow or stem cells) or from umbilical cord.
Adult donor
The British Bone Marrow Registry (BBRM) is a division of NHS Blood and Transplant Service. It works in collaboration with Anthony Nolan, a charity dedicated to saving the lives of patients needing bone marrow or stem cell transplant.[3]
Bone Marrow Donor Worldwide links bone marrow donor registries internationally this is coordinated in UK by BBRM.[5]
White Northern Europeans have a 90% chance of finding an unrelated donor on the registry, falling to less than 40% for black, Asian and minority ethnic groups [2].The chance is proportionate to the ethnicity of the donor panel
Umbilical cord donor
Cord blood is the blood that remains in the placenta and umbilical cord after a baby is born [4]. Some mothers chose to donate cord blood for transplant.
Advantages
- It is rich in stem cells
- It is immunologically naïve
- Readily available once stored
Disadvantages
- The number of cells available from single cord limits its use to younger children
- If there is no count recovery after the SCT it is not possible to get more cells from this type of donation. Therefore children who have an umbilical cord donor will have their own marrow harvested in advance and stored as a “rescue” plan
Stem cell transplant process
Stage 1: HLA matching or ‘tissue typing’
Human leucocyte antigen typing (HLA) is the test used in stem cell transplantation to match a recipient with a compatible donor. HLA are proteins that are on the surface of all cells and they are inherited from your parent.
Usually about 10 HLA markers are checked in testing process. Transplants are described as being “matched” or “mis-matched” depending on how many out of the 10 HLA markers are identical in recipient and potential donor. A 10/10 match is always preferable as the transplant is more likely to be a success and the side-effects fewer. Umbilical cords are matched to 6/6 markers.
Recipient
A sample of blood for HLA typing is taken from the recipient at their PTC and sent to their transplant centre to commence the search
Donors
Donors may be sampled from blood or from saliva depending on who they register with:
- Anthony Nolan, if aged 16 to 30 years can attend a recruitment event or apply on line. Donors use a “Spitkit” to have saliva tested. Results are then stored on a database and further blood testing is carried out if you are a potential match.
- British Bone Marrow Registry if you are aged between 18 and 49 years and a blood donor. Blood sample can be taken at time of blood donation if you consent. Stored on database and if identified as possible match then Anthony Nolan will take over the rest of the process. All donor/recipient information is anonymous. With Anthony Nolan, contact 2 years post transplant is permitted but only if instigated by recipient. Other registries may have different guidelines.
Stage 2: Peripheral blood stem cell (PBSC) collection
Before a PBSC collection the donor will receive either granulocyte-colony stimulating factor (GCSF) or chemotherapy with GCSF; this is called mobilising treatment. The GCSF is given to stimulate stem cell growth and encourage more stem cells than normal to move out from the marrow into the blood stream in their immature state. Approximately a week after starting GCSF, the patient’s CD34 count is checked to see if there are enough stem cells circulating in the peripheral blood to be collected. PBSCs are harvested by an apheresis machine. This process usually takes a few hours and may need to be repeated the next day (if insufficient stem cells are harvested the first time) (Link cancer research UK & link to Anthony Nolan video) The machine removes blood from the patient via an intravenous line, spins it to remove the stem cells, then returns the rest of the blood to the patient via a second intravenous line. The stem cells are then cryopreserved (frozen) until they are required.
Umbilical cord stem cell collection
Stem cells are present in large numbers in the umbilical cord blood. It is possible to collect them at birth, immediately after the cord has been cut, with no harm to the mother or the baby. There are cord banks set up in seven hospitals covering England/Wales [6] but in Scotland/ N.Ireland this is done only on an individual patient basis, where the paediatric haematologist makes a referral for a mother to have stem cells collected at birth. In order to do this the mother transfers her care in advance of due date to the regional maternity centre which will be decided with the patient’s Paediatric Haematologist
Where are stem cell transplants carried out?
Autologous transplants
Most of the UK Principal Treatment Centres will carry out Autologous transplants on their own patients. Where this treatment is not available the child or young person will be referred to their nearest centre,
Allogeneic Transplants
Not all of the CCLG centres will provide this service but there are designated centres across the UK where Children and young people requiring allogeneic transplants will be referred to by their consultant haematologist: Glasgow, Dublin, Manchester, Liverpool, Newcastle, Bristol, Leeds, Oxford, Sheffield, London (Great Ormond street and The Royal Marsden.) Birmingham. Post transplant care will then be shared with the referring centre.
The decision to undertake a transplant is taken only after long and careful discussion with the patient and their family. The procedure is complicated and carries a high risk of transplant related side-effects and possible transplant related mortality. The patient will be in strict isolation to protect them from infection during the transplant process and until they engraft (recover a blood count). They may require total body irradiation (TBI) before the transplant (Link Treatment modalities and TBI fact sheet). The admission period can extend to months, depending on the post-transplant supportive care they require.
Sources of information and support
CCLG produces a range of booklets and factsheets for patients and families about different aspects of stem cell transplantation.
Autologous haematopoietic peripheral blood stem cell (PBSC) harvesting and transplantation factsheet Information for parents and young people
Ben's stem cell transplant A story book explaining allogeneic transplant for young children
Jess's bone marrow donation A story book explaining stem cell donation for young siblings
Ruby's stem cell journey A story book explaining autologous transplant for young children
Stem cell transplant Information for teenagers and young adults preparing for a stem cell transplant
Donating your stem cells to your brother or sister Information for teenagers and young adults
Total body irradiation factsheet Information for parents and young people undergoing TBI in preparation for a stem cell transplant
References
[1] Autologous Haematopoietic Peripheral Blood Stem cell (PBSC) Harvesting and Transplantation – Information for young people and their families. Children’s Cancer and Leukaemia Group Factsheet 2014–https://www.cclg.org.uk/
[2] Anthony Nolan Trust website – anthonynolan.org/
[3] NHS Cord Blood Bank website nhsbt.nhs.uk/cordblood/.
[4] NHSBT British Bone Marrow Registry Website nhsbt.nhs.uk/bonemarrow