9. Bone marrow transplantation Flashcards
Which organ is most resistant to radiation?
CNS
What is a marker of stem cells?
CD34
What is the most expensive and risky elective procedure offered by the health service?
Bone marrow transplant
What is the risk of dying from a bone marrow transplant?
> 50%
How does an autologous transplant work?
- Give growth factor to patient.
- You obtain a CD34+ population of cells from the bone marrow, within which you will find some stem cells
- These are preserved in the freezer
- A high dose of chemotherapy is given to eradicate the bone marrow
- Then you would thaw and reinfuse the stem cells
(6. High dose chemotherapy is also given?)
Who is an autologous transplant suitable for?
Suitable for: acute leukaemia, solid tumours, autoimmune disease
What are the three most common reasons for bone marrow transplantation?
Myeloma, lymphoma, CLL
When is allogeneic transplant used?
- This is used when the patient’s disease is very unlikely to be eradicated from the bone marrow by standard chemotherapy.
- Therefore, you give them a high dose of chemoradiotherapy which completely ablates the bone marrow (malignant and normal cells).
- Then you give them some bone marrow from a healthy donor.
Who is allogeneic transplant suitable for?
Acute leukaemia, chronic leukaemia, myeloma, lymphoma, bone marrow failure, congenital immune deficiencies.
What is the issue with allogeneic bone marrow transplantation?
The issue with bone marrow transplantation, is that the donor immune cells can recognise the patient as foreign and tries to set up a massive immune reaction
What are the principles of transplantation (6 principles)?
- Identify disease that is unlikely to respond to standard treatment.
- Treat patient to remission.
- Identify a donor and collect stem cells.
- Give patient myeloablative therapy.
- Infuse stem cells.
- Continue immunosuppression and support patient through period of cytopaenia.
What are the standard parameters of outcome in transplantation?
Overall survival; disease-free survival; transplant-related mortality; relapse incidence
How do we choose a donor?
Well matched for tissue type (HLA type), ideally a sibling (1 in 4 chance with each sibling). If not, a volunteer unrelated donor or minimally mismatched family member. The probability of having a match with a sibling is = 1-(3/4)^number of siblings.
What are the main classes of HLA based on?
The main classes are based on serological reactions. Serology gives us a low resolution type. It can be increasingly specified by DNA sequencing. Allele frequency also vary depending on ethnicity of patient.
What types of stem cell harvesting are there?
Bone marrow sampling, peripheral blood sampling and umbilical cord stem cells
How does bone marrow sampling work?
- Difficult because it involves anaesthetising the patient and sampling some bone marrow from their pelvis (hip bone).
- Puncturing the bone and getting into the medulla damages it, meaning that the first few millilitres that you collect will contain stem cells, however, the rest of it will be blood flooding into the damages site
- So, you will need to keep re-puncturing the bone, collecting a small amount at a time until you have a good harvest.
How is peripheral blood sampling done?
- Hormones (e.g. G-CSF) can be used to stimulate granulocyte production.
- This leads to the bone marrow releasing some white cells as well as some stem cells.
- When using it for harvesting stem cells, G-CSF is given for 5 days and the stem cells are harvested on the 5th day.
- The donor is connected to a centrifuge device which spins the blood, removes the white cell component, reassembles the red cells and plasma and reinfuses it into the patient.
How are umbilical cord stem cells collected?
Stem cells can be harvested at the time of delivery
Out of all the methods of harvesting, what percentage of the sample does CD34+ stem cells make up?
CD34+ stem cells will only make up about 1% of the sample.
What does success of the transplant depend on?
The number of CD34 cells per kg of weight of the recipient
Why can cord blood stem cells only be used for babies?
The success of the transplant depends on the number of CD34 cells per kg of weight of the recipient. Therefore, with cord blood (in which you only harvest 0.1 L), there will be fewer CD34 cells and so it can only really be used for babies.
What are complications of stem cell transplants?
Graft failure, infections, graft-versus-host disease (allografting only), relapse
What are the factors affecting the outcome of the patient, according to the EBMT risk score criteria?
Age: <20=0, 20-40=1, >40=2. Disease phase: Early=0, int=1, late=2. Gender of R/D: female into male=1. Time to BMT: <1yr=0, >1yr=1. Donor: sib=0, vud=1.
What risk score is used to predict the outcome of the transplant?
EBMT risk score
What are risk factors for infection in transplant?
Neutropenia, breakdown of protective barriers, decreased antibody levels, depressed T-cell immune responses.
How do infections present present in immunodeficiency in allogeneic BM transplantation?
Different infections at different times, immune defect is frequently of long duration, risk of infection is mostly disease-independent
Where is aspergillosis found and what is its mortality like?
This is ubiquitous, and invasive aspergillosis has a high mortality.
CMV is a member of which family of organisms?
Herpes
Why does CMV remain latent?
Because T cells are able to keep it under control
What are risk factors of CMV?
Patient’s serological status, donor’s serological status, type of stem cells donor, type of transplant, CMV viral load
What is graft-versus-host disease?
An immune response when the donor cells recognise the patient as foreign
Which organs does acute GvHD affect?
Skin, GI tract, liver
Which organs does chronic GvHD affect?
Skin, mucosal membranes, lungs, liver, eyes, joints
How does an immune reaction against the host tissue occur, leading to GvHD?
Damaging the skin, GI tract and various other tissues by giving chemotherapy will cause the release of loads of cytokines which activates antigen-presenting cells, which then present the antigens to the donor lymphocytes. This results in an immune reaction against the host tissue.
What could be done to reduce the risk of an immune reaction against the host tissue/GvHD?
You could wait for longer after the chemoradiotherapy for the effects to die down before giving the stem cell transplant, however, this increases the time during which they are susceptible to infection
What are the risk factors for acute GvHD?
Degree of HLA disparity, recipient age, conditioning regimen, R/D gender combination (male donors with female patients get worse GvHD), stem cell source, disease phase, viral infections.
What is used in the treatment of GvHD?
Corticosteroids, cyclosporin A, FK506, mycophenolate mofetil, monoclonal antibodies, photophoresis, total lymphoid irradiation
What can be done/what drugs can we give to prevent GvHD?
Methotrexate, corticosteroids, cyclosporin A, cyclosporin A + methotrexate, FK506, T cell depletion, post-transplant cyclophosphamide
What causes the GvHD reaction, the mature lymphocytes in the donated sample or the lymphocytes produced by the stem cells?
Because GvHD happens quite soon after the transplant, it is likely that the reaction is happening because of the mature lymphocytes in the donated sample rather than because of the lymphocytes that are produced from the stem cells
GvHD is likely due to the mature T lymphocytes in the donated sample, rather than lymphocytes produced by the stem cells. Why is this inevitable?** And why does this prevent relapse?
It is impossible to identify and select out the specific T cells, you just insert a population of cells that contains stem cells (some of the other cells will be mature lymphocytes).
However, you also do NOT want to isolate the stem cells and give them alone because it increases the risk of relapse (i.e. the donor lymphocytes are important in the prevention of relapse).
