Haematopoietic Stem Cell Transplant
There are three types:
- Autograft, where the donor and recipient are the same person
- Allograft, where the donor and recipient are different people; this requires matching of human leukocyte antigen (HLA) of donor and recipient to reduce graft versus host disease
- Syngeneic, where the donor is an identical twin of the recipient (very rare); the safest and potentially most effective type due to complete HLA compatibility but also the most difficult to 'arrange'.
In all situations, the stem cells must be harvested from the peripheral blood prior to conditioning. This usually involves use of stimulants of the haematopoietic system which cause stem cells to migrate into the peripheral blood.
Prior to the transplant itself, the patient undergoes conditioning, which may be myeloablative or non-myeloablative. Myeloablative techniques aim to eradicate all traces of the recipient's bone marrow, and often aim to eradicate the neoplastic process as well. Conditioning can involve cytotoxic chemotherapy, targeted therapy, immune modifiers, and radiotherapy.
Once conditioning is complete, the patient must have a transplantation in order to reconstitute their erythropoietic and immune systems. This may be accomplished by the use of growth stimulants. Medium term problems involve prevention of graft versus host disease; while at the same time preserving a graft versus disease effect.
Indications for haematopoietic stem cell transplant are usually:
- Multiple myeloma (commonly autograft)
- Non-Hodgkin's Lymphoma
- Acute myelogenous leukaemia
- Hodgkin's disease
- Acute lymphoid leukaemia
- Myelodysplastic syndrome
- Chronic myelogenous leukaemia
- Aplastic anaemia
It has also been utilised in some non-haematological diseases, although evidence is mixed. These include several paediatric malignancies (Ewing sarcoma, neuroblastoma) as well as more common adult malignancies such as breast cancer.
Techniques for TBI
There are almost as many techniques as their are centres that deliver TBI. There are some common principles:
- Patients are treated at extended source-surface distance, often 3.9 m
- A perspex sheet or other beam spoiler is used to reduce skin sparing
- Dose calculations need to take into account primary and secondary scatter from the machine head and the bunker, as this will be significant at the extended SSD with the longer treatment times
- Patient position is either standing or lying, and each treatment delivers from opposed angles (either laterals, AP/PA, or both)
- Compensators for the head, lungs and lower limbs are usually required due to their reduced thickness relative to the torso. This is usually several sheets of perspex.
- The beam is aimed at the umbilicus, and the collimator is rotated to 45o, as this maximises the horizontal length of the field (SQRT(402 + 402^^) = 56 cm at isocentre = about 2 metres at 3.9 m)
Inclusion of the CNS or the testes as 'boost' volumes is practiced at some centres but is controversial.
Toxicity of TBI
This is an essential topic.
Early toxicity varies significantly with dose; fatal outcomes are common with single doses over 10 Gy (gastrointestinal syndrome) and 50 Gy (cerebrovascular syndrome); delayed death after exposure above 4 Gy occurs in 50% of people, but therapeutically this is the point.
Acute symptoms during administration of total body irradiation is more common with single fractions and with faster dose rates; this is one reason that TBI is typically administered in a fractionated course with a low dose rate (e.g. 200 MU/minute). They include nausea and vomiting (much reduced with modern 5-HT antagonists), xerostomia, and headache. Single fractions are also associated with parotid gland pain.
Early symptoms in the days and weeks after therapy include similar symptoms; erythema and fatigue may occur. Alopecia occurs at 7-14 days but hair usually regrows within several months.
Due to the entire body being irradiated there are a huge variety of late effects that can occur. It is sometimes difficult to establish the cause of particular late effects (e.g. chemotherapy versus radiotherapy), and chemotherapy-alone myeloablative regimes are often associated with worth toxicity in some areas.
- Lymphopenia, leukopenia and anaemia usually occur (in that order) due to death of stem cells and varied survival of the circulating cells; the exception is the lymphocytes which have a high death rates with minimal dose (e.g. 0.5 Gy); their levels fall within 1-3 days of treatment.
- CNS toxicity is also prevelant in patients undergoing haematopoietic stem cell transplantation; except in children under three the role of total body irradiation in the development of this appears to be similar to patients treated with non-TBI techniques. More severe effects are very rare except with TBI is combined with other radiotherapy treatments to the CNS.
- The optic pathways are most sensitive to cataract formation but other problems are very rare. Cataracts are most likely with single fractions or when a high dose rate is used. Ongoing ophthalmology input after treatment is essential.
- Endocrine abnormalities of any sort can occur; the most common is hypothyroidism in up to 10-15% of patients.
- Oral toxicity, particularly xerostomia and resulting dental decay, are common but less with fractionated radiotherapy. There can be late restoration of salivary function. Tooth developmental abnormalities can occur and dental assessment prior to treatment is essential, as is long term dental follow up.
- Cardiovascular disease is more common in patients treated with stem cell transplant, although the contribution of radiotherapy to this versus cardiotoxicity of chemotherapy (anthracyclines) is relatively small. Several theories as to how radiotherapy may impact cardiac health are present, although indirect effects (such as hypertension or diabetes) are thought to be more relevant than direct cardiotoxicity.
- Pulmonary toxicity is the main limiting factor for total body irradiation Like most other toxicities, there are several contributing factors to pulmonary toxicity and there is likely to be synergistic effects of the various treatments. Limiting total body irradiation doses to 12 Gy in 6 fractions appears to minimise the risk compared to single fractions or to high fractionated doses.
- Abdominal organs may be affected by HSCT, and radiotherapy may play a role. Hepatotoxicity presents with veno-occlusive disease, ascites, and death in severe cases. The incidence is less with fractionated doses, and is thought to be less for low dose rate treatments. Renal function has an incidence of 15-20%, with a variety of mild to severe presentations. Large studies have shown equivalent rates of disease in TBI versus non-TBI HSCT techniques; limiting dose to 12 Gy, low dose rate, and fractionation all seem to reduce the risk of this disease.
- Second malignancies fall into three categories:
- Post-transplant lymphoproliferative disorders occur due to failure of the immune system, and are often EBV related, aggressive and fatal.
- Myelodysplastic disease/acute myelogenous leukaemia are induced by cytotoxic therapy predominately but radiotherapy adds additional risk; the risk is about 5% at 10 years but excess cases continue to occur after this
- Solid tumours are presumably related mostly to total body irradiation and is associated with their development. The risk is about 3% at 20 years.