Conditioning for bone marrow transplantation

The most widely used regimen includes cyclophosphamide alone. High-dose irradiation was too toxic and low-dose total body or total lymphoid irradiation, although reducing the risks of rejection, did not improve overall survival. More recent schedules include ALG or Campath-1H with cyclophosphamide or low cyclophosphamide with fludarabine.

Cyclophosphamide

Cyclophosphamide, at a dose of 50 mg/kg per day intravenously for 4 days, has been used alone in the immunosuppression of patients with aplastic anaemia, although the rejection rate with this regimen is high unless additional post-graft immuno-suppression is given, especially in multiply transfused patients (see below).

Cyclophosphamide is given intravenously, usually in 250500 mL of saline over 0.5-1.0 h. Side-effects include nausea and vomiting (usually relatively mild), haemorrhagic cystitis, cardiomyopathy, fluid retention and alopecia. The haemorrhagic cystitis may be prevented or greatly modified by giving mesna (2-mercapto-ethane sulphonate) intravenously to neutralize the effects of metabolites of cyclophosphamide in the urine. Mesna (40% of the daily cyclophosphamide dose) is given intravenously 30 min before each cyclophosphamide infusion and the same dose is given at 3, 6, 9, 12, 16 and 20 h after each cyclophosphamide dose. This regimen is repeated on each day that the cyclophosphamide is given and the day after the last dose. The cardiotoxicity of cyclophosphamide is not usually a problem at the doses quoted unless there is already cardiac damage. Late haemorrhagic cystitis (after 20 days) may occur in transplant patients but is usually caused by virus infections (particularly adenovirus) rather than cyclophosphamide.

Antilymphocyte globulin

Additional immunosuppression is given with cyclophosphamide to help reduce graft failure. It is given daily on the first 4 days of cyclophosphamide.

For patients over the age of 40 years, in whom HLA identical sibling BMT is being considered, a 'mini' or reduced-intensity conditioning regimen is now recommended, similar to that for matched unrelated donor BMT (see later).

Irradiation

There is now no role for the use of irradiation in BMT for aplastic anaemia. Total body irradiation (TBI) or total lymphoid irradiation (TLI) were previously used in an attempt to reduce graft failure because of their immunosuppressive properties. Their use did reduce graft failure but at the expense of increasing GvHD, interstitial pneumonitis and the later risk of solid tumours, as well as developmental delay and sterility.

Cyclosporin

Cyclosporin was introduced into BMT regimens for aplastic anaemia both to reduce graft failure and to minimize GvHD. Results of BMT for aplastic anaemia have improved considerably since its introduction, mainly because of the reduction in graft failure. It was recognized early in the use of cyclosporin that graft failure may follow if the drug is stopped early and it is usual to continue cyclosporin for a year post transplantation for aplastic anaemia. The dose is adjusted to keep the blood level between 250 and 300 |g/L.

Methotrexate

Methotrexate is added to cyclosporin to reduce GvHD at a dose of 10 mg/m2 intravenously on day 1, then 8 mg/m2 on days 3, 6 and 11. There is an increase in mucositis and liver toxicity with this drug.

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