Myeloablative therapy with bone marrow transplantation

High doses of chemotherapy, such as cyclophosphamide, and radiation both kill cells indiscriminately; myelosuppression is therefore the main dose-limiting toxicity. Thus, without a ‘transplant’ the person would die of bone marrow failure. The indications for this type of treatment are shown

A child with Burkitt, lymphoma
A child with Burkitt, lymphoma

Allogeneic BMT

The donor is usually an HLA-identical brother or sister. The patient (recipient) receives the myeloablative therapy (drugs or drugs plus total body irradiation [TBI]), over a period of several days. The donor supplies approximately 1 litre of bone marrow, aspirated from the posterior iliac crests, which is then given intravenously to the recipient, together with immunosuppressive drugs (e.g. steroids, cyclosporin) to prevent rejection and graft-versus- host disease (GVHD). The patient’s blood count usually recovers within 3-4 weeks.
Allogeneic BMT has a mortality of 25-40%, depending mainly on the person’s age; the main causes of death are infection (bacterial, fungal or viral, cytomegalovirus pneumonitis being the greatest problem) and GVHD. The latter is a syndrome that can occur to varying degrees, in which mature T lymphocytes in the donor marrow infiltrate the skin, gut and liver. Acute GVHD occurs in the first 3 months but may also run a chronic course. Patients who develop GVHD have a lower incidence of recurrent leukaemia than those who do not, e.g. the recipients of syngeneic (twin) transplants. Thus, not only does the ‘marrow ablative’ chemoradiotherapy have an antileukaemic effect, but T cells within the donor marrow appear to have an immunological role, the ‘graft vs. leukaemia’ effect, which itself correlates with the development of GVHD.

Possible indications for the use of myeloablative therapy.
Possible indications for the use of myeloablative therapy.

The use of allogeneic transplantation is primarily limited by donor availability; using a ‘matched unrelated donor’ increases the likelihood of GVHD, which, as mentioned above, is the major cause of mortality and longterm morbidity (chronic GVHD). T-cell depletion of the donor marrow has been attempted but this also removes the putative ‘graft vs. leukaemia’ effect, resulting in an increased risk of recurrence.

Autologous B M T

Using the patient’s own bone marrow is limited by the potential risk of reinfusing malignant cells. A remission is first induced; 1 litre of marrow is then aspirated from the patient’s iliac crests under general anaesthetic and (usually) cryopreserved. The myeloablative therapy is given and the thawed marrow reinfused intravenously, as with an allogeneic transplant. The time to blood count recovery after an autograft is usually somewhat longer than after an allograft. Methods to remove malignant cells, as well as methods to induce a ‘graft vs. leukaemia’ effect, are currently being investigated. The mortality is considerably lower than with allogeneic BMT (5-10%), GVHD not being a problem. Bacterial and fungal infection are the greatest risk; viral and fungal infections can continue to be a problem for up to 1 year afterwards due to a reversal of the normal T helper: suppressor cell ratio.

The use of peripheral blood

progenitor cells (PBPC) instead of autologous bone marrow to support myeloablative therapy It is possible, by using chemotherapy for ablation followed by the growth factor G-CSF (see p. 360), to stimulate haemopoietic progenitor cells in the marrow to proliferate, so that they can be collected from the peripheral blood. PBPC are increasingly being used instead of autologous bone marrow since, because they are more differentiated cells, the time to recovery of the blood count is only 2-3 weeks, with obvious advantages in both human and economic terms. PBPC have predominantly been used in patients with HD and NHL in an experimental setting.

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