Eradication of leukaemic marrow and prevention of leukaemia relapse with total body irradiation and bone marrow transplantation

A series of studies was carried out to determine the effect of allogeneic bone marrow transplantation (BMT) on leukaemia. The study aimed at two different, but strictly linked issues: (1) identification of the eradication capability of BMT, and (2) evaluation of the effect of BMT, both in preventing relapse and in producing long-term disease-free survival. Fifty-four patients allografted for leukaemia were evaluated at various intervals, after bone marrow transplantation, for the presence of host haemopoiesis using red-blood-cell and cytogenetic markers. Among 40 patients in remission, 10 showed functional host and donor haemopoiesis (mixed chimerism), while in 30, host haemopoiesis was never detected (complete chimerism). Seven of the 14 evaluable patients who relapsed showed the reappearance of host haemopoiesis at the time of relapse. The records of received doses of TBI indicate that patients who achieved mixed chimerism, either relapsing or not, received significantly lower doses than complete chimeras. However, some patients with complete chimerism received a TBI dose equivalent to the dose received by those with mixed chimerism, suggesting that the TBI dose is not the only factor determining the reappearance of host haemopoiesis. The data on chimerism and relapse suggest that there is heterogeneity in radiosensitivity between normal marrow cells and leukaemic cells, and further, within the different types of leukaemia. The incidence/severity of acute and chronic graft-vs-host disease (GvHD) was significantly higher in complete chimeras than in mixed chimeras suggesting that mixed chimerism may play a role in the development of tolerance; however, it could be the tolerance (i.e. absence of GvHD) which is responsible for the persistence of host haemopoietic cells. One-hundred-and-sixty-eight patients undergoing allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) and chronic myeloid leukaemia were analyzed for risk factor associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120mg/kg and total body irradiation (TBI) of 330 cGy on days -3, -2, -1. There was a difference of ±18% between the nominal total dose of 990 cGy and the actual received dose as indicated by dosimetric recordings. While interstitial pneumonitis had minimal impact on survival there was a considerable difference in the incidence of relapses. The incidence of relapse was higher in patients receiving less, than in patients receiving more than 1000 cGy respectively and this had a major impact on survival. However, transplant-related mortality was slightly higher in the group of patients receiving higher doses of TBI. These results suggest that a higher dose of TBI, within this schedule, produced long-term disease-free survival in the majority of acute myeloid leukaemia and chronic myeloid leukaemia with minor radiobiological side-effects which, however, tended to be higher as the TBI dose increased. Moreover, a small reduction of the dose may significantly increase the risk of relapse. In addition, the disease status significantly influences the probability of relapse and this is mainly seen in chronic myeloid leukaemia. Moreover, the prevention of graft-vs-host disease plays a relevant role both in relapse as well as in the transplant-related mortality. It is therefore concluded that fine tuning of the conditioning protocol, and of the therapy for graft-vs-host prevention, is needed to improve the results in allogeneic bone marrow transplant.