CFU-c suppressor T cells were generated in vitro by culturing overnight peripheral blood T cells from healthy donors with pokeweed mitogen (PWM), or T cells from patients with severe aplastic anemia (SAA) in remission, with culture medium (RPMI). The supernatants were removed the next morning, the cells harvested and washed, and both tested for CFU-c suppression on normal marrow cells. Cyclosporin A (CyA) was added to this system to test whether it could abrogate or prevent the generation of suppressor cells. CyA was incubated with T cells, at a concentration of 0.1 μg/ ml, for 30 min at 37 °C and then washed away, in two different assays: (a) before T cells were incubated overnight in culture medium with or without PWM, or (b) after T cells had been kept overnight in culture. The results of this study indicate that CyA can prevent the generation of CFU-c suppressor T cells if preincubated with both normal or SAA T cells prior to in vitro priming, whereas it cannot abrogate the suppressor activity of primed T cells.
Summary One‐hundred and five patients undergoing allogeneic bone marrow transplantation (BMT) for acute myeloid leukaemia (AML) (n = 61) and chronic myeloid leukaemia ( n = 44) were analysed for risk factors associated with relapse. All patients received marrow from an HLA identical sibling after preparation with cyclophosphamide 120 mg/kg and total body irradiation (TBI) 330 cGy on each of the three days prior to transplantation. There was a difference of ±18% between the nominal total dose of 990 cGy and the actual dose received as indicated by dosimetric recordings. While interstitial pneumonitis had minimal impact on survival (4%) there was a considerable difference in the incidence of relapses. The incidence of relapse was 55% versus 11% in patients receiving less or more than 990 cGy respectively and this had a major impact on survival (38% v. 74% at 7 years) since transplant‐related mortality was comparable in the two groups. A multivariate Cox analysis indicated that a lower TBI dose (less than 990 cGy) was the most significant factor associated with relapse and the second most important factor associated with recurrence of leukaemia was the absence of chronic graft‐versus‐host‐disease (cGvHD). Actuarial relapse incidence was 62%, 28% and 18% for patients with no, limited or extensive chronic GvHD respectively. However, chronic GvHD had no significant impact on survival. Combined stratification for TBI dose and cGvHD showed that the dose effect of TBI on relapse was evident both in patients with and without cGvHD. Chronic GvHD influenced the risk of relapse only in patients receiving less than 990 cGy. These results suggest that a higher dose of TBI, within this schedule, produced long‐term disease‐free survival in the majority of AMLs and CMLs. Minor radiobiological side effects were experienced, but a small reduction of the dose may significantly increase the risk of relapse.
The cytogenetic and clinical course of three patients allografted for Ph positive chronic myeloid leukaemia are reported. All patients had a peculiar pattern of relapse. Two out of three patients had donor marrow graft pretreated with monoclonal antibody for graft versus host prevention. The cytogenetic relapse was invariably associated with major morphological changes in the marrow indicating that these were also haematological relapses. However, no changes in the peripheral blood count were observed. When relapse occurred in these patients, Ph positive marrow metaphases and host red blood cells ranged from 75% to 100% of the total cell population: thereafter they spontaneously reverted to complete chimaerism. Therefore the presence of leukaemic cells even in considerable amount was not sufficient, per se , to prevail over normal marrow. In addition these observations indicate that relapse was not associated with elimination of the graft: while haemopoiesis was entirely of recipient origin the donor normal stem cells were present and vital although functionally silent. These data suggest that, although TBI remains the more effective tool for eradicating the majority of leukaemic cells, haemopoietic competition between host and donor marrow may have a major impact on leukaemic relapse.
