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Eighty consecutive patients were transplanted with human leukocyte antigen (HLA)-identical sibling marrow for acute myelogenous leukemia (AML, N = 29), acute lymphoid leukemia (ALL, N = 23), or chronic myelogenous leukemia (CML, N = 28). Donor marrow was depleted of lymphocytes using counterflow centrifugation. Median age of the recipients was 31 years. Pretransplant conditioning consisted of cyclophosphamide and fractionated total body irradiation (TBI) with a low (4.1 +/- 0.3 cGy/min) or high (13.1 +/- 1.6 cGy/min) midline average dose rate. In 43 patients, cytosine-arabinoside or anthracyclines were added to the conditioning regimen. Immunoprophylaxis posttransplant consisted of methotrexate (MTX) alone, cyclosporine A (CsA) in combination with MTX, or CsA alone; two patients received no immunoprophylaxis at all. Graft failure occurred in 4 of 77 evaluable patients (5%). The probability of acute graft-versus-host disease (GVHD) greater than or equal to grade 2 at day 100 after transplantation was 15%. The projected 3-year estimate of extensive chronic GVHD was 12%. Only three patients died of cytomegalovirus-interstitial pneumonitis. The projected 3-year probability of relapse was 30% (95% confidence interval [CI], range 8% to 53%) in transplants for AML in first complete remission (CR1), 35% (95% CI, 1% to 69%) after transplantation for ALL in CR1, and 38% (95% CI, 2% to 74%) after transplantation for CML in first chronic phase (CP1). The projected 3-year probability of leukemia-free survival (LFS) was 56% (95% CI, 35% to 77%) after transplantation for AML-CR1, 42% (95% CI, 16% to 69%) in patients transplanted for ALL-CR1, and 49% (95% CI, 18% to 80%) after transplantation for CML-CP1. After transplantation for AML-CR1, ALL-CR1, or CML-CP1, the median follow-up time for leukemia-free survivors was 31+, 30+, and 21+ months, respectively. Probabilities of relapse, survival, and LFS in AML-CR1 and ALL-CR1 transplants were comparable with those reported in recipients of untreated grafts. In patients transplanted for CML-CP1, probability of relapse was higher and probability of LFS was lower than in recipients of untreated grafts. In transplants for leukemia in CR1 and CP1, preparative regimen and immunoprophylaxis posttransplant were not associated significantly with the probability of acute GVHD greater than or equal to grade 2, extensive chronic GVHD, relapse, survival, or LFS. In bone marrow transplantation for leukemia, counterflow centrifugation is a useful technique for the prevention of GVHD.(ABSTRACT TRUNCATED AT 400 WORDS)

Eighty-nine patients were transplanted with allogeneic bone marrow after a standard conditioning regimen consisting of cyclophosphamide and fractionated total body irradiation (2 x 4.5 Gy) with average dose rates of 4.1 and 12.3 cGy/min, respectively. The average rectum and lung dose was 9.2 +/- 0.45 and 7.5 +/- 0.78 Gy. In vivo dosimetry was performed in 71 patients irradiated with 18 MV X-rays from left and right lateral. Forty-three patients (48%) died. After increasing the dose rate the incidence of interstitial pneumonitis increased, but the number of relapses decreased.

Nineteen patients with a median age of 43 years (range 40-48) were transplanted for acute myelogenous leukaemia (AML), refractory anaemia with excess of blasts in transformation (RAEBt), acute lymphoblastic leukaemia (ALL) in first complete remission, multiple myeloma, and chronic myelogenous leukaemia (CML) in chronic or accelerated phase. Their outcome was compared with that of 35 patients with a median age of 34 years (range 30-39), and a group of patients with age younger than 30 years (median 24; range 16-29) transplanted for the same indications. Donors were human leucocyte antigen (HLA)-identical, mixed lymphocyte culture (MLC) negative siblings. All marrow grafts were depleted of lymphocytes by counterflow centrifugation. The estimated event-free survival at 3 years after allogeneic bone marrow transplantation was 60.7% for patients with age greater than 39 years, 57.8% for patients with age less than 30, and 43.0% for the intermediate age group (P greater than 0.3). The estimated transplant-related mortality showed no tendency to increase with older age of recipients. The incidence of acute GVHD greater than grade 1 was 15.7% in patients with age greater than 39 years, 9.5% in patients younger than 30 years, and 23% in the intermediate age group. The incidence of chronic GVHD was higher in the older patients (39% compared to 24% in patients younger than 30 years, 19% in the intermediate age group). Chronic GVHD resolved completely in five out of seven patients aged 40 years or more. Reduction of the incidence of acute graft-versus-host disease by physical lymphocyte depletion allows allogeneic bone marrow transplantation for patients aged 40-50 years without increase of transplant-related mortality resulting in similar event-free survival in patients older than 40 years compared to those younger than 40 years.

Using red cell phenotyping, cytogenetic analysis of blood lymphocytes, chromosome studies of bone marrow cells, and restriction fragment length polymorphism (RFLP) studies of peripheral blood cells, we demonstrated a high number of mixed chimeras after allogeneic bone marrow transplantation (BMT). Donor marrow from HLA-A, -B, and -DR identical, mixed lymphocyte culture (MLC) nonreactive siblings was depleted of 98% of lymphocytes using counterflow centrifugation. Thirty-two of 48 recipients (67%) appeared to be mixed chimeras at 6 months after transplantation. The high number of mixed chimeras is probably a result of lymphocyte depletion of the marrow graft and the high sensitivity of red cell phenotyping for the demonstration of minor cell populations (at levels as low as 0.01%). The probability of relapse-free survival from 6 months to 4 years after BMT was 85% for the mixed chimeras and 65% for the complete donor chimeras. We conclude that in this study, mixed chimerism is not associated with a higher incidence of relapse.

Bone marrow from 22 histocompatible siblings was depleted of 98% of the lymphocytes using a combination of density flotation centrifugation followed by counterflow elutriation. Even with the marrow suppressive influence of methotrexate (MTX), the viability of the hematopoietic stem cells was not affected, as indicated by the normal repopulation after grafting in the evaluable patients. One patient (UPN 9) showed a primary graft failure, possibly resulting from persisting septicemia and long-term antibiotic therapy. Two patients have persistent host lymphocytes, one of whom was examined during relapse; the other remains in remission. Two patients did not receive immunosuppression after bone marrow transplantation (BMT), and acute graft-v-host disease (GVHD) developed in both. Nine patients received MTX as immunosuppression following BMT. GVHD did not develop in any of them, but fatal infections in the immediate posttransplant period developed in five patients. Eleven patients received cyclosporine (CsA) after transplantation. Beginning in week 5 after BMT, CsA was gradually replaced by MTX. Acute GVHD, substantial chronic GVHD, or fatal infections did not develop in any of these patients. Removal of 98% of the lymphocytes by counterflow centrifugation prevents development of acute GVHD, provided that immunosuppression is administered after BMT. Graft rejection was not observed, but the number of evaluable patients is limited at present.