Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Eighty-one patients with acute myeloid leukemia (ANLL, n = 44) or acute lymphoblastic leukemia (ALL, n = 37), aged 10 to 50 years were randomized to receive 1 mg/kg per day (n = 41, group A) or 5 mg/kg per day (n = 40, group B) of cyclosporine A (CyA) from day -1 to day +20 after bone marrow transplant (BMT). All patients received CyA orally thereafter. All patients were prepared with cyclophosphamide (CY) 120 mg/kg and fractionated total body irradiation (TBI), and received unfractionated BM from an HLA-identical sibling. The two groups were comparable for diagnosis, disease status, French-American-British (FAB) classification, WBC count at diagnosis, cytogenetic abnormalities, extramedullary disease before BMT, donor/recipient age and sex, number of cells infused, and number of days with intravenous (IV) CyA. Median follow-up for surviving patients in group A was 983 v 632 days in group B. Patients in group A had lower serum levels of CyA (295 v 686 ng/mL, P = .004), lower bilirubin levels (1.9 v 2.6 mg/dL, P = .07), lower creatinine levels (0.9 v 1.4 mg/dL, P = .06), and a lower proportion of CD8+ cells in the peripheral blood (PB) within day +21 (19% v 28%, P = .07). First day to 0.5 x 10(9)/L neutrophils was comparable in the two groups (13 v 14 days; P = .1). In a Cox model, the actuarial risk of acute graft-v-host disease (GVHD) grade II+, after stratification for age (less than 20 years greater than) was significantly lower in group B patients (0.54, P = .04). The actuarial risk of developing chronic GVHD was comparable (P = .9). Actuarial transplant-related mortality (TRM) at 240 days was 28% and 26% (P = .8) in group A and B: the major cause of death was GVHD in group A (P = .02) and multiorgan toxicity in group B (P = .07). The actuarial risk of relapse at 2 years overall was 20% in group A and 52% in group B (P = .001); it was 9% v 43%, respectively, for patients in first remission (P = .0001) and 48% v 63% for patients in non-first complete remission (CR) (P = .1). Actuarial 2-year disease-free survival (DFS) in group A and B was 58% v 32% (P = .02) for all patients, 71% v 35% (P = .01), in first remissions, and 30% v 23% (P = .2) in advanced disease.(ABSTRACT TRUNCATED AT 400 WORDS). 