Randomized trial of two different conditioning regimens for bone marrow transplantation in thalassemia - The role of busulfan pharmacokinetics in determining outcome

In total, 94 patients with homozygous beta thalassemia were randomized to two different conditioning regimens: busulfan 600mg/m² +cyclophosphamide 200mg/kg or busulfan 16mg/kg+cyclophosphamide 200mg/kg and antilymphocyte globulin (47 in each group), for bone marrow transplantation, to see whether increased myeloablation or increased immunosuppression would reduce rejection. Busulfan pharmacokinetics in determining outcome was evaluated. There was no significant difference in engraftment, graft-versus-host disease, rejection, and overall and disease-free survival in the two groups. Systemic exposure to busulfan was significantly higher in the 600mg/m² group, but in both groups there was a wide interindividual variation in the busulfan kinetics. Six patients rejected the graft, two in the busulfan 600mg group and four in busulfan 16mg group (P = 0.677 CI -0.17, 0.07), but in five patients (pharmacokinetic data not available in one patient) who rejected the graft busulfan first dose trough level (C_min-1) was below 150ng/ml while it was above this level in the 66 of 68 patients with successful engraftment (P≤0.001). This randomized trial shows that rejection is influenced by busulfan levels and suggests that monitoring of busulfan levels and dose adjustment based on first-dose kinetics may reduce the risk of rejection.