RELATIONSHIP OF PLASMA PHARMACOKINETICS OF HIGH-DOSE ORAL BUSULFAN TOTHE OUTCOME OF ALLOGENEIC BONE-MARROW TRANSPLANTATION IN CHILDREN WITH THALASSEMIA

We analyzed plasma pharmacokinetics of busulfan in 64 children and you ng adults (age 2.8-26; median 11 years) with homozygous beta-thalassem ia transplanted with bone marrow from HLA-identical sibling donors. A uniform conditioning regimen was employed, using busulfan 14 or 16 mg/ kg in 12 divided doses, and cyclophosphamide 120 or 200 mg/kg. Three s ets of parameters were examined in this homogenous patient population: (1) factors that affect the plasma kinetics of busulfan, such as age and pre-transplant liver status defined by liver function tests, ferri tin levels and liver biopsy; (2) busulfan-related toxicity: occurrence of veno-occlusive disease, seizures and idiopathic interstitial pneum onitis; and (3) the relationship between busulfan exposure and transpl ant outcome: engraftment delay or rejection, aplasia, occurrence of mi xed chimeras and mortality. Kinetic analysis of first and 10th dose (u sing area under the curve (AUC), maximum and minimum concentration) as comparable, showing no sign of accumulation or decline in busulfan pl asma levels over time. Age and liver status did not influence busulfan metabolism. No relationship was found between busulfan exposure and t oxicities or transplant outcome. We conclude that busulfan monitoring is not predictive in children and young adults with homozygous beta-th alassemia receiving busulfan and high-dose cyclophosphamide along with histocompatable sibling donor marrow.