Abstract 1184

Poster Board I-206

Introduction:

Busulfan shows narrow therapeutic range. High exposure is associated with systemic toxicity such as veno-occlusive disease (VOD) and underexposure is associated with graft failure or relapse. In children, pharmacokinetic variability was found to be high even after the use of intravenous (IV) busulfan. Recently, reduced toxicity myeloablative regimen showed promising results but the data of busulfan pharmacokinetics when combined with fludarabine in children was not reported yet. We performed therapeutic drug monitoring (TDM) after once-daily IV busulfan combined with fludarabine and analyzed the outcomes.

Patients and Methods:

Busulfan (once daily ivs for 4 consecutive days) and fludarabine were used for acute myeloid leukemia (AML) and other diseases. For acute lymphocytic leukemia (ALL) etoposide was added. Busulfan (120 mg/m2) was administered on the first day. Blood samplings were taken before administration and 1, 2, 4hr after the end of infusion. Area under the curve (AUC) was analyzed by high pressure liquid chromatography. Target AUC was 18,125-20,000 ug*h/L/day, and dose adjustment was done when AUC was beyond the range. We initially planned to perform TDM on the first, fourth day, and the day when dose modification was needed, but we changed the design to perform TDM daily after the observation of increased AUC with modified dose on the fourth day showing decreased clearance in two patients. After we observed high incidence of toxicities, the target AUC was reduced to 18,000-19,000 ug*h/L/day.

Results:

A total of 18 patients were enrolled for this study. The diagnoses were AML in 10, ALL in 4, and other diseases in 4 patients. Median age was 9.0 years (range 1.3-18.0 years). After infusion of 120mg/ m2 busulfan on the first day, patients showed AUC ranged from 12,723.0 to 31,659.9 ug*h/L (median 18,638.0 ug*h/L) with clearance of 1.74-6.07 mL/min/kg (median 3.79 mL/min/kg). In 8 patients, busulfan dose increased 1.07-1.53 times compared to the first dose on the second day, and a dose reduction with 0.59-0.95 times compared to the first dose was made in 6 patients. Two patients received same dose of busulfan after target AUC was achieved, but the patients showed increased AUC (27,752.8 and 26,060.1 ug*h/L, respectively) on the fourth day. After then, daily TDM was performed in 15 patients and among the 45 times TDM and dose modification, AUC within the target range was achieved in only 9 times after administration of new targeted modified dose. Higher AUC (104.3-144.6%) than expected was shown in 23 times with decrease of clearance (51.2-97.1% compared to prior day), and lower AUC (79.4-94.2%) with increased clearance (108.8-177.9% compared to prior day) was shown in 13 times. The clearances of each individual changed during the 4 days and further dose modifications were needed on the third and fourth day in 13 and 12 patients, respectively. The total dose of busulfan administered for 4 days ranged from 287.3 mg/m2 to 569.4 mg/m2 (median 467.0 mg/m2) with median total AUC of 77,913.0 ug*h/L (range 72,752.4-83,160.3 ug*h/L). Engraftment was achieved in all patients, and 1 patient developed VOD.

Conclusions:

Busulfan pharmacokinetics was highly variable and unpredictable in all patients and it also changed during 4 consecutive infusions in each patient when combined with fludarabine. Further studies are needed to determine the factors affecting the variability. Intensive monitoring with daily TDM and dose modification are necessary for optimal therapy in children undergoing hematopoietic stem cell transplantation with busulfan plus fludarabine based conditioning regimen.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.

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