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Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation
A M Bolinger1, A B Zangwill, J T Slattery
1University of California at San Francisco, Department of Clinical Pharmacy, San Francisco, CA 94143-0622, USA.
Insights
Targeting busulfan concentrations between 600-900 ng/ml significantly improved bone marrow transplantation engraftment rates in pediatric patients. This approach optimizes outcomes for children undergoing allogeneic transplantation.
Area of Science:
- Hematology
- Pharmacology
- Pediatric Oncology
Background:
- Busulfan steady-state concentration (Bu Css) is critical for successful engraftment in pediatric bone marrow transplantation (BMT).
- Previous studies indicated Bu Css <600 ng/ml correlated with suboptimal engraftment, with no link to regimen-related toxicity (RRT).
Purpose of the Study:
- To prospectively evaluate targeted busulfan concentrations in pediatric patients undergoing allogeneic BMT.
- To determine if achieving a specific Bu Css range (600-900 ng/ml) improves engraftment rates and impacts RRT.
Main Methods:
- 32 pediatric patients with AML, CML, or non-malignant disorders received HLA-matched donor grafts.
- Individual busulfan pharmacokinetics were assessed, and doses adjusted to target a Bu Css of 600-900 ng/ml +/- 10%.
- Busulfan concentrations were re-evaluated post-dose 1 of the conditioning regimen.
Main Results:
- 94% of patients achieved the target Bu Css range.
- Durable engraftment was observed in 94% of patients, a significant improvement from the previous 74% rate (P=0.043).
- Grade 3/4 regimen-related toxicity occurred in 21% of patients.
Conclusions:
- Targeted busulfan dosing within the 600-900 ng/ml range significantly enhances successful allogeneic engraftment in pediatric BMT.
- This strategy optimizes engraftment outcomes in pediatric patients receiving busulfan conditioning.
Abstract:
Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css <600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml +/- 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children.