Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children

Abstract

Busulfan, the corner stone of hematopoietic stem cell transplantation regimens, has a narrow therapeutic window. Therapeutic drug monitoring (TDM)-guided dosing to reach the conventional area under the concentration-time curve (AUC) target range of 900-1500 μmol min/L is associated with better outcomes. We report our experience with busulfan TDM in a large cohort of children. The aims were to investigate the relevance of using a more restricted therapeutic range and investigate the association between busulfan therapeutic range and clinical outcome. This study includes 138 children receiving 16 doses of intravenous busulfan, with the first dose assigned based on weight and doses adjusted to a local AUC target range of 980-1250 μmol min/L. Busulfan TDM combined with model-based dose adjustment was associated with an increased probability of AUC target attainment, for both target range: 90.8% versus 74.8% for the conventional target range and 66.2% versus 43.9% for the local target range (P o 0.001). The median follow-up was 56.2 months. Event-free survival was 88.5%, overall survival was 91.5% and venoocclusive disease occurred in 18.3% of patients. No difference was observed for clinical outcomes depending on the selected target range. Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving target attainment, but using a restricted target range has no impact on clinical outcomes.

Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: a meta-analysis

“…Our meta-analysis also demonstrated that a target value of 1350 μM × min is associated with an increased risk of VOD. This conclusion differs from the 900-1500 μM × min threshold that some publications [11,12,15] have suggested. This is likely due to the fact that those studies are mainly conducted on adults and their subjects of study are relatively limited.…”

“…The European Society for Blood and Marrow Transplantation (EBMT) guidelines recommend a total AUC after 16 doses of 90 mg × h/L (an equivalent of 1370 μM × min after every 6 h dosage) for myeloablative exposure, without strict distinction between children and adults [11]. Numerous observational studies have recommended target Bu exposure ranges at different cut-off values, including 900 [2,[12][13][14][15][16][17], 1000 [18], 1225 [11], 1350 [15][16][17], 1500 [14] and 1575 [11] μM × min for every 6-h dosage. On the contrary, some observational studies found no statistically significant differences in transplant-related toxicity (TRT) or graft failure rate between different Bu AUC [19][20][21].…”

Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: A meta-analysis

“…Our meta-analysis also demonstrated that a target value of 1350 µM × min is associated with an increased risk of VOD. This conclusion differs from the 900-1500 µM × min threshold that some publications [11,12,15] have suggested. This is likely due to the fact that those studies are mainly conducted on adults and their subjects of study are relatively limited.…”

“…Numerous observational studies have recommended target Bu exposure ranges at different cut-off values, including 900 [2,[12][13][14][15][16][17], 1000 [18], 1225 [11], 1350 [15][16][17], 1500 [14] and 1575 [11] µM × min for every 6-hour dosage. On the contrary, some observational studies found no statistically significant differences in transplant-related toxicity (TRT) or graft failure rate between different Bu AUC [19][20][21].…”

Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: A Meta-Analysis

“…The European Society for Blood and Marrow Transplantation (EBMT) guidelines recommend a total AUC after 16 doses of 90 mg*h/L (an equivalent of 1370 µM × min after every 6 hour dosage) for myeloablative exposure, without strict distinction between child and adult [11]. Numerous observational studies have recommended target Bu exposure ranges at different cut-off values, including 900 [2,[12][13][14][15][16][17], 1000 [18], 1225 [11], 1350 [15][16][17], 1500 [14] and 1575 [14] µM × min for every 6-hour dosage. On the contrary, some observational studies found no statistically significant differences in transplant-related toxicity (TRT) or graft failure rate between different Bu AUC [19][20][21].…”