Background
Intravenous-busulfan (IV-busulfan) combined with therapeutic drug
monitoring to guide dosing improves outcomes after allogeneic hematopoietic
cell transplantation (allo-HCT). The best method to estimate busulfan
exposure and the optimal exposure in children/young adults remains unclear.
We therefore evaluated three approaches to estimate IV-Bu exposure
(expressed as cumulative-area-under-the-curve; AUC) and associated
busulfan-AUC with clinical outcomes in children/young adults undergoing
allo-HCT.
Methods
In this retrospective analysis, patients (0.1–30.4 years)
receiving busulfan-based conditioning regimen from 15 centers were included.
Cumulative AUC was calculated by numerical integration using non-linear
mixed effect modeling (AUCNONMEM), non-compartmental analysis
(AUC0-infinity and AUC to the end of the dose interval
AUC0-tau) and by individual centers using a variety of
approaches (AUCcenter). Main outcome of interest was event-free
survival (EFS). Other outcomes of interest were overall survival,
graft-failure, relapse, transplantation related mortality (TRM), acute
toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host
disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival
(GEFS). Propensity score adjusted cox proportional hazard models, Weibull
models, and Fine-Gray competing risk regressions were used.
Results
674 patients were included (41% malignant, 59%
non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan
AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6
mg*h/L). The median AUCNONMEM correlated poorly with
AUCcenter (R2 = 0.254). Patients with optimal
IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years
compared to 66.1% and 49.5% in the low (<78 mg*h/L)
and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011).
Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75
P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in
the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication.
Interpretation
These results demonstrate that improved clinical outcomes may be
achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new
validated pharmacokinetic-model for all indications.
Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg x h/L (95% confidence interval=74 to 82 mg x h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC >74 mg x h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.
High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.
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