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

Abstract

Background Busulfan (Bu) is a key component of several conditioning regimens used before hematopoietic stem cell transplantation (HSCT). However,the optimum systemic exposure (expressed as the area under the concentration-time curve [AUC]) of Bu for clinical outcome in children is controversial. Methods Research on pertinent literature was carried out at PubMed, EMBASE, ClinicalTrials.gov and the Cochrane Library. Observational studies were included, which compared clinical outcomes above and below the area under the concentration-time curve (AUC) cut-off value, which we set as 800, 900, 1000, 1125, 1350, and 1500 µM × min. The primary efficacy outcome was notable in the rate of graft failure. In the safety outcomes, incidents of veno-occlusive disease (VOD) were recorded, as well as other adverse events. Results Thirteen studies involving 548 pediatric patients (aged 0.3-18 years) were included. Pooled results showed that, compared with the mean Bu AUC (i.e., the average value of AUC measured multiple times for each patient) of > 900 µM × min, the mean AUC value of <900 µM × min significantly increased the incidence of graft failure (RR=3.049, 95% CI: 1.285-7.234). The incidence of VOD was significantly decreased with the mean AUC <1350 µM × min (RR=0.370, 95% CI: 0.205-0.666) and <1500 µM × min(RR=0.409, 95% CI: 0182-0.920). Conclusions In children, Bu the mean AUC of 900 µM × min should be considered the lowest threshold associated with its effective prevention of graft failure, while the mean AUC of >1350 µM × min is associated with increased VOD, particularly for the patients not undergoing VOD prophylaxis therapy.

Role of therapeutic drug monitoring of intravenous Busulfan for prevention of sinusoidal obstructive syndrome in children

“…16 A recent meta-analysis revealed that mean Bu AUC every 6 h below 3.7 mg/L*h was associated with risk of graft failure, while the cutoff value of above 6.2 mg/L*h was associated with increased risk of SOS in children. 17 Philippe et al 18 reported that SOS risk was higher in patients with maximum Bu concentration above 1880 ng/mL or increased time spent above 1300 ng/ml. These findings support that longer time and higher intracellular exposure of Bu in addition to glutathione depletion results in increased toxicity.…”

“…The optimal therapeutic goal for Bu is associated with primary disease (malignant or non‐malignant), risk of relapse, the extent of marrow suppression (myeloablative or reduced‐intensity conditioning), and concomitant drug use (e.g., paracetamol, phenytoin, metronidazole, and azole antifungals) 16 . A recent meta‐analysis revealed that mean Bu AUC every 6 h below 3.7 mg/L*h was associated with risk of graft failure, while the cutoff value of above 6.2 mg/L*h was associated with increased risk of SOS in children 17 . Philippe et al 18 reported that SOS risk was higher in patients with maximum Bu concentration above 1880 ng/mL or increased time spent above 1300 ng/ml.…”

“…The risk of SOS is linked to the primary disease, the intensity of conditioning regimen, previous liver injury, use of concomitant drugs, and endothelial activation 11,12 . Both acute GvHD and concomitant chemotherapeutics lead to endothelial activation and cytokine release 17 . Previously, weight gain, hyperbilirubinemia, hepatomegaly, and ascites in the first 20 days after HSCT have been used to identify the diagnosis of SOS 11 .…”

Can Published Population Pharmacokinetic Models of Busulfan Be Used for Individualized Dosing in Chinese Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation? An External Evaluation

“…The US Food and Drug Administration has a recommended range of 900-1350 μM × min. 5 Studies have shown that the efficacy and adverse drug reactions of busulfan therapy are closely related to the AUC and steady-state concentration. 6 An AUC that is too low leads to the risk of transplant failure or disease recurrence, while one that is too high can lead to transplant-related morbidity and/or mortality.…”

“…The area under the concentration‐time curve (AUC) recommended by the European Medicines Agency is 900 to 1500 μM × min for 6‐hourly intravenous busulfan administration. The US Food and Drug Administration has a recommended range of 900–1350 μM × min 5 . Studies have shown that the efficacy and adverse drug reactions of busulfan therapy are closely related to the AUC and steady‐state concentration 6 .…”