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 mean AUC above the cut-off value of 900 µM × min (after every 6-hour dosing) was associated with decreased rates of graft failure, while the cut-off value of 1350 µM × min were associated with increased risk of VOD in children, particularly for the patients without VOD prophylaxis therapy. Further well-designed prospective and multi centric randomized controlled trials with larger sample size are necessary before putting our result into clinical practices.

Population pharmacokinetic model for once‐daily intravenous busulfan in pediatric subjects describing time‐associated clearance

“…Busulfan dose adjustment across the typical 4‐day treatment course can vary across treatment centers 10,22 . Many centers adjust dosing based on the assumption that busulfan CL remains constant over time using product information recommendations 12,23 despite contrary evidence of reduction in CL during the treatment course 1–7 .…”

Individualized busulfan dosing improves outcomes compared to fixed‐dose administration in pre‐transplant minimal residual disease‐positive acute myeloid leukemia patients with intermediate‐risk undergoing allogeneic stem cell transplantation in CR

“…All but 2 patients (n = 85/87; 98%) showed successful engraftment (leukocytes: median Day 11 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] ; platelets: Day 12 (7-117)). Two patients (both from the fixed Bu group) developed graft failure and subsequently underwent a second allograft.…”

“…The patients' characteristics were not different between both groups (Table S3). Engraftment of leukocytes (individualized: median 11 [10][11][12][13][14][15][16][17][18][19][20][21][22][23] versus fixed: median 12, 8-22 p = 0.72) and platelets (individualized: median 11 vs. fixed: median 12 , p = 0.44) was not significantly different between both groups. One patient who received fixed Bu dosage and was pre-transplant MRD negative developed graft failure and underwent second allo-SCT.…”

“…PK‐guided Bu administration was found to be associated with higher engraftment rates in children, 18 lower hepatotoxicity rates, 19,20 and lower relapses in patients with previously untreated chronic myeloid leukemia (CML) 21 . Further studies reported that toxicity is associated with increased area under the curve (AUC), thus, the optimized AUC level led to significantly lower toxicity, lower non‐relapsed mortality (NRM), and higher survival outcomes also in older and/or patients with comorbidities 22–26 .…”

“…8,9 Nevertheless, it was found that patient-individual covariates, such as age, weight, body surface area, or co-medication might affect the clearance or volume of distribution of busulfan leading to inter-individual variability [10][11][12][13][14][15] and intraindividual change of a PK parameter between different doses. 16,17 PK-guided Bu administration was found to be associated with higher engraftment rates in children, 18 lower hepatotoxicity rates, 19,20 and lower relapses in patients with previously untreated chronic myeloid leukemia (CML). 21 Further studies reported that toxicity is associated with increased area under the curve (AUC), thus, the optimized AUC level led to significantly lower toxicity, lower non-relapsed mortality (NRM), and higher survival outcomes also in older and/or patients with comorbidities.…”