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=3.666, 95% CI:1.419, 9.467). 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.

Recent Advances in Hematopoietic Stem Cell Transplantation for Inherited Bone Marrow Failure Syndromes

“…Myeloablative conditioning with busulfan-based regimens is currently recommended for patients with DBA, although treosulfan-based reduced-toxicity regimens have been demonstrating promising results [7,51,52]. It is important to keep in mind that the use of intravenous busulfan and adjustable pharmacokinetic monitoring correlates with better OS and EFS in children transplanted for non-malignant diseases like DBA [53,54]. Patients with DBA should benefit from a pretransplant and early posttransplant iron chelation therapy once the high iron overload is associated with inferior outcomes after HSCT [55,56]…”

Otimização de método analítico em HPLC-PDA para monitoração terapêutica do bussulfano oral em pacientes transplantados de células-tronco hematopoiéticas

“…Baixos valores de ASCT também estão associados a maiores riscos de recaídas em pacientes com leucemia mieloide crônica. A individualização da dose e a monitoração terapêutica podem ser utilizadas como estratégias clínicas para manter a ss C ____ do bussulfano entre 600 ng mL -1 e 900 ng mL -1 e melhorar o desfecho dos transplantes (Tabak et al, 2001;Bullock et al, 2006;Nath & Shaw, 2007;Corbacioglu, Jabbour &, Mohty, 2019;Philippe et al, 2019;Feng et al, 2020).…”