The effect of administration order of BU and CY on toxicity in hematopoietic SCT in humans

Kerbauy, Fábio R.; Tirapelli, B; Akabane, Hugo; Oliveira, José Salvador Rodrigues de

doi:10.1038/bmt.2008.404

Cited by 12 publications

(9 citation statements)

References 6 publications

(3 reference statements)

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“…Kerbauy et al . described the use of CY/BU conditioning in a cohort of 11 patients and reported lower peak serum aminotransferase levels compared to BU/CY-conditioned historical controls [14]. Of note, peak serum total bilirubin levels were not significantly different.…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogeneic Hematopoietic Cell Transplantation: Pharmacokinetics and Clinical Outcomes

Rezvani

McCune

Storer

et al. 2013

Biology of Blood and Marrow Transplantation

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Targeted busulfan/cyclophosphamide (TBU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from TBU/CY to CY/TBU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/TBU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800–900 ng/mL. CY/TBU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to TBU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with TBU/CY for the same indications. In patients with myelofibrosis, CY/TBU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after TBU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/TBU cohort (2% vs. 13%, p=0.01). CY/TBU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/TBU is superior to TBU/CY as conditioning for patients with myelofibrosis.

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Section: Discussionmentioning

confidence: 99%

Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogeneic Hematopoietic Cell Transplantation: Pharmacokinetics and Clinical Outcomes

Rezvani

McCune

Storer

et al. 2013

Biology of Blood and Marrow Transplantation

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“…In this study, there was no statistically significant association between the AUC of Cy (and metabolites) and VOD, non-relapse mortality, relapse or survival [159]. Finally, patients receiving high-dose conditioning Bu and Cy regimens prior to HSCT have a decreased risk of hepatotoxicity when Bu is administered after Cy [160,161], although there is a possibility in these studies that hepatic CYP-induction by supportive care medications (e.g. phenytoin) or other interacting concomitant medications might have aggravated Cy toxicity, thereby contributing to the observed liver toxicities.…”

Section: Busulfan Drug-drug Interactionsmentioning

confidence: 99%

Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review

Myers

Kawedia

Champlin

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Busulfan (Bu) is an alkylating agent with a limited therapeutic margin and exhibits inter-patient variability in pharmacokinetics (PK). Despite decades of use, mechanisms of Bu PK-based drug-drug interactions (DDIs), as well as the negative downstream effects of these DDIs, have not been fully characterized. Areas covered This article provides an overview of Bu PK, with a primary focus on how known and potentially unknown drug metabolism pathways influence Bu-associated DDIs. In addition, pharmacogenomics of Bu chemotherapy and Bu-related DDIs observed in the stem cell transplant clinic (SCT) are summarized. Finally the increasing importance of Bu therapeutic drug monitoring is highlighted. Expert Opinion Mechanistic studies of Bu metabolism have shown that in addition to GST isoenzymes, other oxidative enzymes (CYP, FMO) and ABC/MDR drug transporters likely contribute to the overall clearance of Bu. Despite many insights, results from clinical studies, especially in polypharmacy settings and between pediatric and adult patients, remain conflicting. Further basic science and clinical investigative efforts are required to fully understand the key factors determining Bu PK characteristics and its effects on complications after SCT. Improved TDM strategies are promising components to further investigate, for instance DDI mechanisms and patient outcomes, in the highly complex SCT treatment setting.

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“…For example, liver toxicity could be influenced by CY, including time of its administration relative to BU. 43,44 Higher levels of toxic metabolites of CY in GSTA*B homozygotes can also contribute to VOD development, in which case administration of CY after BU would be detrimental. This finding is nevertheless contrary to the hypothesis that increased activity of GSTA in GSTM1 null individuals might deplete GSH causing damage to liver and occurrence of VOD.…”

Section: Discussionmentioning

confidence: 99%

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

Ansari

Rezgui

Théôret

et al. 2013

Bone Marrow Transplant

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on behalf of the Pediatric Disease Working Parties of the European Blood and Marrow Transplant Group BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (Pp0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (Pp0.03). Gene-dosage effect was also observed (Pp0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P ¼ 0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P ¼ 0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P ¼ 0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.

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The effect of administration order of BU and CY on toxicity in hematopoietic SCT in humans

Cited by 12 publications

References 6 publications

Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogeneic Hematopoietic Cell Transplantation: Pharmacokinetics and Clinical Outcomes

Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogeneic Hematopoietic Cell Transplantation: Pharmacokinetics and Clinical Outcomes

Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

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