Specific Aim 1: To determine whether endogenous metabolomics-based biomarkers obtained before
IV BU administration can predict IV BU clearance.
Specific Aim 2: To characterize IV BU metabolism by metabolomics.
Specific Aim 3: To identify covariates influencing IV BU pharmacokinetics.
The long-range goal of this work is to improve overall survival in hematopoietic stem cell
transplant (HCT) recipients by personalizing their conditioning regimen and/or intravenous
(IV) busulfan (BU) doses using metabolomics. BU is an essential part of the majority of HCT
conditioning regimens, but has a narrow therapeutic index; low BU plasma exposure (caused by
rapid clearance) is associated with an increased risk of rejection or relapse, while high BU
plasma exposure is associated with an increased risk of hepatotoxicity. Although
pharmacokinetic (PK)-based dosing to a target BU exposure is often conducted, relapse and
toxicity continue to be problematic. Furthermore, shorter IV BU courses necessitate
alternative methods to personalize IV BU. IV BU clearance, however, is not associated with
polymorphisms of glutathione S-transferase (GST) A1 and GSTM1, the predominant GSTs in BU
conjugation with glutathione. Therefore, investigators seek to test the working hypothesis
that metabolomic signature, which provides novel insight into the in vivo cellular response
and metabolite identification, is associated with IV BU clearance. Investigators will first
determine if endogenous metabolomics-based biomarkers obtained before BU administration can
predict IV BU clearance. Researchers will evaluate endogenous biomarkers using a targeted
(glutathione pathway) and global analyses via liquid chromatography-mass spectroscopy. In
addition, investigators seek to evaluate IV BU metabolism using metabolomics in parallel with
gas chromatography-mass selective detection in patients receiving PK-based IV BU. Researchers
will evaluate plasma concentrations of eight different metabolites, building upon their
experience with tetrahydrothiophene (THT+). To complement this metabolomic work,
investigators seek to validate covariates associated with IV BU PK, specifically age and body
size, to mitigate a typical challenge for metabolomics research: the lack of understanding of
potentially confounding factors. FHCRC has been a reference clinical laboratory for PK-based
BU dosing since 1996 and thus, FHCRC researchers have the largest database of IV BU PK. Using
population pharmacokinetic (popPK) analysis, investigators will validate covariates for IV BU
PK to guide future metabolomic studies. This popPK analysis can immediately improve patient
care by using covariates to more accurately estimate an IV BU starting dose (i.e., before
PK-based dosing) and by creating a limited sampling schedule to more efficiently use PK-based
dosing. These complementary aims, which seek to identify novel metabolomics-based biomarkers,
could overcome a critical barrier to HCT conditioning of balancing between response and
toxicity. Based on compelling preliminary data, researchers expect to identify an endogenous
metabolomic signature that will influence the choice of an IV BU starting dose with the
intention of improving overall survival for patients receiving IV BU-containing HCT regimens.
- Scheduled to receive targeted intravenous busulfan (any dose, any number of doses, any
dosing frequency) as part of their hematopoietic stem cell transplant conditioning;
- Weight > 21kg.
- Unable to read English;
- Female patients who are pregnant or breastfeeding;
- Life expectancy severely limited by diseases other than malignancy.