Lipidomics of cyclophosphamide 4‐hydroxylation in patients receiving post‐transplant cyclophosphamide

Abstract

Biomarker‐guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration–time curve (AUC) of CY and its metabolites are time‐ and resource‐intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time‐varying differences in CY formation clearance to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY) and 24 h after the first dose of PT‐CY (24‐h post‐CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT.

The presence of busulfan metabolites and pharmacometabolomics in plasma drawn immediately before allograft infusion in hematopoietic cell transplant recipients

“… 11 Allogeneic HCT mice, compared to syngeneic HCT mice and non‐transplant control mice, had significant decreases in reduced GSH and increases in oxidized GSH, indicating early shifts in oxidative stress. 11 With the increasing importance of pharmacometabolomics, 14 , 30 , 31 , 32 , 33 we evaluated EMCs in plasma obtained in the pre‐graft plasma sample. However, this analysis found no association between the pre‐graft EMCs with acute or chronic GVHD (Tables S2 and S3 , respectively).…”

Immunosuppressant adherence in adult outpatient hematopoietic cell transplant recipients

“…29 The other two trials evaluated biomarkers for receiving post-graft immunosuppression with post-transplant cyclophosphamide (Protocol 17422 and 18358). 30,31 All participants were hospitalized; the attending physician determined their discharge date to the outpatient clinic. All participants provided written informed consent before study procedures; their HCT treatment was not affected by study participation.…”