Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ‐glutamyldehydroalanylglycine, ...which is too unstable to be quantitated in vivo. We sought to evaluate if pre‐graft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites' and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non‐relapse mortality, and neutrophil nadir. In pre‐graft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: (1) the presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1‐oxide, sulfolane, and 3‐hydroxysulfolane (N = 124); (2) EMCs using a global metabolomics assay (N = 77); and (3) the association of the busulfan metabolites and the EMCs with clinical outcomes. In the pre‐graft samples, busulfan and THT+ could not be detected. THT 1‐oxide, sulfolane, and 3‐hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pre‐graft samples; their concentrations were not associated with clinical outcomes. Four pre‐graft EMCs were statistically significantly associated with the neutrophil nadir. The pre‐graft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients' plasma immediately before allograft infusion; the neutrophil nadir is associated with pre‐graft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfan's metabolites and EMCs in the pre‐graft plasma from allogeneic HCT recipients.
A challenge that must be addressed when conducting studies with complex natural products is how to evaluate their complexity and variability. Traditional methods of quantifying a single or a small ...range of metabolites may not capture the full chemical complexity of multiple samples. Different metabolomics approaches were evaluated to discern how they facilitated comparison of the chemical composition of commercial green tea Camellia sinensis (L.) Kuntze products, with the goal of capturing the variability of commercially used products and selecting representative products for in vitro or clinical evaluation. Three metabolomic-related methodsuntargeted ultraperformance liquid chromatography–mass spectrometry (UPLC-MS), targeted UPLC-MS, and untargeted, quantitative 1HNMRwere employed to characterize 34 commercially available green tea samples. Of these methods, untargeted UPLC-MS was most effective at discriminating between green tea, green tea supplement, and non-green-tea products. A method using reproduced correlation coefficients calculated from principal component analysis models was developed to quantitatively compare differences among samples. The obtained results demonstrated the utility of metabolomics employing UPLC-MS data for evaluating similarities and differences between complex botanical products.
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.
To our knowledge, this multicenter analysis is the first to test and validate (1) the prognostic impact of comorbidities on 1-year mortality after initial therapy of acute myeloid leukemia (AML) and ...(2) a novel, risk-stratifying composite model incorporating comorbidities, age, and cytogenetic and molecular risks.
To accurately estimate risks of mortality by developing and validating a composite model that combines the most significant patient-specific and AML-specific features.
This is a retrospective cohort study. A series of comorbidities, including those already incorporated into the hematopoietic cell transplantation–comorbidity index (HCT-CI), were evaluated. Patients were randomly divided into a training set (n = 733) and a validation set (n = 367). In the training set, covariates associated with 1-year overall mortality at a significance level of P < .10 constructed a multivariate Cox proportional hazards model in which the impact of each covariate was adjusted for that of all others. Then, the adjusted hazard ratios were used as weights. Performances of models were compared using C statistics for continuous outcomes and area under the curve (AUC) for binary outcomes.
Initial therapy for AML.
Death within 1 year after initial therapy for AML.
A total of 1100 patients, ages 20 to 89 years, were treated for AML between January 1, 2008, and December 31, 2012, at 5 academic institutions specialized in treating AML; 605 (55%) were male, and 495 (45%) were female. In the validation set, the original HCT-CI had better C statistic and AUC estimates compared with the AML comorbidity index for prediction of 1-year mortality. Augmenting the original HCT-CI with 3 independently significant comorbidities, hypoalbuminemia, thrombocytopenia, and high lactate dehydrogenase level, yielded a better C statistic of 0.66 and AUC of 0.69 for 1-year mortality. A composite model comprising augmented HCT-CI, age, and cytogenetic/molecular risks had even better predictive estimates of 0.72 and 0.76, respectively.
In this cohort study, comorbidities influenced 1-year survival of patients with AML, and comorbidities are best captured by an augmented HCT-CI. The augmented HCT-CI, age, and cytogenetic/molecular risks could be combined into an AML composite model that could guide treatment decision-making and trial design in AML. Studying physical, cognitive, and social health might further clarify the prognostic role of aging. Targeting comorbidities with interventions alongside specific AML therapy might improve survival.
Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased ...comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
•In 2 study cohorts, less-intensive therapies increased mortality in each of 3 risk groups defined by age, comorbidities, and cytogenetics.•The differences became nonsignificant after accounting for physician perception of cure, emphasizing the need for a randomized trial.
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The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the ...drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY’s cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) 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 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.
The popularity of botanical and other purported medicinal natural products (NPs) continues to grow, especially among patients with chronic illnesses and patients managed on complex prescription drug ...regimens. With few exceptions, the risk of a given NP to precipitate a clinically significant pharmacokinetic NP-drug interaction (NPDI) remains understudied or unknown. Application of static or dynamic mathematical models to predict and/or simulate NPDIs can provide critical information about the potential clinical significance of these complex interactions. However, methods used to conduct such predictions or simulations are highly variable. Additionally, published reports using mathematical models to interrogate NPDIs are not always sufficiently detailed to ensure reproducibility. Consequently, guidelines are needed to inform the conduct and reporting of these modeling efforts. This recommended approach from the Center of Excellence for Natural Product Drug Interaction Research describes a systematic method for using mathematical models to interpret the interaction risk of NPs as precipitants of potential clinically significant pharmacokinetic NPDIs. A framework for developing and applying pharmacokinetic NPDI models is presented with the aim of promoting accuracy, reproducibility, and generalizability in the literature. SIGNIFICANCE STATEMENT: Many natural products (NPs) contain phytoconstituents that can increase or decrease systemic or tissue exposure to, and potentially the efficacy of, a pharmaceutical drug; however, no regulatory agency guidelines exist to assist in predicting the risk of these complex interactions. This recommended approach from a multi-institutional consortium designated by National Institutes of Health as the Center of Excellence for Natural Product Drug Interaction Research provides a framework for modeling pharmacokinetic NP-drug interactions.
Background.
Approximately 40% of men diagnosed with metastatic prostate cancer experience one or more skeletal‐related events (SREs), defined as a pathological fracture, spinal cord compression, or ...surgery or radiotherapy to the bone. Accurate assessment of their effect on survival, health care resource utilization (HCRU), and cost may elucidate the value of interventions to prevent SREs.
Materials and Methods.
Men older than age 65 years with prostate cancer and bone metastasis diagnosed between 2004 and 2009 were identified from linked Surveillance Epidemiology and End Results–Medicare records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk for death associated with SREs were calculated by using Cox regression. HCRU and costs (in 2013 U.S. dollars) were evaluated in a propensity score‐matched cohort by using Poisson regression and Kaplan‐Meier sample average estimators, respectively.
Results.
Among 3,297 men with prostate cancer metastatic to bone, 40% experienced ≥1 SRE (median follow‐up, 19 months). Compared with men who remained SRE‐free, men with ≥1 SRE had a twofold higher risk for death (HR, 2.29; 95% CI, 2.09–2.51). Pathological fracture was associated with the highest risk for death (HR, 2.77; 95% CI, 2.38–3.23). Among men with ≥1 SRE, emergency department visits were twice as frequent (95% CI, 1.77–2.28) and hospitalizations were nearly four times as frequent (95% CI, 3.20–4.40). The attributable cost of ≥1 SRE was $21,191 (≥1 SRE: $72,454 95% CI, $67,362–$76,958; SRE‐free: $51,263 95% CI, $45,439–$56,100).
Conclusion.
Among men with prostate cancer metastatic to bone, experiencing ≥1 SRE is associated with poorer survival, increased HCRU, and increased costs. These negative effects emphasize the importance of SRE prevention in this population.
Implications for Practice:
This study confirms the substantial adverse clinical and economic effects of skeletal‐related events (SREs) in men with prostate cancer. Compared with men who have prostate cancer metastatic to the bones and no SREs, men with prostate cancer metastatic to the bones experiencing ≥1 SRE had a twofold increase in the risk for death, a twofold increase in the number of emergency department visits, and a fourfold increase in the number of hospitalizations; they also incurred an additional $21,000 in direct medical costs attributed to SREs. Strategies to prevent SREs are potentially of high value in this patient population.
Among men with prostate cancer metastatic to bone, experiencing ≥1 skeletal‐related event is associated with poorer survival, increased health care resource utilization, and increased costs. These negative effects emphasize the importance of preventing SREs in this population.
Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient's clearance, which is estimated with therapeutic drug monitoring. We sought to ...identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, N-acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at P < 0.05, with the first three satisfying the FDR of q < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at P < 0.05 and q < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings.
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