ABSTRACT
Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure-response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration-effect association are needed for QSP modeling.
Subject(s)
Cyclophosphamide , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents , Sirolimus , Humans , Sirolimus/administration & dosage , Graft vs Host Disease/prevention & control , Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Cyclophosphamide/adverse effects , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/pharmacokinetics , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/drug effects , Animals , Models, BiologicalABSTRACT
PURPOSE: 4-hydroxycyclophosphamide (4HCY) is the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY), which is often used as first-line treatment of children with cancer. There is conflicting data regarding the relationship between CY efficacy, toxicity, and pharmacokinetics with the genes encoding proteins involved in 4HCY pharmacokinetics, specifically its formation and elimination. METHODS: We evaluated germline pharmacogenetics in children with various malignancies receiving their first CY dose. Using linear regression, we analyzed the associations between two pharmacokinetic outcomes - how fast a child cleared CY (i.e., CY clearance) and the ratio of the 4HCY/CY exposure, specifically area under the plasma concentration-time curve (AUC), and 372 single nucleotide polymorphisms (SNP) in 14 drug-metabolizing transporters or enzymes involved in 4HCY formation or elimination. RESULTS: Age was associated with the ratio of 4HCY/CY AUC (P = 0.004); Chemotherapy regimen was associated with CY clearance (P = 0.003). No SNPs were associated with CY clearance or the ratio of 4HCY/CY AUC after controlling for a false discovery rate. CONCLUSION: Age and chemotherapy regimen, but not germline pharmacogenomics, were associated with CY clearance or the ratio of 4HCY/CY AUC. Other methods, such as metabolomics or lipidomics, should be explored.
ABSTRACT
Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.
Subject(s)
Pharmacogenomic Testing , Precision Medicine , Humans , Pharmacogenetics , Genetic Testing , Medical OncologyABSTRACT
INTRODUCTION: Medication nonadherence continues to be challenging for allogeneic hematopoietic cell transplant (HCT) recipients. The risk and severity of chronic graft-versus-host disease (GVHD) are associated with low immunosuppressant concentrations (which can be improved with model-informed precision dosing (MIPD)) and with immunosuppressant nonadherence (which can be improved with acceptable interventions). METHODS: With the goals of improving adherence and achieving therapeutic concentrations of immunosuppressants to eliminate GVHD, we characterized the feasibility of using the Medication Event Monitoring (MEMS®) Cap in adult HCT recipients. RESULTS: Of the 27 participants offered the MEMS® Cap at the time of hospital discharge, 7 (25.9%) used it, which is below our a priori threshold of 70%. These data suggest the MEMS® Cap is not feasible for HCT recipients. The MEMS® Cap data were available for a median of 35 days per participant per medication (range: 7-109 days). The average daily adherence per participant ranged from 0 to 100%; four participants had an average daily adherence of over 80%. CONCLUSIONS: MIPD may be supported by MEMS® technology to provide the precise time of immunosuppressant self-administration. The MEMS® Cap was used by only a small percentage (25.9%) of HCT recipients in this pilot study. In accordance with larger studies using less accurate tools to evaluate adherence, immunosuppressant adherence varied from 0% to 100%. Future studies should establish the feasibility and clinical benefit of combining MIPD with newer technology, specifically the MEMS® Button, which can inform the oncology pharmacist of the time of immunosuppressant self-administration.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Adult , Humans , Immunosuppressive Agents/therapeutic use , Transplant Recipients , Pilot Projects , Outpatients , Graft vs Host Disease/drug therapy , Graft vs Host Disease/prevention & control , Medication AdherenceABSTRACT
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.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Busulfan , Transplant Recipients , Graft vs Host Disease/etiology , Glutathione/metabolism , AllograftsABSTRACT
Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (Ki ~2 µM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well-characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4'-glucuronide, and raloxifene 6-glucuronide were evaluated in 16 healthy adults via a three-arm crossover, fixed-sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC0-96h ratio to ~0.60 after both acute and chronic administration, which is below the predefined no-effect range (0.75-1.33). Lack of change in terminal half-life and glucuronide-to-raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC50 , 0.37-12 µM). Another potential mechanism, interruption by green tea of gut microbe-mediated raloxifene reabsorption, prompted a follow-up exploratory clinical study to evaluate the potential for a green tea-gut microbiota-drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT-mediated drug interactions are needed. Informing patients about the risk of co-consuming green tea with raloxifene may be considered.
Subject(s)
Catechin , Tea , Adult , Humans , Catechin/pharmacology , Drug Interactions , Glucuronides , Raloxifene Hydrochloride/pharmacology , Tea/chemistry , Cross-Over StudiesABSTRACT
BACKGROUND: The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively. METHODS: A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with ±15% for busulfan concentrations and ±10% for busulfan plasma exposure. The dose recommendations were deemed accurate. RESULTS: Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values. CONCLUSIONS: The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.
Subject(s)
Busulfan , Hematopoietic Stem Cell Transplantation , Humans , Busulfan/pharmacokinetics , Hematopoietic Stem Cell Transplantation/methods , Laboratory Proficiency Testing , Laboratories , Drug Monitoring/methods , Transplantation Conditioning/methodsABSTRACT
The mTOR inhibitor sirolimus is prescribed to treat children with varying diseases, ranging from vascular anomalies to sporadic lymphangioleiomyomatosis to transplantation (solid organ or hematopoietic cell). Precision dosing of sirolimus using therapeutic drug monitoring (TDM) of sirolimus concentrations in whole blood drawn at the trough (before the next dose) time-point is the current standard of care. For sirolimus, trough concentrations are only modestly correlated with the area under the curve, with R 2 values ranging from 0.52 to 0.84. Thus, it should not be surprising, even with the use of sirolimus TDM, that patients treated with sirolimus have variable pharmacokinetics, toxicity, and effectiveness. Model-informed precision dosing (MIPD) will be beneficial and should be implemented. The data do not suggest dried blood spots point-of-care sampling of sirolimus concentrations for precision dosing of sirolimus. Future research on precision dosing of sirolimus should focus on pharmacogenomic and pharmacometabolomic tools to predict sirolimus pharmacokinetics and wearables for point-of-care quantitation and MIPD.
ABSTRACT
We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Aged , Quality of Life , Prospective Studies , Remission Induction , Leukemia, Myeloid, Acute/therapy , Retrospective StudiesABSTRACT
Intravenous busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplantation (HCT) patients, all had samples collected immediately before busulfan administration (preBU) and 96 had samples collected 2 weeks before busulfan (2-week-preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (< 0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a least absolute shrinkage and selection operator-penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least-squares. When the resulting linear prediction model was applied to the 2-week-preBU samples, it explained 40% of the variation in BuCL (adjusted R2 = 0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by steroid biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses.
Subject(s)
Busulfan , Hematopoietic Stem Cell Transplantation , Humans , Prospective Studies , Precision Medicine , Pharmacogenetics , Metabolomics , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methodsABSTRACT
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.
Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , Lipidomics , Hydroxylation , Cyclophosphamide/adverse effects , LipidsABSTRACT
Wearable non-invasive biosensors for the continuous monitoring of metabolites in sweat can detect a few analytes at sufficiently high concentrations, typically during vigorous exercise so as to generate sufficient quantity of the biofluid. Here we report the design and performance of a wearable electrochemical biosensor for the continuous analysis, in sweat during physical exercise and at rest, of trace levels of multiple metabolites and nutrients, including all essential amino acids and vitamins. The biosensor consists of graphene electrodes that can be repeatedly regenerated in situ, functionalized with metabolite-specific antibody-like molecularly imprinted polymers and redox-active reporter nanoparticles, and integrated with modules for iontophoresis-based sweat induction, microfluidic sweat sampling, signal processing and calibration, and wireless communication. In volunteers, the biosensor enabled the real-time monitoring of the intake of amino acids and their levels during physical exercise, as well as the assessment of the risk of metabolic syndrome (by correlating amino acid levels in serum and sweat). The monitoring of metabolites for the early identification of abnormal health conditions could facilitate applications in precision nutrition.
Subject(s)
Biosensing Techniques , Wearable Electronic Devices , Humans , Monitoring, Physiologic , Sweat/chemistry , NutrientsABSTRACT
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.
Subject(s)
Hematopoietic Stem Cell Transplantation , Area Under Curve , Cyclophosphamide/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Hydroxylation , Transplant RecipientsABSTRACT
Pharmacokinetic drug interactions precipitated by botanical and other natural products (NPs) remain critically understudied. Investigating these complex interactions is fraught with difficulties due to the methodologic and technical challenges associated with the inherently complex chemistries and product variability of NPs. This knowledge gap is perpetuated by a continuing absence of a harmonized framework regarding the design of clinical pharmacokinetic studies of NPs and NP-drug interactions. Accordingly, this Recommended Approach, the fourth in a series of Recommended Approaches released by the Center of Excellence for Natural Product Drug Interaction Research (NaPDI Center), provides recommendations for the design of clinical pharmacokinetic studies involving NPs. Building on prior Recommended Approaches and data generated from the NaPDI Center, such a framework is presented for the design of (1) phase 0 studies to assess the pharmacokinetics of an NP and (2) clinical pharmacokinetic NP-drug interaction studies. Suggestions for NP sourcing, dosing, study design, participant selection, sampling periods, and data analysis are presented. With the intent to begin addressing the gap between regulatory agencies' guidance documents about drug-drug interactions and contemporary NPDI research, the objective of this Recommended Approach is to propose methods for the design of clinical pharmacokinetic studies of NPs and NP-drug interactions.
Subject(s)
Advisory Committees , Biological Products/pharmacokinetics , Drug Interactions , Pharmaceutical Preparations , Guidelines as Topic , Humans , Research DesignABSTRACT
We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m2) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66-3.86) and 1.87 (0.68-5.11), respectively, for relapse; 0.77 (0.30-1.99) and 1.32 (0.54-3.23) for non-relapse mortality; 0.81 (0.42-1.57) and 1.38 (0.72-2.57) for overall mortality; and 0.78 (0.30-2.05) and 1.62 (0.63-4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Antilymphocyte Serum , Busulfan/therapeutic use , Chimerism , Cyclophosphamide/adverse effects , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Leukemia, Myeloid, Acute/complications , Neoplasm Recurrence, Local , Transplantation Conditioning/adverse effects , Vidarabine/analogs & derivatives , Vidarabine/therapeutic useABSTRACT
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.
Subject(s)
Critical Care , Leukemia, Myeloid, Acute , Quality of Life , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Prospective Studies , Retrospective Studies , Risk Factors , Survival RateABSTRACT
BACKGROUND: In vitro data suggest that the growth of rhabdomyosarcoma (RMS) cells is suppressed in a concentration-dependent manner by 4-hydroxycyclophosphamide (4HCY), the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY). Various retrospective studies on the relationship between genes encoding proteins involved in the formation and elimination of 4HCY (i.e., 4HCY pharmacokinetics) and cyclophosphamide (CY) efficacy and toxicity have been conflicting. PROCEDURES: We evaluated germline pharmacogenetics in 262 patients with newly diagnosed intermediate-risk RMS who participated in one prospective Children's Oncology Group clinical trial, ARST0531. Patients were treated with either vincristine/actinomycin/cyclophosphamide (VAC) or VAC alternating with vincristine/irinotecan (VAC/VI). We analyzed the associations between event-free survival and 394 single-nucleotide polymorphisms (SNP) in 14 drug metabolizing enzymes or transporters involved in 4HCY pharmacokinetics. RESULTS: Eight SNPs were associated (p-value < .05 by univariate analysis) with 3-year event-free survival; no SNPs survived a false discovery rate < 0.05. CONCLUSIONS: Our data suggest that a pharmacogenomic approach to therapy personalization of cyclophosphamide in intermediate-risk rhabdomyosarcoma is not viable. Other methods to personalize therapy should be explored.
Subject(s)
Cyclophosphamide , Rhabdomyosarcoma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Cyclophosphamide/therapeutic use , Dactinomycin/therapeutic use , Disease-Free Survival , Humans , Pharmacogenetics , Progression-Free Survival , Prospective Studies , Retrospective Studies , Rhabdomyosarcoma/drug therapy , Rhabdomyosarcoma/genetics , Vincristine/therapeutic useABSTRACT
Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m2 for 1 dose), followed by ASCT. Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM × minute. The primary endpoint was the occurrence of severe sinusoidal obstruction syndrome (SOS) or grade ≥4 pulmonary complications within the first 28 days after completion of consolidation therapy. A total of 146 eligible patients were enrolled, of whom 101 underwent BuMel ASCT. The overall incidence of protocol-defined unacceptable toxicity during consolidation was 6.9% (7 of 101). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation. The median busulfan AUC was 4558 µM × min (range, 3462 to 5189 µM × minute) for patients with SOS and 3512 µM × min (2360 to 5455 µM × minute) (P = .0142). No patients died during consolidation. From the time of study enrollment, the mean 3-year event-free survival for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year overall survival was 74.5 ± 3.7%. The BuMel myeloablative regimen following COG induction was well tolerated, with acceptable pulmonary and hepatic toxicity.
Subject(s)
Hematopoietic Stem Cell Transplantation , Neuroblastoma , Busulfan/adverse effects , Child , Humans , Induction Chemotherapy , Melphalan/adverse effects , Neuroblastoma/drug therapy , Transplantation, AutologousABSTRACT
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.
Subject(s)
Biological Products , Pharmaceutical Preparations , Drug Interactions , Humans , Reproducibility of ResultsABSTRACT
BACKGROUND: Personalizing busulfan doses to target a narrow plasma exposure has improved the efficacy and lowered the toxicity of busulfan-based conditioning regimens used in hematopoietic cell transplant. Regional regulations guide interlaboratory proficiency testing for busulfan concentration quantification and monitoring. To date, there have been no comparisons of the busulfan pharmacokinetic modeling and dose recommendation protocols used in these laboratories. Here, in collaboration with the Dutch Association for Quality Assessment in Therapeutic Drug Monitoring and Clinical Toxicology, a novel interlaboratory proficiency program for the quantitation in plasma, pharmacokinetic modeling, and dosing of busulfan was designed. The methods and results of the first 2 rounds of this proficiency testing are described herein. METHODS: A novel method was developed to stabilize busulfan in N,N-dimethylacetamide, which allowed shipping of the proficiency samples without dry ice. In each round, participating laboratories reported their results for 2 proficiency samples (one low and one high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. All participants were blinded to the answers; descriptive statistics were used to evaluate their overall performance. The guidelines suggested that answers within ±15% for busulfan concentrations and ±10% for busulfan plasma exposure and dose recommendation were to be considered accurate. RESULTS: Of the 4 proficiency samples evaluated, between 67% and 85% of the busulfan quantitation results were accurate (ie, within 85%-115% of the reference value). The majority (88% round #1; 71% round #2) of the dose recommendation answers were correct. CONCLUSIONS: A proficiency testing program by which laboratories are alerted to inaccuracies in their quantitation, pharmacokinetic modeling, and dose recommendations for busulfan in hematopoietic cell transplant recipients was developed. These rounds of proficiency testing suggests that additional educational efforts and proficiency rounds are needed to ensure appropriate busulfan dosing.