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1.
A clinical decision support tool to find the best initial intravenous cyclosporine regimen in pediatric hematopoietic stem cell transplantation
Leclerc, V., Ducher, M., Ceraulo, A., Bertrand, Y., Bleyzac, N.
Journal of clinical pharmacology. 2021
Abstract
In order to optimize cyclosporine A (CsA) dosing regimen in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT), we aimed to provide clinicians with a validated decision support tool for determining the most suitable first dose of intravenous CsA.We used a 10-years monocentric dataset of pediatric patients undergoing HSCT. Discretization of all variables was performed according to literature or thanks to algorithms using Shannon entropy (from information theory) or equal width intervals. The first eight years were used to build the Bayesian network model. This model underwent a 10-fold cross-validation, and then a prospective validation with data of the two last years.There were 3.3% and 4.1% of missing values in the training and the validation dataset respectively. After prospective validation, the Tree-Augmented Naïve Bayesian network shows interesting prediction performances with an average AUC-ROC of 0.804, 32.8% of misclassified patients, a true-positive rate of 0.672, and a false-positive rate of 0.285.This validated model allows good predictions to propose an optimized and personalized initial CsA dose for pediatric patients undergoing HSCT. The clinical impact of its use should be further evaluated. This article is protected by copyright. All rights reserved.
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2.
Impact of a Bayesian Individualization of Cyclosporine Dosage Regimen for Children Undergoing Allogeneic Hematopoietic Cell Transplantation: a Cost-Effectiveness Analysis
Beyron, C., Ceraulo, A., Bertrand, Y., Bleyzac, N., Philippe, M.
Therapeutic drug monitoring. 2021
Abstract
BACKGROUND Cyclosporine (CsA) is the main drug used to prevent graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). CsA therapeutic drug monitoring (TDM) has been performed for ages, with studies revealing clinical benefits, but failing to examine its economic impact. Herein, the main objective was to evaluate the economic impact of the CsA TDM strategy, based on a Bayesian approach, by assessing costs related to its clinical impact. Furthermore, TDM effectiveness was analyzed in terms of pharmacokinetics (PK) and clinical outcomes. METHODS A cost-effective, non-randomized, retrospective, single-center study compared two CsA monitoring and dose adaptation strategies in pediatric patients undergoing HSCT. From 2014 to 2016, CsA TDM was performed using a population PK model-coupled Bayesian approach by a pharmacist ("Pharmacist-assisted individualization", PAI). From 2017 to 2018, CsA TDM was performed by the clinician without a Bayesian approach (non-PAI group). HSCT costs were evaluated from the French National Insurance perspective. Economic and clinical outcomes were assessed by measuring incremental cost-effectiveness ratios. RESULTS The study included 144 patients: 90 and 54 patients in PAI and non-PAI groups, respectively. Both groups were comparable in terms of sociodemographic and clinical characteristics. The mean total cost per patient was significantly lower (p < 0.01) in the PAI group (€85,947) than in the non-PAI group (€100,435). Multivariate analysis revealed that TDM based on the Bayesian approach was a protective factor (OR = 0.86) for severe acute GVHD. We noted that pharmacist-based TDM was the dominant strategy. Bayesian method-based TDM allowed an increase in the percentage of target attainment at any period post-HSCT. CONCLUSIONS CsA TDM with a Bayesian approach is a cost-effective procedure, and highlighted clinical benefits encourage the development of new TDM strategies for HSCT.
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3.
A decision support tool to find the best cyclosporine dose when switching from intravenous to oral route in pediatric stem cell transplant patients
Leclerc, V., Bleyzac, N., Ceraulo, A., Bertrand, Y., Ducher, M.
European journal of clinical pharmacology. 2020
Abstract
PURPOSE Managing the pharmacokinetic variability of immunosuppressive drugs after pediatric hematopoietic stem cell transplantation (HSCT) is a clinical challenge. Thus, the aim of our study was to design and validate a decision support tool predicting the best first cyclosporine oral dose to give when switching from intravenous route. METHODS We used 10-years pediatric HSCT patients' dataset from 2008 to 2018. A tree-augmented naive Bayesian network model (method belonging to artificial intelligence) was built with data from the first eight-years, and validated with data from the last two. RESULTS The Bayesian network model obtained showed good prediction performances, both after a 10-fold cross-validation and external validation, with respectively an AUC-ROC of 0.89 and 0.86, a percentage of misclassified patients of 28.7% and 35.2%, a true positive rate of 0.71 and 0.65, and a false positive rate of 0.12 and 0.14 respectively. CONCLUSION The final model allows the prediction of the most likely cyclosporine oral dose to reach the therapeutic target specified by the clinician. The clinical impact of using this model needs to be prospectively warranted. Respecting the decision support tool terms of use is necessary as well as remaining critical about the prediction by confronting it with the clinical context.
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4.
Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children
Marsit, H., Philippe, M., Neely, M., Rushing, T., Bertrand, Y., Ducher, M., Leclerc, V., Guitton, J., Bleyzac, N., Goutelle, S.
Clinical pharmacokinetics. 2020
Abstract
BACKGROUND Busulfan therapeutic drug monitoring (TDM) is necessary to better achieve the target exposure in children before hematopoietic stem cell transplantation (HSCT). However, TDM-based dosing may be challenging if intra-individual pharmacokinetic variability (also denoted inter-occasion variability [IOV]) occurs during therapy. OBJECTIVES The objectives of this study were to describe and quantify busulfan IOV in children, and to investigate its potential determinants. METHODS We performed a new analysis of published data from children who received intravenous busulfan over 4 days before HSCT. We calculated individual pharmacokinetic parameters on each day of therapy using a published population pharmacokinetic model of busulfan and analyzed their changes. Population estimation of IOV was also performed with non-linear mixed effects (NLME) modeling. Potential predictors of significant decrease in busulfan clearance (CL) were assessed by using machine learning approaches. RESULTS IOV could be assessed in 136 children. Between day (D) 1 and D2, most patients (80%) experienced a decrease in busulfan CL, with a median change of - 7.9%. However, both large decreases (minimum, - 48.5%) and increases in CL (maximum, + 44%) were observed. Over D1-D3 of therapy, mean CL significantly decreased (- 15%), with a decrease of ≥ 20% in 22% of patients. Some patients also showed unstable CL from day to day. NLME modeling of IOV provided a coefficient of variation of 10.6% and 13.1% for volume of distribution (Vd) and CL, respectively. Some determinants of significant decreases in busulfan CL were identified, but predictive performance of the models was limited. CONCLUSIONS Significant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. The main risk is busulfan overexposure. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing.
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5.
Medication adherence after pediatric allogeneic stem cell transplantation: Barriers and facilitators
Hoegy, D., Bleyzac, N., Rochet, C., De Freminville, H., Renard, C., Kebaili, K., Bertrand, Y., Dussart, C., Janoly-Dumenil, A.
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2019;38:1-7
Abstract
PURPOSE Immunosuppressive therapy following pediatric hematopoietic stem cell transplantation is essential for the patient's prognosis, as the antibioprophylaxis and the isolation measures. But medication adherence is suboptimal for children and adolescents, from 52 to 73% in literature. The aim of this study is to provide an understanding of medication adherence after pediatric allogeneic stem cell transplantation (SCT), by identifying facilitators and barriers. METHOD Semi-structured interviews were conducted by a pharmacist with caregivers and healthcare providers in a pediatric centre. Four topics were discussed: transplantation, post-transplantation therapies, caregivers' experience and the healthcare system. Interviews were audiotaped, transcribed and analysed by inductive approach. FINDINGS Semi-structured interviews with 15 caregivers and 21 healthcare providers identified factors of medication adherence and hygiene measures. The long-term nature of therapy and difficult transitions of care were identified as major barriers. Recognizing the benefits of medication and parental involvement are facilitators. Furthermore, caregivers expressed the need to take into consideration the family entity. They would like also to receive earlier information from healthcare providers before hospital discharge. Those needs were not always identified by healthcare providers. CONCLUSION This analysis revealed barriers and facilitators to the medication adherence and to the care. It demonstrated similarities and differences between caregivers and healthcare providers' perceptions and has thereby initiated an improvement process of the healthcare system. As part of this process, medical and paramedical healthcare providers at this French pediatric centre are currently working on a support program for post-alloSCT hospital-home transition.
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6.
Bayesian Networks: A New Approach to Predict Therapeutic Range Achievement of Initial Cyclosporine Blood Concentration After Pediatric Hematopoietic Stem Cell Transplantation
Leclerc, V., Ducher, M., Bleyzac, N.
Drugs in R&D. 2018
Abstract
BACKGROUND Pediatric hematopoietic stem cell transplantation (HSCT) allows the treatment of numerous diseases, both malignant and non-malignant. Cyclosporine, a narrow therapeutic index drug, is the major immunosuppressant used to prevent graft-versus-host disease (GVHD), but may also cause severe adverse effects in case of overdosing. OBJECTIVE The objective of this study is to predict the initial cyclosporine residual blood concentration value after pediatric HSCT, and consequently the dose necessary to reach the therapeutic range, using a mathematical individual predictive model. METHODS Clinical and biological data collected from the graft infusion for 2 months after transplantation in 155 pediatric patients undergoing HSCT between 2008 and 2016 were used to generate synthetic data for 1000 subjects which were used to build a Bayesian network model. We compared the characteristics and sensitivity to clinical or biological missing data of this model with four other methods. RESULTS The tree-augmented Naive Bayesian network showed the best characteristics, with no missing data (area under the curve of the receiving operator characteristics curve [AUC-ROC] of 0.89 +/- 0.02), 18.9 +/- 2.6% of patients misclassified, and positive and negative predictive values of 85.9 +/- 3.4% and 74.2 +/- 5.1%, respectively, and this trend is found in the synthetic dataset from no to 10% missing data. The most relevant variables that could influence whether the initial residual cyclosporine concentration is in the therapeutic range are the last dose before measurement and the mean dose before measurement. CONCLUSIONS We developed and cross-validated an online Bayesian network to predict the first cyclosporine concentration after pediatric HSCT. This model allows simulation of different dosing regimens, and enables the best dosing regimen to reach the therapeutic range immediately after transplantation to be found, minimizing the risk of adverse effects and GVHD occurrence.
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7.
Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children
Philippe, M., Neely, M., Rushing, T., Bertrand, Y., Bleyzac, N., Goutelle, S.
Bone marrow transplantation. 2018
Abstract
Veno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis of data to examine determinants of VOD in children who received IV busulfan for HSCT conditioning. Busulfan PK parameters as well as various indices (maximal concentration-Cmax, area under the concentration-time curve-AUC) were estimated using a validated Bayesian approach. The influence of available PK, demographic, and clinical variables on the incidence of VOD was evaluated by using logistic regression and classification and regression tree (CART) analyses. Among the 293 patients included, the mean age was 6.5 years and the mean actual body weight was 26.3 kg. The incidence of VOD was 25.6%. Busulfan Cmax as well as weight <9 kg or age <3 years were identified as independent predictors of VOD in logistic regression analysis. CART analysis identified busulfan Cmax over the entire regimen as the strongest predictor of VOD. This study suggests that busulfan-associated VOD is in part a concentration-dependent reaction. In addition, the youngest children showed the highest risk of VOD. These findings may have important implications for busulfan dosing and therapeutic drug monitoring practice in HSCT children.
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8.
Impact of a change in protected environment on the occurrence of severe bacterial and fungal infections in children undergoing hematopoietic stem cell transplantation
Libbrecht, C., Goutagny, M. P., Bacchetta, J., Ploton, C., Bienvenu, A. L., Bleyzac, N., Mialou, V., Bertrand, Y., Domenech, C.
European Journal of Haematology. 2016;97(1):70-7
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure with a high infection risk. Strict isolation of patients is the rule to prevent such condition. OBJECTIVE We compared the occurrence of severe infections (bacteremia and invasive fungal infection, IFI) in children undergoing alloHSCT before and after the move to a new protected unit with decreases in isolation methods. METHODS The study was conducted over a 10-year period. Unit 1 (2002-2007) consisted of laminar airflow rooms where caregivers were required to wear a sterile outfit (gown, gloves, hat, and mask). Unit 2 (2008-2012) included spacious positive air pressure rooms with HEPA filters where only a clean gown and mask were required to be worn. RESULTS Two hundred eighty-six alloHSCTs were performed (144 in Unit 1 and 142 in Unit 2). We reported a total incidence of 4.78 infections/1000 hospital-days including 4.4 episodes of bacteremia and 0.38 episodes of IFI. There was no statistical difference in the incidence of infections: n = 4.98/1000 hospital-days in Unit 1 vs. n = 4.6/1000 in Unit 2 (P = 0.63). CONCLUSION The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life. Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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9.
Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis
Bleyzac, N., Cuzzubbo, D., Renard, C., Garnier, N., Dubois, V., Domenech, C., Goutagny, M. P., Plesa, A., Grardel, N., Goutelle, S., et al
Bone Marrow Transplantation. 2016;51(5):698-704
Abstract
There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration 120ng/mL versus 43% with concentration >120ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) 10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.
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10.
Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children
Philippe, M., Goutelle, S., Guitton, J., Fonrose, X., Bergeron, C., Girard, P., Bertrand, Y., Bleyzac, N.
Bone Marrow Transplantation. 2016;51(1):72-8
Abstract
Busulfan, the corner stone of hematopoietic stem cell transplantation regimens, has a narrow therapeutic window. Therapeutic drug monitoring (TDM)-guided dosing to reach the conventional area under the concentration-time curve (AUC) target range of 900-1500mumolmin/L is associated with better outcomes. We report our experience with busulfan TDM in a large cohort of children. The aims were to investigate the relevance of using a more restricted therapeutic range and investigate the association between busulfan therapeutic range and clinical outcome. This study includes 138 children receiving 16 doses of intravenous busulfan, with the first dose assigned based on weight and doses adjusted to a local AUC target range of 980-1250mumolmin/L. Busulfan TDM combined with model-based dose adjustment was associated with an increased probability of AUC target attainment, for both target range: 90.8% versus 74.8% for the conventional target range and 66.2% versus 43.9% for the local target range (P<0.001). The median follow-up was 56.2 months. Event-free survival was 88.5%, overall survival was 91.5% and veno-occlusive disease occurred in 18.3% of patients. No difference was observed for clinical outcomes depending on the selected target range. Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving target attainment, but using a restricted target range has no impact on clinical outcomes.