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.
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.
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.
4.
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.