Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation

Ward, John L.; Kletzel, Morris; Duerst, R.; Fuleihan, Ramsay; Chaudhury, Sonali; Schneiderman, Jennifer; Tse, William T.

doi:10.1016/j.bbmt.2015.05.017

Cited by 12 publications

(11 citation statements)

References 48 publications

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“…In children, it has clearly been demonstrated that Q24H i.v. BU administration is safe [89][90][91]. Most recently, in a prospective cohort study of children and adults with myeloid malignancies, the CIBMTR reported similar outcomes in HCT conditioning regimens using i.v.…”

Section: Faq7: What Is the Optimal Dosing Frequency Of Bu?mentioning

confidence: 96%

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

Palmer

McCune

Perales

et al. 2016

Biology of Blood and Marrow Transplantation

133

187

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The Practice Guidelines Committee of the American Society of Blood or Marrow Transplantation (ASBMT) sought to develop an evidence-based review about personalizing busulfan-based conditioning. The Committee sought to grade the relevant published studies (June 1, 2008 through March 31, 2016) according to criteria set forth by the Steering Committee for Evidence Based Reviews from ASBMT. Unfortunately, the published literature was too heterogeneous and lacked adequately powered and sufficiently controlled studies for this to be feasible. Despite this observation, the continued interest in this topic led the Practice Guidelines Committee to develop a list of most frequently asked questions (FAQs) regarding personalized busulfan dosing. This "Considerations" document is a list of these FAQs and their responses, addressing topics of practical relevance to hematopoietic cell transplantation clinicians.

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Section: Faq7: What Is the Optimal Dosing Frequency Of Bu?mentioning

confidence: 96%

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

Palmer

McCune

Perales

et al. 2016

Biology of Blood and Marrow Transplantation

133

187

View full text Add to dashboard Cite

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“…BU pharmacokinetics varies in children between 3 and 7 years, while the optimum therapeutic range (TR) has not yet been specified due to the limited number of studies on the paediatric population [ 12 , 13 , 14 , 15 , 16 , 17 ]. It is evident, however, that a higher plasma AUC is associated with a high-risk of regimen-related toxicity and, in particular, veno-occlusive disease (VOD) of the liver [ 12 , 14 , 16 ], while low busulfan plasma levels are associated with a higher risk of graft rejection [ 9 ] and leukemia relapse [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing

et al. 2022

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We develop a population pharmacokinetic model to describe Busulfan pharmacokinetics in paediatric patients and investigate by simulations the impact of various sampling schedules on the calculation of AUC. Seventy-six children had 2 h infusions every 6 h. A two-compartment linear model was found to adequately describe the data. A lag-time was introduced to account for the delay of the administration of the drug through the infusion pump. The mean values of clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 10.7 L/h, 39.5 L, 4.68 L/h and 17.5 L, respectively, normalized for a Body Weight (BW) of 70 kg. BW was found to explain a portion of variability with an allometric relationship and fixed exponents of 0.75 on clearance parameters and 1 on volumes. Interindividual variability for clearance and volume of distribution was found to be 28% and 41%, respectively, and interoccasion variability for clearance was found to be 11%. Three sampling schedules were assessed by simulations for bias and imprecision to calculate AUC by a non-compartmental and a model-based method. The latter was found to be superior in all cases, while the non-compartmental was unbiased only in sampling up to 12 h corresponding to a once-daily dosing regimen.

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“…In addition, only a few small, retrospective studies have been performed to determine the optimal AUC of busulfan in children/young adults. 14,16–18 Recent studies in adults and children suggest that a busulfan-AUC of AUC 0-inf 6000 µM*min/day × 4 (equivalent to a cumulative AUC of 100 mg*h/L) reaches optimal efficacy. 10,11,14 The optimal target may however vary with age, diagnosis, concomitant agents included in the preparative regimen and donor source.…”

Section: Introductionmentioning

confidence: 99%

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis

Bartelink

Lalmohamed

Reij

et al. 2016

The Lancet Haematology

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217

234

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Background Intravenous-busulfan (IV-busulfan) combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). The best method to estimate busulfan exposure and the optimal exposure in children/young adults remains unclear. We therefore evaluated three approaches to estimate IV-Bu exposure (expressed as cumulative-area-under-the-curve; AUC) and associated busulfan-AUC with clinical outcomes in children/young adults undergoing allo-HCT. Methods In this retrospective analysis, patients (0.1–30.4 years) receiving busulfan-based conditioning regimen from 15 centers were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modeling (AUCNONMEM), non-compartmental analysis (AUC0-infinity and AUC to the end of the dose interval AUC0-tau) and by individual centers using a variety of approaches (AUCcenter). Main outcome of interest was event-free survival (EFS). Other outcomes of interest were overall survival, graft-failure, relapse, transplantation related mortality (TRM), acute toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival (GEFS). Propensity score adjusted cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions were used. Results 674 patients were included (41% malignant, 59% non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6 mg*h/L). The median AUCNONMEM correlated poorly with AUCcenter (R2 = 0.254). Patients with optimal IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years compared to 66.1% and 49.5% in the low (<78 mg*h/L) and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011). Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75 P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication. Interpretation These results demonstrate that improved clinical outcomes may be achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new validated pharmacokinetic-model for all indications.

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Single Daily Busulfan Dosing for Infants with Nonmalignant Diseases Undergoing Reduced-Intensity Conditioning for Allogeneic Hematopoietic Progenitor Cell Transplantation

Cited by 12 publications

References 48 publications

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing

Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis

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