Busulfan exposure associated with event-free survival in children after allogeneic haematopoietic stem cell transplantation: A retrospective multicenter cohort study

Busulfan exposure associated with event-free survival in children after allogeneic haematopoietic stem cell transplantation: A retrospective multicenter cohort study OBJECTIVE To determine the relationship between busulfan cumulative area under the curve (AUC] and event-free survival lEFS] in children undergoing allogeneic haematopoietic stem cell transplantation (alloHCT). DESIGN Retrospective, multicenter cohort study. METHODS Children who underwent alloHCT in 15 different centres worldwide were included in this study (2000-20131. Participants had to be on intravenous busulfan and pharmacokinetic samples had to be available. Exposure of interest was the cumulative AUC of busulfan, and primary outcome was EFS (time to graft failure, relapse or all-cause mortality). Cox regression models were used to derive relative risks (RR), and the optimal busulfan AUC level was estimated using propensity adjusted Weibull models. RESULTS A total of 674 subjects (41[%] malignant, 59[%] non- malignant) with a median age of 4.5 years (interquartile range 1.4-10.7 years) were included in the analysis. We observed a significant U-shaped relationship between busulfan cumulative AUC and EFS (P = 0.011). The optimal target was estimated at 90 mgh/L (78-101 mgh/L), and was independent of any of the investigated patient characteristics. An AUC below the target increased the risk of graft failure and relapse (relative risk 1.75, P = 0.004), while transplant-related mortality was more pronounced when the AUC was too high (relative risk 2.99, P <0.0011. CONCLUSION This is the largest study on the relationship between busulfan and clinical outcomes in children undergoing alloHCT. Our results strongly advocate the use of therapeutic drug monitoring of busulfan, using 90 mg-h/L (78-101 mg h/L) as a target

Association between the magnitude of intravenous busulfan exposure and development of hepatic veno-occlusive disease in children and young adults undergoing myeloablative allogeneic hematopoietic cell transplantation

BACKGROUND Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight in the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. OBJECTIVE The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen prior to allogeneic HCT. STUDY DESIGN In this observational study we included all patients who received an allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using non-linear mixed effect modelling and expressed as the maximal concentration (Cmax; day 1 and day 1-4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. RESULTS A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier, therefore, we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg*h/L) was associated with increased VOD/SOS risk (12.6% vs. 4.7%; odds ratio (OR) = 2.95, 95% CI 1.13-7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg*h/L) did not further increase the risk of VOD/SOS (15.4% vs. 15.2%; OR = 1.03, 95% CI 0.61-1.75). CONCLUSION The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150514/1/cpt1211.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150514/2/cpt1211_am.pd

Busulfan target exposure attainment in children undergoing allogeneic hematopoietic cell transplantation: a single day versus a multiday therapeutic drug monitoring regimen

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all children receiving busulfan-based allogeneic hematopoietic cell transplantation. Primary outcome was the percentage of patients achieving busulfan target attainment in both TDM regimens. Secondary outcomes were the variance in busulfan exposure and day-4 clearance (Clday4) estimates between both TDM regimens and dosing day 1 and 2. In regimen d1, 84.3% (n = 91/108) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 90.9% was found (n = 30/33, not-significant). Variance of Clday4 estimate based on busulfan day 2 concentrations was significantly smaller than the variance of Clday4 estimates based on day 1 concentrations (p < 0.001). Therefore, day 1-guided TDM (pharmacometric model-based) of busulfan may be sufficient for attaining optimal target exposure, provided that subsequent TDM is carried out if required. However, performing TDM on subsequent days may be beneficial, as measurements on day 2 seemed to reduce the variance in the estimated clearance as compared to day 1 sampling

Quantitative Characterization of CD8+ T Cell Clustering and Spatial Heterogeneity in Solid Tumors

Quantitative characterization of the tumor microenvironment, including its immuno-architecture, is important for developing quantitative diagnostic and predictive biomarkers, matching patients to the most appropriate treatments for precision medicine, and for providing quantitative data for building systems biology computational models able to predict tumor dynamics in the context of immune checkpoint blockade therapies. The intra- and inter-tumoral spatial heterogeneities are potentially key to the understanding of the dose-response relationships, but they also bring challenges to properly parameterizing and validating such models. In this study, we developed a workflow to detect CD8+ T cells from whole slide imaging data, and quantify the spatial heterogeneity using multiple metrics by applying spatial point pattern analysis and morphometric analysis. The results indicate a higher intra-tumoral heterogeneity compared with the heterogeneity across patients. By comparing the baseline metrics with PD-1 blockade treatment outcome, our results indicate that the number of high-density T cell clusters of both circular and elongated shapes are higher in patients who responded to the treatment. This methodology can be applied to quantitatively characterize the tumor microenvironment, including immuno-architecture, and its heterogeneity for different cancer types

Population pharmacokinetics of dimethylacetamide in children during standard and once-daily IV busulfan administration

Purpose: N,N-dimethylacetamide (DMA) is administered to children during high-dose chemotherapy as a solubilizer with the intravenous formulation of busulfan (Busilvex®). DMA has shown liver toxicity in rats. However, little is known regarding its pharmacokinetics (PK) in humans. The aim of this analysis was to compare the PK of DMA after a once-daily dose of Busilvex® with the standard scheme consisting of 3-4 administrations per day in children. Methods: Out of 42 children, aged 0.1-18.9 years, receiving Busilvex®, 18 children received the first dose as a loading dose, giving a double dose of 1.4-2.0 mg/kg over a 4 h infusion followed by 15 doses of 0.7-1.0 mg/kg as 2 h infusions every 6 h. The other 24 children received Busilvex® as 3 h infusions once-daily for 4 consecutive days with a targeted busulfan AUC of 4,263 μM*min. Using NONMEM™ plasma, concentration-time data were analyzed. Assuming an increase in clearance overtime as found in our previous investigation, separate time factors for the two different dosing schedules included in the dataset were tested. Results: A one-compartment model with clearance increasing over time described the DMA kinetics sufficiently. Peak plasma concentrations of DMA, up to 3.09 mmoL/L (median 0.75 mmoL/L) for the current licensed dose regimen and up to 8.77 mmoL/L (median 3 mmoL/L) for the once-daily application, were observed. The examined increase in clearance was found to be 58 mL/h/kg and 6.1 mL/h/kg per day for the current licensed and the once-daily dose regimen, respectively. Conclusion: N,N-dimethylacetamide as solvent of lipophilic drugs such as busulfan has a linear PK in children of all ages using a dose split into one or four administrations per day. The rapid clearance with different dosing in patients of different body weights indicates that it is safe to use DMA in children in both a once and four times daily regimen