Bayesian non-parametric survival regression for optimizing precision dosing of intravenous busulfan in allogeneic...

Allogeneic stem cell transplantation (allo-SCT) is now part of standard of care for acute leukemia (AL). To reduce toxicity of the pre-transplant conditioning regimen, intravenous busulfan is usually used as a preparative regimen for AL patients undergoing allo-SCT. Systemic busulfan exposure, characterized by the area under the plasma concentration versus time curve (AUC), is strongly associated with clinical outcome. An AUC that is too high is associated with severe toxicities, while an AUC that is too low carries increased risks of disease recurrence and failure to engraft. Consequently, an optimal AUC interval needs to be determined for therapeutic use. To address the possibility that busulfan pharmacokinetics and pharmacodynamics vary significantly with patient characteristics, we propose a tailored approach to determine optimal covariate-specific AUC intervals. To estimate these personalized AUC intervals, we apply a flexible Bayesian nonparametric regression model based on a dependent Dirichlet process and Gaussian process, DDP-GP. Our analyses of a dataset of 151 patients identified optimal therapeutic intervals for AUC that varied substantively with age and whether the patient was in complete remission or had active disease at transplant. Extensive simulations to evaluate the DDP-GP model in similar settings showed that its performance compares favorably to alternative methods. We provide an R package, DDPGPSurv, that implements the DDP-GP model for a broad range of survival regression analyses.