Association between busulfan exposure and survival in patients undergoing a CD34+ selected stem cell transplantation.

Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoetic cell transplantation (allo-HCT). A myeloablative conditioning regimen including busulfan is commonly used in patients undergoing a T cell depleted (TCD), allo-HCT, but data on the optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target a area-under-curve (AUC) exposure of 55-66mg*h/L over 3 days using an non-compartmental analysis (NCA) model (Phoenix WinNonLin, Certara USA, Princeton, NJ). We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (InsightRX, Inc, 2021) and correlated it with outcomes. To define an optimal exposure, univariable models were performed with P splines wherein hazard ratio plots were drawn and thresholds were found graphically as the points where the confidence interval crossed 1. Cox proportional hazard models and competing risk models were used for analyses. 176 patients were included with a median age 59 years (2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg*h/L (46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg*h/L). 5-yr overall survival with busulfan exposure ≥59.5 vs. <59.5 mg*h/L was 67% (95% CI 59-76%) vs. 40% (95% CI 53%-68%), respectively, p=0.02, and this association remained in a multivariate -analyses (HR 0.5, 95% 0.29, 0.88, p=0.02). In patients undergoing a TCD allo-HCT, busulfan exposure is significantly associated with overall survival. Using a published popPK model to optimize exposure may significantly improve OS.