Association patient characteristics on fludarabine exposure in patients with hematopoietic allogenic stem cell transplantation

Abstract

ABSTRACT Background Hematopoietic allogenic stem cell transplantation provides a potential curative treatment for patients suffering from malignant or non-malignant diseases. Conditioning by fludarabine and busulfan forms an essential step during this procedure. Fludarabine is currently dosed based on body surface area. A retrospective study from Langenhorst showed association of fludarabine exposure with event outcomes in patients after allogenic SCT. In contrast, a RCT TARGET study did not find significant differences in between classical and TDM dosing of fludarabine. It was partially hypothesized that this discrepancy was related towards applied inclusion criteria of TARGET study. Aim This study evaluated whether patient characteristics applied as inclusion criteria of TARGET study explain the difference in between retrospective study of Langenhorst and TARGET study. Therefore, main aim of this research was to study the association of TARGET inclusion criteria towards fludarabine AUC attainment. Method A retrospective study was conducted whereby criteria from RCT TARGET study were applied on the patient population from the study of Langenhorst. Patients complied to all criteria were placed in cohort named “included” and who did not in “excluded”. These cohorts were compared on the following outcomes: Primary outcome: Fludarabine AUC attainment Secondary outcome: 2-year Event Free Survival Probability after Allogenic stem cell transplantation. Furthermore, a multivariate logistic and stepwise regression analysis was performed to find patient characteristics that were associated towards target attainment. Main results For AUC attainment it was found that rate of underexposure in between included (n=93) and excluded (n=99) was significantly different. For optimal and above optimal exposure difference was insignificant. For event-free-survival, overexposure showed a significantly increased event-risk in comparison to optimal exposure (HR 3.355) within excluded cohort. Within included cohort this was insignificant. Suboptimal exposure risk on events within included and excluded was insignificant towards optimal exposure within both cohorts. Multivariate logistics regression analysis showed for children, multiple myeloma and auto-immune disease and moderate kidney function to be significantly associated towards target attainment. In addition, from stepwise regression analysis underlying disease, age category (kids or adults) and renal function were included as predictors for target attainment. Discussion and conclusion This study showed association of patient characteristics applied as criteria from TARGET study on fludarabine AUC attainment. Comparison of both cohorts based on event-free-survival remains however explorative. Further follow-up research including sufficient patients for all characteristics should be considered to evaluate the effect of characteristics on event outcomes.