Tandem Meetings 2026 | Using PK modeling to determine the optimal fludarabine exposure following alloSCT with PTCy

So in this study, we examined the specific conditioning platform that is used currently in our allogeneic transplant patients, which incorporate a drug called fludarabine. It’s pretty commonly used in our conditioning platforms, but particularly in the context of post-transplant cyclophosphamide as a GVHD prophylaxis regimen, which is also very commonly used now. The idea was, or the hypothesis of this study is to determine a specific fludarabine exposure that could be associated with improved outcomes and maybe decrease toxicity post-transplant. We used a pharmacokinetic model that’s been published in the past by Langenhorst et al., in which they measured actual fludarabine drug level in the blood and then they performed mixed modeling and established the body weight and the GFR, not the body surface area, which is what we dose our fludarabine with now, is basically what determined the fludarabine AUC or the fludarabine exposure. 

We, in our large cohort of patients of more than 400 patients, we demonstrated that the fludarabine exposure when dosed by BSA using this pharmacokinetic model, population PK model, it demonstrates about five to six folds distribution, AUC distribution, suggesting that this is a very wide distribution, it’s not really consistent dosing. We also demonstrate that the GFR and the kidney function and the body weight is basically more important in determining the fludarabine exposure than body surface area. 

We performed a maximal selected logistic regression, which is a statistical method that tests or separates two groups of patients by best survival or best non-relapse mortality using maximally selected logistic regressions and establish a cut point or exposure cut point that we can determine after which the survival decreases or the NRM increases. And in our course, we demonstrated that the AUC of about 25 or about 23 to 25 is maybe associated with an improved survival. And when we examined patients who, this happened in about one third of the patients, who actually have a higher fludarabine exposure, meaning that they have a fludarabine exposure more than 28 or more than 25. And when we examine the survival outcomes based on the fludarabine exposure, we showed that patients who achieved fludarabine exposure of less than 28, that was associated with a significant improved overall survival by the first year. And this was mostly driven by an increase in non-relapse mortality. And particularly, we characterized the non-relapse mortality by causes of death. And particularly, we observed an increase in infection in patients who were exposed or overexposed to fludarabine during their transplant. 

I think what this study suggests is that the optimum dosing of fludarabine has not been reached yet. And there is an opportunity to use a population, an informed population PK model to inform the fludarabine exposure, fludarabine dosing in our patients and reaching to an optimal exposure in our patients, which will lead to improved survival and decrease in toxicity of fludarabine that could eventually result in a decrease in non-relapse mortality.

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