Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial

Abstract

Treosulfan is given off-label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan-fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two-compartment model. During follow-up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC_(0-∞) ) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23-1.74), and the hazard ratio for low engraftment was 0.61 (0.36-1.04). A cumulative AUC_(0-∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC_(0-∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease.

Figure 1

Visual predictive check of the final treosulfan pharmacokinetic model stratified for first and third doses. Shaded areas are the 95% confidence intervals of the 2.5th, 50th, and 97.5th percentiles of the model simulated data; lines are the corresponding percentiles of the raw data.

Figure 2

Short‐term toxicity National Cancer Institute (NCI) grade in the main study vs. cumulative area under the curve from zero to infinity (AUC_(0‐∞)). Significance according to the Kruskal–Wallis test by rank shown in brackets.

Figure 3

Left side: Pharmacodynamic model fit of the quadratic expression describing the change in probability of success (vertical axis) with increasing cumulative area under the curve from zero to infinity (AUC_(0‐∞)) (horizontal axis). Black line and associated shaded area is the model fit and 95% confidence interval, open circles are AUC_(0‐∞) for patients with successful outcomes; crosses are for patients with ≤ 20% engraftment, triangles are for patients with < 5% engraftment, and black points are patients who died. Vertical dashed line gives AUC_(0‐∞) at which probability of success is maximized, vertical shaded area gives AUC_(0‐∞) region covering 80% probability of success. Right side: Kaplan–Meier curve for 12‐month overall survival in patients above and below the upper success probability AUC_(0‐∞) cutoff.

Figure 4

Simulated comparison of dosing used in our study against dosing proposed by Medac on cumulative area under the curve from zero to infinity (AUC_(0‐∞)) with age. The lower two plots give target attainment if doses were based on the covariates in the pharmacokinetic model (either age and weight, or age, weight, and creatinine). Dashed horizontal lines give the upper and lower cumulative AUC_(0‐∞) targets with overall probability of target attainment printed on each plot.