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.

Treosulfan–fludarabine–thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies

“…Unlike previous reports [22][23][24][25], we observed a rather limited variability in interindividual PKs of treosulfan. The BSA-banded dose calculation applied in this trial achieved equivalent treosulfan exposure (AUC, C max ) in all dose groups.…”

“…Furthermore, several reports have been published that show an indication for treosulfan-based conditioning in children undergoing alloHSCT for nonmalignant and malignant disorders [12][13][14][15][16][17][18][19][20][21]. In addition, pharmacokinetic (PK) investigations on treosulfan in children have been conducted in order to derive dose recommendations for all pediatric age groups [22][23][24][25]. We therefore, prospectively evaluated treosulfan/fludarabine conditioning in pediatric patients with hematological malignancies during this extended clinical phase II trial.…”

Modelling of neutrophil dynamics in children receiving busulfan or treosulfan for haematopoietic stem cell transplant conditioning

“…individualisation based on therapeutic drug monitoring (TDM) is feasible [9][10][11][12]. This fact is also applied to busulfan, for which TDM is currently done in the clinical setting [6].…”

“…Therefore, personalizing busulfan doses to a target AUC is thought to improve the clinical outcomes [6,7]. Treosulfan is considered to have a wider therapeutic index which has made it an attractive candidate for the use in conditioning regimens as an alternative to busulfan [8], but recent evidence suggests treosulfan dose individualisation may also be required [9,10]. A relatively high inter-individual variability, but low interoccasion variability has been reported for treosulfan pharmacokinetics (PK) so…”

Allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

“…35 Most experience to date has been with fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel), or fludarabine/ treosulfan (Flu/Treo)-based reduced intensity conditioning incorporating serotherapy (alemtuzumab or ATG) for in vivo T-cell depletion. Recent improvements in conditioning regimens for nonmalignant diseases such as PID have primarily come from pediatric centers and include the introduction of treosulfan, 36,37 the use of targeted busulfan, 24,38 and personalized serotherapy dosing. 34,35,39 The use of PTCy or αβTCR depletion to remove alloreactive T cells has facilitated the use of haploidentical donors in older recipients with hematologic malignancies, without prohibitive risks of GVHD and/or graft rejection.…”