High Predicted Thiotepa Exposure is Associated with Increased Risk of Thrombotic Microangiopathy and Non-Relapse Mortality in Pediatric Patients Undergoing Alpha-Beta T-Cell Depleted Haploidentical Transplantation.

Authors

Christopher C Dvorak, Willem Collier, Soohee Cho, Lucia Holbrook-Brown, Candelaria Deimundo Roura, Julie-An Talano, Anant Vatsayan, Nahal Lalefar, Eric Anderson, Timothy Olson, Christine S Higham, Paibel Aguayo-Hiraldo, Neena Kapoor, Julie M Waldhart, Maryanne C Odinakachukwu, David A Jacobsohn, Ron J Keizer, Jordan Brooks, Michael A Pulsipher, Janel R Long-Boyle

Published in

Transplantation and cellular therapy. Aug 19, 2026. Epub Aug 19, 2026.

Abstract

Thiotepa is commonly included in combination with other agents to prevent rejection and relapse following alpha-beta-T-cell/CD19-depleted (AB-TCD) haploidentical hematopoietic cell transplant (HCT) for pediatric patients with hematologic malignancies. A standard regimen of 5 mg/kg for two doses was developed in adults and has been extrapolated to the pediatric population OBJECTIVES: We hypothesized that outlier (low or high) thiotepa exposures would be associated with inferior event-free- (EFS) and overall- (OS) survival due to increased rejection and non-relapse mortality (NRM) in pediatric patients undergoing AB-TCD haploidentical HCT. We also hypothesized that there would be an increased incidence of transplant-associated thrombotic microangiopathy (TA-TMA) in patients with high thiotepa exposure.
Utilizing a validated pharmacokinetic model, we retrospectively predicted total exposure of thiotepa and its active metabolite TEPA combined as a cumulative area under the curve (cAUC_total) in 203 patients with hematologic malignancy undergoing AB-TCD haploidentical HCT at nine centers on two prospective trials between 2015 and 2025. No actual PK samples were available.
The median thiotepa dose was 5.0 mg/kg (range, 3.4-5.3) administered in two doses 12 hours apart resulting in a median predicted cAUC_total of 50.3 mg*hr/L (range, 36.8-64.7). We first modeled time-to-event (rejection, relapse, or death) as a function of thiotepa cAUC_total using fitted "b-splines" under Cox regression with complexity limited to control over-fitting. We identified the cAUC_total level that maximized the 3-year event-free survival (EFS) probability as approximately 45 mg*hr/L (95% CI, 43-52). We next established conservative cut-points to identify an optimal range of exposure to account for residual variability in the PK model, classifying patients as having low (<42 mg*hr/L; n=21), medium (42-50 mg*hr/L; n=78), or high (>50 mg*hr/L; n=104) exposure. Low thiotepa exposure was significantly associated with a higher 1-year cumulative incidence of rejection (23.8% vs. 4.5% for ≥42 mg*hr/L; p<0.001) and high thiotepa exposure was significantly associated with a higher 3-year NRM (20% vs. 6.8% for <50 mg*hr/L; p=0.007). Furthermore, a thiotepa cAUC_total of ≥53 mg*hr/L was associated with development of TA-TMA; the 1-year cumulative incidence was significantly higher in those with thiotepa exposure ≥53 mg*hr/L (25.6% vs. 7.5% for <53 mg*hr/L; p<0.001). No statistically significant associations were found between thiotepa exposure and Day 100 sinusoidal obstruction syndrome (p=0.337), 3-year relapse (p=0.449), or 3-year EFS (p=0.212). However, 3-year OS was significantly lower in those with high thiotepa exposure (68.9% vs. 85.8% for <50 mg*hr/L; p=0.007). We then sought to evaluate whether key thiotepa exposure-outcome associations were explained by potential confounders (patient / donor age, anti-thymocyte globulin exposure, etc.). To contrast outcomes across groups defined by high relative to medium/low exposure, propensity scores were used to re-weight the dataset to balance confounders across groups. The propensity score weighted hazard ratio (HR) for NRM was 3.19 (high relative to medium/low exposure; 95% CI, 1.14-19.89). The data did not support propensity score reweighting to contrast low relative to medium/high thiotepa exposure, and we instead used adjusted Cox regression. The adjusted HR for rejection was 6.81 (low relative to medium/high exposure 95% CI, 1.55-29.83). The associations between thiotepa exposure and key outcomes such as NRM and rejection did not appear to be explained by measured confounders.
For pediatric patients undergoing AB-TCD haploidentical HCT for treatment of hematologic malignancies, we found predicted cAUC_total of thiotepa was associated with increased risk of rejection (low exposure), TA-TMA and NRM (high exposure), as well as overall mortality (high exposure). The identified optimal cAUC_total of 45 mg*hr/L was well below the median of 50.3, suggesting that the conventional regimen of 5 mg/kg x 2 doses may be supra-therapeutic for many patients. Model-based dosing of thiotepa to achieve optimal exposure may lower toxicity and improve outcomes and should be tested in prospective trials.

PMID:
42617872
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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