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.
In 203 pediatric patients undergoing alpha-beta T-cell/CD19-depleted haploidentical transplantation, retrospectively predicted low thiotepa/TEPA exposure was associated with more graft rejection, while high predicted exposure was associated with more TA-TMA, non-relapse mortality, and lower overall survival.
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In 203 pediatric patients undergoing alpha-beta T-cell/CD19-depleted haploidentical transplantation, retrospectively predicted low thiotepa/TEPA exposure was associated with more graft rejection, while high predicted exposure was associated with more TA-TMA, non-relapse mortality, and lower overall survival.
Research significance
The observational evidence supports an exposure–outcome relationship but not a dosing intervention; it suggests, as a testable inference, that prospectively validated model-informed thiotepa dosing toward an intermediate cAUCtotal near 45 mg·hr/L could reduce rejection from underexposure and toxicity or mortality from overexposure.
Source abstract
BACKGROUND: 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. STUDY DESIGN: 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 (cAUCtotal) 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. RESULTS: 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 cAUCtotal 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 cAUCtotal using fitted "b-splines" under Cox regression with complexity limited to control over-fitting. We identified the cAUCtotal 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 cAUCtotal 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. CONCLUSIONS: For pediatric patients undergoing AB-TCD haploidentical HCT for treatment of hematologic malignancies, we found predicted cAUCtotal 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 cAUCtotal 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.