Optimal Rabbit Antithymocyte Pharmacokinetics (PK) Is Associated with Improved Disease-Free Survival (DFS) in TCR-Αβ/CD19-Depleted Pediatric Haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

Rabbit antithymocyte globulin (rATG; Thymoglobulin®) is often included as part of conditioning prior to TCR-αβ/CD19-T-cell depleted (AB-TCD) haploidentical hematopoietic cell transplantation (haplo-HCT) for pediatric patients with hematologic malignancies. PK models demonstrate that weight-based dosing of rATG generally results in higher exposure pre- and post-HCT for older patients. We hypothesized that the inferior DFS noted in patients ≥10 years of age undergoing AB-TCD haploidentical HCT in our earlier manuscript (Pulsipher, Blood 2022) was due to excessive rATG exposure.We identified patients undergoing AB-TCD haplo-HCT with rATG at nine centers on two prospective trials. Exposure of rATG pre- and post-HCT was retrospectively predicted using a validated PK model for clearance accounting for weight, admission absolute lymphocyte count, and number/dose/timing of rATG relative to cell infusion (InsightRx, Inc). Quadratic regression was used to identify optimal target windows of rATG exposure related to non-relapse mortality (NRM), relapse, and DFS.Between 2015 and 2023, 163 patients underwent AB-TCD haplo-HCT for treatment of ALL (n=98), AML/MDS (n=49), or other heme malignancies (n=16), with a median age of 13 years (range 0.4-27.4). The 3-year cumulative incidence of NRM, relapse, and DFS were 14.4% (95% CI 7.9-20.9%), 23.8% (95% CI 16.2-31.4%), and 65.1% (95% CI 56.9-73.3%), respectively. We identified four quadrants of predicted pre- and post-HCT ATG exposure that associated with outcomes: Q1 (n=52) with high pre-HCT AUC (≥50 AU*day/mL) and low post-HCT (<12 AU*day/L), Q2 (n=47) with both low pre-HCT and post-HCT AUCs, Q3 (n=13) with low pre-HCT AUC and high post-HCT, and Q4 (n=51) with both high pre-HCT and post-HCT (Fig. 1). Q1 had the highest 3-year DFS: 86.5% (95% CI 76.3-96.7%), compared to Q2 (64.6%; 95% CI 49.1-80.1%), Q3 (32.9%; 95% CI 0.1-80.5%), or Q4 (48.2%; 95% CI 22.1-63.3%) (p<0.001; Fig. 2). On multivariate analysis, the only factors associated with increased hazard of 1-DFS were MRD-positivity by best available methodology (HR=3.2; 95% CI 1.3-7.6; p=0.01) and high post-HCT ATG exposure – Q3 (HR=7.0; 95% CI 2.0-25.2; p=0.003); and Q4 (HR=6.4; 95% CI 2.6-16.2; p<0.001). For patients who were MRD-negative, those with optimal rATG exposure (Q1) had a 3-year DFS of 90.6% (95% CI 80.4-99.9%) compared to 61.5% (95% CI 49.5-73.5%) for those with sub-optimal exposure (Q2-4; p=0.01; Fig. 3). For patients who were MRD-positive, those with optimal rATG exposure (Q1) had a 3-year DFS of 74.5% (95% CI 48.8-99.9%) compared to 36.7% (95% CI 17.1-56.3%) for those with sub-optimal exposure (Q2-4; p=0.01; Fig. 3).Low exposure to rATG pre- HCT and/or high exposure post-HCT is associated with inferior DFS following AB-TCD haplo-HCT for pediatric patients with hematologic malignancies. Using model-based dosing of rATG to achieve optimal exposure may improve DFS.