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Clinical Trial
. 2024 Dec 10;8(23):6003-6014.
doi: 10.1182/bloodadvances.2024012670.

Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19-depleted pediatric haploidentical HCT for hematologic malignancy

Christopher C Dvorak  1 , Janel R Long-Boyle  1 , Lucia Holbrook-Brown  2 , Hisham Abdel-Azim  3 , Alice Bertaina  4 , Anant Vatsayan  5 , Julie-An Talano  6 , Nancy Bunin  7 , Eric Anderson  8 , Allyson Flower  9 , Nahal Lalefar  10 , Christine S Higham  1 , Neena Kapoor  11 , Orly Klein  4 , Maryanne C Odinakachukwu  5 , Soohee Cho  2 , David A Jacobsohn  5 , Willem Collier  12 , Michael A Pulsipher  2
Affiliations
Clinical Trial

Effect of rabbit ATG PK on outcomes after TCR-αβ/CD19-depleted pediatric haploidentical HCT for hematologic malignancy

Christopher C Dvorak et al. Blood Adv. .

Abstract

We hypothesized that the inferior disease-free survival (DFS) seen in older patients who underwent αβ-T-cell/CD19-depleted (AB-TCD) haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies is caused by excessive exposure to rabbit antithymocyte globulin (rATG; Thymoglobulin). Between 2015 and 2023, 163 patients with a median age of 13 years (range, 0.4-27.4) underwent AB-TCD haploidentical HCT for the treatment of acute lymphoblastic leukemia (n = 98), acute myeloid leukemia/myelodysplastic syndrome (n = 49), or other malignancies (n = 16) at 9 centers in 2 prospective trials. Exposures to rATG before and after HCT were predicted using a validated pharmacokinetic model. Receiver operating characteristic curves were used to identify the optimal target windows for rATG exposure in terms of outcomes. We identified 4 quadrants of rATG exposure, namely quadrant 1 (n = 52) with a high pre-HCT area under curve (AUC; ≥50 arbitrary units [AU] per day per milliliter) and a low post-HCT AUC (<12 AU per day per liter); quadrant 2 (n = 47) with a low pre- and post-HCT AUC; quadrant 3 (n = 13) with a low pre-HCT and a high post-HCT AUC; and quadrant 4 (n = 51) with a high pre- and post-HCT AUC. Quadrant 1 had a 3-year DFS of 86.5%, quadrant 2 had a DFS of 64.6%, quadrant 3 had a DFS of 32.9%, and for quadrant 4 it was 48.2%. An adjusted regression analysis demonstrated additional factors that were associated with an increased hazard for worse DFS, namely minimal residual disease (MRD) positivity and cytomegalovirus (CMV) R+/D- serostatus. Nonoptimal rATG exposure exhibited the strongest effect in unadjusted and adjusted (MRD status or CMV serostatus) analyses. High exposure to rATG after HCT was associated with inferior DFS following AB-TCD haploidentical HCT for pediatric patients with hematologic malignancies. Model-based dosing of rATG to achieve optimal exposure may improve DFS. These trials were registered at www.ClinicalTrials.gov as #NCT02646839 and #NCT04337515.

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Conflict of interest statement

Conflict-of-interest disclosure: C.C.D. reports being a consultant for and serving on advisory boards of Jazz Pharmaceuticals, Alexion Inc, and AlloVir. J-A.T. reports receiving study support from Miltenyi. H.A.-A. reports serving on the advisory boards for Adaptive, Vertex, and Johnson & Johnson, and receiving study support from Adaptive. M.A.P. reports serving on advisory boards for Novartis, Equillium, bluebird bio, Medexus, Pfizer, GentiBio, and Vertex; engaging in educational activities for Novartis; and receiving study support from Miltenyi (not for this trial) and Adaptive. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Identification of predicted rATG pre- and post-HCT exposure quadrants.P values were determined using the 2-sided log-rank test.
Figure 2.
Figure 2.
DFS. DFS as predicted by rATG (A) exposure quadrants, (B) optimal exposure, and (C) optimal exposure and age. P values were determined using the 2-sided log-rank test.
Figure 3.
Figure 3.
Chronic GVHD-free relapse-free survival by predicted rATG optimal exposure.P value was determined using the 2-sided log-rank test.
Figure 4.
Figure 4.
Predicted rATG optimal exposure and MRD status effects on cumulative incidence of relapse (A) and DFS (B).P values were determined using the 2-sided log-rank test.
See this image and copyright information in PMC

References

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