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

•Nonoptimal rATG exposure increases nonrelapse mortality, relapse, and chronic GVHD and worsens DFS in pediatric AB-TCD haploidentical HCT.•Targeting rATG dosing to a predicted exposure may improve immune reconstitution and preserve graft-versus-leukemia. [Display omitted] We hypothesized that the i...

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Published in:Blood advances 2024-12, Vol.8 (23), p.6003-6014
Main Authors: Dvorak, Christopher C., Long-Boyle, Janel R., Holbrook-Brown, Lucia, Abdel-Azim, Hisham, Bertaina, Alice, Vatsayan, Anant, Talano, Julie-An, Bunin, Nancy, Anderson, Eric, Flower, Allyson, Lalefar, Nahal, Higham, Christine S., Kapoor, Neena, Klein, Orly, Odinakachukwu, Maryanne C., Cho, Soohee, Jacobsohn, David A., Collier, Willem, Pulsipher, Michael A.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Animals
Antigens, CD19 - immunology
Antilymphocyte Serum - therapeutic use
Child
Child, Preschool
Female
Hematologic Neoplasms - therapy
Hematopoietic Stem Cell Transplantation - methods
Humans
Infant
Male
Rabbits
Receptors, Antigen, T-Cell, alpha-beta
Transplantation
Transplantation, Haploidentical
Treatment Outcome
Young Adult
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Summary:•Nonoptimal rATG exposure increases nonrelapse mortality, relapse, and chronic GVHD and worsens DFS in pediatric AB-TCD haploidentical HCT.•Targeting rATG dosing to a predicted exposure may improve immune reconstitution and preserve graft-versus-leukemia. [Display omitted] 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 (
ISSN:2473-9529
2473-9537
2473-9537
DOI:10.1182/bloodadvances.2024012670