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

Christopher C. Dvorak, Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, Department of Clinical Pharmacy, University of California San Francisco Benioff Children's Hospitals, San Francisco, CA.
Janel R. Long-Boyle, Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, Department of Clinical Pharmacy, University of California San Francisco Benioff Children's Hospitals, San Francisco, CA.
Lucia Holbrook-Brown, Division of Hematology and Oncology, Section of Transplantation Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, UT.
Hisham Abdel-Azim, Cancer Center, Children's Hospital and Medical Center, Loma Linda University School of Medicine, Loma Linda, CA.
Alice Bertaina, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
Anant Vatsayan, Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC.
Julie-An Talano, Division of Pediatric Hematology, Oncology, and Blood and Marrow Transplant, Medical College of Wisconsin, Milwaukee, WI.
Nancy Bunin, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
Eric Anderson, Division of Pediatric Hematology-Oncology, Rady Children's Hospital, University of California San Diego, San Diego, CA.
Allyson Flower, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, New York Medical College, Valhalla, NY.
Nahal Lalefar, Division of Hematology, University of California San Francisco Benioff Children's Hospitals, Oakland, CA.
Christine S. Higham, Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, Department of Clinical Pharmacy, University of California San Francisco Benioff Children's Hospitals, San Francisco, CA.
Neena Kapoor, Division of Pediatric Hematology, Oncology, and Transplantation and Cellular Therapy, University of Southern California Children's Hospital Los Angeles, Los Angeles, CA.
Orly Klein, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
Maryanne C. Odinakachukwu, Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC.
Soohee Cho, Division of Hematology and Oncology, Section of Transplantation Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, UT.
David A. Jacobsohn, Division of Blood and Marrow Transplantation, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC.
Willem Collier, Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA.
Michael A. Pulsipher, Division of Hematology and Oncology, Section of Transplantation Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at The University of Utah, Salt Lake City, UT.

Document Type

Journal Article

Publication Date

12-10-2024

Journal

Blood advances

Volume

8

Issue

23

DOI

10.1182/bloodadvances.2024012670

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.

Department

Pediatrics

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