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Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation.

Authors
  • Scordo, Michael1
  • Bhatt, Valkal2
  • Hilden, Patrick3
  • Smith, Melody4
  • Thoren, Katie5
  • Cho, Christina4
  • Shah, Gunjan L4
  • Maloy, Molly A6
  • Papadopoulos, Esperanza B4
  • Jakubowski, Ann A4
  • Avecilla, Scott T5
  • O'Reilly, Richard J7
  • Castro-Malaspina, Hugo4
  • Tamari, Roni4
  • Shaffer, Brian C4
  • Boelens, Jaap J7
  • Perales, Miguel-Angel4
  • Giralt, Sergio A4
  • 1 Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York. Electronic address: [email protected]
  • 2 Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 3 Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 4 Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.
  • 5 Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 6 Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7 Pediatric Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Pediatrics, Weill Cornell Medical College, New York, New York.
Type
Published Article
Journal
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Publication Date
Aug 01, 2019
Volume
25
Issue
8
Pages
1526–1535
Identifiers
DOI: 10.1016/j.bbmt.2019.02.021
PMID: 30831208
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG. Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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