Cytokines Induced by Antithymocyte Globulin in Transplantation Conditioning and Associated Infusional Side Effects

Antithymocyte globulin (ATG; Thymoglobulin) infusion may result in infusional side effects (ISEs) resembling cytokine release syndrome. This study aimed to identify cytokines associated with ISEs, factors predicting ISEs, and the impact of ISEs on hematopoietic cell transplantation (HCT) outcomes. We studied 211 allogeneic HCT recipients who received 3 infusions of ATG, on days -2, -1, and 0. The focus was on the first infusion. ISE was defined as a maximum temperature ≥38°C, maximum heart rate >125/minute, minimum systolic blood pressure <90 mmHg, or supplemental oxygen use between the start of the first infusion and the start of the second infusion. In 158 of the 211 patients, we determined the post-first infusion serum levels of 34 cytokines using Luminex and compared the levels in patients with ISEs and patients without ISEs using a signed-rank test with Bonferroni correction for multiple comparisons. In all 211 patients, we compared overall survival (OS), relapse-free survival (RFS), and moderate to severe chronic graft-versus-host disease (cGVHD)- and relapse-free survival (GRFS) between patients with ISEs and those without ISEs using Cox regression, as well as in the incidences of acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, and nonrelapse death using Fine-Gray regression. At least 1 ISE occurred in 93 patients (44%). Median levels of the following cytokines were significantly higher in the patients with ISEs: interleukin-1 receptor antagonist (IL1-RA) (30,166 pg/mL versus 6394 pg/mL; P < .001), interleukin-6 (IL-6) (188 pg/mL versus 49 pg/mL; P < .001), and interferon gamma-induced protein-10 (IP-10) (106 pg/mL versus 70 pg/mL; P = .004). Patients with ISEs and those without ISEs did not differ in terms of weight; body mass index; day -2 leukocyte, neutrophil, monocyte, or lymphocyte count; post-first infusion ATG level; or ATG area under the time-concentration curve. There were no significant between-group differences in OS (hazard ratio [HR], 0.83; P = .43), RFS (HR, 0.85; P = .38), or GRFS (HR, 1.01; P = .98). There also were no significant differences in the rates of grade II-IV aGVHD, grade III-IV aGVHD, moderate to severe cGVHD, relapse, or nonrelapse death. IL-6, IP-10, and IL1-RA appear to be involved in the pathogenesis of ISEs; however, ISEs appear to have no significant impact on HCT outcomes. © 2025 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.