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

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 -3and/or -2. An ATG dosing cutoff of 450mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450mg, and 25 (8%) received a total dose >450mg. 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 >450mg or ≤450mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3years post-HCT, for patients who received a total dose of ATG >450mg or ≤450mg, 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 >450mg 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.