Rabbit Anti-Thymocyte Globulin (ATG) Exposure after Ex Vivo T-Cell Depleted Hematopoietic Cell Transplantation Is Highly Variable and Impacts Immune Reconstitution in Pediatric and Young Adult Patients

Abstract

<h3>Background</h3> Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host-disease and graft failure. Its main and unpredictable toxicity includes poor immune reconstitution (IR) associated with higher mortality: patients who early reconstitute CD4+ have lower non-relapse mortality (NRM) and higher survival. Recently, a population pharmacokinetic (PK) pharmacodynamic rATG model described the optimal ATG exposure in various T-replete HCT settings. No data is however available in EX VIVO T-Cell Depleted (TCD) HCT. The goal of this study is to determine the optimal exposure of rATG in a pediatric and young adult patient EX VIVO TCD HCT setting, allowing early IR. <h3>Methods</h3> Pediatric and young adult patients receiving their first allogeneic EX VIVO TCD HCT at Memorial Sloan Kettering Cancer Center (2008–2018) were included. No restrictions were applied in terms of donor source, indication, conditioning, and age. Only patients receiving rATG (alone) or no ATG were included in analyses. We estimated exposure of rATG, before, after and total as area under the curve; (AUC) (mg*d/L) for all patients using an established PK model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+ IR,defined as CD4+ levels >50/uL at two consecutive measures within 100 days, overall survival (OS), and NRM. We evaluated the association between ATG exposures and IR using a smoothed exposure to define optimal ATG exposure after HCT.Cox proportional hazard models, and multi-state competing risk models were used for analyses. <h3>Results</h3> 223 underwent a TCD HCT. 186 were included in the analysis as they received rATG (n=165) or no ATG (n=21).120(65%) had malignant and 66 (35%) had non-malignant indications for HCT. Median age was 10.5 (0.2–44) years. For those who received rATG, median rATG exposure after HCT was 34.2(range 0.622-104). A lower post AUC was associated with higher probability of IR (p<0.0001:Fig 1), increased OS(p=0.01), and lower NRM (p=0.01). The threshold for better IR and outcomes was found to be <20mg*d/L. Probability of CD4+ IR varied depending on the ATG exposure; No ATG vs.<20 vs. >20 (p<0.0001:Fig 2). There was a difference in NRM according to the ATG exposure;<20 vs. >20 (p=0.03:Fig 3), and in NRM according CD4 IR at day 100 (IR:CI 4+/- 4% vs. No IR; CI 30+/-10%;p <0.0001). <h3>Conclusions</h3> In patients who received EX VIVO TCD graft, rATG plays crucial role in probability of CD4+ IR. Patients who had rATG exposure <20 mg*d/L had highest IR, higher OS and lower NRM. These results emphasize the importance of individualizing ATG dosing to target to a low ATG exposure after HCT to improve early CD4+ reconstitution, decrease NRM, and increase survival chances.