Antithymocyte globulin exposure in CD34+ T-cell depleted allogeneic hematopoietic cell transplantation.

Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+IR) leading to higher mortality. In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+ ≥50/µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to define an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used. 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0-101). Low post-HCT AUC (<30AU*d/L) was associated with lower risk of NRM (p<0.01) and higher probability of achieving CD4+IR (p<0.001). Patients who attained CD4+IR had a 7-fold lower 5-year NRM (p<0.0001). Probability of achieving CD4+IR was 2.5-fold and 3-fold higher in the <30AU*d/L-group, compared to 30-55AU*d/L and ≥55AU*d/L-groups, respectively. In multivariable analyses, post-HCT rATG-exposure ≥55AU*d/L was associated with an increased risk of NRM (HR 3.42,95%CI 1.26-9.30). In the malignancy subgroup (n=515) a 10-fold and 7-fold increased NRM, was observed in the >55AU*d/L and 30-55AU*d/L groups, respectively, compared to <30AU*d/L group. Post-HCT rATG exposure ≥55AU*d/L was associated with higher risk of acute GVHD (HR 2.28,95%CI 1.01-5.16). High post-HCT rATG-exposure is associated with higher NRM secondary to poor CD4+IR after TCD-HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.