Individualized Dosing of Anti-Thymocyte Globulin Led to Reduced CMV/EBV Reactivation and Superior Overall Survival in Adult Unmanipulated Haploidentical Peripheral Blood Stem Cell Transplantation: A Prospective Phase II Study

Objective: Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation for its efficacy of promoting engraftment and reduction of GVHD. However, CMV/EBV reactivation remained unsolved and the optimal using of ATG is not clear. Previous studies on ATG dose investigated various fixed doses aiming to maximize its efficacy and minimize its fatal adverse effects. In our previous study, an optimal individualized dose model was established with monitoring ATG concentrations. This model was proved in its original group of patients for the benefits on outcomes of transplantation. The current study aims to prove this individualized dose model in a single arm study by prospective intervention of ATG dose into the optimal range. The safety and efficacy of individualized ATG dosing based on ATG concentration monitoring in haplo-PBSCT patients will be evaluated.

Methods: Our previous ATG monitoring study showed that CMV/EBV reactivation could be reduced up to 20% without increment of acute GVHD or damage on overall survival in patients with the active ATG total area under the concentration-time curve (AUC) between 140-148.5 UE/mL/day. Considering 10% cases lost to follow-up, the number of cases needed in this prospective study is 66 (α = 5%, β = 20%). Sixty-three recipients with malignant hematologic diseases for unmanipulated haploidentical peripheral blood hematopoietic stem cell transplantation (haplo-PBSCT) were enrolled. The concentration of active ATG was examined by flow-cytometry. The individualized doses of ATG at -3d and -2d was administered according the concentration of active ATG detected on -5d and -4d, aiming the total active ATG AUC falling into the optimal range. The primary study endpoints were CMV/EBV reactivation at +180d. The secondary endpoints included engraftment at +28d, aGVHD, disease recurrence, non-relapse mortality, disease-free survival, and overall survival. A total of 102 patients who received haplo-PBSCT during the same period comprised historic control. This study was registered at https://clinicaltrials.gov/ (NCT04778618).

Results: Sixty-three subjects with a median age of 34 (14-65) years were enrolled in this study from December 1, 2020, to January 14, 2022 and followed up to July 14, 2022. The median follow-up was 414 (181-596) days. The 180d CI of CMV reactivation in the individualized dose group was 36.7%, which was significantly lower than that in the historic control group (70.8%, p < 0.001). The 180d CI of EBV reactivation in the individualized dose group was also significantly lower than in the historical control group (58.7% vs 76.0%, p = 0.024). No difference was found for incidence of acute GVHD grade II-IV or III-IV, relapse or NRM between the two groups. The 1-yr DFS in the individualized dose group and historic control group were 80.1% and 67.6%, respectively (p = 0.064). The 1-yr OS in the individualized dose group was significantly higher than that in control group (90.2% vs 73.5%, p = 0.033). It was found that CD4+ T-cell reconstruction on day 100 in the individualized dose group was superior to that in controls (76.8% vs 54.1%, p = 0.040).

Conclusion: Individualized dosing of ATG based on ATG concentration monitoring can effectively reduce reactivation of CMV/EBV after haplo-PBSCT, lead to superior overall survival without increment of GVHD or relapse. The advantage of individualized dosage of ATG on transplantation outcomes may be associated with its accelerated immune reconstitution.

No relevant conflicts of interest to declare.