Individualized dosing of r-ATG in Allo-HSCT

Allogenic hematopoietic stem cell transplantation

Rabbit anti-thymocyte globulin (r-ATG), a potent T-lymphocyte depleting agent, is now an integral part of many allogeneic hematopoietic stem cell transplantation (Allo-HSCT) protocols due to its role in preventing graft vs host disease (GvHD), a deadly complication of Allo-HSCT. It has been postulated that the dose of r-ATG used in allo-HSCT is critical in maintaining a delicate balance between preventing GvHD and timely T-cell reconstitution.
However, the current weight-based r-ATG dosing strategies may be empiric at best. In allo-HSCT patients, it may not yield optimal patient outcomes. The challenges with weight-based r-ATG strategies include poor T-cell reconstitution, reduced graft versus leukaemia effect, and increased relapse and non-relapse mortality. Population pharmacokinetics modelling studies considered to be the gold standard for establishing drug exposure, have revealed that individualized optimal r-ATG exposure may lead to more optimal patient outcomes with r-ATG.

Association between r-ATG exposure and CD4+ immune reconstitution¹

In a retrospective analysis of 251 pediatric allo-HSCT patients, observed that chances of successful immune reconstitution were reduced with increasing r-ATG exposure measured by AUC after allo-HSCT. This analysis reported that successful immune reconstitution by day 100 leads to improved overall survival and decreased NRM relapse mortality. The investigators found that the AUC threshold = 40 AU/day/ml for substantially reduced acute and chronic GvHD.¹

Association between r-ATG exposure and the 5-year overall survival outcome²

Another study found that r-ATG exposure after allo-HSCT was the best predictor of 5-year overall survival and event-free survival in 146 patients with acute lymphoid leukaemia, acute myeloid leukaemia, and Myelodysplastic syndrome. The optimum r-ATG exposure after transplantation = 60-95 AU/day/mL. The model revealed ALC modelled dosing is better than weight-based dosing for optimal target exposure of r-ATG, especially in patients weighing over 50 kg.²

PARACHUTE study³

The PARACHUTE study, a prospective study of an individualized r-ATG dosing regimen, was where pediatric allo-HSCT patients were given an individualized dosing regimen at the time of r-ATG initiation. Results showed that 80% of the subjects met their primary endpoints within 100 days, which is 20% more than outcomes from weight-based dosing from the historical cohort. The ALC-based dosing regimen resulted in optimal r-ATG exposure in 97% of patients compared to 30-53% of patients using the weight-based dosing method.³

Other studies on weight- and ALC-based r-ATG nomogram dosing

Srinivasan A, et al. reported similar findings in a pediatric HSCT cohort in the US where approx. 18 patients received individualized r-ATG and had an overall survival rate of 88% after a median follow-up of 1.3 years.⁴
Wang H et al. conducted a single-centred prospective study and showed that an optimal total AUC range of 110 to 148.⁵ UE/mL/day was optimal for reduced virus reactivation and prevention of grade II to IV and grade III to IV acute GvHD.⁵

Finally, dose individualization did not result in a rise in GvHD or graft failure. With an increasing body of data supporting individualized r-ATG dosing for optimal allo-HSCT outcomes, a randomized phase 3 trial with the endpoint of overall survival would provide a more definitive judgment on the added value of individualized r-ATG dosing.

References

Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. The Lancet Haematology. 2015;2(5):e194–203.
Admiraal R, Nierkens S, de Witte MA, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a retrospective, pharmacodynamic cohort analysis. The Lancet Haematology. 2017;4(4):e183–91.
Admiraal R, Nierkens S, Bierings MB, et al. Individualised dosing of anti-thymocyte globulin in paediatric unrelated allogeneic haematopoietic stem-cell transplantation (PARACHUTE): a single-arm, phase 2 clinical trial. The Lancet Haematology. 2022;9(2):e111–20.
Srinivasan A, Shah RK, Anderson M, et al. Retrospective Review of Use of Individualized Dosing of Rabbit Anti-Thymocyte Globulin on Outcomes in Pediatric Post Allogeneic Stem Cell Transplant Patients: A Single Center Experience. Biology of Blood and Marrow Transplantation. 2019;25(3):S196–7.
Wang H, Zhao Y, Fang S, et al. Optimal active anti-thymocyte globulin exposure associated with minimum risk of virus reactivation and comparable acute graft-Versus-Host disease under adult myeloablative haploidentical peripheral blood stem cell transplantation. Transplantation and Cellular Therapy. 2022;28(6):332–e1.