Comparison of Weight-Based and Lymphocyte Count-Based Dosing of Anti- Thymocyte Globulin in Matched Unrelated Donor Stem Cell Transplantation

Abstract

Introduction Graft versus host disease (GVHD) is a significant comorbidity following allogeneic stem cell transplantation. Anti-thymocyte globulin (ATG) is used to reduce the incidence and severity of GVHD, yet optimum dosing has yet to be determined. We have previously demonstrated that 2.5 mg/kg of ATG in conditioning can reduce the incidence of GVHD in unrelated donor transplants. Recent literature has suggested that weight-based dosing of ATG is not ideal and that dosing based on absolute lymphocyte count (ALC) could lead to more optimum exposure of the drug. Objectives We sought to determine if ALC at the time of transplant could impact clinical outcomes. Methods We conducted a retrospective single-center study analyzing all consecutive patients at The Ottawa Hospital (TOH) who received a matched unrelated donor stem cell transplant with ATG between 2009 and 2014. Patients received rabbit ATG (Thymoglobulin®) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1. Univariate and multivariate analysis were used to determine if any patient or transplant related factors, including weight, ALC, and total ATG dose given, impacted GVHD, relapse, or mortality. Incidence of acute and chronic GVHD were defined as GVHD requiring systemic immunosuppression at less or more than 100 days post-transplant respectively. Results One hundred and nineteen patients who underwent matched unrelated donor stem cell transplant with ATG at TOH were identified. The median age was 50 years. The most common diagnoses were AML (42.8%), ALL (10.1%) and lymphoma (10.9%). The mean weight at time of conditioning was 80.5 kg. The mean ALC on day -2 was 2.15 × 10^9/L (17.5). The mean total dose of ATG received was 201.2 mg (51.4). If patients had received ALC based dosing according to the previously published calculation (Admiraal, R et al., Lancet Haematology 2017), the mean ALC based dose would have been 1151 mg, more than five times the amount that was actually given based on weight. In this analysis, the incidence of acute and chronic GVHD was 37.0% and 20.2% respectively. In a multivariate Cox model, the total weight-based dose of ATG given to patients was not associated with GVHD (HR=1.08, 95% CI 0.96-1.2), relapse (HR=1.10, 95% CI 0.94-1.27) or mortality (HR=1.06, 95% CI 0.89-1.25). Similarly, the pre-transplant ALC was not associated with GVHD (HR=1.06, 95% CI 0.77-1.45), relapse (HR=1.01, 95% CI 0.76-1.34) or mortality (HR=1.12, 95% CI 0.86-1.47). Conclusion The standard practice of weight-based ATG dosing has recently been challenged by better understanding of the mechanism of ATG in preventing GVHD. In our single center experience with ATG doses of 2.5 mg/kg, GVHD rates are comparable to other studies with higher doses of ATG. Furthermore, ALC was not independently associated with outcomes, suggesting ALC based dosing may not be needed. Prospective comparisons of a weight based versus ALC based dosing strategy are still warranted.