Exposure-response analysis of alemtuzumab in pediatric allogeneic HSCT for nonmalignant diseases: the ARTIC study

Alemtuzumab (anti-CD52 antibody) is frequently prescribed to children with nonmalignant diseases undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft failure (GF) and acute graft-versus-host disease (aGVHD). The aim of this multicenter study was the characterization of alemtuzumab population pharmacokinetics to perform a novel modelbased exposure-response analysis in 53 children with nonmalignant immunological or hematological disease and a median age of 4.4 years (interquartile range [IQR], 0.8-8.7). The median cumulative alemtuzumab dose was 0.6 mg/kg (IQR, 0.6-1) administered over 2 to 7 days. A 2-compartment population pharmacokinetics model with parallel linear and nonlinear elimination including allometrically scaled bodyweight (median, 17.50 kg; IQR, 8.76-33.00) and lymphocyte count at baseline (mean, 2.24 x 10(9)/L; standard deviation +/- 1.87) as significant pharmacokinetic predictors was developed using nonlinear mixed effects modeling. Based on the model-estimated median concentration at day of HSCT (0.77 mu g/mL; IQR, 0.33-1.82), patients were grouped into a low- (<= 0.77 mu g/mL) or high- (>0.77 mu g/mL) exposure groups. High alemtuzumab exposure at day of HSCT correlated with delayed CD4(+) and CD8(+) T-cell reconstitution (P value <.0001) and increased risk of GF (P value =.043). In contrast, alemtuzumab exposure did not significantly influence the incidence of aGVHD grade >= 2, mortality, chimerism at 1 year, viral reactivations, and autoimmunity at a median follow-up of 3.3 years (IQR, 2.5-8.0). In conclusion, this novel population pharmacokinetics model is suitable for individualized intravenous precision dosing to predict alemtuzumab exposure in pediatric allogeneic HSCT for nonmalignant diseases, aiming at the achievement of early T-cell reconstitution and prevention of GF in future prospective studies.

Automated summary

This multicenter study characterized the pharmacokinetics of alemtuzumab in children with nonmalignant diseases and found that high exposure on the day of hematopoietic stem cell transplantation correlated with delayed T-cell reconstitution and increased risk of graft failure, while not significantly affecting other outcomes.