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 non-malignant diseases undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft failure (GF) and acute graft-versus-host disease (aGvHD). This multicenter study aimed at the characterization of alemtuzumab population pharmacokinetics to perform a novel model-based exposure-response analysis in 53 children with non-malignant immunological or hematological disease and a median age of 4.4 years (IQR 0.8, 8.7). Median cumulative alemtuzumab dose was 0.6 mg/kg (IQR 0.6-1) administered over 2-7 days. A 2-compartment population pharmacokinetic model with parallel linear and non-linear elimination including allometrically scaled bodyweight [median 17.50 kg (IQR 8.76, 33.00)] and lymphocyte count at baseline [mean 2.24 10*9/L (SD 1.87)] as significant pharmacokinetic predictors was developed using non-linear mixed effects modelling (NONMEM). According to the model estimated median concentration at day of HSCT (0.77 µg/mL, IQR 0.33-1.82), patients were grouped into a low (</equal 0.77 µg/mL) or high (>0.77 µg/mL) exposure group. High alemtuzumab exposure at day of HSCT correlated with delayed CD4+ and CD8+ T-cell reconstitution (p-value <0.0001) and increased risk of graft failure (p-value=0.043). In contrast, alemtuzumab exposure did not significantly influence the incidence of aGvHD ≥ grade II, 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 PK model is suitable for individualized intravenous precision dosing to predict alemtuzumab exposure in pediatric allogeneic HSCT for non-malignant diseases, aiming at the achievement of early T-cell reconstitution and prevention of graft failure in future prospective studies.