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

• Published in: Blood advances Vol. 7; no. 16; pp. 4462 - 4474
• Main Authors: Achini-Gutzwiller, Federica R., Schilham, Marco W., von Asmuth, Erik G. J., Jansen-Hoogendijk, Anja M., Jol-van der Zijde, Cornelia M., van Tol, Maarten J. D., Bredius, Robbert G. M., Güngör, Tayfun, Lankester, Arjan C., Moes, Dirk Jan A. R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.08.2023; The American Society of Hematology
• Subjects: Transplantation
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2022009051

•An alemtuzumab population pharmacokinetic model has been developed for more accurate intravenous dosing in pediatric HSCT.•Optimal exposure is associated with early T-cell recovery and prevention of graft failure. [Display omitted] 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 model–based 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 × 109/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 μg/mL; IQR, 0.33-1.82), patients were grouped into a low- (≤0.77 μg/mL) or high- (>0.77 μg/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.