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

Achini-Gutzwiller, F.R.; Schilham, M.W.; Asmuth, E.G.J. von; Jansen-Hoogendijk, A.M.; Zijde, C.M. van der; Tol, M.J.D. van; ... ; Moes, D.J.A.R. (2023)

Article / Letter to editor

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.

• All authors: Achini-Gutzwiller, F.R.; Schilham, M.W.; Asmuth, E.G.J. von; Jansen-Hoogendijk, A.M.; Zijde, C.M. van der; Tol, M.J.D. van; Bredius, R.G.M.; Gungor, T.; Lankester, A.C.; Moes, D.J.A.R.
• Date: 2023-08-12
• Journal: Blood Advances
• Volume: 7
• Issue: 16
• Pages: 4462 - 4474
• DOI: doi:10.1182/bloodadvances.2022009051
• Link: https://ashpublications.org/bloodadvances/article/7/16/4462/496180/Expos...