High Exposure of Intravenous Alemtuzumab is Associated with Increased Risk of Adenovirus reactivation in Patients with Non-Malignant Disease Undergoing Allogeneic HCT.

INTRODUCTION: Alemtuzumab, a recombinant humanized immunoglobulin G1 monoclonal antibody directed against human CD52, is a widely used serotherapy strategy in pediatric allogeneic hematopoietic stem cell transplantation (HCT) in non-malignant diseases (NMD) to help reduce the risk of graft rejection (GR) and graft versus host disease (GVHD). Excessive exposure to alemtuzumab potentially delays immune reconstitution and increases the risk of infections.

METHOD: We conducted a retrospective analysis at a single institution of 95 pediatric patients with NMD who underwent HCT and received intravenous alemtuzumab as part of their conditioning regimen between 2012-2024. Individualized alemtuzumab pharmacokinetic parameters, including pre- and post-HCT area under the curve (AUC) and day 0 concentrations, were estimated using a validated population pharmacokinetic model.

RESULTS: Receiver operating characteristic (ROC) analysis identified thresholds that associated with increased adenoviral infection of 55 mcg/mL*day for pre-HCT AUC and 10 mcg/mL*day for post-HCT AUC. Baseline absolute lymphocyte count (ALC) was the strongest determinant of post-HCT alemtuzumab concentrations. Higher pre- or post-HCT alemtuzumab exposure was associated with significantly more adenovirus reactivation (pre-HCT: 32.6% vs. 8.2%, p=0.007; post-HCT: 34.5% vs. 10.7%, p=0.008) and 2 or more viral reactivations (pre-HCT: 24% vs. 6%, p=0.023; post-HCT: 28.2% vs. 6.8%, p=0.008) during the first 180 days post-HCT. Higher pre-HCT exposure was also associated with increased HHV-6 reactivation (6.2% vs 23.7%, p=0.028). Alemtuzumab exposure was not associated with GR, graft loss, mixed chimerism, acute or chronic GVHD, transplant-related mortality (TRM), event-free survival (EFS), or overall survival (OS). Lower day 0 alemtuzumab concentrations (≤0.77 mcg/mL) were associated with more patients reaching CD4 recovery by day 180 (88.2% vs 56.9%, p<0.001).

CONCLUSIONS: Higher pre- or post HCT alemtuzumab levels are associated with a higher risk of adenovirus reactivation. Individualized, model-based alemtuzumab dosing may reduce excessive post-transplant exposure while maintaining excellent engraftment and survival outcomes. Targeting lower post-HCT alemtuzumab exposure may decrease viral complications without compromising transplant success, supporting pharmacokinetic-guided dosing strategies in pediatric HSCT for nonmalignant diseases.