Precision myeloablation with TDM-guided busulfan in pediatric primary immunodeficiencies: a real-world study of 28 patients

Background: Optimizing busulfan (Bu) exposure is critical for balancing engraftment and toxicity in pediatric patients with primary immunodeficiencies (PID) undergoing hematopoietic stem cell transplantation (HSCT). This study evaluates the outcomes of a therapeutic drug monitoring (TDM)-guided, personalized Bu/fludarabine (Flu) regimen.

Methods: We retrospectively analyzed 28 pediatric PID patients [11 severe combined immunodeficiency (SCID) and 17 with non-SCID] who underwent first allogeneic HSCT (allo-HSCT) between March 2022 and September 2025. All patients received Flu (150–180 mg/m²) and TDM-guided Bu with target cumulative area under the curve (AUC) of 60–70 mg·h/L for SCID and 85–95 mg·h/L for non-SCID. Primary endpoints were overall survival (OS) and event-free survival (EFS). Secondary endpoints included engraftment, regimen-related toxicity (RRT), graft-versus-host disease (GVHD), and immune reconstitution.

Results: Only 11/28 patients (39.3%) achieved target AUC after the first Bu dose, confirming the necessity of TDM. With a median follow-up of 829.5 days [interquartile range (IQR), 376–1,046 days], 2-year OS and EFS were 96.42%. Sustained engraftment with complete or high-level donor chimerism was achieved in 96.42% of patients. Severe RRT was minimal: grade 3–4 mucositis (n=1, 3.5%) and definite veno-occlusive disease (VOD) (n=1). No grade 3–4 acute GVHD occurred. Chronic GVHD (cGVHD) occurred in 7/27 patients (25.9%), predominantly pulmonary-limited. Cytomegalovirus (CMV) reactivation occurred in 11 patients (39.2%) without CMV disease. All surviving patients discontinued immunoglobulin replacement within one year.

Conclusions: A risk-adapted, TDM-guided Bu/Flu conditioning regimen achieves an optimal balance between efficacy and toxicity in pediatric PID HSCT. With a 2-year OS of 96.4%, minimal severe RRT, and universal intravenous immunoglobulin (IVIG) independence by 12 months, this precision myeloablative approach should be considered the preferred standard for this vulnerable population.