2026-07-11 | Precision myeloablation with TDM-guided busulfan in pediatric primary immunodeficiencies: a real-world study of 28 patients.
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. 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. 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. 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.
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2026-07-09 | TTC7A deficiency: A retrospective international study on treatment and outcomes from the Inborn Errors Working Party of EBMT.
Tetratricopeptide repeat domain 7A (TTC7A) deficiency is a primary immunodeficiency due to mutations in the TTC7A gene. It causes intestinal disease and a poorly characterized immunodeficiency, with poor long-term survival. We describe the clinical and immunological characteristics, management, and outcomes of an international cohort of patients with genetically confirmed TTC7A deficiency. Data from 61 patients from 13 countries were retrospectively analyzed. Overall survival was 64% (median follow-up 4.2 years), significantly higher in the inflammatory bowel disease than in the hereditary multiple intestinal atresia group (80 vs. 48%, P < 0.05). Infections represent the leading cause of death. Allogeneic stem cell transplantation was performed in 16 patients to correct the immunodeficiency but was associated with a significant transplant-related mortality (44%). Solid organ transplantation of the small bowel remains exceptionally rare (two patients). Malignancy/autoimmune disorders developed in 4 (6.5%) and 17 (28%) patients, respectively. TTC7A remains difficult to treat, and prognosis is dismal for affected patients. Further understanding of the disease mechanisms and development of innovative treatment approaches are required.
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