Real World Experience in the United States Following FDA Approval of Cultured Thymus Tissue Implantation in Congenital Athymia Patients at Duke University.

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Introduction Cultured thymus tissue implantation (CTTI), pioneered at Duke University (Durham, NC) received US Food and Drug Administration (FDA) approval in 2021 (RETHYMIC, Sumitomo USA), for the treatment of congenital athymia (CA). CA is a rare immunodeficiency with increased risk of infection, autoimmunity, malignancy , and early mortality. Duke University is the only center in the United States approved to provide CTTI. Objective Herein, we describe outcomes of patients receiving CTTI since 2021. Methods This IRB-approved retrospective study includes 34 patients with CA who received RETHYMIC from 2022 to July 2024 (Figure 1). Results Median time from referral to CTTI was 32.6 (range: 5.7-61.7) months. By 2024, median age at CTTI and time to CTTI from referral decreased significantly to 22 and 18 months respectively. Patients with typical phenotype were younger at CTTI (Figure 2A-C). Most patients (79.4%) underwent surgical interventions (mostly cardiac) prior to CTTI. No operative adverse events were observed post-CTTI. Infections post-CTTI occurred in 50% of patients (76.4% viral). One patient with atypical phenotype (AP) developed EBV+ post-transplant lymphoproliferative disorder and was successfully treated with 4 doses of rituximab . Overall survival (OS) at 1-year post-CTTI was 94% (Figure 2D). At 6 and 12 months post-CTTI, evidence of immune reconstitution (CD3 ≥ 200 cells/μL) was present in 45% and 91% of patients respectively. Immune thrombocytopenic purpura (37.5%) and autoimmune hemolytic anemia (AIHA) (25%) were seen mainly in AP patients with a median onset of 8.3 (range 4.3- 23.5) months from CTTI. Except for one case with spontaneous recovery, all patients were successfully treated with immunoglobulin . One patient presented with AIHA before CTTI due to autologous GVHD . At median follow-up of 10.5 (range 0.5-28.7) months, 50% of patients continued to have global developmental delays . Speech delay was still present in 26.4%. Of school eligible patients, 40% attend school and 50% have an individualized education program. Surgical interventions post-CTTI occurred in 20.5% of the patients due to pre-CTTI cardiac and orthopedic issues. Death occurred in 2 patients; one due to multiorgan failure related to autologous T-cell activation and the other due to intracranial hemorrhage . Conclusion While viral reactivation is common post-CTTI, the procedure is associated with high OS and evidence of immune reconstitution . Since FDA approval, early CTTI patients were older primarily due to no previously approved therapies available and time to insurance approval. With improvements in access, insurance authorization and medical clearance to reduce time to treatment , CTTI shows promise in enhancing patient survival and immune recovery.

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