Timing of Immune Reconstitution in Patients With Congenital Athymia After Treatment With Allogeneic Processed Thymus Tissue-agdc

Abstract

Congenital athymia is a rare pediatric condition characterized by the absence of a functioning thymus resulting in extremely low naïve T-cell numbers and severe immune deficiency. Allogeneic processed thymus tissue-agdc is approved for immune reconstitution in these patients. In clinical studies, naïve T-cell numbers increased from baseline through year 2 after allogeneic processed thymus tissue-agdc implantation. Based on these studies, immune reconstitution sufficient to overcome infection (>100 naïve CD4+ T cells/mm3) is unlikely to develop before 6–12 months after implantation and may take 2 years in some patients (Figure 1). This analysis aims to identify clinical features associated with delayed naïve T-cell development and impacts on clinical outcomes. In this post hoc analysis of data at year 1 (Y1) after allogeneic processed thymus tissue-agdc implantation, we evaluated clinical features of patients with < 100 naïve CD4+/mm3. Of 95 patients implanted in clinical trials, all 65 patients with baseline measurements had < 50 naïve CD4+/mm3. Of patients with Y1 measurements, 30/45 (66.7%) achieved >100 naïve CD4+/mm3 and 15/45 (33.3%) had < 100 naïve CD4+/mm3 (Tables 1, 2). Among patients with < 100 naïve CD4+/mm3 at Y1, 11/15 (73.3%) had atypical complete DiGeorge Syndrome (cDGS); all 11 atypical patients received glucocorticoids pre-implantation and calcineurin inhibitors pre- and post-implantation, and 6/11 received glucocorticoids post-implantation. Four of 15 patients (26.7%) with < 100 naïve CD4+/mm3 at Y1 had typical cDGS; 1 received calcineurin inhibitors pre- and post-implantation and 2 received glucocorticoids (pre-implantation only). Of 15 patients with < 100 naïve CD4+/mm3 at Y1, 10 (66.7%) experienced infection-related adverse events starting >1 year post-implantation. These events were reported for 8 atypical patients (all on pre-or post-implantation immunosuppressive therapy) and 2 typical patients (with no immunosuppressive therapy); most events resolved. At the time of last follow-up, 93.3% of patients (14/15) were alive; 1 patient died 7.6 years post-treatment (respiratory failure). In summary, most patients (66.7%) with available data achieved >100 naïve CD4+/mm3 by Y1 after allogeneic processed thymus tissue-agdc implantation. Amongst patients who did not, many had atypical cDGS and received immunosuppressive medications. No infection-related deaths were reported in patients with delayed naïve CD4+ T-cell reconstitution. [Display omitted] Table 1(abstract: 100) Characteristics of Patients With < 100 Naïve CD4+ T Cells/mm3 at Year 1 and Year 2 After ImplantationPatientAge at implantation, yearscDGS phenotypeGenetic backgroundaAlive at last follow-upInfection-related AE>1 year post-implantationImmunosuppression useCIPatients with <100 cells/mm3 at the year 1 visit10.8AtypicalHemizygous 22q11.2 deletion✓✓✓✓21.1AtypicalHemizygous 22q11.2 deletion✓No✓✓32.2AtypicalNo known mutation✓No✓✓40.7AtypicalCHARGE✓✓✓✓50.8AtypicalNo known mutation✓✓✓✓60.7AtypicalCHARGE✓✓✓✓71.3AtypicalCHARGE✓✓✓✓80.7TypicalHemizygous 22q11.2 deletion✓No✓✓92.3TypicalHemizygous 22q11.2 deletion✓NoNo✓10c0.2TypicalCHARGE✓✓NoNo110.4TypicalNo known mutationNod✓NoNoPatients with <100 cells/mm3 at the year 1 and year 2 visits121.4AtypicalHemizygous 22q11.2 deletion✓✓✓✓131.2AtypicalCHARGE✓No✓✓140.7AtypicalNo known mutation✓✓✓✓151.8AtypicalCHARGE✓✓✓✓Patients with <100 cells/mm3 at the year 2 visite160.3TypicalHemizygous 22q11.2 deletion✓✓NoNo170.9TypicalHemizygous 22q11.2 deletion✓✓NoNoAE, adverse event; cDGS, complete DiGeorge syndrome; CHARGE, coloboma, heart defect, choanal atresia, growth and developmental delay, genital hypoplasia, and ear anomalies or deafness syndrome; CHD7, chromodomain-helicase DNA-binding protein 7; CI, calcineurin inhibitor; EAS, efficacy analysis set; GC; glucocorticoids. Data based on EAS population (N = 95).aCHARGE includes CHD7mutation or other unknown CHARGE mutations.bIncludes methylprednisolone with anti-thymocyte globulin [rabbit] administered just before implantation.cPatient had renal impairment (defined as serum creatinine levels >0.4 mg/dL at baseline).dPatient died 7.6 years after allogeneic processed thymus tissue-agdc implantation (due to respiratory failure).eNaïve CD4+ T-cell data at the year 1 visit was not available for these patients.Table 2Naive CD4+ T cells/mm3 Over Time After Allogeneic Processed Thymus Tissue-agdc ImplantationaPatientNaïve CD4+ T cells/mm30.5–0.9 years1.0–1.4 years1.5–1.9 years≥2 yearsPatients with <100 cells/mm3 at the year 1 visit165.5NA48721046, 80NA2813101475NA4NA90, 521NA454511.9,51.0NA119.9, 219.3356.662.7,22.954.0NA218.5711,0NA7481250,100276NA9NA27NA10NA67.6359.9NA11NA47.9294.4NAPatients with <100 cells/mm3 at the year 1 and year 2 visits1246456454131068NA94.7, 149144,2339.934.466.4,1091518.534.072.939.9Patients with <100 cells/mm3 at the year 2 visitb1616273355173.9NA6967EAS, efficacy analysis set; NA, not available.Data based on EAS population (N = 95).aBased on available naïve CD4+ T-cell data.bNaïve CD4+ T-cell data at the year 1 visit was not available for these patients.