M Louise Markert1, Stephanie E Gupton2, Elizabeth A McCarthy2. 1. Department of Pediatrics, Division of Allergy, Immunology, and Pulmonary Medicine, Duke School of Medicine, Durham, NC; Department of Immunology, Duke School of Medicine, Durham, NC. Electronic address: m.markert@duke.edu. 2. Department of Pediatrics, Division of Allergy, Immunology, and Pulmonary Medicine, Duke School of Medicine, Durham, NC.
Abstract
BACKGROUND: Currently, there are no approved therapies to treat congenital athymia, a condition of immune deficiency resulting in high early mortality due to infection and immune dysregulation. Multiple syndromic conditions, such as complete DiGeorge syndrome, 22q11.2 deletion syndrome, CHARGE (coloboma, heart defects, choanal atresia, growth or mental retardation, genital hypoplasia, and ear anomalies and/or deafness) syndrome, diabetic embryopathy, other genetic variants, and FOXN1 deficiency, are associated with congenital athymia. OBJECTIVE: Our aims were to study 105 patients treated with cultured thymus tissue (CTT), and in this report, to focus on the outcomes of 95 patients with treatment-naive congenital athymia. METHODS: A total of 10 prospective, single-arm open-label studies with patient enrollment from 1993 to 2020 form the basis of this data set. Patients were tested after administration of CTT for T-cell development; all adverse events and infections were recorded. RESULTS: A total of 105 patients were enrolled and received CTT (the full analysis set). Of those patients, 10 had diagnoses other than congenital athymia and/or received prior treatments. Of those 105 patients, 95 patients with treatment-naive congenital athymia were included in the efficacy analysis set (EAS). The Kaplan-Meier estimated survival rates at year 1 and year 2 after administration of CTT in the EAS were 77% (95% CI = 0.670-0.844) and 76% (95% CI = 0.657-0.834), respectively. In all, 21 patients died in the first year before developing naive T cells and 1 died in the second year after receipt of CTT; 3 subsequent deaths were not related to immunodeficiency. A few patients developed alopecia, autoimmune hepatitis, psoriasis, and psoriatic arthritis after year 1. The rates of infections, autologous graft-versus-host-disease manifestations, and autoimmune cytopenias all decreased approximately 1 year after administration of CTT. CONCLUSION: Treatment with CTT led to development of naive T cells with a 1-year survival rate of 77% and a median follow-up time of 7.6 years. Immune reconstitution sufficient to prevent infections and support survival typically develops 6 to12 months after administration of CTT.
BACKGROUND: Currently, there are no approved therapies to treat congenital athymia, a condition of immune deficiency resulting in high early mortality due to infection and immune dysregulation. Multiple syndromic conditions, such as complete DiGeorge syndrome, 22q11.2 deletion syndrome, CHARGE (coloboma, heart defects, choanal atresia, growth or mental retardation, genital hypoplasia, and ear anomalies and/or deafness) syndrome, diabetic embryopathy, other genetic variants, and FOXN1 deficiency, are associated with congenital athymia. OBJECTIVE: Our aims were to study 105 patients treated with cultured thymus tissue (CTT), and in this report, to focus on the outcomes of 95 patients with treatment-naive congenital athymia. METHODS: A total of 10 prospective, single-arm open-label studies with patient enrollment from 1993 to 2020 form the basis of this data set. Patients were tested after administration of CTT for T-cell development; all adverse events and infections were recorded. RESULTS: A total of 105 patients were enrolled and received CTT (the full analysis set). Of those patients, 10 had diagnoses other than congenital athymia and/or received prior treatments. Of those 105 patients, 95 patients with treatment-naive congenital athymia were included in the efficacy analysis set (EAS). The Kaplan-Meier estimated survival rates at year 1 and year 2 after administration of CTT in the EAS were 77% (95% CI = 0.670-0.844) and 76% (95% CI = 0.657-0.834), respectively. In all, 21 patients died in the first year before developing naive T cells and 1 died in the second year after receipt of CTT; 3 subsequent deaths were not related to immunodeficiency. A few patients developed alopecia, autoimmune hepatitis, psoriasis, and psoriatic arthritis after year 1. The rates of infections, autologous graft-versus-host-disease manifestations, and autoimmune cytopenias all decreased approximately 1 year after administration of CTT. CONCLUSION: Treatment with CTT led to development of naive T cells with a 1-year survival rate of 77% and a median follow-up time of 7.6 years. Immune reconstitution sufficient to prevent infections and support survival typically develops 6 to12 months after administration of CTT.
Authors: Ales Janda; Petr Sedlacek; Manfred Hönig; Wilhelm Friedrich; Martin Champagne; Tadashi Matsumoto; Alain Fischer; Benedicte Neven; Audrey Contet; Danielle Bensoussan; Pierre Bordigoni; David Loeb; William Savage; Nada Jabado; Francisco A Bonilla; Mary A Slatter; E Graham Davies; Andrew R Gennery Journal: Blood Date: 2010-06-07 Impact factor: 22.113
Authors: Thomas B Kepler; Min He; John K Tomfohr; Blythe H Devlin; Marcella Sarzotti; M Louise Markert Journal: Bioinformatics Date: 2005-06-14 Impact factor: 6.937
Authors: M Louise Markert; José G Marques; Bénédicte Neven; Blythe H Devlin; Elizabeth A McCarthy; Ivan K Chinn; Adriana S Albuquerque; Susana L Silva; Claudio Pignata; Geneviève de Saint Basile; Rui M Victorino; Capucine Picard; Marianne Debre; Nizar Mahlaoui; Alain Fischer; Ana E Sousa Journal: Blood Date: 2010-10-26 Impact factor: 22.113
Authors: M Louise Markert; Marilyn J Alexieff; Jie Li; Marcella Sarzotti; Daniel A Ozaki; Blythe H Devlin; Debra A Sedlak; Gregory D Sempowski; Laura P Hale; Henry E Rice; Samuel M Mahaffey; Michael A Skinner Journal: Blood Date: 2004-04-20 Impact factor: 22.113
Authors: M Louise Markert; Jie Li; Blythe H Devlin; Jeffrey C Hoehner; Henry E Rice; Michael A Skinner; Yi-Ju Li; Laura P Hale Journal: J Immunol Date: 2008-05-01 Impact factor: 5.422
Authors: Henry E Rice; Michael A Skinner; Samuel M Mahaffey; Keith T Oldham; Richard J Ing; Laura P Hale; M Louise Markert Journal: J Pediatr Surg Date: 2004-11 Impact factor: 2.545