CONGENITAL ATHYMIA
Congenital athymia is an ultra-rare condition in which children are born without a thymus, causing
vulnerability to life-threatening infections and immune dysregulation. The estimated incidence of
congenital athymia in the US is approximately 17 to 24 infants per 4 million live births annually. The
thymus is responsible for the development of mature T cells and is the only organ where thymocytes can
mature, be selected, and survive to become naive T cells. T cells originate in the bone marrow as
progenitor cells; however, the bone marrow does not contain the specialized tissue required for T-cell
maturation. Without a functioning thymus, the inability to produce immunocompetent T cells leads to
immunodeficiency manifested as increased susceptibility to infection. With only supportive care, children
with congenital athymia typically do not survive beyond 2 to 3 years of age. Congenital athymia is often
associated with other conditions, such as DiGeorge syndrome (a.k.a., 22q11.2 deletion syndrome);
mutations in the genes TBX1, CHD7 (CHARGE syndrome - coloboma, heart defects, choanal atresia,
growth or mental retardation, genital hypoplasia, and ear anomalies and/or deafness), and FOXN1
(FOXN1 deficiency); and diabetic embryopathy. These systemic conditions make the complex treatment
of congenital athymia even more complicated. Early detection of congenital athymia is critical, as the
sooner it is identified, the sooner isolation, infection prevention measures, and prophylactic antimicrobials
can be initiated. Newborn screening plays a crucial role in early detection. Congenital athymia is initially
detected through T-cell receptor rearrangement excision circle (TREC) screening, also known as severe
combined immunodeficiency (SCID) screening. TREC screening provides the first indication of an
immunologic issue in an infant’s T-cell development, and it is a standard part of the newborn screening
panel, required in all 50 US states as of 2018. Low or undetectable TREC levels (i.e., a positive screening
result) indicate the need for further testing including flow cytometry and genetic testing to confirm a
diagnosis of congenital athymia.
COMPLETE DIGEORGE SYNDROME
Complete DiGeorge Syndrome (cDGS) is a rare disorder in which children have no detectable thymus (athymia). Some individuals have DiGeorge syndrome as part of a larger disorder, specifically chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Both of these disorders have symptoms affecting multiple systems of the body. DiGeorge syndrome typically refers to individuals who have T cell counts less than the 10th percentile for age, plus they have heart defects and/or low calcium levels. Many but not all of infants with 22q11.2 deletion syndrome and CHARGE syndrome have T cell counts less than the 10th percentile for age and are often referred to as having DiGeorge syndrome. (Children with 22q11.2 deletion syndrome or CHARGE syndrome who have normal T cell counts are not considered as having DiGeorge syndrome).
Only about 1% of children with DiGeorge syndrome have absence of the thymus. To determine that a child had no thymus, blood testing must not detect T cells emerging from the thymus. Newly developed T cells emerging from the thymus have special proteins on the cell surface. Those T cells are called “naïve" T cells. Children with 22q11.2 deletion syndrome or CHARGE syndrome who have very low naïve T cells counts (less than 50 per mm3 in the blood) are said to have complete DiGeorge syndrome. Children with complete DiGeorge syndrome are all athymic by definition. For affected infants who are infants of diabetic mothers and other infants with no identifiable genetic defects or syndromes, the cause of athymia remains unknown.
Researchers have identified several genes that, when altered (mutated), can cause absence of the thymus. These genes include the FOXN1, TBX1, TBX2, and the PAX1 genes.
ALLOGENEIC PROCESSED THYMUS TISSUE-AGDC (RETHYMIC)
Allogeneic processed thymus tissue–agdc (Rethymic) was approved by the US Food and Drug Administration (FDA) in October 2021 for immune reconstitution in pediatric patients with congenital athymia. It is the first treatment to be approved for this fatal condition. The thymus tissue is obtained from donors less than or equal to 9 months of age undergoing cardiac surgery. The manufacturing process preserves the thymic epithelial cells and tissue structure and depletes most of the donor thymocytes from the tissue. The proposed mechanism of action involves the migration of recipient T cell progenitors from the bone marrow to the implanted thymus tissue, where they develop into naïve immunocompetent recipient T cells. Evidence of thymic function will be observed by the development of naïve T cells in the peripheral blood occurring at least 6 months after treatment.
The efficacy of Rethymic leading to FDA approval was evaluated in 10 prospective, single-center, open-label studies that enrolled a total of 105 individuals, including 95 individuals in the primary efficacy analysis.
The demographics and baseline characteristics of the individuals enrolled in the clinical studies were similar
across studies. Across the efficacy population, 59% were male; 70% were White, and 22% were Black.
The median age at the time of treatment was 9 months (range of 1 to 36 months). The diagnosis of
congenital athymic was based on flow cytometry documenting fewer than 50 naïve T cells/mm3
(CD45RA+, CD62L+) in the peripheral blood or less than 5% of total T cells being naïve in phenotype for
most patients (91 of 95). In addition congenital athymia, individuals also had complete DiGeorge syndrome
(cDGS; also referred to as complete DiGeorge anomaly (cDGA)) if they also met at least one of the
following criteria: congenital heart defect, hypoparathyroidism (or hypocalcemia requiring calcium
replacement), 22q11 hemizygosity, 10p13 hemizygosity, CHARGE syndrome, or CHD7 mutation. Across
the efficacy population, 93 individuals (98%) were diagnosed with cDGS, and the most common DiGeorge
gene mutations or syndromic associations were chromosome 22q11.2 deletion (36 individuals; 38%) and
CHARGE syndrome (23 individuals; 24%). There were 35 individuals with missing or no identified genetic
mutations. Two (2%) individuals had FOXN1 deficiency, and 1 individual (1%) had a TBX variant. There were
50 (53%) individuals with typical cDGS; these individuals had congenital athymia with the absence of a T cellrelated rash. There were 42 (44%) individuals diagnosed with atypical cDGS; these individuals may have had a
rash, lymphadenopathy, or oligoclonal T cells. Individuals who did not have congenital athymia (e.g., SCID)
and individuals with prior transplants, including thymus and HCT, were excluded from the efficacy analysis
population. Individuals with heart surgery anticipated within 4 weeks prior to, or 3 months after, the planned
Rethymic treatment date, individuals with human immunodeficiency virus (HIV) infection, and individuals who
were not considered good surgical candidates were excluded from study participation. Individuals in the
efficacy population received Rethymic in a single surgical procedure at a dose of 4,900 to 24,000 mm2 of
Rethymic per recipient body surface area (BSA) in m2
. Patients were assigned to receive
immunosuppressive therapy prior to and/or after treatment according to their disease phenotype and pre-Rethymic phytohemagglutinin (PHA) response. No individuals were retreated with Rethymic.
The Kaplan-Meier estimated survival rates were 77% (95% CI [0.670, 0.841]) at 1 year and 76% (95% CI
[0.658, 0.832]) at 2 years. For individuals who were alive at 1 year after treatment, the survival rate was 94%
at a median follow-up of 10.7 years. Without treatment, congenital athymia is fatal in childhood. In a
natural history population observed from 1991 through 2017, 49 individuals diagnosed with congenital
athymia received supportive care only. The 2-year survival rate was 6%, with all individuals dying by 3 years
of age. The most common cause of death was infection in 26 (53%) individuals. Other common causes
(≥10%) included support withdrawn in 7 (14%) individuals, respiratory arrest in 5 (10%) individuals, and cardiac
arrest in 5 (10%) individuals. Rethymic also significantly reduced the number of infections over time. In the
first year after treatment, the number of individuals with an infection event onset 6 to ≤12 months after
treatment decreased by 38% (from 63 to 39) relative to the number of individuals with an infection event
onset in the first 6 months post-treatment. A two-year analysis showed a decrease in both the number of individuals with an infection event and the mean number of infection events per individual, with an onset in the
first 12 months post-treatment as compared to 12 to ≤24 months after treatment. There was a mean
difference of 2.9 events (p<0.001) per individual. Following Rethymic treatment., naïve CD4+ and CD8+ T
cells reconstituted over the first year, with a durable increase through Year 2. Median (minimum,
maximum) naïve CD4+ T cells/mm3
increased from a baseline of 1 (0, 38) to values of 42 (0, 653), 212 (1,
751), and 275 (33, 858) at 6, 12, and 24 months after treatment, respectively. Median naïve CD8+ T
cells/mm3
increased from a baseline of 0 (0, 46) to values of 9 (0, 163), 58 (0, 304), and 86 (6, 275) at 6,
12, and 24 months after treatment, respectively. This was accompanied by functional improvements
based on T cell proliferative responses to PHA.
