Diagnosing congenital athymia
Early diagnosis is key to making the right supportive care decisions1
Newborn screening plays a crucial role in the early detection of congenital athymia. T cell receptor excision circle (TREC) screening, a test mandated in all 50 states in the US, provides the first indication of naive T-cell deficiency, signaling a need for further testing. TREC screening may identify severe combined immunodeficiency (SCID) as well as congenital athymia.1
Congenital athymia and SCID are distinct conditions
Although they’re both primary immunodeficiency disorders and detected through the same screening test, congenital athymia and SCID have different underlying causes. Distinguishing between the two is critical as they have different treatment requirements.1
Differentiating typical vs atypical phenotypes
There are two phenotypes of congenital athymia, typical and atypical, with different characteristics. These include2:
Typical congenital athymia2
- T-cell lymphopenia
- Absence of rash or lymphadenopathy
- Lack of mitogen-stimulated T-cell proliferation
Atypical congenital athymia2
Signs and symptoms of autologous graft versus host disease (GVHD):
- Rash
- Lymphadenopathy
- High numbers of circulating T cells (from oligoclonal T-cell expansion)
- T-cell proliferation in response to mitogens (eg, phytohemagglutinin)
For currently unknown reasons, some patients with typical congenital athymia can, over time, develop the atypical phenotype.2
The sooner congenital athymia is detected, the sooner isolation and infection prevention measures can be initiated—and the less likely a patient will be treated with potentially inappropriate therapies.1
RETHYMIC is a first-of-its-kind, FDA-approved tissue-based treatment for congenital athymia engineered to help patients develop an immune system sufficient to fight infections.3,4
Learn how to access RETHYMIC and begin the referral process.
Enzyvant CONNECT provides support and resources for patients with congenital athymia and their caregivers.
Indication and Important Safety Information
Important Safety Information
Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6-12 months after treatment with RETHYMIC. Given the immunocompromised condition of athymic patients, follow infection control measures until the development of thymic function is established as measured through flow cytometry. Monitor patients closely for signs of infection including fever. If a fever develops, assess the patient by blood and other cultures and treat with antimicrobials as clinically indicated. Patients should be maintained on immunoglobulin replacement therapy until specified criteria are met, and two months after stopping, IgG trough level should be checked. Prior to and after treatment with RETHYMIC, patients should be maintained on Pneumocystis jiroveci pneumonia prophylaxis until specified criteria are met.
RETHYMIC may cause or exacerbate pre-existing graft versus host disease (GVHD). Monitor and treat patients at risk for the development of GVHD. Risk factors for GVHD include atypical complete DiGeorge anomaly phenotype, prior hematopoietic cell transplantation (HCT) and maternal engraftment. GVHD may manifest as fever, rash, lymphadenopathy, elevated bilirubin and liver enzymes, enteritis, and/or diarrhea.
Autoimmune-related adverse events occurred in patients treated with RETHYMIC. These events included: thrombocytopenia, neutropenia, proteinuria, hemolytic anemia, alopecia, hypothyroidism, autoimmune hepatitis, autoimmune arthritis, transverse myelitis, albinism, hyperthyroidism, and ovarian failure. Monitor for the development of autoimmune disorders, including complete blood counts with differential, liver enzymes, serum creatinine, urinalysis, and thyroid function.
Pre-existing renal impairment is a risk factor for death.
In the clinical studies of RETHYMIC, 4 out of 4 patients with pre-existing cytomegalovirus infection died. The benefits/risks of treatment should be considered prior to treating patients with pre-existing CMV infection.
Because of the underlying immune deficiency, patients who receive RETHYMIC may be at risk of developing post-treatment lymphoproliferative disorder. Patients should be monitored for the development of lymphoproliferative disorder.
Transmission of infectious disease may occur because RETHYMIC is derived from human tissue and because product manufacturing includes porcine- and bovine-derived reagents.
Immunizations should not be administered in patients who have received RETHYMIC until immune-function criteria have been met.
All patients should be screened for anti-HLA antibodies prior to receiving RETHYMIC. Patients testing positive for anti-HLA antibodies should receive RETHYMIC from a donor who does not express those HLA alleles. HLA matching is required in patients who have received a prior HCT or a solid organ transplant. Patients who have received a prior HCT are at increased risk of developing GVHD after RETHYMIC if the HCT donor did not fully match the recipient.
Of the 105 patients in clinical studies, 29 patients died, including 23 deaths in the first year (< 365 days) after implantation.
The most common (>10%) adverse events related to RETHYMIC included: hypertension, cytokine release syndrome, rash, hypomagnesemia, renal impairment/failure, thrombocytopenia, and graft versus host disease.
To report suspected adverse reactions, please contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch
Indication
RETHYMIC® (allogeneic processed thymus tissue–agdc) is indicated for immune reconstitution in pediatric patients with congenital athymia.
Limitations of Use:
RETHYMIC is not indicated for the treatment of patients with severe combined immunodeficiency (SCID).
References: 1. Collins C, Sharpe E, Silber A, Kulke S, Hsieh EWY. Congenital athymia: genetic etiologies, clinical manifestations, diagnosis, and treatment. J Clin Immunol. 2021;41(5):881-895. doi:10.1007/s10875-021-01059-7 2. Markert ML, Gupton SE, McCarthy EA. Experience with cultured thymus tissue in 105 children. J Allergy Clin Immunol. 2022;149(2):747-757. doi:10.1016/j.jaci.2021.06.028 3. RETHYMIC [package insert]. Marlborough, MA: Sumitomo Pharma America, Inc; 2023. 4. Enzyvant Therapeutics GmbH. Enzyvant receives FDA approval for RETHYMIC® (allogeneic processed thymus tissue-agdc), a one-time regenerative tissue-based therapy for pediatric congenital athymia. Enzyvant Therapeutics, Inc. October 8, 2021. Accessed March 3, 2023. https://enzyvant.com/enzyvant-receives-fda-approval-for-rethymic-allogeneic-processed-thymus-tissue-agdc-a-one-time-regenerative-tissue-based-therapy-for-pediatric-congenital-athymia/