Background

Rethymic is a product derived from donor thymus tissue that is surgically implanted into pediatric patients with congenital athymia to restore immune function. The dosage is determined by the total surface area of the Rethymic slices and recipient body surface area (BSA) and is calculated and adjusted by the manufacturer. It is important to note that it takes 6-12 months after treatment with Rethymic for immune reconstitution to occur. Thus, patients must still follow infection control precautions and delay immunizations until immune function criteria have been met.

Congenital athymia is an ultra-rare condition with an incidence of approximately 17-24 live births per year in the United States. Patients with this condition are born without a thymus causing them to have profound immunodeficiency. Without treatment, these patients typically die from infections or autoimmune symptoms by 2 or 3 years of age. The thymus controls the development and maturation of T-lymphocytes (also called T-cells), which are essential for protection against infections. Without a thymus gland, T-cell progenitors from the bone marrow are unable to develop into naïve T-cells. This condition often occurs in babies who have certain genetic problems, especially DiGeorge syndrome or 22q11.2 deletion syndrome. In fact, the term congenital athymia was previously used interchangeably with complete DiGeorge anomaly or DiGeorge syndrome. However, current research indicates that there are distinct genetic and nongenetic conditions associated with congenital athymia. Other genetic conditions associated with congenital athymia include coloboma, heart defects, atresia choanae, retardation of growth and development, genital hypoplasia, and ear anomalies/deafness (CHARGE syndrome), as well as forkhead box protein N1 (FOXN1) deficiency. Nongenetic environmental factors (e.g., maternal diabetes; exposure to alcohol, retinoids, or bis-dichloroacetylamine) have also been associated with congenital athymia.

Congenital athymia is sometimes mistaken for severe combined immunodeficiency (SCID); patients with either disorder present with very low T-cell counts. Both congenital athymia and SCID are primary immunodeficiency disorders, but they are 2 separate conditions. SCID is caused by a dysfunction of hematopoietic stem cells of the bone marrow, whereas congenital athymia is associated with a dysfunction or absence of the thymus. These conditions can be differentiated by flow cytometry results, genetic testing for genes associated with either condition, or testing of hematopoietic stem cells using an artificial thymic organoid (ATO) system.

Policy

The use of Rethymic is MEDICALLY NECESSARY for the treatment of Congenital Athymia when the following criteria has been met:

• Used for immune reconstitution in pediatric patients; AND
• Patient has a diagnosis of congenital athymia 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 (Note: Requests for naïve T-cell counts ≥50 cells/mm3 will be handled on a case-by-case basis); AND
  • Patient has athymia with a diagnosis of FOXN1 deficiency, OR
  • Patient has complete DiGeorge syndrome (cDGS), also referred to as complete DiGeorge anomaly (cDGA); AND
• Will not be used for the treatment of patients with severe combined immunodeficiency (SCID); AND
• Will not be used in patients with heart surgery anticipated within 4 weeks prior to, or 3 months after, Rethymic treatment, HIV infection, or those deemed to be poor surgical candidates; AND
• Benefits and risks of treatment have been discussed with patient who have a pre-existing CMV infection or who have renal impairment; AND
• Patient has been screened for anti-HLA antibodies (Note: Patients who had previously received a transplant with a mismatched allele require HLA matching of the thymus to that allele); AND
• Patient will receive IVIG replacement and prophylactic antimicrobials prior to and after transplant until immune reconstitution (according to infection control protocols) occurs (Note: immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6-12 months after treatment with Rethymic); AND
• Patient will not receive live or inactivated vaccine until IVIG/immunosuppressive therapy is discontinued and immune reconstitution has occurred; AND
• Patients with elevated baseline T cell proliferative response to PHA ≥ 5,000 cpm or > 20- fold over background or have evidence of maternal engraftment will receive combination therapy with immunosuppressive agents (e.g., rabbit antithymocyte globulin with or without calcineurin inhibitors and/or steroids

Definition of complete DiGeorge syndrome (cDGS) or complete DiGeorge anomaly (cDGA)

Athymia plus one of the following criteria:

• • congenital heart defect
  • hypoparathyroidism (or hypocalcemia requiring calcium replacement)
  • 22q11 hemizygosity
  • 10p13 hemizygosity
  • CHARGE (coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear defects including deafness) Syndrome
  • CHD7 mutation

References

1. Rethymic [package insert]. Enzyvant Therapeutics, Inc. Cambridge, MA. Updated October 2021.
2. Rethymic (allogeneic processed thymus tissue-agdc) New Drug Review. IPD Analytics. Updated October, 2021.
3. Markert ML, Gupton SE, McCarthy EA.(2022) 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.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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