Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Allogenic processed thymus tissue-agdc (e.g., Rethymic)

Description:

Allogeneic processed thymus tissue–agdc (e.g., Rethymic) was approved by the US Food and Drug Administration (FDA) October 8, 2021, a one-time regenerative therapy for the treatment of pediatric individuals with congenital athymia, also referred to as complete DiGeorge anomaly/DiGeorge syndrome (DGS), or 22qll.2 deletion syndrome. Rethymic is not indicated for the treatment of individuals with severe combined immunodeficiency (SCID), a condition that is often mistaken for 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 can be observed with the development of naïve T-cells in the peripheral blood; this is unlikely to be observed until 6-12 months after treatment with Rethymic. Rethymic is administered by a surgical procedure. Dosing is based on total surface area of Rethymic slices and recipient body surface area (BSA).

Congenital athymia is considered an ultra-rare (defined as prevalent in no more than 1:50,000) inherited condition in children, who are born without a thymus and suffer profound T cell deficiency, occurring in approximately 20 live births in the U.S each year. Clinical manifestations in congenital athymia include T cell immunodeficiency, recurrent and persistent infections, and autologous GVHD which contributes to the increased risk of mortality and increased susceptibility to infection in these individuals. Congenital athymia is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary abnormalities, and Ear anomalies), and either typical or atypical Complete DiGeorge Syndrome (Collins,2021). The known genetic mutations associated with congenital athymia include 22q11.2 deletion, and mutations in chromodomain helicase DNA binding protein 7 (CHD7), Forkhead Box Protein N1 (FOXN1), T Box transcription factor 1and 2 (TBX1), (TBX2) and Paired Box 1 (PAX1). T cell deficiency is normally identified during newborn screenings for SCID required in the United States. Despite optimal supportive care, children with congenital athymia typically die by age 2 or 3due to infection or immune dysfunction.

Regulatory Status

The FDA granted approval for Allogeneic processed thymus tissue–agdc in October 2021. With this approval, Enzyvant has obtained a priority review voucher (PRV) under the Rare Pediatric Disease Program. It was also granted multiple FDA designations including Regenerative Medicine Advanced Therapy (RMAT), Breakthrough Therapy, Rare Pediatric Disease, and Orphan Drug designations.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Prior Approval is required for Allogeneic processed thymus tissue–agdc (e.g., Rethymic)

The initial use of this drug requires documentation of direct physician (MD/OD) involvement in the ordering and evaluation as well as a signature in the medical records submitted for prior approval.

Effective August 22, 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The implantation of allogeneic processed thymus tissue–agdc (e.g., Rethymic) as a one-time single administration meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with congenital athymia when ALL the following criteria are met:

The individual is <18 years old AND
Has been ordered under the supervision of a pediatric immunologist or other specialist with expertise in the management of congenital athymia AND
The individual has a confirmed diagnosis of congenital athymia (laboratory and/or medical record documentation of the flow cytometry and genetic testing results confirming the diagnosis must be submitted.)

a. Flow cytometry must show fewer than 50 naïve T cells/cubic millimeters (CD45RA+, CD62L+) in the peripheral blood or less than 5% of total T cells being naïve in phenotype. AND

4. The diagnosis of severe combined immunodeficiency (SCID) has been ruled out (i.e., no SCID-causing genetic defects identified) AND

5. The individual has been, or will be, screened for anti-HLA antibodies prior to receiving Rethymic and individuals testing positive for anti-HLA antibodies should receive allogeneic processed thymus tissue-agdc (e.g., Rethymic) from a donor who does not express those HLA alleles AND

6. The individual will have HLA matching if they have received prior hematopoietic cell transplantation (HCT) or solid organ transplant. To minimize risk of graft-versus-host-disease, confirm HLA matching of Rethymic to recipient alleles that were not expressed in the HCT donor AND

7. Implantation of allogeneic processed thymus tissue–agdc (e.g., Rethymic) will be done by a qualified surgical team in a single surgical session at a qualified hospital AND

8. The individual has not previously received thymus tissue implantation for the treatment of congenital athymia in their lifetime AND

9. Must be dosed in accordance with the FDA label.

Dosing and Administration

Dosing per FDA Guidelines

The recommended dose of allogeneic processed thymus tissue–agdc implantation is a single, one-time dose, up to 22,000 square millimeters of allogeneic processed thymus tissue-agdc/square meters recipient BSA, not to exceed 42 slices, (as calculated and supplied by the manufacturer). Implantation will not exceed this dosage and will be rendered by a qualified surgical team in a single surgical session.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of allogeneic processed thymus tissue–agdc (e.g., Rethymic) for any indication or circumstance other than those described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For individuals with contracts without primary coverage criteria, allogeneic processed thymus tissue–agdc (e.g., Rethymic) for any indication or circumstance other those decirbed above are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Transplantation of fetal thymus tissue to correct cDGS was discovered more than 50 years ago, but it was met with limited success. Use of postnatal thymus tissue obtained from infant donors undergoing cardiac surgery for congenital heart disease started at Duke University in 1993; removal of thymus tissue is necessary for cardiac surgery in these infants. The removed thymus requires culturing for 13-20 days before transplantation to deplete thymocytes while preserving the thymic stroma. This process has been shown to be consistent between slices of the same thymus and between different thymus cultures. The stromal cells retain over 90% estimated viability and the thymus donor is not tissue type-matched with the recipient.

The efficacy of Rethymic was evaluated in 10 prospective, single-center, open-label studies that enrolled a total of 105 patients, including 95 patients in the primary efficacy analysis. The median (range) age at the time of treatment was 9 months (1-36). The diagnosis of congenital athymia 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 in 91/95 patients (range 0-98 naïve T cells/mm3). In addition to congenital athymia, patients also had complete DiGeorge syndrome (cDGS) if they also met at least one of the following criteria: congenital heart defect, hypoparathyroidism, 22q11 hemizygosity, 10p13 hemizygosity, CHARGE (coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear defects including deafness) syndrome, or CHD7 mutation. Across the efficacy population, 93 patients (98%) were diagnosed with cDGS. Patients who did not have congenital athymia (e.g., SCID) and patients with prior transplants, including thymus and HCT, were excluded from the efficacy analysis population. Additionally, patients with heart surgery anticipated within 4 weeks prior to, or 3 months after, the planned Rethymic treatment date, patients with HIV infection, and patients who were not considered good surgical candidates were excluded from study participation.

Patients 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 patients 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 patients who were alive at 1 year after treatment with Rethymic, the survival rate was 94% at a median follow-up of 10.7 years.

Of the 105 patients that have received cultured thymus tissue (CCT), 76 are still alive. Of the 29 patients who died, 23 passed away within 12 months of the implantation. Of the 6 patients who died more than 1 year post implantation, the deaths were considered unrelated to study treatment (2 patients died due to respiratory failure and 1 patient each died following cardiopulmonary arrest, intracranial hemorrhage, infection, and unknown cause).

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

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.

Rethymic (allogeneic processed thymus tissue-agdc) New Drug Review. IPD Analytics. Updated October, 2021.

Rethymic [package insert]. Enzyvant Therapeutics, Inc. Cambridge, MA. Updated October 2021.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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