Allogeneic Processed Thymus Tissue–agdc (Rethymic)

Number: 1055

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses allogeneic processed thymus tissue–agdc (Rethymic) for commercial medical plans.

1. Exclusions 

   Aetna will considers members not eligible for Rethymic when any of the following apply:

   1. The member has a diagnosis of severe combined immunodeficiency (SCID);
   2. The member has preexisting cytomegalovirus infection (CMV) or human immunodeficiency virus (HIV) infection;
   3. The member has previously received thymus tissue transplantation or been treated with Rethymic in his or her lifetime.

2. Prescriber Specialties

   This medication must be prescribed by or in consultation with a pediatric immunologist.

3. Criteria for Initial Approval

   Aetna considers a single administration of allogeneic processed thymus tissue–agdc (Rethymic) medically necessary for for immune reconstitution in the pediatric member (less than or equal to 18 years of age) with congenital athymia when all of the following criteria are met:

   1. Congenital athymia is confirmed via flow cytometry as less than 50 naïve T cells/mm³ in the peripheral blood or less than 5% of total T cells being naïve in phenotype; and
   2. Documentation that infection control measures, including immunoprophylaxis, can reasonably be maintained until the development of thymic function is established; and
   3. Absence of comorbidities, in the opinion of the treating clinician, that are reasonably likely to result in severe complications, including death from administration of allogeneic processed thymus tissue (for example, pre-existing renal impairment, or cytomegalovirus or Epstein-Barr virus infection); and
   4. The member should be screened for anti-HLA antibodies prior to receiving Rethymic; and
   5. If the member is positive for anti-HLA antibodies, then the member must receive Rethymic from a donor who does not express HLA alleles; and
   6. The member's dosage will not exceed a single, one-time dose up to 22,000 mm² of Rethymic surface area per m² recipient body surface area (BSA), not to exceed 42 slices as calculated and supplied by the manufacturer.

   Aetna considers all other indications as experimental, investigational, or unproven.

Dosage and Administration

Allogeneic processed thymus tissue–agdc is supplied as Rethymic which consists of yellow to brown slices of allogeneic processed thymus tissue with varying thickness and shape for administration by surgical implantation. Surgical implantation of Rethymic should be done by a qualified surgical team in a single surgical session at a qualified hospital. Rethymic should be implanted in the quadriceps muscle in accordance with the instructions provided below. Implantation of Rethymic into the quadriceps requires a healthy bed of muscle tissue.

Three to 11 drug product containers, with a total of 10 to 42 Rethymic slices, are provided for each recipient. Each drug product container provides up to 4 Rethymic slices of variable size.

The dosage is determined by the total surface area of the Rethymic slices and recipient body surface area (BSA). The total dose is based on the number of slices administered to the recipient with the recommended dose range of 5,000 to 22,000 mm² of Rethymic surface area/m² recipient BSA.

The manufacturer calculates the dose in advance for the specific patient; the amount of product provided is adjusted at the manufacturing facility to ensure the maximum dose for the patient cannot be exceeded. Up to 42 cultured Rethymic slices will be provided for each patient. At the time of surgery, the manufacturing personnel communicate to the surgical team the portion of the product that represents the minimum dose.

Patients with evidence of maternal engraftment or an elevated response to phytohemagglutinin (PHA) should receive Rethymic with immunosuppressive medications.

Surgical implantation of Rethymic should be done by a qualified surgical team in a single surgical session at a qualified hospital. Rethymic should be implanted in the quadriceps muscle in accordance with the instructions provided below. Implantation of Rethymic into the quadriceps requires a healthy bed of muscle tissue.

Refer to full prescribing information for Rethymic for administration instructions.

Source: Sumitomo Pharma America, 2023

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
Administration by surgical implantation of thymus tissue–agdc (Rethymic) –no specific code
Other CPT codes related to the CPB:
86359	T cells; total count
86360	absolute CD4 and CD8 count, including ratio
86361	absolute CD4 count
86828 – 86835	Antibody to human leukocyte antigens (HLA)
HCPCS codes covered if selection criteria are met:
Thymus tissue–agdc (Rethymic) –no specific code
ICD-10 codes covered if selection criteria are met:
Q89.2	Congenital malformation, of other endocrine glands [athymia]
ICD-10 codes not covered for indications listed in the CPB:
B20	Human immunodeficiency virus [HIV] disease
B25.9	Cytomegaloviral disease, unspecified
D81.0	Severe combined immunodeficiency [SCID] with reticular dysgenesis
D81.1	Severe combined immunodeficiency [SCID] with low T- and B-cell numbers
D81.2	Severe combined immunodeficiency [SCID] with low or normal B-cell numbers
D81.31	Severe combined immunodeficiency due to adenosine deaminase deficiency
D81.9	Combined immunodeficiency, unspecified
P35.1	Congenital cytomegalovirus infection
Z21	Asymptomatic human immunodeficiency virus [HIV] infection status

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Rethymic 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).

Allogeneic processed thymus tissue–agdc is available as Rethymic (Sumitomo Pharma America, Inc.). Rethymic consists of yellow to brown slices of allogeneic processed thymus tissue for administration by surgical implantation. Thymus tissue is harvested from donors less than or equal to 9 months of age undergoing cardiac surgery. This thymus tissue is aseptically processed and cultured for 12 to 21 days to produce Rethymic slices. Each product is made from a single unrelated donor and one product lot treats a single patient. The thymic epithelial cells and tissue structure are preserved while most of the donor thymocytes from the tissue are depleted during the manufacturing process. The Rethymic slices are then surgically implanted into patients with congenital athymia (FDA, 2021; Sumitomo Pharma America, 2023).

The suggested mechanism of action for Rethymic involves the migration of recipient T cell progenitors from the bone marrow to the implanted Rethymic slices for development into naïve immunocompetent recipient T cells. Observed thymic function can be evidenced from the development of naïve T cells in the peripheral blood. However, thymic function may unlikely be apparent prior to 6-12 months post-treatment with Rethymic (Sumitomo Pharma America, 2023).

According to the prescribing information, Rethymic carries the following warnings and precautions:

• Immune reconstitution sufficient to protect from infection is unlikely to develop prior to 6 to 12 months after treatment with Rethymic. Given the immunocompromised condition of athymic patients, infection control measures should be followed until the development of thymic function can be established.
• Monitor and treat patients at risk for the development of graft versus host disease (GVHD).
• 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.
• Pre-existing cytomegalovirus infection may result in death prior to the development of thymic function.
• Monitor for the development of lymphoproliferative disorder (blood cancer).
• Transmission of infectious diseases may occur because Rethymic is derived from human tissue.
• Immunizations should not be administered in patients who have received Rethymic until immune-function criteria have been met.
• Patients should be tested for anti-HLA antibodies prior to treatment.

The most common (>10%) adverse events related to Rethymic included: hypertension (high blood pressure, 19%), cytokine release syndrome (18%), rash (15%), hypomagnesemia (low magnesium, 16%), renal impairment / failure (decrease of kidney function, 12%), thrombocytopenia (low platelets, 12%), and graft versus host disease, (10%).

On October 8, 2021, the U.S. Food and Drug Administration approved allogeneic processed thymus tissue (Rethymic) for the treatment of pediatric patients with congenital athymia. This approval was for the first thymus tissue product in the U.S. (FDA, 2021).

The FDA approval was based on supporting data evaluating the safety and efficacy of Rethymic in 10 prospective, single-center, open-label studies for a total of 105 pediatric patients (median age 9 months [range: 33 days to 16.9 years], including 95 pediatric patients (median age 9 months [range: 33 days to 3 years] in the primary efficacy analysis. The demographics and baseline characteristics of the patients enrolled in the clinical studies were similar across studies. 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; 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 (coloboma, heart defect, choanal atresia, growth and development retardation, genital hypoplasia, ear defects including deafness) syndrome, or CHD7 mutation. 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. The baseline demographics and disease characteristics were similar in the safety population. Patients with heart surgery anticipated within 4 weeks prior to, or 3 months after, the planned Rethymic treatment date, patients with human immunodeficiency virus (HIV) infection, and patients who were not considered good surgical candidates were excluded from study participation (Sumitomo Pharma America, 2023).

Patients in the efficacy population received Rethymic in a single surgical procedure at a dose of 4,900 to 24,000 mm² of Rethymic / recipient 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 (Sumitomo Pharma America, 2023).

The analysis of efficacy demonstrated that Rethymic significantly reduced the number of infections over time. In the first year after treatment with Rethymic, the number of patients with an infection event onset 6 to ≤ 12 months after treatment decreased by 38% (from 63 to 39) relative to the number of patients with an infection event onset in the first 6 months post-treatment. A two-year analysis showed a decrease in both the number of patients with an infection event and the mean number of infection events per patient, 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 patient (Sumitomo Pharma America, 2023).

Additionally, within the safety population of 105 patients, survival was similar across age groups. Adverse reactions were noted at similar frequencies across the age groups and were generally of similar types and severities (Sumitomo Pharma America, 2023).

Congenital athymia is an extremely rare disease characterized by the absence of a functioning thymus. This disorder can affect both males and females and its exact incidence and prevalence are unknown. Based on observational data from 1991 through 2017, where 49 afflicted with congenital athymia received supportive care only, the 2-year survival rate was 6%, with all patients dying by 3 years of age. Without treatment, congenital athymia is fatal in childhood. It can be an isolated occurrence or be associated with 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 anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from changes in genes that impact thymic organ development such as FOXN1 and PAX1 or from variants in genes that function in the development of the entire midline region of the body, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. The diagnosis of congenital athymia is based on the identification of characteristic symptoms, a detailed individual and family history and a thorough clinical evaluation. Individuals with congenital athymia have significant immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD) (NORD, 2023; Sumitomo Pharma America, 2023).

Prior to the use of Rethymic, treatment for individuals prioritized the risk reduction of infection until the underlying immune deficiency could be corrected. Treatment and management includes isolation as soon as diagnosis is suspected, prophylactic antibiotic therapy, immunoglobulin replacement, avoidance of live vaccines, checking for blood product contamination as necessary prior to administration to the affected person, immunosuppression therapy, and anti-thymocyte globulin administration prior to receiving a cultured thymus tissue implantation. The main form of therapy is implantation of cultured thymus tissue. In 2021, the U.S. Food and Drug Administration (FDA) approved the use of cultured thymus tissue (Rethymic) for the treatment of pediatric patients with congenital athymia. Several tissue slices, following culture, are implanted into the thigh muscle of an athymic individual to help improve immune function. The implanted Rethymic slices will produce the T cells missing from the affected infant's immune system. The most common adverse effect of Rethymic therapy is autoimmunity in the first year prior to production of diverse T cells (Collins et al., 2021; NORD, 2023).

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References