allogeneic processed thymus tissue (Rx)

>10%

Hypertension (19%)

Cytokine release syndrome (18%)

Hypomagnesemia (16%)

Rash (15%)

Renal impairment/failure (12%)

Thrombocytopenia (12%)

1-10%

Graft versus host disease (GVHD) (10%)

Neutropenia (9%)

Respiratory distress (8%)

Proteinuria (7%)

Pyrexia (6%)

Acidosis (6%)

Diarrhea (5%)

Seizure (5%)

Contraindications

None

Cautions

Preexisting renal impairment is a risk factor for death

Preexisting CMV infection may result in death before development of thymic function; benefits/risks of treatment should be considered prior to treating patients with preexisting CMV infection

Because of underlying immune deficiency, patients may be at risk of posttreatment lymphoproliferative disorder

Monitoring

• Monitor for development of autoimmune disorders, including complete blood cell counts with differential, liver enzymes, serum creatinine, urinalysis, and thyroid function
• Monitor complete blood counts with differential weekly for first 2 months post-treatment and then monthly through 12 months post-treatment
• Liver enzymes including aspartate aminotransferase and alanine aminotransferase, serum creatinine levels, and urinalysis should be performed monthly for 3 months and then every 3 months through 12 months post-treatment
• Thyroid function studies should be performed prior to treatment and then at 6 months and 12 months post-treatment; after 12 months, testing should be performed annually
• Patients should be tested for EBV and CMV using PCR prior to and 3 months following treatment, or after any exposure to or suspected infection with CMV or EBV
• If fever develops, assess patient by blood and other cultures and treat with antimicrobials as clinically indicated

Graft versus host disease

• Monitor and treat patients at risk of developing graft versus host disease (GVHD); risk factors include atypical complete DiGeorge anomaly phenotype, prior hematopoietic cell transplant, and maternal engraftment
• Patients with elevated baseline T-cell proliferative response to phytohemagglutinin (PHA) >5,000 cpm or >20-fold over background should receive immunosuppressive therapies to decrease risk of GVHD; development of GVHD symptoms should be closely monitored and promptly treated
• GVHD may manifest as fever, rash, lymphadenopathy, elevated bilirubin and liver enzymes, enteritis, and/or diarrhea

Infection control and immunoprophylaxis

• Immune reconstitution sufficient to protect from infection is unlikely to develop until 6-12 months after implantation; given the immunocompromised condition of athymic patients, follow infection control measures until the development of thymic function can be established

• Maintain on immunoglobulin until all following criteria met

  • No longer on immunosuppression (≥10% of CD3+ T-cells are naïve in phenotype)
  • ≥9 months posttreatment
  • PHA response within normal limits
  • Normal serum IgA is desirable but not required

• 2 months after stopping immunoglobulin, IgG trough level should be checked

  • If IgG trough level is normal range for age, patient can remain off immunoglobulin replacement
  • If IgG trough level is lower than normal range for age, restart immunoglobulin replacement therapy and continue for a year before being retested using the above guidelines

• Before and after treatment, maintain patient on Pneumocystis jirovecii pneumonia prophylaxis until all following criteria met

  • No longer on immunosuppression (≥10% of CD3+ T-cells are naïve in phenotype)
  • ≥9 months posttreatment
  • PHA response within normal limits
  • CD4+ T-cell count >200 cells/mm³

Transmission of serious infections and transmissible infections

• Transmission of infectious disease may occur because the implants are derived from human tissue
• Screen donors for increased risk of infection with HIV, human T-cell lymphotropic virus, HBV, HCV, Treponema pallidum, Trypanosoma cruzi, West Nile virus, transmissible spongiform encephalopathy agents, vaccinia, and Zika virus
• Screen donors screened for clinical evidence of sepsis and communicable disease risks associated with xenotransplantation (eg, CMV)

HLA

• Anti-HLA antibodies

  • Screen for anti-HLA antibodies before treatment
  • Patients testing positive for anti-HLA antibodies should receive allogeneic processed thymus tissue from a donor who does not express those HLA alleles

• HLA typing

  • HLA matching required in patients who have received a prior hematopoietic cell transplantation (HCT) or a solid organ transplant
  • Patients who have received a prior HCT are at increased risk of developing GVHD after allogeneic processed thymus tissue if the HCT donor did not fully match the recipient
  • Minimize this risk by HLA matching to recipient alleles that were not expressed in the HCT donor

Immunizations

• Do no administer immunizations after implantation until immune-function criteria have been met

• Inactivated vaccines: May administer once all of the criteria are met

  • Immunosuppressive therapies have been discontinued
  • IgG replacement therapy has been discontinued
  • Total CD4+ T-cell count >200 cells/mm³ and there are more CD4+ T cells than CD8+ T cells (CD4+ > CD8+)
  • Limit inactivated vaccines to 2 vaccines/month

• Live vaccines

  • Live virus vaccines should not be administered until patients have met the criteria for inactivated vaccines and received vaccinations with inactivated agents (eg, tetanus toxoid)
  • No additional vaccines (live or inactivated), except the inactivated influenza vaccine, should be given within 6 months after vaccination with a measles-containing vaccine or within 2 months after the varicella vaccine
  • Consider verifying response to vaccination with appropriate testing, in particular varicella and measles

Mechanism of Action

Allogeneic processed thymic tissue is intended to reconstitute immunity in patients who are athymic

Proposed mechanism of action involves migration of recipient T-cell progenitors from the bone marrow to the surgically implanted allogeneic thymic tissue slices, where they develop into naïve immunocompetent recipient T cells

The thymus is responsible for T-cell selection to fight infections; 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 surgical implantation

Congenital athymia is an ultra-rare condition in which children are born without a thymus, causing profound immunodeficiency, vulnerability to potentially fatal infections, and life-threatening immune dysregulation

Implant Preparation

A manufacturing team assists the surgical team for the implantation procedure within the sterile field

Surgical Implantation

A qualified surgical team performs the surgical implantation in a single surgical session at a qualified hospital

Slices providing the prespecified dose are implanted in the quadriceps muscle in accordance with the instructions provided in prescribing information

Implantation into the quadriceps requires a healthy bed of muscle tissue

Storage

Store at room temperature in the polycarbonate container in the insulated shipping box until ready for use

Do not refrigerate, freeze, agitate, or sterilize