Thymus Transplantation Dose in DiGeorge #932
Condition: DiGeorge Anomaly; DiGeorge Syndrome; Complete DiGeorge Anomaly; Complete DiGeorge Syndrome
MeSH terms: DiGeorge Syndrome; Congenital Abnormalities; Syndrome
Intervention: Cultured Thymus Tissue Implantation (CTTI); Cultured Thymus Tissue Implantation with Parathyroid Transplantation
Intervention description: Thymus tissue (from unrelated donor), thymus donor, and thymus donor's birth mother screened for safety. CTTI was done under general anesthesia. Cultured thymus tissue was implanted into quadriceps. Thymus dose at least 4grams/m2 body surface area (0.2 grams/kg body weight) and not >18 grams/m2 body surface area (1.0 grams/kg body weight). At time of CTTI, skin biopsy was obtained to look for preexisting T cells. 2-3 months post-CTTI allograft biopsy was done to evaluate for thymopoiesis & graft rejection. At time of biopsy, skin biopsy done to look for T cell clonal populations. (Allograft biopsy not done if subject medically unstable.) Post-CTTI, subjects followed by immune evaluations, using blood samples.; Parental parathyroid donors screened for eligibility and safety. If both parents meet eligibility criteria, the parathyroid will be harvested from parent who shares the most Human Leukocyte Antigens (HLA) alleles with thymus donor. Parathyroid harvest & transplant preferably done at same time as CTTI. (If parathyroid transplant cannot be done at same time, then it is done within 3-8 weeks of CTTI.) Parathyroid harvest done under general anesthesia. One parathyroid gland is minced & placed in quadriceps muscle; there is no dose in mg. No biopsy done of the parathyroid. Parathyroid donors are monitored as outpatients until recipients' discharge. Recipients' calcium and PTH levels are monitored indefinitely.
Intervention MeSH terms: Parathyroid Hormone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Healthy volunteers: No
Keywords: Thymus Transplantation; DiGeorge Syndrome; DiGeorge Anomaly; Athymia; Parathyroid Transplantation; Hypocalcemia; Hypoparathyroidism; Low T cell numbers; Immunoreconstitution; Immunodeficiency; Complete DiGeorge; Complete DiGeorge Anomaly; Typical DiGeorge; Cultured Thymus Tissue Implantation (CTTI)

Summary:

      One purpose of this study is to determine whether the amount of cultured thymus tissue
      implanted into DiGeorge anomaly infants has any effect on the immune outcome. Another purpose
      of this study is to determine whether parental parathyroid transplantation (in addition to
      cultured thymus tissue implantation (CTTI) can help both the immune and the calcium problems
      in DiGeorge infants with hypocalcemia. [Funding Source - FDA Office of Orphan Products
      Development (OOPD)]
    

Eligibility criteria:

        Thymus Transplant Inclusion Criteria:

          -  A parent or guardian of the DGS subject signed the consent form.

          -  Medical screening was completed.

          -  For a diagnosis of DGS, the subject had to have one of the following:

               -  Congenital heart disease;

               -  Hypocalcemia requiring replacement;

               -  22q11.2 hemizygosity or 10p13 hemizygosity;

               -  CHARGE association or CHD7 mutation;

               -  A subject with abnormal ears whose mother had diabetes (type I, type II, or
                  gestational).

          -  To meet the criteria of typical complete DiGeorge Anomaly (cDGA), the subject had to
             have either:

               -  Circulating CD3+ T cell count by flow cytometry < 50/mm3 OR

               -  Circulating CD3+ T cells that were also positive for Cluster of Differentiation
                  45RA (CD45RA)+ CD62L+ and were < 50/mm3 or less than 5% of total T cells.

        Thymus Transplant Exclusion Criteria:

          -  Had heart surgery less than 4 weeks prior to projected implant date;

          -  Heart surgery anticipated within 3 months after the proposed time of implantation;

          -  Present or past lymphadenopathy;

          -  Rash associated with T cell infiltration of the dermis and epidermis;

          -  Rejection by the surgeon or anesthesiologist as surgical candidate;

          -  Lack of sufficient muscle tissue to accept a transplant of 4 g/m2 body surface area
             (BSA) or 0.2 g/kg subject bodyweight;

          -  Had human immunodeficiency virus (HIV) infection;

          -  Had prior attempts at immune reconstitution, such as bone marrow transplant or
             previous thymus transplantation;

          -  Ventilator support or positive pressure support: Subjects had to be off ventilator or
             other pressure support such as continuous positive airway pressure (CPAP) or bi-level
             positive airway pressure (BiPAP) support for 2 weeks prior to enrollment. If the
             subject was enrolled and was placed back on ventilator or pressure support, the
             subject had to be able to be weaned off and remain off ventilator or pressure support
             for 2 weeks. If the subject could not be successfully weaned off ventilator or
             pressure support, the subject was to be withdrawn from the study.

        Additional Inclusion Criteria for Parathyroid Transplant Recipient:

          -  2 tests in patient showing: intact parathyroid hormone (PTH) < 5 pg/ml when ionized
             calcium < 1.1 mmol/L

          -  All inclusion criteria for thymus transplant must be met

          -  2 involved parents

        Exclusion for Parathyroid Transplant Recipient:

          -  Parents do not meet enrollment criteria.

          -  Parent(s) decline to be parathyroid donor(s).

        Parental Parathyroid Donor Inclusion:

          -  > 18 years old

          -  Answers all questionnaire items and meets safety screening criteria

          -  Normal serum calcium

          -  Normal PTH function

          -  HLA typing consistent with parentage

          -  Parent chosen for donation will share HLA-DR allele in thymus donor; if not
             applicable, then either parent will be selected (if meet all other criteria).

          -  Must not be on anticoagulation or can come off for donation/transplantation

        Parental Parathyroid Donor Exclusion:

          -  Donor is only living involved parent or caretaker of the recipient

          -  Hypoparathyroidism - low parathyroid hormone (PTH) in presence of low serum calcium
             and high serum phosphate

          -  Hyperparathyroidism (or history of) - elevated PTH in presence of high serum calcium
             and low serum phosphate

          -  History of cancer

          -  Evidence of any of following: HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B,
             hepatitis C, West Nile virus, or Trypanosoma Cruzi (Chagas disease)

          -  Elevated AST, ALT, alkaline phosphatase > 3 times upper limit of normal

          -  History including receipt of a xenograft or risk factors for SARS, Mad Cow - Disease
             or smallpox. Note: if parent has Mad Cow Disease risk factors (but not active
             disease), parent(s) may give permission for transplantation.

          -  CMV positive urine

          -  Positive CMV IgM antibodies

          -  Positive IgM anti-EBV VCA

          -  On blood thinners and cannot stop for the parathyroid donation

          -  Elevated PT or PTT (> ULN)

          -  Platelets < 100,000

          -  Positive Toxoplasma IgM

          -  The donor will receive a history and physical; may be excluded based on PI's medical
             judgment

          -  Hemoglobin < 9 g/dl

          -  Infectious lesion on head or neck

          -  Goiter on ultrasound

          -  Abnormal fiberoptic laryngoscopy of vocal cords

          -  Pregnancy

          -  Positive HSV IgG is not an exclusion; however, post transplantation prophylaxis is
             needed

          -  Positive VZV IgG is not an exclusion; however, post transplantation prophylaxis is
             needed

          -  Medical concern of otolaryngologist

          -  Concern by medical psychologist or social worker. Parents are interviewed together and
             separately regarding following areas: medical history; health habits; substance use;
             relationships and support; education/work history; mental status/psychological
             history; readiness for donation.

          -  Questionnaire (safety screening) responses can lead to exclusion.

        Biological Mother of DiGeorge Subject Inclusion Criteria:

          -  Competent to provide consent

          -  Willing to provide blood for testing (No other inclusion/exclusion for mother)