Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: Phase I/II Thymus Transplantation With Immunosuppression #950

Summary: The study purpose is to determine if thymus transplantation with immunosuppression is a safe and effective treatment for atypical complete DiGeorge anomaly. This study will also evaluate whether thymus and parathyroid transplantation with immunosuppression is a safe and effective treatment for atypical complete DiGeorge anomaly and hypoparathyroidism.

Detailed description: Complete DiGeorge anomaly is a congenital disorder characterized by athymia. Without successful treatment, children remain immunodeficient and usually die by age 2 years. In infants with complete DiGeorge anomaly and no T cells, thymus transplantation without immunosuppression resulted in diverse T cell development and good T cell function. Some infants with no thymus have some T cells that presumably developed extrathymically; these T cells can reject a thymus graft. The purpose of this study is to design better immunosuppression use for complete DiGeorge anomaly subjects who have some T cells and different T cell function levels. This protocol includes 3 immunosuppression regimens to allow subjects with different T cell function levels to be suppressed adequately.
  DiGeorge infants who have successful thymus transplants but remain with hypoparathyroidism must go to the clinic for frequent calcium levels and to the hospital for calcium infusions; these infants are at risk for seizures from low calcium. This study had a parental parathyroid transplant arm for subjects with hypoparathyroidism who require calcium replacement.
  Whether or not a subject was enrolled in the parathyroid arm, the immunosuppression regimen the subject received was dependent on the immune findings as stated in the clinical protocol.

Eligibility: Tx Inclusion:
  -  Must have 1 of following: 22q11 or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart defect; CHARGE association or CHD7 mutation; or abnormal ears plus mother w/diabetes (type I, type II, gestational).
  -  <50 CD3+ T cells/cumm or <50 CD3+ T cells/cumm that are CD62L+ CD45RA+, or <5% of CD3+ count being CD62L + CD45RA+
  Atypical DiGeorge: Must have, or have had, a rash. If rash present, rash biopsy must show T cells in skin. If rash & adenopathy resolved, must have >50/cumm T cells & naive T cell must be <50/cumm or <5% of T cells.
  Typical DiGeorge: CD3+ CD45RA+ CD62L+ T cells <50/mm3 or <5% of total T cells
  - Must be eligible for 1 of 3 Regimens:
  R#1 - Typical DiGeorge with PHA response >5000 cpm and >20 fold response. Must have PHA response <50,000cpm. If PHA response >50,000 pre-tx, subject will move to R#2.
  R#2 - Typical DiGeorge with PHA responses >50,000 cpm; or atypical DiGeorge with PHA response <75,000cpm (when not on immunosuppression) or <40,000 cpm to PHA while on immunosuppression.
  R#3 - Atypical DiGeorge with PHA responses >75,000cpm while on no immunosuppression or PHA responses >40,000cpm while on immunosuppression pre-tx.
  Parathyroid Tx Additional Inclusion:
  -  2 studies which PTH<5 pg/ml when ionized calcium <1.1 mmol/L. Can be done anytime pre-tx; 1 must be done while at Duke Hospital.
  -  Parent(s) willing & eligible to be donors
  Tx Exclusion:
  -  Heart surgery <4 wks pre-tx
  -  Heart surgery anticipated w/in 3 months after proposed tx
  -  Rejection by surgeon or anesthesiologist as surgical candidate
  -  Lack of sufficient muscle tissue to accept transplant of 4 grams/m2 BSA
  -  HIV infection
  -  Prior attempts at immune reconstitution, such as bone marrow tx or previous thymus tx
  -  CMV(>500 copies/ml blood by PCR on 2 tests)
  -  Ventilator dependence
  Parathyroid Donor Inclusion:
  •>18 years of age
  -  Serum calcium in normal range
  -  Normal PTH function
  -  HLA typing consistent with parentage
  -  Not on anticoagulation or can come off
  -  Parent chosen will share HLA-DR allele with thymus donor that was not inherited by the recipient. If no HLA matching at all, then either parent acceptable if meet other criteria.
  Parathyroid Donor Exclusion:
  -  <18 years old
  -  Hypoparathyroidism-low PTH in presence of low serum calcium & high serum phosphate
  -  Hyperparathyroidism(or history)-elevated PTH in presence of high serum calcium and low serum phosphate.
  -  History of cancer
  -  Donor only living involved parent/guardian of recipient
  -  Evidence of HIV-1, HIV-2, HTLV-1, HTLV-2, syphilis, hepatitis B, hepatitis C, West Nile virus, or Chagas disease
  -  Creutzfeldt Jakob disease (CJD)
  -  Elevated liver function studies: AST, ALT, alkaline phosphatase >3x upper normal limit
  -  Receipt of xenograft or risk factors for SARS, CJD and/or smallpox exposure. {If CJD risk factors but not active disease, parent may give permission for parathyroid use.}
  -  Urine CMV positive
  -  Positive CMV IgM
  -  Positive IgM anti-EBV VCA
  -  On blood thinners and cannot stop for parathyroid donation
  -  Elevated PT or PTT (>ULN)
  -  Platelets<100,000
  -  Positive Toxoplasma IgM
  -  Donor will receive a history and physical; may be excluded based on PI's medical judgment.
  -  Hemoglobin <9g/dl
  -  Infectious head or neck lesion
  -  Goiter on ultrasound
  -  Abnormal fiberoptic laryngoscopy of vocal cords
  -  HLA inconsistent with parentage
  -  Pregnancy
  -  Positive HSV IgG isn't exclusion; post-tx prophylaxis needed for recipient if donor is HSV IgG+.
  -  Positive VZV IgG isn't exclusion; post-tx prophylaxis needed if donor is VZV IgG+.
  -  Medical concern of independent otolaryngologist.
  -  Concern by medical psychologist/social worker that potential donor isn't competent or does not understand risks.
  -  Questionnaire responses can lead to exclusion.
  Biological Mother Inclusion:
  • Provides consent to use blood/buccal sample. No exclusions except unwillingness to consent; or, provide blood/buccal sample.

Relevance to patient case: not relevant