Thymus Transplantation Safety-Efficacy

Complete DiGeorge anomaly (cDGA) is a disorder in which there is no thymus function. With no thymus function, bone marrow stem cells do not develop into educated T cells, which fight infection. Without successful treatment, patients with cDGA must remain in reverse isolation to prevent infection and subsequent death.

Cultured thymus tissue with and without immunosuppression (drugs given before and after implantation) has resulted in the development of good T cell function in subjects with complete DiGeorge anomaly.

This expanded access study continues cultured thymus tissue safety and efficacy research for the treatment of complete DiGeorge anomaly. Eligible participants receive cultured thymus tissue. Immune function testing is continued for one year post-implantation.

Complete DiGeorge anomaly (cDGA) is a congenital disorder characterized by athymia. Without successful treatment, patients with cDGA must remain in reverse isolation to prevent infection and subsequent death. In patients with cDGA, implantation of cultured thymus tissue with and without immunosuppression has resulted in diverse T cell development and good T cell function. Protocol specified studies continue until approximately one year post-implantation. Study participation lasts two years.

Patients with Typical complete DiGeorge Anomaly usually have a) less than 50 naive T cells/mm3 or naive T cells that are less than 5% of T cells and b) a low proliferative responses to mitogens (e.g. \< a 20 fold response to the mitogen phytohemagglutinin or a response of fewer than 5,000 cpm). These patients do not have diffuse rashes or lymphadenopathy. Occasional patients with typical complete DiGeorge anomaly have proliferative responses to mitogens. Patients with the typical phenotype can develop an atypical phenotype with time.

Patients with Atypical complete DiGeorge Anomaly meet the criteria for athymia (less than 50/mm3 naive T cells or less than 5% of the T cells having the naive phenotype). Patients with the atypical phenotype have developed rash, lymphadenopathy, and oligoclonal T cells. The T cells may infiltrate the liver resulting in elevated liver transaminases. The oligoclonal T cells developing in patients with DiGeorge anomaly may or may not respond to the mitogen phytohemagglutinin (PHA) in vitro.

The purpose of this expanded access study is to continue cultured thymus tissue safety and efficacy research for the treatment of athymia in patients with cDGA. Until administration of cultured thymus tissue is FDA approved as standard care for cDGA, research study participation is the only means by which a patient may have access to this potentially life-saving procedure.

This protocol includes 4 groups: one for subjects who do not require immunosuppression; and 3 immunosuppression groups for subjects with different T cell function levels to be suppressed adequately.

Group 1 :

Typical cDGA No Immunosuppression group. Subjects receive thymus transplant. Subjects do not receive any pre or post-transplantation immunosuppression.

Group 2 :

Typical and Atypical cDGA Immunosuppression group. Subjects receive thymus transplant. Subjects receive three doses of 2 mg/kg of rabbit anti-thymocyte globulin IV pre- transplantation.Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.

Group 3 :

Atypical cDGA Immunosuppression group. Subjects receive thymus transplant. Subjects receive Pre-transplant cyclosporine (Csa) as soon as complete DiGeorge anomaly is diagnosed. Csa continues with target trough levels of 180 to 220 ng/ml. When trough levels are outside of range, dosing is modified appropriately. If subject cannot tolerate Csa, the Csa may be changed to tacrolimus (FK506) with target trough level 7 to 10 ng/ml. When trough levels are outside of this target range, dosing will be modified appropriately. Pre-transplant steroids are used for atypical subjects if pre-transplant T cells \>4,000/mm3. Three doses of 2 mg/kg of rabbit anti-thymocyte globulin IV are given pre-transplant. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin.

Group 4:

Atypical cDGA Additional Immunosuppression group. Subjects receive thymus transplant. Subjects receive Pre-transplant cyclosporine (Csa) and steroids are started after atypical complete DiGeorge anomaly is diagnosed. After PHA response is documented \>40,000 cpm on suppression, peri-transplant Csa is maintained at target levels 250 to 300 ng/ml. (When levels outside of range, dose modified.) If subject cannot tolerate Csa then may be changed to tacrolimus (FK506) with target level 10 to 15 ng/ml. When levels are outside of range, dosing is modified. Three doses of 2 mg/kg rabbit anti-thymocyte globulin IV are given pre-transplantation. Medications (diphenhydramine, steroids, and acetaminophen) are given with rabbit anti-thymocyte globulin. Additional immunosuppression: Basiliximab, 5 mg/kg single dose IV; Mycophenolate Mofetil (MMF), 15 mg/kg/dose every 8 hours IV or enteral.

Protocol pre-specified concomitant medications

Drug: Rabbit anti-thymocyte globulin Other Names: RATGAM Three IV doses of 2 mg/kg RATGAM are given prior to implantation of cultured thymus tissue for immune suppression groups 2, 3, and 4. Each dose is given over 12 hours. RATGAM is usually given on days -5, -4, and -3 prior to implantation of cultured thymus tissue.

Drug: Cyclosporine Other Names: Csa Csa may be given every 8 or every 12 hours orally or IV before and after implantation of cultured thymus tissue for immune suppression groups 3 and 4. The Csa dose is dependent on T cell numbers and the target CSA trough levels. Csa is weaned as per protocol.

Drug: Tacrolimus Other Names: FK506 If unable to tolerate cyclosporine, then FK506 is given. FK506 may be given every 8 or every 12 hours orally or IV before and after implantation of cultured thymus tissue. FK506 dose is dependent on T cell numbers and the target FK506 trough levels. FK506 is weaned as per protocol.

Drug: Methylprednisolone or Prednisolone Other Names:Steroids Steroids IV or orally may be given before and/or after implantation of cultured thymus tissue. Steroid administration and dosage depends on T cell numbers. Steroids are weaned as per protocol.

Drug: Mycophenolate mofetil Other Names: MMF, CellCept Mycophenolate mofetil (MMF) may be given if the T cell count remains elevated 5 days after implantation of cultured thymus tissue. If MMF is given, the dose is 15 mg/kg/dose every 8 hours IV or orally. MMF may be stopped at 35 days or continued for up to six months after implantation of cultured thymus tissue.

Eligibility Criteria:
Inclusion criteria for implantation of cultured thymus tissue:

* Must have 1 of following: 22q11.2ds or 10p13 hemizygosity; hypocalcemia requiring replacement; congenital heart disease; or CHARGE syndrome or CHD7 mutation
* Complete DiGeorge: \<50 CD3+ T cells/cumm or \<50 CD3+ T cells/cumm that are CD62L+ CD45RA+, or \<5% of CD3+ cells are CD62L+ CD45RA+
* Atypical DiGeorge subjects must have, or have had, a rash.

Group 1

•Typical cDGA whose T cells have a phytohemagglutinin (PHA) response of \< 5,000 counts per minute (cpm) and \< 20 fold PHA response.

Group 2

•Typical cDGA whose T cells have a PHA response of \>5,000 cpm and \<50,000 cpm and \>20 fold PHA response.

Group 3

* Typical cDGA whose T cells have a PHA response of \>50,000 cpm.
* Typical cDGA with maternal engraftment
* Atypical cDGA whose T cells have a PHA response of \<40,000 cpm when on immunosuppression or \<75,000 cpm to PHA when not on immunosuppression.
* Atypical cDGA with group 3 PHA response \& maternal engraftment

Group 4

* Atypical cDGA with PHA responses of \>75,000 cpm while on no immunosuppression or a PHA responses of \>40,000 cpm while on immunosuppression.
* Atypical cDGA with maternal engraftment and group 4 PHA response

Exclusion criteria for implantation of cultured thymus tissue:

* Heart surgery conducted less than 4 weeks prior to projected implantation date.
* Heart surgery anticipated within 3 months after the proposed time of implantation
* Rejection by surgeon or anesthesiologist as surgical candidate
* Lack of sufficient muscle tissue to accept a transplant
* HIV infection
* Prior attempts at immune reconstitution, such as bone marrow transplant or previous thymus transplant
* CMV infection: For Groups 2, 3, and 4 CMV infection documented by \>500 copies/ml in the blood by PCR on two consecutive assays.
* Ventilator Dependence or Positive Pressure Support: Ventilator support or positive pressure support, such as Continuous Positive Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP) support for a condition that is deemed to be severe or irreversible or which renders the subject too clinically unstable to undergo the procedures.