Thymus Transplantation Safety-Efficacy

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.