Clinical trial NCT00579709: Thymus Transplantation With Immunosuppression
Official title: Thymus Transplantation With Immunosuppression, #884
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: DiGeorge Syndrome
DiGeorge Anomaly
Complete DiGeorge Anomaly
Complete DiGeorge Syndrome
Keywords: Thymus Transplantation
DiGeorge Anomaly
DiGeorge Syndrome
Athymia
Low T cell numbers
Immunoreconstitution
Immunodeficiency
Complete DiGeorge
Typical DiGeorge
Atypical DiGeorge
Complete DiGeorge Anomaly
Lead sponsor: Sumitomo Pharma Switzerland GmbH
Sponsor class: INDUSTRY
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2007-12-24
Enrollment: 15
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The research purpose is to determine if thymus transplantation with immunosuppression is a safe and effective treatment for complete DiGeorge anomaly. The research includes studies to evaluate whether thymus transplantation results in complete DiGeorge anomaly subjects developing a normal immune system.

Detailed description: DiGeorge anomaly is a complex of cardiac defects, parathyroid deficiency, and thymus absence, resulting in profound T-cell deficiency. There is a spectrum of disease in DiGeorge anomaly with respect to all three defects. For complete DiGeorge anomaly subjects with severe T cell defect, the PI had shown that thymus transplantation is safe and efficacious without pretransplantation immunosuppression and with pretransplantation Thymoglobulin and cyclosporine.

Some DiGeorge patients have very poor T cell function and are at risk of death from infection or other immune problems; however, these patients have enough T cell function to reject grafts. This protocol was designed for these patients. Atypical phenotype and some typical phenotype DiGeorge subjects were included in this protocol.

Atypical complete DiGeorge anomaly patients have rash, lymphadenopathy, and oligoclonal T cell proliferations. The T cells have no markers of thymic function (they do not co-express CD45RA and CD62L; they do not contain T cell receptor rearrangement excision circles, TRECs).

Typical complete DiGeorge anomaly patients in this protocol are those whose PHA response \>20 fold. Although these patients have very low T cell function, it may be enough to reject a transplant, so Thymoglobulin was used.

Eligibility criteria: Transplant Inclusion

* No age limit
* Thyroid studies must be done and if abnormal, must be on therapy

DiGeorge diagnosis - must have 1 symptom from the following list:

* Heart defect
* Hypocalcemia requiring replacement
* 22q11 hemizygosity
* 10p13 hemizygosity
* CHARGE association
* Abnormal ears plus mother with diabetes (type I, type II, or gestational)

Atypical Diagnosis:

* Must have, or have had, a rash. If rash present, biopsy of rash must show T cells in skin. If rash \& adenopathy resolved, must still have oligoclonal T cells.
* Within 1 month of tx must have PHA response \>20 fold above background or \>5,000 cpm, whichever is higher, or response can be \< this.
* Circulating CD3+ T cells \>50/mm3 but CD45RA+CD62L+CD3+ T cells \<50/mm or \<5% of CD3 count, whichever is higher (must be done 2x)
* Immunoscope with \>40% oligoclonal TCRBV families. A 2nd test per sponsor discretion if T cell numbers increase or activation status changes.
* If TREC done pre-tx must have TRECs \<100 per 100,000 CD3+ cells.

Typical Diagnosis:

* Circulating CD3+ CD45RA+ CD62L+ T cells and \<50/mm3 or \<5% of total T cells
* PHA response \>20 fold above background or \>5,000 cpm, whichever is higher.
* 2 studies must show similar immunological findings qualify for this study.
* TRECs, if done, should be \<100/100,000 CD3 cells

Transplant Exclusion:

* Heart surgery \<4 weeks pre-tx date
* Heart surgery anticipated w/in 3 months of proposed tx
* Rejection by surgeon or anesthesiologist as surgical candidates
* Lack of sufficient muscle tissue to accept 0.2 grams/kg transplant

Primary outcomes:
measure: Safety & tolerability of Thymoglobulin and cyclosporine followed by thymus transplantation: Survival at 1 year post-transplantation.
timeFrame: 1 year post-transplantation
Secondary outcomes:
measure: Use of additional post transplant immunosuppression after that listed in the protocol.
timeFrame: The post thymus transplantation period
measure: Allograft biopsy used to evaluate graft rejection
timeFrame: 2 to 4 months post-transplant
measure: CD3 count
timeFrame: 10 - 14 months post-transplantation
measure: Thymopoiesis
timeFrame: 2-4 months after thymus transplantation
measure: CD4 count
timeFrame: 10-14 months after thymus transplantation
measure: CD8 count
timeFrame: 10-14 months after thymus transplantation
measure: naive CD4 count
timeFrame: 10-14 months after thymus transplantation
measure: naive CD8 count
timeFrame: 10-14 months after thymus transplantation
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University Medical Center, Pediatrics, Allergy & Immunology
name: M. Louise Markert, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, Le Deist F, Alexieff MJ, Li J, Hauser ER, Haynes BF, Rice HE, Skinner MA, Mahaffey SM, Jaggers J, Stein LD, Mill MR. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003 Aug 1;102(3):1121-30. doi: 10.1182/blood-2002-08-2545. Epub 2003 Apr 17.
citation: Chinn IK, Olson JA, Skinner MA, McCarthy EA, Gupton SE, Chen DF, Bonilla FA, Roberts RL, Kanariou MG, Devlin BH, Markert ML. Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation. J Allergy Clin Immunol. 2010 Oct;126(4):814-820.e8. doi: 10.1016/j.jaci.2010.07.016. Epub 2010 Sep 15.
citation: Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sedlak DA, Sempowski GD, Hale LP, Rice HE, Mahaffey SM, Skinner MA. Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome. Blood. 2004 Oct 15;104(8):2574-81. doi: 10.1182/blood-2003-08-2984. Epub 2004 Apr 20.
citation: Markert ML, Devlin BH, McCarthy EA. Thymus transplantation. Clin Immunol. 2010 May;135(2):236-46. doi: 10.1016/j.clim.2010.02.007. Epub 2010 Mar 16.
citation: Markert ML and Devlin BH. Thymic reconstitution (in Rich RR, Shearer WT, Fleischer T, Schroeder HW, Weyand CM, Frew A, eds., Clinical Immunology 3rd edn., Elsevier, Edinburgh) p 1253-1262, 2008.
citation: Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, Chinn IK, Hale LP, Kepler TB, He M, Sarzotti M, Skinner MA, Rice HE, Hoehner JC. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007 May 15;109(10):4539-47. doi: 10.1182/blood-2006-10-048652. Epub 2007 Feb 6.
citation: Selim MA, Markert ML, Burchette JL, Herman CM, Turner JW. The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol. 2008 Apr;35(4):380-5. doi: 10.1111/j.1600-0560.2007.00816.x.
citation: Chinn IK, Devlin BH, Li YJ, Markert ML. Long-term tolerance to allogeneic thymus transplants in complete DiGeorge anomaly. Clin Immunol. 2008 Mar;126(3):277-81. doi: 10.1016/j.clim.2007.11.009. Epub 2007 Dec 26.
citation: Markert ML, Li J, Devlin BH, Hoehner JC, Rice HE, Skinner MA, Li YJ, Hale LP. Use of allograft biopsies to assess thymopoiesis after thymus transplantation. J Immunol. 2008 May 1;180(9):6354-64. doi: 10.4049/jimmunol.180.9.6354.
citation: Hudson LL, Louise Markert M, Devlin BH, Haynes BF, Sempowski GD. Human T cell reconstitution in DiGeorge syndrome and HIV-1 infection. Semin Immunol. 2007 Oct;19(5):297-309. doi: 10.1016/j.smim.2007.10.002. Epub 2007 Nov 26.
citation: Markert ML, Devlin BH, Chinn IK, McCarthy EA, Li YJ. Factors affecting success of thymus transplantation for complete DiGeorge anomaly. Am J Transplant. 2008 Aug;8(8):1729-36. doi: 10.1111/j.1600-6143.2008.02301.x. Epub 2008 Jun 28.
citation: Markert ML, Devlin BH, McCarthy EA, Chinn IK, Hale LP. Thymus Transplantation in Thymus Gland Pathology: Clinical, Diagnostic, and Therapeutic Features. Eds Lavinin C, Moran CA, Morandi U, Schoenhuber R. Springer-Verlag Italia, Milan, 2008, pp 255-267.
citation: Markert ML, Devlin BH, Chinn IK, McCarthy EA. Thymus transplantation in complete DiGeorge anomaly. Immunol Res. 2009;44(1-3):61-70. doi: 10.1007/s12026-008-8082-5.
citation: Markert ML, Marques JG, Neven B, Devlin BH, McCarthy EA, Chinn IK, Albuquerque AS, Silva SL, Pignata C, de Saint Basile G, Victorino RM, Picard C, Debre M, Mahlaoui N, Fischer A, Sousa AE. First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases. Blood. 2011 Jan 13;117(2):688-96. doi: 10.1182/blood-2010-06-292490. Epub 2010 Oct 26.
citation: Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, Sempowski GD, Rhein ME, Szabolcs P, Hale LP, Buckley RH, Coyne KE, Rice HE, Mahaffey SM, Skinner MA. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases. J Allergy Clin Immunol. 2004 Apr;113(4):734-41. doi: 10.1016/j.jaci.2004.01.766.
citation: Albuquerque AS, Marques JG, Silva SL, Ligeiro D, Devlin BH, Dutrieux J, Cheynier R, Pignata C, Victorino RM, Markert ML, Sousa AE. Human FOXN1-deficiency is associated with alphabeta double-negative and FoxP3+ T-cell expansions that are distinctly modulated upon thymic transplantation. PLoS One. 2012;7(5):e37042. doi: 10.1371/journal.pone.0037042. Epub 2012 May 10.
citation: Chinn IK, Milner JD, Scheinberg P, Douek DC, Markert ML. Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3- T cells in complete DiGeorge anomaly. Clin Exp Immunol. 2013 Jul;173(1):140-9. doi: 10.1111/cei.12088.