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Preliminary data suggested a better approach available
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Study Design: SCID infants receiving an unconditioned haploidentical transplant will be started on Sirolimus (0.05 mg/kg/day) day -5 for Acute Graft-Versus-Host Disease (aGVHD) prophylaxis. Sirolimus levels will be monitored with goal sirolimus trough level of 5-8 ng/mL. Patients will be monitored for signs of aGVHD as defined by UCSF SOP CL 221.06 through day +100. Sirolimus will be tapered once T-regulatory cell to CD4 effector cell ratio is > or = 9%.
Setting: Inpatient BMT Unit Benioff Children's Hospital at UCSF Medical Center
Study Subjects: 15 infants with diagnosis of maternally engrafted T cells SCID by CA Newborn screen receiving unconditioned haploidentical HSCT
Main Outcome Measures: Incidence of aGVHD (dermatitis, hepatitis, enteritis) as defined by SOP CL 221.06 by Day +100.
Hypothesis 1. Patients placed on sirolimus prophylaxis will have lower incidence of aGVHD compared to historical controls.
Hypothesis 2. Lower doses of sirolimus milligram per kilogram will be required to maintain goal troughs of 5-8 ng/mL.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sirolimus | Experimental | Sirolimus (0.05 mg/kg/day) day -5 for aGVHD prophylaxis through day +100 or until T-regulatory cells >9% of CD4 effector cells; whichever comes first. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus | Drug |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of aGVHD | Incidence of aGVHD (dermatitis, hepatitis, enteritis) as defined by UCSF SOP CL 221.06 by Day +100. | 105 days |
| Measure | Description | Time Frame |
|---|---|---|
| T-regulatory cell enumeration | T-regulatory cell enumeration studies by blood draw prior to prophylaxis and at day +30, day+60, day+100. | 105 days |
| Sirolimus therapeutic drug monitoring | Sirolimus therapeutic drug monitoring will be done via blood draws(after initial 4th dose; thereafter every 4th dose with adjustment; once stable it will be measured weekly). We will determine the average dose in milligrams per kilograms that would be needed to reach therapeutic trough levels of 5-8 ng/mL. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Chris Dvorak, MD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Benioff Children's Hospital at UCSF Medical Center | San Francisco | California | 94143 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 10021471 | Background | Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL, Myers LA, Ward FE. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999 Feb 18;340(7):508-16. doi: 10.1056/NEJM199902183400703. | |
| 17968328 | Background | Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008 Jan;41(2):119-26. doi: 10.1038/sj.bmt.1705890. Epub 2007 Oct 29. |
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| ID | Term |
|---|---|
| D016511 | Severe Combined Immunodeficiency |
| ID | Term |
|---|---|
| D000081207 | Primary Immunodeficiency Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D007232 | Infant, Newborn, Diseases |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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| 105 days |
| 11535520 | Background | Muller SM, Ege M, Pottharst A, Schulz AS, Schwarz K, Friedrich W. Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients. Blood. 2001 Sep 15;98(6):1847-51. doi: 10.1182/blood.v98.6.1847. |
| 19744131 | Background | Pulsipher MA, Wall DA, Grimley M, Goyal RK, Boucher KM, Hankins P, Grupp SA, Bunin N. A phase I/II study of the safety and efficacy of the addition of sirolimus to tacrolimus/methotrexate graft versus host disease prophylaxis after allogeneic haematopoietic cell transplantation in paediatric acute lymphoblastic leukaemia (ALL). Br J Haematol. 2009 Dec;147(5):691-9. doi: 10.1111/j.1365-2141.2009.07889.x. Epub 2009 Sep 10. |
| 20717025 | Background | Cutler C, Antin JH. Sirolimus immunosuppression for graft-versus-host disease prophylaxis and therapy: an update. Curr Opin Hematol. 2010 Nov;17(6):500-4. doi: 10.1097/MOH.0b013e32833e5b2e. |
| 24497539 | Background | Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014 Mar 27;123(13):2017-25. doi: 10.1182/blood-2013-10-534297. Epub 2014 Feb 4. |
| 18481161 | Background | Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol. 2008 Sep;28(5):581-7. doi: 10.1007/s10875-008-9196-1. Epub 2008 May 15. |
| 19543393 | Background | Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside TL. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One. 2009 Jun 22;4(6):e5994. doi: 10.1371/journal.pone.0005994. |
| 23165499 | Background | Fujioka T, Tamaki H, Ikegame K, Yoshihara S, Taniguchi K, Kaida K, Kato R, Inoue T, Nakata J, Ishii S, Soma T, Okada M, Ogawa H. Frequency of CD4(+)FOXP3(+) regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD. Bone Marrow Transplant. 2013 Jun;48(6):859-64. doi: 10.1038/bmt.2012.232. Epub 2012 Nov 19. |
| D049914 | DNA Repair-Deficiency Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |