CD40 Deficiency, CD40 Ligand Deficiency, Chronic Granulomatous Disease, Common Variable Immunodeficiency (CVID), DiGeorge Syndrome, GATA2 Associated Immunodeficiency, Hypomorphic RAG1 Deficiency, Hypomorphic RAG2 Deficiency, Immune Dysregulation, Immune Dysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome, Mendelian Susceptibility to Mycobacterial Disease, Omenn Syndrome, Primary Immune Regulatory Disorder, STAT 1 Gain of Function, STAT 3 Gain of Function
Conditions
Keywords
HSCT, CVID, PIRD, primary immune regulatory disorder, common variable immunodeficiency, IPEX like syndromes, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome), DiGeorge Syndrome, Combined Immunodeficiency, Chronic Granulomatous Disease, STAT 1 Gain of Function, STAT 3 Gain of Function, Hypomorphic RAG 1 and RAG 2, CD40 or CD40L deficiency, Mendelian Susceptibility to Mycobacterial Disease, GATA2 Associated Immunodeficiency, Inflamed Cartilage Syndrome (MAGIC)
Brief summary
This is a research protocol that will examine Hematopoietic Stem Cell Transplantation (HSCT) using a reduced conditioning regimen (RIC) with total body Irradiation (TBI) in those diagnosed with Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD).
Detailed description
Hematopoietic stem cell transplant (HSCT) with reduced-intensity conditioning has been demonstrated as the best definitive therapy to correct many of these inheritable immune defects (Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD). This is a single center, open label, non-randomized, Phase II study in which subjects receive an allogenic, fully (8 of 8 match) or partially Human Leukocyte Antigen (HLA)-matched (6-7/8 HLA-matched), stem cell transplant utilizing a conditioning regimen of alemtuzumab/Campath, anti-thymocyte globulin/rabbit (ATG), Fludarabine and Melphalan and Total Body Irradiation (TBI). Graft sources include bone marrow or mobilized peripheral blood stem cells from either a related or unrelated donor. After stem cell infusion, subjects are followed for 2 years per standard of care practices.
Interventions
BIOLOGICALHematopoietic stem cell transplant (HSCT)
The participant will receive an allogenic, fully (8 of 8 match) or partially HLA-matched (6-7/8 HLA-matched), stem cell transplant utilizing a conditioning regimen of alemtuzumab/Campath, anti-thymocyte globulin/rabbit ATG, Fludarabine and Melphalan and total body irradiation.
Sponsors
Paul Szabolcs
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
single center, open label, non-randomized
Eligibility
Sex/Gender
ALL
Age
5 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
1. Patient, parent, or legal guardian must have given written informed consent. For pediatric subjects who are developmentally able, assent or affirmation will be obtained. 2. Male or female, 5 through 40 years old, inclusive, at the time of informed consent. 3. Patients must have evidence of common variable immunodeficiency (CVID) or other autoimmune manifestation of a primary immune regulatory disorder (PIRD). Genetic screening is required by a targeting gene panel to determine presence of genetic variations that may lead to inborn errors of immunity. Examples of such diseases include, but are not limited to: * Common variable immunodeficiency (CVID) * Combined Immunodeficiency (CID) * Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX syndrome), IPEX like syndromes * Combined immunodeficiency with defects in T-cell-mediated immunity, including Omenn syndrome and DiGeorge Syndrome * Chronic Granulomatous Disease (CGD) * Signal Transducer and Activator of Transcription (STAT 1) Gain of Function (STAT1 GOF) * Signal Transducer and Activator of Transcription (STAT 3) Gain of Function (STAT3 GOF) * Hypomorphic Recombination-Activating Genes (RAG) 1 and RAG 2 * CD40 or CD40L deficiency * Mendelian Susceptibility to Mycobacterial Disease * GATA-binding factor 2 (GATA2) Associated Immunodeficiency * Mouth and Genital Ulcers with Inflamed Cartilage Syndrome (MAGIC) 4. Must have previously failed, due to lack of response or intolerance, mycophenolate mofetil and a B cell-depleting antibody, such as Rituximab 5. Glomerular Filtration Rate (GFR) ≥50 mL/min/1.73 m2 6. Aspartate Aminotransferase (AST) ≤4x upper limit of normal 7. Alanine Aminotransferase (ALT) ≤4x upper limit of normal 8. Direct bilirubin ≤ 2.5 mg/dL 9. Human Immunodeficiency Virus (HIV) negative by serology and PCR 10. Human T-cell Lymphotropic Virus (HTLV) negative by serology 11. Cardiac ejection fraction ≥ 40% or shortening fraction ≥26% 12. Forced Vital Capacity (FVC) and Forced Expiratory Volume in 1 second (FEV1) ≥40% predicted for age 13. Peripheral Capillary Oxygen Saturation (SpO2) of \>92% at rest on room air 14. Subjects must be a minimum of 8 weeks post-solid organ transplant prior to start of conditioning, if applicable 15. Negative pregnancy test for females \>10 years old or who have reached menarche, unless surgically sterilized. 16. All females of childbearing potential and sexually active males must agree to use a FDA approved method of birth control for up to 12 months after stem cell transplant or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause birth defects. 17. Subject and/or parent guardian informed of the potential risks of infertility following stem cell transplant and advised to discuss sperm banking or oocyte harvesting. 18. Transplant endorsement from clinical immunologist
Exclusion criteria
1. Allergy to Dimethylsulfoxide (DMSO) or any other ingredient used in the manufacturing of the stem cell product 2. Uncontrolled systemic infection, as determined by the appropriate confirmatory testing e.g. blood cultures, Polymerase chain reaction (PCR) testing, etc. 3. Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of stem cell transplant 4. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the subject's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival post-HSCT | 2 years post transplant | review of the existing medical records to check on the participant's survival status |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| engraftment, based upon chimerism data | 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months | review of chimerism test results in the existing medical records to check on degree of donor engraftment measured by the percentage of donor-derived blood cells in the HSCT recipient |
| Assess myeloid, B and T cell chimerism | up to 2 years post translant | review test results from medical records to check how donor and recipient cells populate different immune lineages post-transplant |
| Assess Immunoglobulin A (IgA), Immunoglobulin (IgM), and Immunoglobulin E (IgE) reconstitution | up to 2 years post transplant | review of the existing medical records to check on the participant's humoral immune recovery. |
| independence of immunoglobulin replacement (IVIG, IgG) | 1 and 2 year post transplant | Determine and probability |
| incidence of acute graft versus host disease (GVHD) | 6 months post transplant | grades 3-4 |
| chronic graft-versus-host-disease | 1 year post transplant | grades 3-4 |
Countries
United States
Contacts
CONTACTShawna A McIntyre, RN
PRINCIPAL_INVESTIGATORPaul Szabolcs, MD
UPMC Children's Hospital of Pittsburgh
Outcome results
None listed