Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)

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.

• Hematopoietic stem cell transplant (HSCT) (Biological): 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.

Primary outcomes

• Survival post-HSCT [2 years post transplant]: review of the existing medical records to check on the participant's survival status

Secondary outcomes

• 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

Sex: All, ages: 5 Years to 40 Years

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.

• Paul Szabolcs, MD, Principal investigator, UPMC Children's Hospital of Pittsburgh