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

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).

Study Overview

• Status: Recruiting
• Conditions: Chronic Granulomatous Disease; DiGeorge Syndrome; Immune Dysregulation; Common Variable Immunodeficiency (CVID); Omenn Syndrome; CD40 Ligand Deficiency; Mendelian Susceptibility to Mycobacterial Disease; Primary Immune Regulatory Disorder; STAT 1 Gain of Function; STAT 3 Gain of Function; Hypomorphic RAG1 Deficiency; GATA2 Associated Immunodeficiency; CD40 Deficiency; Hypomorphic RAG2 Deficiency; Immune Dysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome
• Intervention / Treatment: Biological: Hematopoietic stem cell transplant (HSCT)

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.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shawna A McIntyre, RN; Phone Number: 1-412-692-5552; Email: mcintyresm@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • UPMC Children's Hospital of Pittsburgh
      • Contact: A
      • Contact: Shawna McIntyre; Phone Number: 4126925552; Email: mcintyresm@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Hematopoietic 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	Biological: Hematopoietic 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival post-HSCT	review of the existing medical records to check on the participant's survival status	2 years post transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
engraftment, based upon chimerism data	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	1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months
Assess myeloid, B and T cell chimerism	review test results from medical records to check how donor and recipient cells populate different immune lineages post-transplant	up to 2 years post translant
Assess Immunoglobulin A (IgA), Immunoglobulin (IgM), and Immunoglobulin E (IgE) reconstitution	review of the existing medical records to check on the participant's humoral immune recovery.	up to 2 years post transplant
independence of immunoglobulin replacement (IVIG, IgG)	Determine and probability	1 and 2 year post transplant
incidence of acute graft versus host disease (GVHD)	grades 3-4	6 months post transplant
chronic graft-versus-host-disease	grades 3-4	1 year post transplant

Collaborators and Investigators

• Sponsor: Paul Szabolcs
• Investigators: Principal Investigator: Paul Szabolcs, MD, UPMC Children's Hospital of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2026
• Primary Completion (Estimated): May 4, 2030
• Study Completion (Estimated): February 1, 2031

Study Registration Dates

• First Submitted: December 8, 2025
• First Submitted That Met QC Criteria: December 8, 2025
• First Posted (Actual): December 16, 2025

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Chronic Granulomatous Disease; HSCT; DiGeorge Syndrome; CVID; common variable immunodeficiency; enteropathy; Combined Immunodeficiency; Immune dysregulation; PIRD; primary immune regulatory disorder; IPEX like syndromes; polyendocrinopathy; X-linked (IPEX syndrome); 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)
• Additional Relevant MeSH Terms: Primary Immunodeficiency Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Chronic Disease; Disease Attributes; Genetic Diseases, Inborn; Metabolic Diseases; Immune System Diseases; Digestive System Diseases; Gastrointestinal Diseases; Infant, Newborn, Diseases; Leukocyte Disorders; Hematologic Diseases; Immunologic Deficiency Syndromes; Lymphatic Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Parathyroid Diseases; Cardiovascular Abnormalities; Heart Defects, Congenital; Abnormalities, Multiple; Blood Protein Disorders; Genetic Diseases, X-Linked; DNA Repair-Deficiency Disorders; Phagocyte Bactericidal Dysfunction; Chromosome Disorders; Dysgammaglobulinemia; Lymphatic Abnormalities; Hypoparathyroidism; 22q11 Deletion Syndrome; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Hemic and Lymphatic Diseases; Intestinal Diseases; Severe Combined Immunodeficiency; Granulomatous Disease, Chronic; Common Variable Immunodeficiency; Hyper-IgM Immunodeficiency Syndrome; DiGeorge Syndrome; Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome; Therapeutics; Surgical Procedures, Operative; Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Stem Cell Transplantation
• Other Study ID Numbers: STUDY25080140

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No