Reduced-intensity hematopoietic stem cell transplant for CVID and other primary immune regulatory disorders

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

This will try a reduced-intensity hematopoietic stem cell transplant with low-dose total body irradiation to correct or improve severe CVID and related primary immune regulatory disorders in people aged 5 to 40.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 5 Years to 40 Years
• Sex: All
• Sponsor: University of Pittsburgh (other)
• Drugs / interventions: Rituximab, alemtuzumab, Fludarabine
• Locations: 1 site (Pittsburgh, Pennsylvania)
• Trial ID: NCT07284641 on ClinicalTrials.gov

What this trial studies

This single-center, open-label Phase II study gives allogeneic hematopoietic stem cell transplants to patients with common variable immunodeficiency or other primary immune regulatory disorders using a reduced-intensity conditioning regimen. Conditioning combines alemtuzumab (Campath) or rabbit ATG, fludarabine, melphalan and low-dose total body irradiation, and grafts come from 8/8 or 6–7/8 HLA-matched related or unrelated donors using bone marrow or mobilized peripheral blood. The protocol is non-randomized and subjects are followed for two years after infusion according to standard clinical care. The study targets patients with genetic or clinical evidence of PIRD/CVID and uses a targeted gene panel as part of screening.

Who should consider this trial

Good fit: Ideal candidates are people aged 5–40 with genetically or clinically confirmed CVID or other PIRD who have significant immune dysregulation or autoimmune disease and are appropriate candidates for allogeneic HSCT with a suitable 6–8/8 HLA-matched donor.

Not a fit: Patients with mild, well-controlled CVID, those without a suitable donor, or those with serious comorbidities that increase transplant risk may not benefit and could face significant harms from the procedure.

Why it matters

Potential benefit: If successful, this approach could correct underlying immune defects and reduce or eliminate recurrent infections and autoimmune complications, potentially providing long-term benefit or cure for selected patients.

How similar studies have performed: Allogeneic HSCT with reduced-intensity conditioning has produced curative results for many inherited immune regulatory disorders in prior reports, though outcomes for broader CVID populations are more variable and depend on the specific genetic diagnosis.

Eligibility criteria

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.

Where this trial is running

Pittsburgh, Pennsylvania

• UPMC Children's Hospital of Pittsburgh — Pittsburgh, Pennsylvania, United States (RECRUITING)

Study contacts

• Principal investigator: Paul Szabolcs, MD — UPMC Children's Hospital of Pittsburgh
• Study coordinator: Shawna A McIntyre, RN

Conditions: Common Variable Immunodeficiency, Primary Immune Regulatory Disorder, Immune Dysregulation, DiGeorge Syndrome, STAT 1 Gain of Function, STAT 3 Gain of Function, Hypomorphic RAG1 Deficiency, CD40 Ligand Deficiency