Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases (BOLT+BMT)

• ClinicalTrials.gov Identifier: NCT01852370
• Recruitment Status: Enrolling by invitation
• First Posted: May 13, 2013
• Last Update Posted: November 8, 2022
• Sponsor: Paul Szabolcs
• Information provided by (Responsible Party): Paul Szabolcs, University of Pittsburgh

Study Description

Brief Summary:

The purpose of this study is to determine whether bilateral orthotopic lung transplantation (BOLT) followed by cadaveric partially-matched hematopoietic stem cell transplantation (HSCT) is safe and effective for patients aged 5-45 years with primary immunodeficiency (PID) and end-stage lung disease.

Condition or disease	Intervention/treatment	Phase
Severe Combined Immunodeficiency (SCID); Immunodeficiency With Predominant T-cell Defect, Unspecified; Severe Chronic Neutropenia; Chronic Granulomatous Disease (CGD); Hyper IgE Syndromes; Hyper IgM Deficiencies; Wiskott-Aldrich Syndrome; Mendelian Susceptibility to Mycobacterial Disease; Common Variable Immune Deficiency (CVID)	Biological: CD3/CD19 negative allogeneic hematopoietic stem cells	Phase 1; Phase 2

Detailed Description:

This is an original IND for an investigator initiated phase I/II study. The primary purpose of the study is to evaluate the safety and efficacy of performing bilateral orthotopic lung transplantation (BOLT) followed by cadaveric, partially HLA-matched CD3+/CD19+-depleted hematopoietic stem cell transplantation (HSCT) from the same donor for patients with primary immunodeficiency diseases (PID) and end-stage lung disease. For many patients with primary immunodeficiencies, HSCT is a curative, life-saving therapy, resulting in restoration of function in the immune system. Patients with primary immunodeficiencies often develop pulmonary complications as a result of chronic or recurrent infections, making them ineligible for HSCT due to the high risk of mortality and pulmonary complications. Lung transplant prior to HSCT would allow for restoration of pulmonary function prior to HSCT, allowing PID patients to proceed to HSCT, which would be curative for the patient's underlying immunodeficiency. As a secondary aim after successful engraftment with donor bone marrow, there is realistic hope for tolerating planned withdrawal of immunosuppression achieving eventual freedom from all immunosuppressive drugs and attaining a tolerant state.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 16 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bilateral Orthotopic Lung Transplant in Tandem With CD3+ and CD19+ Cell Depleted Bone Marrow Transplant From Partially HLA-Matched Cadaveric Donors
• Actual Study Start Date: June 20, 2013
• Estimated Primary Completion Date: November 2023
• Estimated Study Completion Date: November 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: BOLT+BMT; All patients will receive a double lung transplant followed by a hematopoietic stem cell transplant. The lungs and stem cells are from the same partially HLA-matched cadaveric donor. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device.	Biological: CD3/CD19 negative allogeneic hematopoietic stem cells; Negative selection for CD3/CD19 will be performed on a CliniMACS® depletion device within 36 hours of collection and given at time no less than 8 weeks post lung transplant.

Outcome Measures

Primary Outcome Measures :

1. Safety: Death [ Time Frame: Up to 2 years post stem cell transplant ]
   How many, if any, patients die.
2. Safety: Engraftment syndrome [ Time Frame: Up to 2 years post stem cell transplant ]
   How many, if any, patients develop engraftment syndrome.
3. Safety: Engraftment failure [ Time Frame: Up to 2 years post stem cell transplant ]
   How many patients, if any, develop engraftment failure.
4. Safety: Rituximab [ Time Frame: Up to 2 years post stem cell transplant ]
   The number of grade 4 and 5 events potentially related to rituximab.
5. Efficacy: BOS score [ Time Frame: 1 year post stem cell transplant ]
   Bronchiolitis Obliterans Syndrome (BOS) score for all patients who receive both lungs and stem cell transplants.
6. Efficacy: T-cell chimerism [ Time Frame: 1 year post stem cell transplant ]
   The number of patients who have ≥ 25% donor T-cell chimerism.
7. Efficacy: Myeloid chimerism [ Time Frame: 1 year post stem cell transplant ]
   The number of patients with myeloid disorders (e.g. CGD) who attain ≥ 10% myeloid chimerism.
8. Efficacy: B-cell chimerism [ Time Frame: 1 year post stem cell transplant ]
   The number of patients with B-cell disorders who attain ≥ 10% B-cell chimerism.

Secondary Outcome Measures :

1. Feasibility of meeting BMT eligibility critieria [ Time Frame: Up to 2 years post stem cell transplant ]
   The number of patients who are able to proceed to BMT within 6 months following lung transplant.
2. Tolerance [ Time Frame: Up to 2 years post stem cell transplant ]
   Development of tolerance to both the host and pulmonary graft.
3. Long-term complications [ Time Frame: Up to 2 years post stem cell transplant ]
   Long-term complications of combined solid organ and BMT.
4. Graft failure [ Time Frame: Up to 2 years post stem cell transplant ]
   The number of patients who develop graft failure.
5. Acute cellular rejection [ Time Frame: Up to 2 years post stem cell transplant ]
   The number of patients who develop acute cellular rejection.
6. Acute graft-versus-host disease (GVHD) [ Time Frame: Up to 2 years post stem cell transplant ]
   The number of patient who develop acute graft-versus-host disease (GVHD).
7. Chronic graft-versus-host disease (GVHD) [ Time Frame: Up to 2 years post stem cell transplant ]
   The number of patient who develop chronic graft-versus-host disease (GVHD).
8. Ability to withdraw immunosuppression [ Time Frame: 1 year post stem cell transplant ]
   The number of patients who are able to start immunosuppression withdrawal.
9. Time to withdraw immunosuppression [ Time Frame: Up to 2 years post stem cell transplant ]
   Time from BMT to withdrawal of immunosuppression.
10. Pathogen-specific immunity [ Time Frame: Up to 2 years post stem cell transplant ]
    Time from BMT to independence from treatment dose antimicrobial drugs.
11. Lymphocyte count - for T-cell lymphopenias [ Time Frame: 1 year post stem cell transplant ]
    The number of patients who are able to achieve an age adjusted, low limit normal range lymphocyte count.
12. Chronic lung allograft dysfunction [ Time Frame: 1 year post lung transplant ]
    The number of patients who develop chronic lung allograft dysfunction post-lung transplant for all subjects, lung only and lung+stem cell transplant.
13. Allograft failure [ Time Frame: 1 year post lung transplant ]
    The number of patients who develop allograft failure post-lung transplant for all subjects, lung only and lung+stem cell transplant.
14. Rituximab related adverse events [ Time Frame: From the time of the first dose of rituximab up to the start of BMT conditioning. ]
    The number of grade 4 or 5 adverse events possibly related to the use of rituximab.

Eligibility Criteria

• Ages Eligible for Study: 5 Years to 45 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

1. Subject and/or parent guardian must be able to understand and provide informed consent.
2. Male or female, 5 through 45 years old, inclusive, at the time of informed consent.

3. Patients must have evidence of an underlying primary immunodeficiency for which BMT is clinically indicated.

   Examples of such diseases include, but are not limited to:

   • Severe Combined Immunodeficiency
   • Combined immunodeficiency with defects in T-cell-mediated immunity, including Omenn syndrome and DiGeorge Syndrome
   • Severe Chronic Neutropenia
   • Chronic Granulomatous Disease
   • Hyper IgE Syndrome or Job Syndrome
   • CD40 or CD40L deficiency
   • Wiskott-Aldrich Syndrome
   • Mendelian Susceptibility to Mycobacterial Disease [6]
   • GATA2 Associated Immunodeficiency NOTE: A genetic diagnosis is recommended, but not required.
4. Patients must have evidence of end-stage lung disease and be candidates for bilateral orthotopic lung transplant as determined by the lung transplant team.
5. GFR ≥ 50 mL/min/1.73 m2.
6. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL, normal INR.
7. Cardiac ejection fraction ≥ 40% or shortening fraction ≥26%.
8. Negative pregnancy test for females >10 years old or who have reached menarche, unless surgically sterilized.
9. All females of childbearing potential and sexually active males must agree to use a FDA approved method of birth control for up to 24 months after BMT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause birth defect.
10. Subject and/or parent guardian will also be counseled regarding the potential risks of infertility following BMT and advised to discuss sperm banking or oocyte harvesting.

Exclusion Criteria

Individuals who meet any of these criteria are not eligible for this study:

1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol.
2. Patients who have underlying malignant conditions.
3. Patients who have non-malignant conditions not requiring hematopoietic stem cell transplantation.
4. HIV positive by serology or PCR, HTLV positive by serology.
5. Females who are pregnant or who are lactating.
6. Allergy to DMSO or any other ingredient used in the manufacturing of the stem cell product.
7. Uncontrolled pulmonary infection, as determined by radiographic findings and/or significant clinical deterioration. NOTE: Pulmonary colonization with multiple organisms is common, and will not be considered an exclusion criterion.
8. Uncontrolled systemic infection, as determined by the appropriate confirmatory testing e.g. blood cultures, PCR testing, etc.
9. Recent recipient of any licensed or investigational live attenuated vaccine(s) within 4 weeks of transplant.
10. 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 participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

Eligibility Criteria to proceed to Bone Marrow Transplant

1. GFR ≥ 50 mL/min/1.73 m2.
2. AST, ALT ≤ 4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL.
3. Cardiac ejection fraction ≥ 40% or shortening fraction of at least 26%.
4. HIV negative by serology and PCR.
5. HTLV serology negative.
6. FVC and FEV1 ≥40% predicted for age and SpO2 of >90% at rest on room air AND with clearance by the lung transplant team.
7. Absence of uncontrolled infection as determined by positive blood cultures and radiographic progression of previous sites in particular pulmonary densities during the past 2 weeks prior to chemotherapy.
8. Absence of clinically significant Acute Cellular Rejection (A2-A4 and/or B2R rejection).

Contacts and Locations

Locations

United States, Pennsylvania

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

Sponsors and Collaborators

Paul Szabolcs

Investigators

• Principal Investigator: Paul Szabolcs, MD; Division of BMT and Cellular Therapy, Children's Hospital of Pittsburgh of UPMC

More Information

• Responsible Party: Paul Szabolcs, Chief, Division of Blood and Marrow Transplant, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01852370
• Other Study ID Numbers: STUDY19090108
• First Posted: May 13, 2013
• Last Update Posted: November 8, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Paul Szabolcs, University of Pittsburgh:

Lung transplantation; Bone Marrow Transplantation; Unrelated Donor; Cadaveric Donor; Deceased Donor; HLA-mismatch; BOLT; BMT; HSCT

Additional relevant MeSH terms:

Mycobacterium Infections; Neutropenia; Granulomatous Disease, Chronic; Wiskott-Aldrich Syndrome; Job Syndrome; Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes; Common Variable Immunodeficiency; Syndrome; Disease; Pathologic Processes; Immune System Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Hematologic Diseases; Phagocyte Bactericidal Dysfunction; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Primary Immunodeficiency Diseases; Infant, Newborn, Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hemorrhagic Disorders; Lymphopenia; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections