Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases

Phase 1

• Conditions: 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)
• Interventions: Biological: CD3/CD19 negative allogeneic hematopoietic stem cells

• Registration Number: NCT01852370
• Lead Sponsor: Paul Szabolcs

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.

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 Timeline

• Study First Submitted: 2013-04-26
• Study First Submitted QC: 2013-05-08
• Study First Posted: 2013-05-13
• Study Start: 2013-06-20
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-22
• Last Update Posted: 2024-11-26
• Primary Completion: 2025-11
• Study Completion: 2026-11

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BOLT+BMT	CD3/CD19 negative allogeneic hematopoietic stem cells	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Graft failure	Up to 2 years post stem cell transplant	The number of patients who develop graft failure.
Acute graft-versus-host disease (GVHD)	Up to 2 years post stem cell transplant	The number of patient who develop acute graft-versus-host disease (GVHD).
Lymphocyte count - for T-cell lymphopenias	1 year post stem cell transplant	The number of patients who are able to achieve an age adjusted, low limit normal range lymphocyte count.
Chronic graft-versus-host disease (GVHD)	Up to 2 years post stem cell transplant	The number of patient who develop chronic graft-versus-host disease (GVHD).
Ability to withdraw immunosuppression	1 year post stem cell transplant	The number of patients who are able to start immunosuppression withdrawal.
Allograft failure	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.
Tolerance	Up to 2 years post stem cell transplant	Development of tolerance to both the host and pulmonary graft.
Acute cellular rejection	Up to 2 years post stem cell transplant	The number of patients who develop acute cellular rejection.
Time to withdraw immunosuppression	Up to 2 years post stem cell transplant	Time from BMT to withdrawal of immunosuppression.
Feasibility of meeting BMT eligibility critieria	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.
Long-term complications	Up to 2 years post stem cell transplant	Long-term complications of combined solid organ and BMT.
Pathogen-specific immunity	Up to 2 years post stem cell transplant	Time from BMT to independence from treatment dose antimicrobial drugs.
Chronic lung allograft dysfunction	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.
Rituximab related adverse events	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.

Trial Locations

Locations (1)

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States