Emphysema or COPD, Idiopathic Pulmonary Fibrosis
Conditions
Keywords
Lung Transplantation, Stem Cell Transplantation, Idiopathic Pulmonary Fibrosis, Emphysema or COPD, Bone marrow transplantation, Cadaveric donor, Unrelated donor, HLA-Mismatch, BMT, HSCT, IPF, Pulmonary fibrosis
Brief summary
The purpose of this study is to determine whether a lung transplantation prior to bone marrow transplantation (BMT) would allow for restoration of pulmonary function prior to BMT, allowing to proceed to BMT, to restore hematologic function.
Detailed description
The primary purpose of the study is to evaluate the safety and efficacy of performing lung transplantation followed by cadaveric, partially HLA-matched (≥1/6 HLA-match with an identical ABO blood type) CD3+/CD19+ depleted bone marrow transplantation in bone marrow failure and end-stage lung disease. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease for which lung transplantation is the only therapy shown to prolong survival. Given the association of IPF with hematologic cytopenias and bone marrow failure, it is proposed that a tandem lung transplantation and bone marrow transplantation from a single cadaveric donor could be successful. This protocol focuses on performing combined transplantation for candidates that are unable to undergo standard lung transplantation. Lung transplantation prior to bone marrow transplantation (BMT) would allow for restoration of pulmonary function prior to BMT, and to restore hematologic function post BMT transplantation. The secondary objectives are to evaluate the feasibility and long-term complications associated with combined solid organ and BMT including the ability to initiate and successfully withdraw from immunosuppression following BMT and to attain independence from growth factors, red blood cell or platelet transfusions.
Interventions
BIOLOGICALCD3/CD19 negative hematopoietic stem cells
Negative selection for CD3/CD19 will be performed on CliniMACS® depletion device and given at time no less than 8 weeks post lung transplantation
DRUGRituximab
Transplantation Conditioning
DRUGAlemtuzumab
Transplantation Conditioning
DRUGFludarabine
Transplantation Conditioning
DRUGThiotepa
Transplantation Conditioning
DRUGG-CSF
Transplantation conditioning
DRUGHydroxyurea
Transplantation Conditioning
Sponsors
Paul Szabolcs
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Individuals must meet all of the following criteria in order to be eligible for this study. 1. Subject must be able to understand and provide informed consent. 2. Male or female, 18 through 60 years old, inclusive, at the time of informed consent. 3. Meet criteria for UNOS listing for lung transplantation. 4. Patients must have evidence of end stage lung disease. Examples of such diseases include but are not limited to: * Pulmonary Fibrosis * COPD/Emphysema 5. Patients must have evidence of bone marrow failure with abnormal low cell count in at least one hematopoietic line, making the patient a poor candidate for long-term immunosuppressive therapy. Eligible patients must meet at least one of the following criteria: * Unexplained, non-drug induced neutropenia with absolute neutrophils counts of \<1500/µL the previous year, confirmed by repeat testing * Unexplained, non-drug induced thrombocytopenia with mean platelets counts of \<100,000/µL the previous year, confirmed by repeat testing * Unexplained, non-hemolytic anemia, with a hemoglobin level of \< 12 g/dL the previous year, confirmed by repeat testing 6. GFR ≥45 mL/min/1.73 m2. 7. AST, ALT ≤4x upper limit of normal, total bilirubin ≤ 2.5 mg/dL, normal INR, albumin \>3.0 g/dL 8. Cardiac ejection fraction ≥ 40% or shortening fraction ≥26%. 9. Negative pregnancy test for females, unless surgically sterilized. 10. 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. 11. Subject 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 BMT. 4. HIV positive by serology or PCR, HTLV positive by serology. If HTLV serology is positive, it will be confirmed by nucleic acid testing (NAT). If HTLV NAT is negative, subject will remain eligible regardless of HTLV serology result. 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 infection, as determined by the appropriate imaging and/or 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Restoration of blood cell count (in absence of growth factors) | at 12 months post stem cell transplant | Absolute neutrophil count (ANC)≥1000 per microliter of blood, platelets ≥50000 per microliter of blood and hematocrit ≥8 grams per deciliter of blood |
| Myeloid chimerism | at 12 months post stem cell transplant | The number of patients with myeloid disorders who attain ≥ 10% myeloid chimerism |
| T-cell Chimerism | at 12 months post stem cell transplant | The number of patients who have ≥25% donor T-cell chimerism |
| Hematological events | after 30 days post stem cell transplant | Any Grade 4 hematological events |
| Non-hematologic events | Up to 2 years post stem cell transplant | Any Grade 4 event that happens at any time points |
| Death | Up to 2 years post stem cell transplant | How many, if any, patients die |
| Engraftment failure | Up to 2 years post stem cell transplant | How many, if any, develop engraftment failure |
| BOS Score | at 1 year post lung transplant | Bronchiolitis Obliterans Syndrome (BOS) score based off patient pulmonary function testing. Graded on scale (BOS0 to BOS3), BOS0 having a better outcome then BOS3 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ability to withdrawal immunosuppression | By 1 year post stem cell transplant | The number of patients who are able to start immunosuppression withdrawal. |
| Prophylactic antimicrobial drugs | Up to 2 years post stem cell transplant | Time from BMT to independence for prophylactic antimicrobial drugs |
| Treatment antimicrobial drugs | up to 2 years post stem cell transplant | Time from BMT to independence from treatment 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. |
| Time to withdraw immunosuppression | Up to 2 years post stem cell transplant | Time from BMT to withdrawal of immunosuppression |
| Independence | up to 2 years post stem cell transplant | The number of patients who are able to be independent from transfusions and growth factors for at least 7 days |
| Tolerance development to both host and pulmonary grafting | Up to 2 years post stem cell transplant | Development of tolerance to both the host and pulmonary graft |
| Feasibility of patients able to proceed to BMT within 6 months following lung transplantation | Up to 2 years post stem cell transplant | The number of patients who are able to proceed to BMT within 6 months following lung transplantation |
| Long-term complications | Up to 2 years post stem cell transplant | Long-term complications of combined solid organ and BMT |
| Acute cellular rejection | Up to 2 years post stem cell transplant | The number of patients who develop acute cellular rejection |
| Acute graft-versus-host-disease (GVHD) | Up to 2 years post stem cell transplant | The number of patients who develop acute graft-versus-host-disease (GVHD) |
| Chronic graft-versus-host-disease (GVHD) | Up to 2 years post stem cell transplant | The number of patients who develop chronic graft-versus-host-disease (GVHD) |
Other
| Measure | Time frame | Description |
|---|---|---|
| In vitro immune tolerance | Up to 2 years post stem cell transplant | The number of patients who have in vitro immune tolerance |
| Mixed chimerism | at Months 1, 3, 6 and 12 post stem cell transplant | The number of patients who have the incidence of mixed chimerism (.5% host cells) |
| Pace of immune reconstitution | Up to 2 years post stem cell transplant | The pace of immune reconstitution, systemically and in mucosal surfaces |
Countries
United States
Contacts
Primary ContactPaul Szabolcs, M.D.
Backup ContactShawna H McIntyre, RN
Outcome results
None listed