Lung and Bone Marrow Transplantation for Lung and Bone Marrow Failure

Lung Transplant in Tandem With Bone Marrow Transplant for Combined Lung and Bone Marrow Failure

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.

Study Overview

• Status: Recruiting
• Conditions: Idiopathic Pulmonary Fibrosis; Emphysema or COPD
• Intervention / Treatment: Drug: Rituximab; Drug: Alemtuzumab; Drug: Thiotepa; Biological: CD3/CD19 negative hematopoietic stem cells; Drug: Fludarabine; Drug: G-CSF; Drug: Hydroxyurea

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.

• Study Type: Interventional
• Enrollment (Estimated): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Paul Szabolcs, M.D.; Phone Number: 412-692-5427; Email: Paul.Szabolcs@chp.edu
• Study Contact Backup: Name: Shawna H McIntyre, RN; Phone Number: 4126925552 412-692-5552; Email: mcintyresm@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC
      • Principal Investigator: Paul Szabolcs, MD
      • Contact: Shawna H McIntyre, RN; Phone Number: 412-692-5552; Email: mcintyresm@upmc.edu
    • Pittsburgh, Pennsylvania, United States, 15214
      • Recruiting
      • UPMC Presbyterian
      • Contact: John McDyer, MD; Phone Number: 412-648-6161; Email: mcdyerjf@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

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

Experimental: Lung and Bone Marrow Transplantation; All patients will undergo a cadaveric, partially HLA-matched lung transplantation followed by a CD3+/CD19+ depleted BMT from the same donor. In this study, the investigators will use a ≥1/6 HLA-matched T cell depleted bone marrow transplantation from a cadaveric organ donor with an identical ABO blood type as the recipient. Prior to transplantation, the marrow will be negatively selected for CD3/CD19 using a CliniMACS® depletion device. Subjects will undergo lung transplantation utilizing standard induction regimens selected by the CO-PIs based on the subject's underlying comorbidities and allosensitization. Rituximab may be initiated prior to the lung transplantation with tacrolimus as the ongoing maintenance immunosuppression. Subjects will undergo BMT utilizing CD3+/CD19+-depleted bone marrow with bone marrow conditioning beginning no less than 8 weeks after lung transplantation. Bone marrow will be recovered alongside solid organs and will be processed and cryopreserved.

Drug: Rituximab; Transplantation Conditioning; Other Names: Rituxan; Drug: Alemtuzumab; Transplantation Conditioning; Other Names: Campath-1H; Drug: Thiotepa; Transplantation Conditioning; Biological: CD3/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; Drug: Fludarabine; Transplantation Conditioning; Other Names: Fludara, Oforta; Drug: G-CSF; Transplantation conditioning; Other Names: Neupogen, Granix, Zarxio, Filgrastim; Drug: Hydroxyurea; Transplantation Conditioning

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	How many, if any, patients die	Up to 2 years post stem cell transplant
Engraftment failure	How many, if any, develop engraftment failure	Up to 2 years post stem cell transplant
Non-hematologic events	Any Grade 4 event that happens at any time points	Up to 2 years post stem cell transplant
Hematological events	Any Grade 4 hematological events	after 30 days post stem cell transplant
BOS Score	Bronchiolitis Obliterans Syndrome (BOS) score based off patient pulmonary function testing. Graded on scale (BOS0 to BOS3), BOS0 having a better outcome then BOS3	at 1 year post lung transplant
T-cell Chimerism	The number of patients who have ≥25% donor T-cell chimerism	at 12 months post stem cell transplant
Myeloid chimerism	The number of patients with myeloid disorders who attain ≥ 10% myeloid chimerism	at 12 months post stem cell transplant
Restoration of blood cell count (in absence of growth factors)	Absolute neutrophil count (ANC)≥1000 per microliter of blood, platelets ≥50000 per microliter of blood and hematocrit ≥8 grams per deciliter of blood	at 12 months post stem cell transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of patients able to proceed to BMT within 6 months following lung transplantation	The number of patients who are able to proceed to BMT within 6 months following lung transplantation	Up to 2 years post stem cell transplant
Independence	The number of patients who are able to be independent from transfusions and growth factors for at least 7 days	up to 2 years post stem cell transplant
Independence	The number of patients who are able to be independent from transfusions and growth factors for at least 1 month	Up to 2 years post stem cell transplant
Tolerance development to both host and pulmonary grafting	Development of tolerance to both the host and pulmonary graft	Up to 2 years post stem cell transplant
Long-term complications	Long-term complications of combined solid organ and BMT	Up to 2 years post stem cell transplant
Acute cellular rejection	The number of patients who develop acute cellular rejection	Up to 2 years post stem cell transplant
Acute graft-versus-host-disease (GVHD)	The number of patients who develop acute graft-versus-host-disease (GVHD)	Up to 2 years post stem cell transplant
Chronic graft-versus-host-disease (GVHD)	The number of patients who develop chronic graft-versus-host-disease (GVHD)	Up to 2 years post stem cell transplant
Ability to withdrawal immunosuppression	The number of patients who are able to start immunosuppression withdrawal.	By 1 year post stem cell transplant
Time to withdraw immunosuppression	Time from BMT to withdrawal of immunosuppression	Up to 2 years post stem cell transplant
Prophylactic antimicrobial drugs	Time from BMT to independence for prophylactic antimicrobial drugs	Up to 2 years post stem cell transplant
Treatment antimicrobial drugs	Time from BMT to independence from treatment antimicrobial drugs	up to 2 years post stem cell transplant
Chronic lung allograft dysfunction	The number of patients who develop chronic lung allograft dysfunction post lung transplant for all subjects, lung only and lung +stem cell transplant.	1 year post lung transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pace of immune reconstitution	The pace of immune reconstitution, systemically and in mucosal surfaces	Up to 2 years post stem cell transplant
Mixed chimerism	The number of patients who have the incidence of mixed chimerism (.5% host cells)	at Months 1, 3, 6 and 12 post stem cell transplant
In vitro immune tolerance	The number of patients who have in vitro immune tolerance	Up to 2 years post stem cell transplant

Collaborators and Investigators

• Sponsor: Paul Szabolcs

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2018
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 30, 2018
• First Submitted That Met QC Criteria: April 9, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Stem Cell Transplantation; Unrelated donor; Bone marrow transplantation; BMT; HSCT; Pulmonary fibrosis; Idiopathic Pulmonary Fibrosis; IPF; Lung Transplantation; Emphysema or COPD; Cadaveric donor; HLA-Mismatch
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Lung Diseases, Interstitial; Chronic Disease; Fibrosis; Pulmonary Emphysema; Emphysema; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Bone Marrow Failure Disorders; Pancytopenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Antisickling Agents; Rituximab; Fludarabine; Hydroxyurea; Thiotepa; Alemtuzumab
• Other Study ID Numbers: PRO17110400

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