Multicenter Analysis of Efficacy and Outcomes of Extracorporeal Photopheresis as Treatment of Chronic Lung Allograft Dysfunction

Lung transplantation is an established therapy for end-stage lung disease such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis and pulmonary hypertension. However, Chronic Lung Allograft Dysfunction (CLAD) is a major cause of morbidity and mortality in long-term survivors. The 5-year survival rate is reported to be 50%, which is considerably inferior compared to other solid organ transplantation. In addition, the financial burden of CLAD (around 80.000 euro/year for a patient with CLAD) is considerable. No curative therapy is available yet. To date, the two most effective treatment are azithromycin and extracorporeal photopheresis. Azithromycin is used as first-line treatment and it is effective in stopping FEV1 decline, however its effects are only limited to a set of patients. ECP can be used as second-line treatment in patients unresponsive to azithromycin. ECP has been firstly developed for treatment of cutaneous T cell lymphomas and later used in a variety of other indications including solid organ transplantation. The process starts with leukapheresis, followed by incubation of the isolated cells with 8-methoxypsoralen (8-MOP) and subsequent activation of 8-MOP with ultraviolet A radiation. At the end, the cells are reinfused into the patient. 8-MOP is a biologically inert substance, but in the presence of UVA light it cross-links DNA by forming covalent bonds with pyrimidine bases and causes apoptosis. ECP is effective in the palliative treatment of cutaneous T-cell lymphoma but its effectiveness was also shown in several other T-cell-mediated diseases, particularly in the treatment and prevention of acute and chronic graft-versus-host disease. In depth knowledge on the mechanisms whereby ECP manipulates the immune system are still unclear. Most of the experimental studies have been performed in murine models of GvHD. Apoptotic cells isolated during ECP treatment have the potential to induce IL-10 secretion, reduce dendritic cells activation and increase percentage of Tregs. In addition, ECP reduces the production of IL-6 and TNF-α and increases TGF-β production. In lung transplantation, ECP treatment is used as second-line treatment of CLAD and it has the potential to stabilize lung function decline and to improve long-term graft. According to the published literature, however, approximately 30 to 40% of treated recipients did not profit from ECP. Greer and colleagues found that RAS patients as well as rapid lung function decliners showed lower rate of response and worse long-term outcomes. On the contrary in a more recent analysis only BOS diagnosis was associated with better outcomes. A single prospective interventional study was published by our group and it confirmed results from other previous retrospective analysis. Up to now, no clear predictors for response have been identified yet.

Study Overview

• Status: Active, not recruiting
• Conditions: Lung Transplant Rejection
• Intervention / Treatment: Device: Extracorporeal photopheresis

• Study Type: Observational
• Enrollment (Anticipated): 800

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Lung transplant recipients with chronic lung allograft dysfunction who received extracorporeal photopheresis as treatment

Description

Inclusion Criteria:

Diagnosis of CLAD Adult transplant recipients (>18 years)

Exclusion Criteria:

ECP for other diagnosis Recipients of multi-organ transplantation Recipients of single lung transplantation

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Lung transplant recipients with chronic lung allograft dysfunction; Lung transplant recipients with chronic lung allograft dysfunction, who underwent extracorporeal photopheresis

Device: Extracorporeal photopheresis; ECP can be used as second-line treatment in patients unresponsive to azithromycin. ECP has been firstly developed for treatment of cutaneous T cell lymphomas and later used in a variety of other indications including solid organ transplantation. The process starts with leukapheresis, followed by incubation of the isolated cells with 8-methoxypsoralen (8-MOP) and subsequent activation of 8-MOP with ultraviolet A radiation. At the end, the cells are reinfused into the patient. 8-MOP is a biologically inert substance, but in the presence of UVA light it cross-links DNA by forming covalent bonds with pyrimidine bases and causes apoptosis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in forced expiratory value in 1 second at 3 months after start of extracorporeal photopheresis	Percentage change in FEV1 within 3 months after start of extracorporeal photopheresis	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in maximal expiratory flow (50%) at 3 months after start of extracorporeal photopheresis	Percentage change in MEF50 within 3 months after start of extracorporeal photopheresis	3 months
Change in forced expiratory value in 1 second/dorced vital capacity ratio at 3 months after start of extracorporeal photopheresis	Percentage change in FEV1/FVC within 3 months after start of extracorporeal photopheresis	3 months
Change in total lung capacity at 3 months after start of extracorporeal photopheresis	Percentage change in TLC within 3 months after start of extracorporeal photopheresis	3 months
Patients' survival	Patients' survival	Within 5 years from start of extracorporeal photopheresis
Graft survival	Graft survival	Within 5 years from start of extracorporeal photopheresis
Adverse events on extracorporeal photopheresis	Adverse events on extracorporeal photopheresis	Within 5 years from start of extracorporeal photopheresis

Collaborators and Investigators

• Sponsor: Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2005
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: February 25, 2021
• First Submitted That Met QC Criteria: March 9, 2021
• First Posted (Actual): March 10, 2021

Study Record Updates

• Last Update Posted (Actual): March 10, 2021
• Last Update Submitted That Met QC Criteria: March 9, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Other Study ID Numbers: 1541/2020

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No