Extracorporeal Photopheresis as Induction Therapy in Lung Transplantation for Cystic Fibrosis: A Pilot Randomized Trial

Ilaria Righi¹Claudio Fenizia²Daria Trabattoni³Mario Nosotti^1,2Giacomo Grisorio^1,4*Claudia Vanetti^2,3Sonia Di Tella⁵Cristina Mocellin⁶Norma Fantini⁶Daniele Prati⁶Letizia Corinna Morlacchi²Valeria Rossetti⁷Francesco Blasi^2,7Lorenzo Rosso^1,2Mario Clerici^2,8

• ¹Thoracic Surgery and Lung Transplant Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milano, Lombardy, Italy
• ²Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy, Milano, Lombardy, Italy
• ³Department of Biomedical and Clinical Sciences, Faculty of Medicine and Surgery, University of Milan, Milan, Lombardy, Italy
• ⁴University of Milan, Milan, Italy
• ⁵Faculty of Psychology, Catholic University of the Sacred Heart, Milan, Milan, Lombardy, Italy
• ⁶Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, Milano, Italy
• ⁷Adult Cystic Fibrosis Center, Department of Internal Medicine, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital, Milan, Lombardy, Italy
• ⁸Fondazione Don Carlo Gnocchi Onlus (IRCCS), Milan, Lombardy, Italy

Extracorporeal photopheresis (ECP) is a viable treatment that slows the progression of chronic lung allograft dysfunction. Despite its immunoregulatory potential, data on extracorporeal photopheresis as an induction therapy remain rateher limited. We conducted a pilot randomized controlled study on ECP as induction therapy in cystic fibrosis patients undergoing primary lung transplantation. Primary endpoints included safety, assessed based on the incidence of adverse events, treatment-related toxicity, and procedure-related complication rates; and feasibility, evaluated through the completion rate of scheduled ECP sessions, patient tolerability, and treatment discontinuation rates. Secondary endpoint consisted of an exploratory assessment of efficacy, using a composite measure that included three key components: freedom from biopsy-proven acute rejection within the first 12 months, absence of chronic lung allograft dysfunction at 36 months, and optimal graft function, defined as a predicted forced expiratory volume in the first second ≥ 90% at 36 months. Finally, exploratory endpoints included cell phenotypic and functional analyses, secreted immune protein profiling, and gene expression analysis for mechanistic insights. Patients were randomly assigned to receive either standard immunosuppressive therapy alone or standard therapy plus six sessions of extracorporeal photopheresis, with a follow-up period of 36 months. Among 36 cystic fibrosis patients who underwent lung transplantation between 2018 and 2021 and met the eligibility criteria, 21 were randomized (9 to the study group and 12 to the control group). No patients in the treatment group experienced adverse events. The enrollment rate was 61%, and the treatment discontinuation rate was 22%. The clinical composite endpoint was achieved by 28.6% of patients in the treatment group and 16.7% in the control group. Exploratory endpoint analyses revealed significant decreases in pro-inflammatory cytokines, degranulating CD8⁺ T lymphocytes, and NK cells in the treatment group. Moreover, significant increases in Treg lymphocytes, IL-10-producing NK cells, and anti-inflammatory cytokines appeared to be associated with improved pulmonary function in the treatment group. Induction therapy with extracorporeal photopheresis is safe and feasible in lung transplantation for cystic fibrosis. Some clinical benefits appear to persist for the first 36 months of follow-up. Interestingly, a correlation between immunological modulation induced by extracorporeal photopheresis and pulmonary function was observed.