Aerosolized Liposomal Cyclosporine A in the Prevention of Bronchiolitis Obliterans Syndrome Following Lung Transplantation

Long-term survival after lung transplantation (LTx) is limited by chronic allograft dysfunction/bronchiolitis obliterans syndrome (BOS). Currently, no effective treatment or prevention is available. This study investigated the impact of locally augmented immunosuppression on the outcome after LTx. In a randomized, double-blind, placebo-controlled, multi-center phase III study, 180 adult LTx recipients were planned to receive either aerosolized liposomal cyclosporine A (L-CsA) or placebo in addition to triple-drug immunosuppression with tacrolimus, mycophenolate mofetil and steroids. L-CsA was administered twice daily in doses of 5 or 10 mg via eFlow nebulizer in single (SLTX) or double lung transplant (DLTX) recipients, respectively. Treatment started within 6-32 weeks post LTX and continued for 2 years. The primary study endpoint was BOS-free survival. 11 LTx centers enrolled 130 (DLTX n=90) of the anticipated 180 patients before the study was terminated prematurely due to funding constraints. Baseline characteristics of both groups were comparable. Median follow-up was 13.3 months. Although, Kaplan-Meier estimates revealed a 2-year actuarial difference in BOS-free survival of 14.1% in favor of L-CsA in the overall study population, the study failed to meet its primary endpoint (p=0.243). However, per protocol analysis of SLTX recipients (L-CsA n=12, placebo n=12) resulted in a treatment difference of 58.2% approaching statistical significance (p=0.053). Similar differences were not observed in DLTX (L-CsA n=22, placebo n=26) recipients (p=0.973). L-CsA was well tolerated without increased rates of infections. L-CsA inhalation did not result in systemic drug accumulation and demonstrated an excellent safety profile. The study was terminated prematurely for funding reasons and failed to meet its primary endpoint. Decision for study discontinuation was not based on futility or safety concerns. Thus, the results with respect to efficacy are only preliminary and L-CsA therapy warrants further investigation. We speculate that differences between DLTX and SLTX patients are partially explained by the delayed onset of BOS in DLTX recipients. At this point, we demonstrated that inhalation of L-CsA is well tolerated, safe and may offer advantage in SLTX recipients.