Association Between FEV1 Time Course and Mortality in Lung Transplant Patients Treated with Liposomal Aerosolized Cyclosporine for BOS

Abstract

<h3>Purpose</h3> Pulmonary allograft function is commonly used as a surrogate marker for a survival end-point in clinical trials of lung transplantation (LTx). However, an association between progression of BOS, FEV₁ trajectory and mortality has not been defined. We sought to determine whether an association exists between longitudinal FEV₁ change (% of FEV₁ from randomization) and mortality from a prior trial of liposomal aerosol cyclosporine (L-CsA) for BOS therapy. <h3>Methods</h3> Analyses performed include all patients from a randomized controlled trial using L-CsA for BOS treatment*. A joint statistical model was utilized combining a linear mixed model for FEV₁ trajectory and Cox regression to assess a correlation between survival and FEV₁ changes. <h3>Results</h3> 21 cases were enrolled (10 single 10,11 double); Mean age 61.3 ± 13.3 years (range: 32 - 81); Maximum FEV₁ post transplant 2.5 ± 0.6 l (range: 1.4 - 3.8); Randomization FEV₁ 1.7 ± 0.6 l (range: 1.1 - 3.0 l); follow up 7.5 years (median 35 months). A significant time by treatment interaction was observed with a more pronounced decline of FEV1 using standard of care (p<0.001). In the Phase II study a borderline significant association between change in FEV₁ and survival (1% decline in FEV₁ /1.076-fold mortality increase; p=0.055) was detected indicating that a 1% decline in FEV1 is associated with a 7.6% increased death risk, 95% confidence interval:(-0.0% - 16.1%) (Figure). <h3>Conclusion</h3> A 7.5 year follow-up analysis of the clinical trial using L-CsA for BOS patients reveals an association between subject longitudinal FEV₁ deterioration and mortality. FEV₁ deterioration may be a reliable surrogate marker of survival having implications for future study designs and interpretations. *A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation. ERJ Open Res 2019; 5: 00167-2019 [https://doi.org/10.1183/23120541.00167-2019].