CFTR Modulators and Lung Transplantation: Factors to Consider - A UK Transplant Centre Experience

Abstract

<h3>Purpose</h3> Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are drugs that act on the defective CFTR protein in people with cystic fibrosis (pwCF), resulting in improved CFTR protein function and thus improved CF symptoms. Evidence is increasing of their positive impact on extra-pulmonary features of CF, which remains problematic in pwCF post-lung transplantation (LTx). Elexacaftor/tezacaftor/ivacaftor (ele/tez/iva) was licensed in the UK in August 2020. It has been debated since if ele/tez/iva has a role post-LTx for ongoing non-pulmonary CF symptoms. We aim to highlight the practical issues faced when considering this drug in the post-LTx CF population in a single large UK LTx unit. <h3>Methods</h3> Retrospective analysis of electronic records of pwCF post-LTx with ongoing extra-pulmonary manifestations considered for initiation of ele/tez/iva August 2020-2021, including demographics, potential benefits, contraindications and outcomes. <h3>Results</h3> 5 pwCF with LTx have been discussed with their CF physicians to consider initiating ele/tez/iva (some had more than one problem):- sinus (n = 2); bowels (n = 2); weight (n = 2); other (n = 2). All were at least 12 months post-LTx (median 42 months; range 21-191 months). Discussions were initiated by the patient in 1 case, the CF team in 2, and transplant team in 2. 3 were not initiated - 1 due to potential side effects on mental health and 2 were contraindicated with deranged liver tests and ongoing bowel symptoms. 2 were initiated on ele/tez/iva. Of these, one is on tacrolimus, needed no immunosuppression adjustment, but stopped due to drop in FEV1 (CT and biopsy negative for features of rejection) which recovered. The other is on sirolimus, needed significant reduction in immunosuppression (9mg to 4mg) and remains on ele/tez/iva. <h3>Conclusion</h3> Extra-pulmonary manifestations of CF are varied and continue post-LTx. With increasing evidence supporting using CFTR modulators to manage extra-pulmonary symptoms, it is important to establish the role these drugs can have in the post-LTx CF population, but also the potential risks. Our experience so far shows mixed results and that discussion between CF and transplant physicians, with patient involvement is vital to ensure correct decisions are taken. Randomised controlled trials are needed to ensure modulator use in pwCF post-LTx is supported by robust evidence.