Challenges in targeted therapy for cystic fibrosis in a patient with the complex allele [L467F; F508del]: from failure of first-line modulator therapy to successful use of vanzacaftor+tezacaftor+deutivacaftor combination

Abstract

Cystic fibrosis (CF) is the most common inherited autosomal recessive disorder, caused by mutations in the CFTR gene. The introduction of CFTR modulators has fundamentally changed the prognosis and quality of life of patients. However, the presence of complex alleles may significantly affect the efficacy of targeted therapy, necessitating a personalized approach to the selection of pharmacological strategies. The aim. To present a clinical observation of a 16­year­old female patient with cystic fibrosis carrying the genotype [L467F;F508del]/CFTRdele2,3, which illustrates the challenges of selecting CFTR modulator therapy in the presence of a complex allele, and the possibility of successful treatment adjustment using next generation targeted agents based on an intestinal organoid test (forskolin­induced swelling). Conclusion. This clinical case demonstrated that therapy with elexacaftor+tezacaftor+ivacaftor may provide only a partial clinical response in a patient with a complex CF allele. Despite the improvement in nutritional status and the frequency of bronchopulmonary exacerbations, high sweat chloride concentrations (119 – 121 mmol/L) persisted and there was no improvement in pulmonary function tests. An adverse reaction developed upon the attempt to switch to a generic formulation of elexacaftor+tezacaftor+ivacaftor. Given the identified complex allele, targeted therapy was discontinued. Subsequently, the positive result of the intestinal organoid functional assay demonstrated sensitivity to the novel triple combination vanzacaftor+tezacaftor+ivacaftor and prompted therapy re initiation that led to a significant clinical improvement.