Heterogeneity of short-term elexacaftor-tezacaftor-ivacaftor response in cystic fibrosis using ¹²⁹Xe MRI.

Abstract

Personalised management of cystic fibrosis (CF) lung disease in the era of CF transmembrane conductance regulator (CFTR) modulator therapy will require novel approaches to assess treatment response and monitor longitudinal progression. We evaluated the heterogeneity of short-term response to elexacaftor-tezacaftor-ivacaftor (ETI) using ¹²⁹Xe MRI, multiple breath washout (MBW) and spirometry. For CFTR modulator-naïve people ≥6 years old starting commercial ETI, we measured same-day ¹²⁹XeMRI ventilation defect per cent (VDP), lung clearance index (LCI), forced expiratory volume in 1 s (FEV₁) and CF Questionnaire-Revised respiratory-domain (CFQ-R(R)) at pre-ETI baseline and up to 4 months post-ETI. Baseline versus follow-up measures were compared using Wilcoxon-signed-rank tests with r effect size coefficients. Abnormal follow-up measures determined using z-scores and upper/lower limits of normal; correlations evaluated using Spearman ρ coefficients. VDP, FEV₁, LCI and CFQ-R(R) significantly improved in the total group (n=40; all p<0.001, r=0.69, r=0.79, r=0.70, r=0.77) and both ≥12-year-old subgroups (n=15 FEV₁<80%, p=0.005/r=0.69, p<0.001/r=0.87, p=0.004/r=0.70, p<0.001/r=0.88; n=17 FEV₁≥80%, p=0.003/r=0.54, p=0.003/r=0.74, p=0.01/r=0.56, p=0.006/r=0.73). VDP (p=0.008/r=0.89), LCI (p=0.03/r=0.83) and percent-predicted FEV₁ (p=0.03/r=0.83) significantly improved in the 6-11-year-old subgroup, with VDP having the greatest effect size in children. VDP remained abnormal at follow-up in 21 participants with normal FEV₁, whereas LCI was abnormal in 12. Baseline VDP (ρ=0.39/p=0.01) and LCI (ρ=0.43/p=0.008) were significantly correlated with the change in CFQ-R(R). Though all outcome measures showed a positive response, response to ETI was heterogeneous between individuals and between ¹²⁹XeMRI, MBW and spirometry. Leveraging the rich information provided by multimodal tools will be critical to understanding the nature of CF lung disease and measuring response to future therapies in the era of CFTR modulators.