(165) Xe MRI detects lung ventilation improvement in children with CF treated with ELX/TEZ/IVA in a multi-site study

Background: Hyperpolarized xenon gas ventilation magnetic resonance imaging (Xe MRI) assesses regional airflow and ventilation heterogeneity in obstructive lung diseases. Xe MRI can detect early airflow obstruction in people with CF with normal spirometry, and its primary outcome measure Xe ventilation defect percentage (VDP) correlates with the lung-clearance index (LCI) a measure of global ventilation inhomogeneity [1]. Xe MRI is a promising outcome measure for trials of new therapies in CF and airway disease, but data in a multi-center setting assessing treatment response are lacking currently. We hypothesized Xe MRI would be sensitive to elexacaftor/tezacaftor/ivacaftor (ETI) treatment response in children with CF.

Methods: As part of the ongoing HyPOINT (HyperPOlarized Imaging for New Treatments) study, 19 children with CF (9 males, 10 females; mean age ± SD: 12±3 years) across four sites were assessed at two study visits: baseline and 30 days±14 days following clinical initiation of ETI. Coronal Xe ventilation images were acquired with a resolution of 3x3x15mm³ using a 2D gradient-echo sequence at 3 Tesla, with a Xe gas mixture dosed at 1/6^th predicted total-lung capacity and breath-hold duration of ≤16 seconds. Xe VDP was measured using a semi-automated segmentation, with defects defined as voxels with signal < 60% of the mean whole-lung Xe signal and quantified as a percent of whole-lung volume. Median and interquartile range (IQR) were used to describe VDP and FEV₁ %-predicted, with changes post-ETI assessed using Wilcoxon signed rank tests. Spearman correlation was used to assess the relationship between changes in VDP and FEV₁. VDP improvement was defined as ≥2% decrease [2].

Results: Baseline median VDP was 10.3% (IQR=5.7% - 17.5%) and improved to 6.5% (IQR=2.9% - 12.2%) with ETI (p=0.0004; Panel A). The median change in VDP was -2.4% (IQR=-7.2%; -0.5%). Baseline median FEV₁ was 87% (IQR=71% - 100%) and increased to 99% (IQR=78% - 107%) with ETI (p=0.018; Panel B). The median change in FEV₁ %-predicted was 6% (IQR=4% - 12.6%). In Panel C, change in FEV₁ had a negative correlation with change in VDP(r=-0.652, p=0.0025). Of this cohort, 11/19 (58%) participants had an improvement in VDP ≥2% with ETI.

Conclusions: Ventilation improvement was observed with Xe MRI after ~30 days of ETI in a cohort of children with CF. Changes in VDP correlated with FEV₁, an established outcome for CF interventional trials. Importantly, Xe MRI detected ventilation improvement in patients who did not have change in FEV₁. Ongoing work will compare these short term Xe MRI changes to LCI and other clinical outcomes, as the HyPOINT study continues to assess sustainability of the therapeutic response for Xe MRI, pulmonary-function measures, and clinical outcomes at 6 and 12 months post-ETI therapy initiation in this cohort.

Acknowledgements: This work was supported by the Cystic Fibrosis Foundation (WOODS19A0). This abstract is presented on behalf of the HyPOINT study team.

References: [1] Kanhere N, Couch MJ, Kowalik K, Zanette B, Rayment JH, Manson D, Subbarao P, Ratjen F, Santyr G. Am J Respir Crit Care Med. 2017 196(8):1073-1075. doi: 10.1164/rccm.201611-2228LE.
[2] Eddy RL, Svenningsen S, McCormack DG, Parraga G. Eur Respir J. 2018 51: 1800324; DOI: 10.1183/13993003.00324-2018.