(160) Monitoring Response to Elexacaftor/Tezacaftor/Ivacaftor Treatment in Pediatric Cystic Fibrosis Lung Disease using Free-Breathing Magnetic Resonance Imaging

Background: Hyperpolarized 129-Xenon MRI (Xe-MRI) has been shown to be a sensitive measure of pulmonary ventilation in children with Cystic Fibrosis (CF) [1]. However, Xe-MRI is not widely available and necessitates a gas inhalation and a breath-hold maneuver, which can be difficult for sick and/or very young children. Alternatively, free-breathing lung MRI does not require hyperpolarized gas and has been shown to be responsive to treatment of pulmonary exacerbations in CF [2]. To date, free-breathing MRI has not been used to monitor changes in ventilation following CFTR-modulator treatment, specifically the combination of elexacaftor/tezacaftor/ivacaftor. As part of an ongoing, multi-site study (HyPOINT), we assessed the responsiveness of free-breathing MRI to CFTR-modulator treatment in CF children.

Methods: To date, 8 CF subjects (mean±SD: 16±2 years of age) have been recruited. Participants performed Xe-MRI and free-breathing MRI as previously described [2], prior to and one month following elexacaftor/tezacaftor/ivacaftor treatment. Fractional ventilation (FV) maps were calculated from the free-breathing images using the phase-resolved functional lung (PREFUL) method [3]. Ventilation Defect Percentage was calculated for each subject from the FV maps using k-means clustering (VDP_FV) and compared to that obtained from Xe-MRI (VDP_Xe) based on a threshold of 60% of the mean xenon ventilation signal [2]. Treatment effects observed by VDP_FV and VDP_Xe were determined using a Wilcoxon’s ranked sign test and percent changes of each were correlated using a Spearman ranked correlation test.

Results: Figure 1a shows FV and Xe-MRI ventilation maps for a representative CF patient pre- and post-treatment. VDP_FV and VDP_Xe decreased significantly with median changes of -80.1% (IQR [-88.7,-55.7%], p=0.02) and -55.8% (IQR [-60.9,-41.8%], p=0.008) relative to baseline, respectively across the cohort (Figure 1b). The changes in VDP_FV and VDP_Xe were significantly correlated (ρ=0.92, p= 0.001).

Conclusions: Free-breathing MRI with PREFUL was able to detect a significant improvement in ventilation following elexacaftor/tezacaftor/ivacaftor treatment, similarly to Xe-MRI. The change with intervention is consistent with previous work showing that VDP_FV and VDP_Xe significantly decreased in pediatric CF children undergoing intravenous antibiotic treatment for a pulmonary exacerbation [2]. Free-breathing MRI provides a responsive pulmonary ventilation measure for following CFTR-modulator treatment in CF lung disease and may be a more accessible alternative to Xe-MRI.

Acknowledgements: The work was supported by: The Hospital for Sick Children, Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant [RGPIN 217015-2013], the Cystic Fibrosis Foundation (CFF), Canadian Institutes of Health Research (CIHR) operating and project grants [MOP 123431, PJT 153099].

References: [1] Santyr G, Kanhere N, Morgado F, et al. Hyperpolarized Gas Magnetic Resonance Imaging of Pediatric Cystic Fibrosis Lung Disease. Acad. Radiol. 2019;26(3):344-354
[2] Munidasa S, Couch MJ, Rayment JH, et al. Free-breathing MRI for Monitoring Ventilation Changes following Antibiotic Treatment of Pulmonary Exacerbations in Pediatric Cystic Fibrosis. Eur. Respir. J. 2020;59(3): 2003104
[3] Voskrebenzev A, Gutberlet M, Klimeš F, et al. Feasibility of quantitative regional ventilation and perfusion mapping with phase-resolved functional lung (PREFUL) MRI in healthy volunteers and COPD, CTEPH, and CF patients. Magn Reson Med. 2018;79(4):2306-2314