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Observational Study
. 2024 Sep 5;64(3):2400004.
doi: 10.1183/13993003.00004-2024. Print 2024 Sep.

Impact of elexacaftor/tezacaftor/ivacaftor therapy on lung clearance index and magnetic resonance imaging in children with cystic fibrosis and one or two F508del alleles

Mirjam Stahl  1   2   3   4 , Martha Dohna  5   4 , Simon Y Graeber  6   2   3   4 , Olaf Sommerburg  7   8   4 , Diane M Renz  5 , Sophia T Pallenberg  9   10 , Andreas Voskrebenzev  5 , Katharina Schütz  9   10 , Gesine Hansen  9   10   11 , Felix Doellinger  12 , Eva Steinke  6   2   3 , Stephanie Thee  6   2   3 , Jobst Röhmel  6   2   3 , Sandra Barth  13   14 , Claudia Rückes-Nilges  13   14 , Julian Berges  7   8 , Susanne Hämmerling  7 , Mark O Wielpütz  8   15 , Lutz Naehrlich  13   14   16 , Jens Vogel-Claussen  5   10   16 , Burkhard Tümmler  9   10   16 , Marcus A Mall  6   2   3   16 , Anna-Maria Dittrich  9   10   16
Affiliations
Observational Study

Impact of elexacaftor/tezacaftor/ivacaftor therapy on lung clearance index and magnetic resonance imaging in children with cystic fibrosis and one or two F508del alleles

Mirjam Stahl et al. Eur Respir J. .

Abstract

Background: We recently demonstrated that elexacaftor/tezacaftor/ivacaftor (ETI) improves the lung clearance index (LCI) and abnormalities in lung morphology detected by magnetic resonance imaging (MRI) in adolescent and adult patients with cystic fibrosis (CF). However, real-world data on the effect of ETI on these sensitive outcomes of lung structure and function in school-age children with CF have not been reported. The aim of this study was therefore to examine the effect of ETI on the LCI and the lung MRI score in children aged 6-11 years with CF and one or two F508del alleles.

Methods: This prospective, observational, multicentre, post-approval study assessed the longitudinal LCI up to 12 months and the lung MRI score before and 3 months after initiation of ETI.

Results: A total of 107 children with CF including 40 heterozygous for F508del and a minimal function mutation (F/MF) and 67 homozygous for F508del (F/F) were enrolled in this study. Treatment with ETI improved the median (interquartile range (IQR)) LCI in F/MF (-1.0 (-2.0- -0.1); p<0.01) and F/F children (-0.8 (-1.9- -0.2); p<0.001) from 3 months onwards. Further, ETI improved the median (IQR) MRI global score in F/MF (-4.0 (-9.0-0.0); p<0.01) and F/F children (-3.5 (-7.3- -0.8); p<0.001).

Conclusions: ETI improves early abnormalities in lung ventilation and morphology in school-age children with CF and at least one F508del allele in a real-world setting. Our results support early initiation of ETI to reduce or even prevent lung disease progression in school-age children with CF.

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Conflict of interest statement

Conflicts of interest: M. Stahl, S.Y. Graeber and S. Thee are participants of the Berlin Institute of Health (BIH)-Charité Clinician Scientist Program, and J. Röhmel is participant of the Case Analysis and Decision Support (CADS) program funded by Charité – Universitätsmedizin Berlin and the BIH. M. Stahl reports an Independent Research Innovation Award and honoraria for lectures and participation in advisory boards, all by Vertex Pharmaceuticals Incorporated, outside of the submitted work; she is Chairman of the German CF Research Council (FGM), Treasurer of the German Society of Paediatric Pulmonology (GPP) and was Secretary of the Group CF of the Paediatric Assembly of the ERS. M. Dohna is a participant of the Ellen-Schmidt Habilitationsförderung funded by the Hannover Medical School. S.Y. Graeber reports grants from the German CF Foundation and Vertex Pharmaceuticals Incorporated, and honoraria from Chiesi GmbH and Vertex Pharmaceuticals Incorporated for lectures and participation in advisory boards, outside of the submitted work. O. Sommerburg reports grants and honoraria from Vertex Pharmaceuticals Incorporated for lectures, outside of the submitted work. S.T. Pallenberg is a member of the Else-Kröner Forschungskolleg TITUS. A. Voskrebenzev reports a grant and honoraria for lectures from Siemens Healthineers, outside of the submitted work, holds a patent for a method of quantitative magnetic resonance lung imaging (Voskrebenzev, Gutberlet, Vogel-Claussen; number EP3107066, US-2016-0367200-Al 22.12.2016), and is a stockholder and CEO of BioVisioneers GmbH. K. Schütz reports payments for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated, outside of the submitted work. G. Hansen reports receipt of consultation fees from Sanofi GmbH, outside of the submitted work. F. Doellinger reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Bayer Vital, Berlin-Chemie Menarini, Boehringer Ingelheim and Chiesi GmbH, payment for expert testimony from Calyx, and support for attending meetings from Bayer. E. Steinke reports grants from Berlin Institute of Health at Charité Berlin, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceuticals Incorporated. S. Thee reports honoraria for lectures and payment for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated and Viatris, outside of the submitted work. J. Röhmel reports honoraria for lectures from Vertex Pharmaceuticals Incorporated, outside the submitted work; additionally, he is work package leader in BEAT-PCD (ERS-CRC). M.O. Wielpütz reports a grant from Vertex Pharmaceuticals Incorporated, and receipt of consulting fees and honoraria for lectures from Vertex Pharmaceuticals Incorporated and Boehringer Ingelheim, outside of the submitted work. L. Naehrlich reports receipt of fees for a data quality project of the German CF Registry. He is the medical lead of the German CF Registry, the pharmacovigilance study manager of the European Cystic Fibrosis Society Patient Registry and part of the Trial Steering Committee for CF STORM. He also reports grants from the German Center for Lung Research, Vertex Pharmaceuticals and Mukoviszidose Institute, and receipt of medical writing services from Articulate Science. J. Vogel-Claussen reports grants from BMBF, Siemens Healthineers, AstraZeneca, Boehringer Ingelheim and GSK, royalties or licenses from Siemens Healthineers, receipt of consulting fees from AstraZeneca, honoraria for lectures from Siemens Healthineers, AstraZeneca, Boehringer Ingelheim, GSK, Roche, Coreline Soft and Bayer, payments for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated, Bayer, GSK and AstraZeneca, and holds a patent for a method of quantitative magnetic resonance lung imaging (Voskrebenzev, Gutberlet, Vogel-Claussen; number EP3107066, US-2016-0367200-Al 22.12.2016). B. Tümmler reports support for the present study from Bundesministerium für Forschung und Technologie, grants from the German Research Foundation (DFG; CRC 900; Excellence cluster “RESIST”), consultancy fees from Helmholtz Institut für Infektionsforschung, payment or honoraria for lectures, presentations, manuscript writing or educational events from Vertex Pharmaceutical (Germany) Incorporated, participation on a data and safety monitoring board or advisory board with Vertex Pharmaceuticals Incorporated, and leadership roles with Christiane Herzog Stiftung and the Microbiome/Metagenome Group of the German Center for Lung Research (DZL). M.A. Mall reports grants from the German Research Foundation (DFG; SFB-TR 84, and project 450557679) and the German Innovation Fund (01NVF19008), outside of the submitted work. Additionally, he reports receipt of consulting fees from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense and Vertex Pharmaceuticals Incorporated, of honoraria for lectures from Vertex Pharmaceuticals Incorporated and participation in advisory boards from AbbVie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Pari and Vertex Pharmaceuticals Incorporated, and of payment for travel from Vertex Pharmaceuticals Incorporated and Boehringer Ingelheim, all outside of the submitted work. He is a Fellow of ERS (FERS). A-M. Dittrich reports support for the present study from the German Center for Lung Research (DZL), Vertex Pharmaceuticals Incorporated and European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN), grants from Vertex Pharmaceuticals Incorporated, ECFS-CTN, DFG and Christiane Herzog Stiftung, consultancy fees from the c4c consortium, GSK and European Cystic Fibrosis Society. The remaining authors have no potential conflicts of interest to disclose.

Figures

None
Overview of the study. LCI: lung clearance index; N2: nitrogen; MRI: magnetic resonance imaging.
FIGURE 1
FIGURE 1
Flowchart of recruited patients with cystic fibrosis, heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F). CFTRm: cystic fibrosis transmembrane conductance regulator modulator; ETI: elexacaftor/tezacaftor/ivacaftor; MBW: multiple-breath washout; MRI: magnetic resonance imaging.
FIGURE 2
FIGURE 2
Effects of elexacaftor/tezacaftor/ivacaftor (ETI) on sweat chloride concentration (SCC), forced expiratory volume in 1 s (FEV1) % pred and body mass index (BMI) z-score in children with cystic fibrosis with at least one F508del allele. Paired determinations of SCC and quarterly assessments of FEV1 % pred and BMI were performed. Investigation of a–c) children heterozygous for F508del and a minimal function mutation (F/MF) (n=40) and d–f) children homozygous for F508del (F/F) (n=67). a, d) Dots represent individual values of children at both time-points, dotted horizontal lines represent the 25th and the 75th percentiles, and solid horizontal lines represent the group median. ***: p<0.001 compared with baseline. b, c, e, f) Data are shown as median and error bars represent the median absolute deviation of the respective group. *: p<0.05; ***: p<0.001 for the longitudinal course throughout the whole study period.
FIGURE 3
FIGURE 3
Effects of elexacaftor/tezacaftor/ivacaftor (ETI) on the lung clearance index (LCI) in children with cystic fibrosis with at least one F508del allele. Quarterly assessment of the LCI from baseline up to 12 months after initiation of ETI therapy in a) children compound heterozygous for F508del and a minimal function mutation (F/MF) and b) children homozygous for F508del (F/F). Data are shown as median and error bars represent the median absolute deviation of the respective group. ***: p<0.001 for the longitudinal course throughout the whole study period.
FIGURE 4
FIGURE 4
Examples of structural changes and abnormal perfusion in cystic fibrosis lung disease and their response to elexacaftor/tezacaftor/ivacaftor (ETI) detected by magnetic resonance imaging (MRI). a, b) Representative MRI studies of a) a child compound heterozygous for F508del and a minimal function mutation (F/MF) and b) a child homozygous for F508del (F/F) at baseline and 3 months after initiation of ETI. The initial MRI studies revealed contrast-enhancing airway wall thickening (black arrows) and mucus plugging with high signal intensity on T2-weighted sequences (white arrows) of upper and lower lung lobes. Peripheral consolidations together with pleural enhancement were present in the middle lobe and lingula in F/F (black arrowheads). Wedge-shaped perfusion abnormalities were identified on the subtracted perfusion map (white arrowheads). After initiation of ETI, airway wall thickening and enhancement, mucus plugging and consolidations were substantially reduced. Most perfusion defects resolved and a more homogeneous perfusion was restored.
FIGURE 5
FIGURE 5
Effects of elexacaftor/tezacaftor/ivacaftor on abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) in children with cystic fibrosis with at least one F508del allele. Paired studies of lung MRI at baseline and 3 months after initiation of ETI therapy in children heterozygous for F508del and a minimal function mutation (F/MF) and children homozygous for F508del (F/F). Summary of a) the MRI global score (F/MF, n=19; F/F, n=30), representing the sum of b) the MRI morphology score (F/MF, n=19; F/F, n=34) and c) the MRI perfusion score (F/MF, n=19; F/F, n=30). Summary of d) the MRI wall thickening/bronchiectasis subscore (F/MF, n=19; F/F, n=34) and e) the MRI mucus plugging subscore (F/MF, n=19; F/F, n=34) that contribute to the MRI morphology score. Bars represent the group median and error bars represent 25th and 75th percentile. *: p<0.05; **: p<0.01; ***: p<0.001 compared with baseline.
FIGURE 6
FIGURE 6
Relationship between changes in the lung clearance index (LCI), percent predicted forced expiratory volume in 1 s (FEV1) and lung magnetic resonance imaging (MRI) scores in response to 3 months of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis with at least one F508del allele. a) Relationship between absolute change of the LCI and absolute change of FEV1 % pred (n=83). b–f) Relationship between absolute change of the LCI and b) absolute change in the MRI global (n=41), c) morphology (n=45) and d) perfusion (n=41) scores, as well as e) MRI wall thickening/bronchiectasis (n=45) and f) mucus (n=45) subscores. Closed circles indicate individual patients compound heterozygous for F508del and a minimal function mutation (F/MF). Open circles represent individual patients homozygous for F508del (F/F). Solid lines represent simple linear regression for the whole study population (r=Spearman correlation coefficient). Dashed lines indicate zero change.
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Comment in

References

    1. Barry PJ, Mall MA, Alvarez A, et al. Triple therapy for cystic fibrosis Phe508del-gating and -residual function genotypes. N Engl J Med 2021; 385: 815–825. doi: 10.1056/NEJMoa2100665 - DOI - PMC - PubMed
    1. Burgel PR, Durieu I, Chiron R, et al. Rapid improvement after starting elexacaftor–tezacaftor–ivacaftor in patients with cystic fibrosis and advanced pulmonary disease. Am J Respir Crit Care Med 2021; 204: 64–73. doi: 10.1164/rccm.202011-4153OC - DOI - PubMed
    1. Griese M, Costa S, Linnemann RW, et al. Safety and efficacy of elexacaftor/tezacaftor/ivacaftor for 24 weeks or longer in people with cystic fibrosis and one or more F508del alleles: interim results of an open-label phase 3 clinical trial. Am J Respir Crit Care Med 2021; 203: 381–385. doi: 10.1164/rccm.202008-3176LE - DOI - PMC - PubMed
    1. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019; 394: 1940–1948. doi: 10.1016/S0140-6736(19)32597-8 - DOI - PMC - PubMed
    1. Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381: 1809–1819. doi: 10.1056/NEJMoa1908639 - DOI - PMC - PubMed

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