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Multicenter Study
. 2022 Dec;57(12):2992-2999.
doi: 10.1002/ppul.26123. Epub 2022 Sep 6.

Profiling the response to lumacaftor-ivacaftor in children with cystic between fibrosis and new insight from a French-Italian real-life cohort

Matthieu Cornet  1 , Geneviève Robin  2 , Fabiana Ciciriello  3 , Tiphaine Bihouee  4 , Christophe Marguet  5 , Valérie Roy  6 , Muriel Lebourgeois  5 , Frédérique Chedevergne  5 , Anne Sophie Bonnel  5 , Mairead Kelly  1 , Philippe Reix  7 , Vincenzina Lucidi  3 , Véronique Stoven  6 , Isabelle Sermet-Gaudelus  1
Affiliations
Multicenter Study

Profiling the response to lumacaftor-ivacaftor in children with cystic between fibrosis and new insight from a French-Italian real-life cohort

Matthieu Cornet et al. Pediatr Pulmonol. 2022 Dec.

Abstract

Introduction: Clinical trials for CFTR modulators consider mean changes of clinical status at the cohort level, and thus fail to assess the heterogeneity of the response. We aimed to study the different response profiles to lumacaftor-ivacaftor according to age in children with cystic fibrosis (CF).

Methods: A mathematical framework, including principal component analysis, data clustering, and data completion, was applied to a multicenter cohort of 112 children aged 6-18 years, treated with lumacaftor-ivacaftor. Studied parameters at baseline and 6 months included body mass index (BMI), number of days of antibiotics (ATB), Sweat test (ST), forced expiratory volume in 1 s expressed in percentage predicted (ppFEV1 ), forced vital capacity (ppFVC), and forced expiratory flow at 25%-75% of FVC (ppFEF25-75 ).

Results: Change in ppFEV1 was the most significant parameter in characterizing response heterogeneity among the 12-18-year-old patients. Patients with minimal changes in ppFEV1 were further separated by change in BMI and ATB course. In the 6-12-year-old children both BMI and ppFEV1 evolution were the most relevant. ST change was not associated with a clinical response.

Conclusions: Change in ppFEV1 , BMI, and ATB course are the most relevant outcomes to discriminate clinical response profiles in children treated with lumacaftor-ivacaftor. Prepubertal and pubertal children display different response profiles.

Keywords: children; lumacaftor-ivacaftor; principal component analysis.

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Conflict of interest statement

ISG has participated to scientific Board of Vertex Therapeutics and received Academic Funding from Vertex Therapeutics. The other authors do not declare any conflict of interest.

Figures

Figure 1
Figure 1
Circle of correlation between clinical parameters and the first three PCA components for patients aged 12 years and older. (A) Graphical representation of PC1 and PC2. (B) Graphical representation of PC2 and PC3. Each parameter is represented by a vector whose abscissa and ordinate provide its correlation with PCA components. % of explained overall variance of the data are displayed alongside the PC they correspond to. ATB, days of antibiotics in the last 6 months; BMI, body mass index; ppFEF, percent predicted forced expiratory flow between 25% and 75% of FVC; PC, principal components; PCA, principal component analysis; ppFEV1, percent predicted forced expiratory volume in 1 s; ppFVC, percent predicted forced vital capacity; ST, sweat test. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Projection of the patients on the three‐dimensional space with coordinates of the first three principal components (PC1, PC2, and PC3). Each point corresponds to one patient and each color corresponds to a cluster. Coordinates for each patient were obtained by a linear combination of the outcome parameters contributing to the PCs, according to PCA methodology. PC, principal components; PCA, principal component analysis. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Distribution of parameters in the four clusters for 12–18‐year‐old patients. Values for the first three PCs were obtained by a linear combination of the outcome parameters contributing to the PCs, according to PCA methodology. ATB, days of antibiotics in the last 6 months; BMI, body mass index; PC, principal components; PCA, principal component analysis; ppFEF, percent predicted forced expiratory flow between 25% and 75% of FVC; ppFEV1: percent predicted forced expiratory volume in 1 s; ppFVC, percent predicted forced vital capacity; ST, sweat test. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
Circle of correlation between clinical parameters and the first two PCA components, for patients younger than 12 years old. Each parameter is represented by a vector whose abscissa and ordinate provide its correlation with PCA components. % of explained overall variance of the data are displayed alongside the PC they correspond to. ATB, days of antibiotics in the last 6 months; BMI, body mass index; PC, principal components; PCA, principal component analysis; ppFEF, percent predicted forced expiratory flow between 25% and 75% of FVC; ppFEV1, percent predicted forced expiratory volume in 1 s; ppFVC, percent predicted forced vital capacity; ST, sweat test.
See this image and copyright information in PMC

References

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