Approved treatment lowers inflammatory cell levels in study of CF
Reductions seen with Kaftrio more pronounced in those with better lung function
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One year of treatment with Kaftrio lowered levels of certain immune cells implicated in inflammation, led to fewer pulmonary exacerbations, and reduced detection of Pseudomonas aeruginosa in people with cystic fibrosis (CF), a real-world study found.
The reductions in neutrophils and monocytes — types of white blood cells involved in the body’s immune response — tended to be more pronounced among patients who had better lung function before starting treatment. Kaftrio is sold as Trikafta in the U.S.
The study, “Changes in peripheral blood leukocyte profiles during elexacaftor/tezacaftor/ivacaftor therapy in cystic fibrosis according to baseline lung function,” was published in Respiratory Medicine.
Kaftrio shows benefits in lung function, life quality
CF is caused by mutations in the CFTR gene, which lead to the buildup of thick mucus in several organs, including the lungs. This interferes with the lungs’ ability to clear microbes and contributes to persistent infections, inflammation, and progressive lung damage.
Chronic infection with P. aeruginosa is a major concern in CF, because it is associated with faster lung function decline and a greater risk of death.
Kaftrio is a CFTR modulator marketed by Vertex Pharmaceuticals that aims to improve the production and function of faulty CFTR protein in eligible patients. Multiple benefits have been shown in clinical trials, including better lung function, nutritional status, and quality of life, as well as fewer pulmonary exacerbations, or periods of acute worsening of respiratory symptoms. Increasing evidence also indicates that Kaftrio may influence immune cell activity and reduce the frequency of P. aeruginosa infections.
Both neutrophils and monocytes contribute to progressive tissue injury, with neutrophils in particular playing a key role in CF airway inflammation. Higher levels of both of these cell types have been proposed as markers of body-wide inflammatory activity in CF.
However, real-world data regarding Kaftrio’s impact on immune cell levels remain limited, particularly when associated with lung function.
Neutrophil counts much lower after 6, 12 months of Kaftrio treatment
To learn more, researchers in Poland assessed 28 CF patients, age 12 and older, who had received Kaftrio for at least one year at a single center.
White blood cell counts were assessed before treatment and after six and 12 months. The researchers also recorded pulmonary exacerbations requiring intravenous, or into-the-vein, antibiotics and whether respiratory samples tested positive for P. aeruginosa.
Participants were divided into two groups according to their pre-treatment FEV1/FVC, a ratio of the amount of air forcefully exhaled in the first second to the total amount exhaled after a deep breath. A lower ratio can indicate obstructed airflow.
Fifteen patients had an FEV1/FVC ratio higher than the fifth percentile and were considered to have preserved lung function. The remaining 13 had a ratio below the fifth percentile and were categorized as having reduced lung function.
Across the entire group, neutrophil counts were significantly lower after six and 12 months of Kaftrio treatment than before therapy. However, the clearest changes were seen among patients with preserved lung function, particularly as comparisons between individual time points in participants with reduced lung function did not reach statistical significance.
Monocyte counts also declined significantly in both groups, but, again, this benefit was more pronounced in patients with preserved lung function. In the group with reduced lung function, the reduction in monocytes was statistically significant at the one-year mark, but not at six months of treatment.
Overall, our observations are consistent with previous reports describing beneficial clinical and anti-inflammatory effects of CFTR modulators in CF.
Notably, although results showed a reduction in the number of pulmonary exacerbations requiring intravenous antibiotic therapy after one year of Kaftrio, the team cautioned that the small number of participants made it impossible to conduct statistical comparisons. Of note, no exacerbations were recorded during follow-up among participants with preserved baseline lung function.
No significant changes were seen in levels of other immune cells. Basophil counts, however, were higher in patients with poorer baseline lung function. The clinical meaning of this difference remains uncertain, the scientists said, although they suggested it might be due to more advanced inflammatory changes in the context of airway disease
The proportion of participants with P. aeruginosa detected in sputum (phlegm) or throat swabs fell from 32.1% before Kaftrio to 17.9% after both six and 12 months of treatment. The decline was greater in people with preserved lung function.
“Overall, our observations are consistent with previous reports describing beneficial clinical and anti-inflammatory effects of CFTR modulators in CF,” the researchers wrote. The reduced levels of neutrophil and monocytes “may reflect attenuation of chronic systemic [body-wide] inflammation accompanying improvement in CFTR function and mucociliary clearance [a self-clearing defense mechanism of the respiratory tract].”
The researchers added that “larger prospective studies with longer follow-up are needed to better define the long-term immunological and microbiological effects of [Kaftrio] across different stages of CF lung disease.”
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