ROCK STUDY in CF: sustained anti-inflammatory effects of lumacaftor–ivacaftor in sputum and peripheral blood samples of adult patients with cystic fibrosis—an observational study

Abstract

Background Previous studies showed that the combination of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) corrector and potentiator, lumacaftor–ivacaftor (LUMA–IVA) provides meaningful clinical benefits in patients with cystic fibrosis who are homozygous for the Phe508del CFTR mutation. However, little is known about the effect of LUMA–IVA on Proinflammatory Cytokines (PICs).Objectives To investigate the impact of LUMA–IVA CFTR modulation on circulatory and airway cytokines before and after 12 months of LUMA–IVA treatment in a real-world setting.Methods We assessed both plasma and sputum PICs, as well as standard clinical outcomes including Forced Expiratory Volume in one second (FEV1) %predicted, Body Mass Index (BMI), sweat chloride and pulmonary exacerbations at baseline and prospectively for one year post commencement of LUMA–IVA in 44 patients with cystic fibrosis aged 16 years and older homozygous for the Phe508del CFTR mutation.Results Significant reduction in plasma cytokines including interleukin (IL)-8 (p<0.05), tumour necrosis factor (TNF)-α (p<0.001), IL-1ß (p<0.001) levels were observed while plasma IL-6 showed no significant change (p=0.599) post-LUMA–IVA therapy. Significant reduction in sputum IL-6 (p<0.05), IL-8 (p<0.01), IL-1ß (p<0.001) and TNF-α (p<0.001) levels were observed after LUMA–IVA therapy. No significant change was noted in anti-inflammatory cytokine IL-10 levels in both plasma and sputum (p=0.305) and (p=0.585) respectively. Clinically significant improvements in FEV1 %predicted (mean+3.38%, p=0.002), BMI (mean+0.8 kg/m2, p<0.001), sweat chloride (mean −19 mmol/L, p<0.001), as well as reduction in intravenous antibiotics usage (mean −0.73, p<0.001) and hospitalisation (mean −0.38, p=0.002) were observed after initiation of LUMA–IVA therapy.Conclusion This real-world study demonstrates that LUMA–IVA has significant and sustained beneficial effects on both circulatory and airway inflammation. Our findings suggest that LUMA–IVA may improve inflammatory responses, which could potentially contribute to improved standard clinical outcomes.