Blood platelet reduction after elexacaftor/tezacaftor/ivacaftor treatment in people with cystic fibrosis may depend on systemic inflammation reduction.

The elexacaftor/tezacaftor/ivacaftor (ETI) combination for cystic fibrosis transmembrane regulator modulators is a safe and effective treatment in both adults and children who are homozygous or compound heterozygous for the F508del variant. However, few cases involving a significant reduction in blood platelets and an increase in the alanine aminotransferase/platelet ratio have been described in adult and pediatric patients receiving ETI therapy. In the present study, we describe 272 people with cystic fibrosis (pwCF) (166 adult and 106 pediatric pwCF) who were independently followed at two centers; moreover, these individuals were homozygous or compound heterozygous for the F508del variant, were treated with ETI for at least one year, and exhibited monitored platelet and leukocyte counts (together with liver and inflammatory biochemical indices). As controls, 272 healthy subjects (HCs) matched for sex and age were evaluated. At baseline, both adult and pediatric pwCF demonstrated significantly (p < 0.01) greater blood platelet and leukocyte counts compared with HCs. One year of treatment significantly reduced blood platelet counts (adults: 248*103/mmc vs. 288*103/mmc, p < 0.01; children: 283*103/mmc vs. 320*103/mmc, p < 0.01) and leukocyte counts (adults: 6.5*103/mmc vs. 7.6*103/mmc, p < 0.01; children: 6.8*103/mmc vs. 7.9*103/mmc, p < 0.01). In addition, the serum C-reactive protein (CRP) level was significantly (p < 0.01) decreased after therapy, whereas the alanine aminotransferase (ALT) level and the ALT/platelet ratio were significantly increased (p < 0.01). After the second year of therapy, the laboratory parameters were not further altered in approximately half of the patients. The reduction in platelets was significantly correlated with a decrease in leukocytes (rs: 0.352, p < 0.001), serum CRP levels (rs: 0.392, p < 0.001) and exacerbations (oral antibiotic cycles, rs: 0.241, p = 0.002; intravenous antibiotic cycles, rs: 0.153, p = 0.049). These findings suggest that the normalization of platelets may be dependent on the reduction in systemic inflammation induced by ETI therapy.