KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma - Impact on Airway Remodeling measured by MDCT

RATIONALE: Mast cells release bronchoactive mediators and cytokines that contribute to airway remodeling. Stem cell factor (SCF) and its tyrosine kinase receptor cKit (KIT) are central to mast cell survival. This sub-study analyzed the impact of imatinib on airway remodeling using multidetector computed tomographic (MDCT) imaging.

METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was conducted over a 24-week period in patients with severe persistent asthma. We compared MDCT images before and after treatment with imatinib or placebo using Apollo software (VIDA Diagnostics, Iowa City). Wall thickness percent (WT%) and wall area percent (WA%) were obtained from segmental airways at 6 different pathways.

RESULTS: In 49 patients, CT scans (22 imatinib and 27 placebo) at baseline and 24 weeks post-treatment were analyzed. Baseline measures were similar between groups except that FEV₁% predicted was higher in the imatinib group (73.1 vs 63.7%, P=0.025). In segmental airways, there was significantly greater improvement in WT% and WA% observed with imatinib compared to placebo (delta WT%: -0.14 vs -0.07%, P=0.036; WA%: -0.19 vs 0.01%, P=0.028). Post-hoc analysis of segmental airways in patients who had airflow obstruction at baseline (FEV₁% <80% predicted) treated with imatinib compared to placebo demonstrated an even greater improvement in WT% and WA% (-0.41 vs 0.09% P=<0.001; -0.89 vs 0.20%, P<0.001).

CONCLUSIONS: These data suggest that inhibiting mast cells with imatinib may decrease the extent of airway remodeling in patients with severe asthma, especially in those with significant airflow obstruction. The SCF/KIT pathway shows promise for future drug development targeting airway remodeling and its underlying pathology.