Imatinib decreased airway mast-cell counts and airway hyperresponsiveness in adults with asthma, who were not responding well to maximal therapy, according to a report published online May 17 in the New England Journal of Medicine.
Imatinib is an inhibitor of the stem-cell factor receptor KIT, which is essential for mast-cell development and survival in bodily tissues. This study’s findings suggest that KIT-dependent processes and mast cells contribute to the pathobiology of severe asthma.
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The researchers undertook this study because imatinib is known to reduce bone-marrow mast cells and tryptase levels in chronic myeloid leukemia and to reduce serum tryptase in patients with pulmonary hypertension. Tryptase is a marker of mast-cell burden and activation when detected in extracellular fluids, and it is elevated in the bronchoalveolar lavage fluid from patients with uncontrolled asthma.
To examine whether imatinib would decrease mast-cell counts and activation in the airways of adults with severe, refractory asthma, the investigators performed the randomized double-blind proof-of-principle trial at seven academic centers across the United States over the course of 5 years. A total of 62 patients were assigned to 24 weeks of either oral imatinib (32 participants) or a matching placebo (30 participants). Fifty patients, 24 in the imatinib group and 26 in the placebo group, completed the trial.
The primary outcome measure was the change in airway hyperresponsiveness at 6 months, as measured by the increase in the concentration of methacholine that causes significant bronchoconstriction (PC20). Imatinib decreased airway hyperresponsiveness to a greater degree than did placebo. Imatinib increased PC20 by a mean of 1.20 doubling doses at 3 months and by a mean of 1.73 doubling doses at 6 months, compared with 0.03 and 1.07, respectively, for placebo.
The small improvement in the placebo group is consistent with a phenomenon reported in other studies, in which patients show a delayed improvement in airway hyperresponsiveness for several months after they started inhaled glucocorticoids, Dr. Cahill and her associates noted (N Engl J Med. 2017 May 18. doi: 10.1056/NEJMoa1613125).
Imatinib also reduced mast-cell activity as measured by serum and airway levels of tryptase. Serum tryptase decreased by 43% in the imatinib group, compared with a 12% decline in the placebo group. And tryptase levels in bronchoalveolar lavage fluid tended to decrease in the imatinib group but to increase in the placebo group.
Imatinib also increased mean forced expiratory volume in 1 second (FEV1).
“Although the increase in FEV1 may not seem substantial, it suggests that mast-cell–dependent processes contribute to airway obstruction in these patients despite high-dose, anti-inflammatory glucocorticoid therapy. The near–50-mL difference in the change in baseline FEV1 between the imatinib and placebo groups is small, but it is likely to be important in light of the population we studied,” Dr. Cahill and her associates wrote.
In addition, exploratory analyses showed that the reduction in airway hyperresponsiveness with imatinib “negatively correlated with baseline blood eosinophil counts, and baseline numbers of neutrophils in bronchoalveolar lavage fluid were strongly correlated with increases in FEV1. Together, these findings support a role for mast cells in noneosinophilic asthma. Since almost half of the patients with severe asthma have neutrophilic airway inflammation, we speculate that KIT inhibition might represent an important approach to treatment for this group,” they said.
This study was supported by the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Vinik family, and the Kaye family; Novartis provided imatinib free of charge. The authors’ financial disclosures are available at www.nejm.org.