KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.

Abstract

BACKGROUND:

Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.

METHODS:

We conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy.

RESULTS:

Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P=0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P=0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group.

CONCLUSIONS:

In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694 .).

• Authors: Katherine N Cahill, Howard R Katz, Jing Cui, Juying Lai, Shamsah Kazani, Allison Crosby-Thompson, Denise Garofalo, Mario Castro, Nizar Jarjour, Emily DiMango, Serpil Erzurum, Jennifer L Trevor, Kartik Shenoy, Vernon M Chinchilli, Michael E Wechsler, Tanya M Laidlaw, Joshua A Boyce, Elliot Israel
• Journal: The New England journal of medicine (N Engl J Med) Vol. 376 Issue 20 Pg. 1911-1920 (05 18 2017) ISSN: 1533-4406 [Electronic] United States
• PMID: 28514613 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Protein Kinase Inhibitors
• Methacholine Chloride
• Imatinib Mesylate
• Tryptases

Topics

• Adult
• Asthma (drug therapy, immunology, physiopathology)
• Bronchial Hyperreactivity (drug therapy)
• Bronchial Provocation Tests
• Cell Count
• Double-Blind Method
• Female
• Forced Expiratory Volume (drug effects)
• Humans
• Imatinib Mesylate (adverse effects, therapeutic use)
• Male
• Mast Cells (metabolism)
• Methacholine Chloride
• Middle Aged
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Quality of Life
• Tryptases (blood, metabolism)