TY - JOUR
T1 - KIT inhibition by imatinib in patients with severe refractory asthma
AU - Cahill, Katherine N.
AU - Katz, Howard R.
AU - Cui, Jing
AU - Lai, Juying
AU - Kazani, Shamsah
AU - Crosby-Thompson, Allison
AU - Garofalo, Denise
AU - Castro, Mario
AU - Jarjour, Nizar
AU - DiMango, Emily
AU - Erzurum, Serpil
AU - Trevor, Jennifer L.
AU - Shenoy, Kartik
AU - Chinchilli, Vernon M.
AU - Wechsler, Michael E.
AU - Laidlaw, Tanya M.
AU - Boyce, Joshua A.
AU - Israel, Elliot
N1 - Funding Information:
Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694. Supported by grants from the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH U01 HL102225, RO1 HL117945, RO1 AI078908, R37 AI052353, T32 AI007306-23, and K23 AI118804), and by contributions from the Vinik family and the Kaye family. Novartis provided imatinib free of charge. We thank Sumit Narula, Bryce Robinson, Vanessa Curtis, Sylvia Johnson, Necole Harris, Michele Wolff, Holly Eversoll, Gina Crisafi, and Jacqueline Sharp for project management assistance; Stephanie Dutile for assistance in preparing the grant proposal and preparation and execution of the trial protocol; Loren Denlinger for clinical support; Geneline Sajol and Anya Cutler for technical assistance; Usha Govindarajula for statistical assistance; and the members of the data and safety monitoring board: Reynold A. Panettieri, Jr., David Schoenfeld, Mark Liu, Robert Wood, and Carol Freund Taylor.
Publisher Copyright:
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
PY - 2017/5/18
Y1 - 2017/5/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85019781627&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1613125
DO - 10.1056/NEJMoa1613125
M3 - Article
C2 - 28514613
AN - SCOPUS:85019781627
SN - 0028-4793
VL - 376
SP - 1911
EP - 1920
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 20
ER -