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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 .).

SUBMITTER: Cahill KN

PROVIDER: S-EPMC5568669 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.

Cahill Katherine N KN Katz Howard R HR Cui Jing J Lai Juying J Kazani Shamsah S Crosby-Thompson Allison A Garofalo Denise D Castro Mario M Jarjour Nizar N DiMango Emily E Erzurum Serpil S Trevor Jennifer L JL Shenoy Kartik K Chinchilli Vernon M VM Wechsler Michael E ME Laidlaw Tanya M TM Boyce Joshua A JA Israel Elliot E

The New England journal of medicine 20170501 20

<h4>Background</h4>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 ...[more]

PMID: 28514613

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Project description:BackgroundData on mepolizumab in patients with severe eosinophilic asthma (EA) and comorbidities are needed to assess whether randomized controlled trial results are applicable in the real world.ObjectiveTo evaluate real-life effectiveness and the presence/absence of predictors of treatment response in patients with one or more comorbidities (nasal polyps, allergic rhinitis, gastro-esophageal reflux disease, nonallergic rhinitis with eosinophilia syndrome, obesity, bronchiectasis) who received mepolizumab (MEPO) for the treatment of severe EA.MethodsWe performed a single-center retrospective study in patients with severe asthma and presence of comorbidities treated with mepolizumab at the respiratory outpatient clinic, Policlinico-Vittorio Emanuele, Catania, Italy. Health records of 31 severe asthmatic patients were retrieved and analyzed. Asthma control test (ACT) score, blood eosinophil count, forced expiratory volume in 1 s (FEV1), FEV1% of predicted and FEV1/FVC (Forced Vital Capacity) ratio, oral corticosteroid (OCS) dosage, and exacerbations were recorded at baseline (T0), after 3 (T1), 6 (T3), 9 (T6), and 12 months (T12). Clinical response was defined when 3 of these 4 criteria were fulfilled: i) 30% exacerbation decrease; ii) 80% blood eosinophilia reduction; iii) 3 point ACT increase; iv) FEV1 increase ≥200 mL.Results83.87% of patients were classified as responsive to MEPO treatment. Substantial depletion of the blood eosinophils (>80%) was found in 87.1% of patients, FEV1 > 200 mL was seen in 54.84% of patients, a 3-point ACT improvement from baseline was recorded in 80.65% 25 of patients and a 30% reduction of exacerbations rates was seen in 96.77% of patients. Moreover, the majority 38.71% of patients met 3/4 parameters after 12 months. Neither the comorbidities nor other characteristics (sex, BMI, age, smoking) influenced treatment response.ConclusionsMEPO in patients with severe EA is effective regardless of the presence of comorbidities.

Project description:ObjectivesWe hypothesised that severe asthmatics taking a statin drug, in addition to inhaled corticosteroids/long-acting ?-agonist inhaler therapy, would have better asthma symptom control and improved lung function compared to their controls.Study designA retrospective, cross-sectional study of 165 patients with severe asthma seen from 2001-2008. Hierarchical linear and logistic regression models were used for modelling fitting.SettingUniversity of California, Davis Medical Center (Sacramento, California, USA). Academic, single-centre, severe asthma subspecialty clinic.Participants612 screened, 223 eligible and 165 adult patients were included in the final study (N=165; 31 statin users and 134 non-users).Primary and secondary outcome measuresThe primary endpoint was asthma control as measured by the Asthma Control Test (ACT). The secondary endpoints included lung function, symptoms and the need for corticosteroid burst and peripheral eosinophil count.ResultsAt baseline, statin users compared to non-users were older, had lower lung function (FEV1% predicted, FEV1, forced vital capacity and FEF25-75%) and had a higher prevalence of comorbid conditions. Statin use was associated with more aspirin and ipratropium inhaler use than in non-users. Patients in both groups were obese (body mass index ? 30). Statin users had better asthma symptom control compared to non-users (higher adjusted mean ACT score by 2.2±0.94 points, p<0.02). Median statin use was for 1 year. There were no statistically significant differences in lung function, corticosteroid or rescue bronchodilator use or peripheral eosinophilia between the two groups.ConclusionsIn our severe asthma referral population, statin users already taking inhaled controller therapy achieved better asthma control compared to non-users. The implications of this study is that patients with severe asthma could potentially benefit from added statin treatment. Because our study population was on average obese, the obese severe asthmatic may be a viable asthma subphenotype for further studies. Prospective randomised clinical trials evaluating the safety and efficacy of statins in severe asthma are warranted.

Dataset Information

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.

Publications

KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.

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