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 hyper-responsiveness, 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.)

The contribution of mast cells to bacterial and fungal infection immunity

“…However, there is a possibility that we will obtain some insight into this question with the use of therapies that target mast cells in humans. For example, blocking the effects of c‐KIT in mast cells by using the tyrosine kinase inhibitor, imatinib, produces a profound decrease in mast cells in patients with chronic myeloid leukemia (CML) and severe asthma . Thus far, a small study with 23 CML patients showed no increase in the frequency of severe bacterial or fungal infections after treatment with imatinib.…”

The vascular endothelial specific IL-4 receptor alpha–ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions

“…Consistent with this argument, long-term treatment with imatinib caused a profound MC deficiency in mice and patients with PH + CML 89 . Furthermore, a recent study examined the clinical utilization of Imatinib for treatment of severe refractory asthmatic patients and demonstrated that Imatinib had excellent efficacy, reducing mast cell counts and activation and asthma symptoms 90 .…”

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

“…5), in the present study, we observed significant mast cell infiltration of the airways that was unaffected by Dex. In a study just published, treatment of severe asthmatics with imatinib -which targets KIT, a molecule expressed by mast cells -reduced AHR, even though mast cells numbers were reduced (but not eliminated) only after prolonged treatment (54). Mast cells are known to be long-lived, and given that they can contribute to AHR, the potential for type 1 inflammation to promote their accumulation in the airways highlights another detrimental effect of IFN-γ in establishment of SA and the poor response of this disease state to CS.…”