Since 2001, imatinib has revolutionized care for patients with Chronic Myeloid Leukemia (CML) and has altered the field of oncology. The result of a rational drug design, imatinib specifically targeted BCR-ABL, the molecular switch that controlled growth of CML cells. Over time, imatinib has also been shown to affect tumors that express KIT, a proto-oncogene tyrosine-protein kinase receptor that is expressed in 85% of gastrointestinal stromal tumors (GIST). Historically, GIST was associated with gastrointestinal bleeding and rapid deterioration. However, with the introduction of imatinib, survival rates in patients with metastatic GIST improved significantly. KIT is also essential for mast-cell development and survival in tissues, and imatinib has been shown to reduce bone marrow mast-cell numbers and serum tryptase in patients with CML. Mast cells are also associated with airway hyperresponsiveness and asthma disease severity. If imatinib has allowed patients with certain types of cancer to achieve remission, can it benefit patients with severe asthma?
In this week’s issue of NEJM, Cahill and colleagues report the results of a randomized, double-blind, proof-of-principle trial in the United States in which imatinib and placebo were compared in 62 patients with poorly controlled, severe asthma. Severe refractory asthma was defined as asthma symptoms despite treatment with high-dose inhaled glucocorticoids and at least one additional controller medication. The primary endpoint 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). Secondary and exploratory endpoints included measurements of tryptase in both serum and bronchoalveolar lavage (BAL) fluid.
Imatinib reduced airway reactivity to a greater extent than placebo. At 6 months, methacholine PC20 increased by a mean of 1.73 doubling doses in the imatinib group versus 1.07 doubling doses in the placebo group (P=0.048). Patients treated with imatinib also had lower levels of serum tryptase (P=0.02), a finding consistent with airway mast cell deactivation.
Although the number of total and severe adverse events did not vary between the two groups, patients treated with imatinib were more likely to experience muscle cramps and hypophosphatemia. Despite hematological toxicities associated with imatinib, only one patient discontinued the drug because of neutropenia and there were no reports of thrombocytopenia.
This was an innovative and inspiring study but as a proof of concept trial it is not clinically directive. The results provide new evidence for the biological mechanisms of severe asthma and an alternative use for an existing drug. Antagonism of KIT did result in inhibition of mast cells and improved airway responsiveness in patients with severe asthma. In an accompanying editorial, Dr. Galli suggests that the results should be interpreted with caution because patient selection is key. Imatinib may confer benefit in allergic asthma where mast cells significantly contribute to the pathobiology. However, a larger study specifically in this population is required to evaluate biological effect and clinical benefit.
Browse more From Pages to Practice »
Ramya Ramaswami is a 2016-2017 NEJM editorial fellow. She is a medical oncologist within the National Health Services of the United Kingdom. Ramya received her medical degree, postgraduate medical and oncology training from Imperial College London, and a masters in public health from Columbia University, Mailman School of Public Health. Her clinical and research interests include cancer prevention, viral driven cancers, as well as disparities and access issues in global oncology.