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Tiny mutation triggers drug resistance for patients with one type of leukemia
Date:5/28/2014

A multi-institutional team of researchers has pinpointed exactly what goes wrong when chronic lymphocytic leukemia (CLL) patients develop resistance to ibrutinib, a highly effective, precisely targeted anti-cancer drug. In a correspondence published online May 28 in the New England Journal of Medicine, they show how the mutation triggers resistance. Their finding could guide development of new agents to treat drug-resistant disease.

Ibrutinib received accelerated approval from the Food and Drug Administration for use in chronic lymphocytic leukemia in February. It has revolutionized treatment, transforming CLL from a deadly disease to a chronic one. But about eight percent of patients develop resistance to this lifesaving drug.

In this study, the researchers describe a point mutation in one participant enrolled in a multi-center clinical trial. This patient stopped responding to treatment after almost 20 successful months. The mutation destabilized the binding of ibrutinib to its target, a protein that regulates cell replication, allowing leukemic cells to multiply freely.

"In a way, we are repeating, at a faster pace, the story of Gleevec (imatinib), a landmark drug that transformed care for a different type of leukemia," said study senior author Y. Lynn Wang, MD, PhD, professor of pathology at the University of Chicago. "That story began with development of an effective drug with few side effects, but in many patients the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance."

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York City, one of several sites for a phase 1 clinical trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Wang, who recently moved from Cornell to the University of Chicago, arranged to track the progres
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Contact: John Easton
john.easton@uchospitals.edu
773-795-5225
University of Chicago Medical Center
Source:Eurekalert

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