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Scientists Decipher Resistance to Ibrutinib (Imbruvica) in CLL Patients

Evidence points to gene mutations

Researchers at the Ohio State University Comprehensive Cancer Center have discovered how resistance develops in patients taking ibrutinib (Imbruvica, Pharmacyclics/Janssen Biotech), a new treatment for patients with chronic lymphocytic leukemia (CLL).

The study, published in the New England Journal of Medicine, identifies gene mutations as the likely culprits.

“Importantly, we saw none of these mutations in patients before they used ibrutinib,” said co-principal investigator Amy Johnson, PhD.

Ibrutinib works by permanently binding with a protein called Bruton’s tyrosine kinase (BTK), a molecule that CLL cells need for growth and proliferation. BTK is one in a chain of proteins that relays growth signals from the surface of CLL cells to genes in the cell nucleus. By blocking BTK, ibrutinib halts the flow of these growth signals, and the CLL cells die.

The researchers found, however, that CLL cells can develop a mutation in BTK itself that weakens the ability of ibrutinib to bind with this protein. This leaves the drug less able to block BTK’s action. The researchers also found two mutations in a protein that comes after BTK in the signaling pathway. Those mutations allow growth signals to travel the pathway even when BTK is blocked, rendering ibrutinib ineffective.

An estimated 15,700 new cases of CLL are expected in the U.S. in 2014, along with 4,600 deaths from the disease, which still has no cure. Clinical trials have shown that ibrutinib is an effective treatment for CLL and that it causes few serious side effects. Patients with relapsed CLL have shown a 71% overall response rate, and another 15% to 20% have achieved a partial response. The estimated progression-free survival is 75% at 26 months.

“At this point, few patients taking ibrutinib have relapsed,” said first author Jennifer Woyach, MD. “But as more patients use the drug, it becomes more important to learn how resistance occurs and to have effective alternative therapies for patients who need them. And as other irreversible kinase inhibitors are developed for key signaling pathways in cancer, it will be important to learn if this is a general pattern of resistance."

Source: Ohio State University; May 29, 2014.

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