Resistance to ibrutinib in chronic lymphocytic leukemia explained

Resistance to ibrutinib in chronic lymphocytic leukemia explained
Resistance to ibrutinib in chronic lymphocytic leukemia explained

A new study has discovered how resistance develops in patients taking ibrutinib (Imbruvica), a new and highly effective drug for the treatment of chronic lymphocytic leukemia (CLL). Gene mutations are found to be the cause of ibrutinib resistance in CLL patients.

"Knowledge of these mutations is the first step in the development of drugs or drug combinations that might prevent or treat ibrutinib-resistant CLL," said co-principal investigator John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center­–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James) in Columbus.

"Importantly, we saw none of these mutations in patients before they used ibrutinib," said co-principal investigator Amy Johnson, PhD, also of OSUCCC–James. The study was published in the New England Journal of Medicine (2014; doi:10.1056/NEJMoa1400029).

An estimated 15,700 new cases of CLL are expected in the United States in 2014, along with 4,600 deaths from the disease, which still has no cure.

Ibrutinib works by permanently binding with a protein called Bruton tyrosine kinase (BTK), a molecule that CLL cells need to grow and proliferate. 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 the 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.

Clinical trials have shown that ibrutinib is a highly effective drug for CLL and that it causes few serious side effects. An overall response rate of 71% has been seen in patients with relapsed CLL, and another 15% to 20% of patients taking the drug 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, also of OSUCCC–James. "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," Woyach said.

For this study, Byrd, Woyach, Johnson, and their colleagues examined samples from six patients with CLL in whom resistance to ibrutinib developed. The samples were obtained before treatment started and after resistance developed.

They found that a mutation in BTK at the ibrutinib binding site may be at least partially responsible for ibrutinib resistance. Greater genomic instability, such as deletions in chromosomes 17 and 11, suggests the greatest risk of relapse.

"Overall, our findings emphasize the importance of this pathway in ibrutinib's mechanism of action in CLL," said Byrd.

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