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Mechanisms of ibrutinib resistance identified in chronic lymphocytic leukemia

COLUMBUS, Ohio A new study has discovered how resistance develops in patients taking ibrutinib, a new and highly effective drug for the treatment of chronic lymphocytic leukemia (CLL).

The study was published in the New England Journal of Medicine and led by researchers at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC James). It identifies gene mutations that cause 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," says co-principal investigator John C. Byrd, MD, director, division of hematology, and professor of medicine, of medicinal chemistry and of veterinary biosciences at Ohio State.

"Importantly, we saw none of these mutations in patients before they used ibrutinib," says Amy Johnson, PhD, associate professor of medicine in the division of hematology, an OSUCCC James researcher and a co-principal investigator of the study.

Ibrutinib (Imbruvica) works by permanently binding with a protein called Bruton's 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 (see illustration below).

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.

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.

Clinical trials have shown that ibrutinib is a highly effective drug for CLL and that it causes few serious side effects. Patients with relapsed CLL have shown a 71-percent overall response rate, and another 15-20 percent achieved a partial response. The estimated progression-free survival is 75 percent at 26 months.

"At this point, few patients taking ibrutinib have relapsed," says first author Jennifer Woyach, MD, assistant professor in the division of hematology and an OSUCCC James researcher. "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 important to learn if this is a general pattern of resistance," she says

For this study, Byrd, Woyach, Johnson and their colleagues examined samples from six CLL patients who had developed ibrutinib resistance. The samples were obtained before treatment started and after resistance developed. Key technical findings included:

  • Ibrutinib resistance is due at least in part to a cysteine-to-serine mutation in BTK at the ibrutinib binding site and to mutations in a protein called PLC gamma 2;
  • Patients with lymphocytosis, which is an increase in the number of lymphocytes in the blood, showed no evidence of the resistance mutations;

  • The risk of relapse may be greatest for cases of CLL that show greater genomic instability, such as those with deletions in chromosomes 17 and 11.

"Overall, our findings emphasize the importance of this pathway in ibrutinib's mechanism of action in CLL," says Byrd, who holds the D. Warren Brown Designated Chair in Leukemia Research, directs the OSUCCC James CLL Experimental Therapeutics Laboratory and co-leads the Leukemia Research Program.

Contact: Amanda Harper
Ohio State University Wexner Medical Center

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