A new study helps confirm that a molecule targeted by the experimental drug ibrutinib is critical for the development of chronic lymphocytic leukemia (CLL), the most common form of adult leukemia.

In clinical trials, ibrutinib has often shown exceptional activity in people with CLL. The agent targets a molecule called Bruton’s tyrosine kinase (BTK). It permanently incapacitates the molecule, and this stops the transmission of an important signal that promotes cell growth and proliferation.

But ibrutinib also inhibits other molecules in CLL cells. Like BTK, these molecules are proteins called kinases, and they might be important for CLL-cell survival, the researchers say.

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“Ibrutinib’s lack of selectivity might mean that BTK is not the critical target in CLL, and that future drugs developed for CLL should focus on other molecules,” said Amy Johnson, PhD, principal investigator and associate professor of medicine in the Division of Hematology, and a researcher at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus (OSUCCC–James). However, the findings, published in Blood (2013; doi:10.1182/blood-2013-07-515361), validated BTK inhibition.

“This study shows that BTK is an important therapeutic target in CLL,” said first author Jennifer Woyach, MD, assistant professor in the Division of Hematology and an OSUCCC–James researcher. “Inactivating BTK alone delayed CLL development in a mouse model, confirming that BTK is a clinically important target in CLL. This suggests that development of selective BTK inhibitors—in addition to multikinase inhibitors like ibrutinib—is reasonable in CLL.”

To investigate the role of BTK in CLL, Johnson, Woyach, and their colleagues used CLL cells from patients and two CLL mouse models, one of which spontaneously develops a malignancy very similar to human CLL. The researchers blocked BTK activity in two ways—genetically and pharmacologically—using ibrutinib.

They found that inhibiting BTK expression in human CLL cells significantly decreased survival in tumor cells from 31 patients. Also, a mouse model with inactive BTK due to a point mutation survived significantly longer than mice with active BTK (18.3 vs 13.2 months, respectively). In a mouse model of spontaneous CLL, animals treated with ibrutinib survived significantly longer than controls from the time of leukemia diagnosis (46 vs 24 days, respectively). In the same mouse model, treatment with ibrutinib significantly delayed leukemia onset compared with controls (10.7 vs 7.0 months) and extended overall survival (14.5 vs 12.3 months, respectively).

“Overall,” Johnson said, “our findings validate BTK as a target for CLL therapy and strongly suggest that selective kinase-inhibitors might work in CLL like the drug imatinib does in chronic myeloid leukemia.”