The targeted cancer drug ibrutinib has recently transformed the treatment of chronic lymphocytic leukemia, adding years to the lives of patients with hard-to-treat disease who were told they had just months to live.
But ibrutinib has several off-target effects that may contribute to an increased risk of bleeding, especially in older patients who take blood thinners for heart disease. A recent study published in the New England Journal of Medicine suggests that a similar class of drug, acalabrutinib (ACP-196), has the same cancer-fighting ability as ibrutinib but reduces the risk of bleeding in CLL patients.
“Ibrutinib represented a major advance in the treatment of CLL, the most common leukemia in adults. But there are risks with its use; it alters the activity of blood cells known as platelets whose function is to prevent bleeding,” says one of the study’s principal investigators, Columbia’s Thomas Diacovo, MD, who showed in the new study that acalabrutinib has less effect on platelet function than ibrutinib.
In the study, a phase l/ll trial of 61 patients with relapsed CLL, 95 percent of those treated with the new drug responded at 14 months with no major bleeding events.
Dr. Diacovo says the bleeding risk with acalabrutinib is low because the drug hits its target with greater precision. Acalabrutinib and ibrutinib are both designed to inhibit a cancer-promoting molecule called Bruton’s tyrosine kinase (BTK), but ibrutinib also blocks other molecules essential for platelet function, leading to multiple side effects including hemorrhaging.
Although the full safety profile for acalabrutinib will not be known until hundreds of patients are tested, Dr. Diacovo’s preclinical experiments suggest that the bleeding risk will remain low. Platelets from patients taking acalabrutinib retained their ability to form blood clots when infused into a novel genetically modified animal model that serves as an avatar (a technology developed by Dr. Diacovo). In contrast, platelets from patients taking ibrutinib had a reduced ability to form clots, demonstrating how the ibrutinib increases bleeding risk in patients.
“Acalabrutinib appears to achieve the anti-cancer benefits of ibrutinib without significant drawbacks,” says Dr. Diacovo. Based on the study’s clinical and laboratory results, a phase III trial comparing the two drugs is now under way.
Dr. Diacovo received a grant from Acerta Pharma during the study to conduct animal research.
The study was supported by Acerta Pharma, the National Cancer Institute (P01 CA095426, T32 CA09338, K23 CA178183, R35 CA197734, R01 CA169162, R01 HD081281 and R01 CA177292), Leukemia and Lymphoma Society, Four Winds Foundation, Sullivan Chronic Lymphocytic Leukemia Research Fund, Mr. and Mrs. Michael Thomas, Al and Midge Lipkin, and the D. Warren Brown Foundation.