Dosing Schedules May Affect Outcomes With Acalabrutinib in CLL
Posted: Tuesday, May 26, 2020
When does 200 not equal 100 x 2? The answer is when the discussion is about acalabrutinib dosing in chronic lymphocytic leukemia (CLL) and whether the Bruton’s tyrosine kinase (BTK) inhibitor given at 100 mg twice daily or 200 mg once daily yields different results in terms of inhibiting oncogenic signaling. The results of a randomized phase II study revealed that twice-daily dosing maintained higher, near-complete BTK occupancy in blood and tissues, according to Adrian Wiestner, MD, PhD, of the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and colleagues. Twice-daily dosing “achieved more potent pathway inhibition…and more profoundly inhibit[ed] oncogenic signaling than once-daily dosing.”
Writing in the journal Blood, the authors posited that “small increments in occupancy attained by twice-daily dosing relative to once-daily dosing compounded over time to augment downstream biological effects.” Their study included 48 patients with relapsed/refractory or high-risk treatment-naive CLL.
Inhibiting the B-cell receptor pathway, specifically of BTK, is an established therapeutic strategy in B-cell malignancies, including CLL. “Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors,” according to the investigators. “However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition, and clinical outcomes remain undefined.”
The results may help to hone that definition. With twice-daily dosing, acalabrutinib yielded an overall response rate of 95.8% and an estimated progression-free survival rate at 24 months of 91.5%. With once-daily dosing, the overall response rate was 79.2%, with an estimated progression-free survival rate at 24 months of 87.2%.
Acalabrutinib was well tolerated by the patients, noted Dr. Wiestner and co-investigators. Further research, they said, may help determine “the impact of BTK occupancy on long-term clinical outcomes.”
Disclosure: The study authors’ disclosure information can be found at ashpublications.org.
