SOTA: Research Based Dosing of Ibrutinib in Chronic Lymphocytic Leukemia

Ibrutinib has transformed treatment of B-cell malignancies; this oral drug covalently binds and inactivates Bruton’s tyrosine kinase (BTK), a pivotal enzyme in the B-cell receptor (BCR) pathway. For ibrutinib, dose was selected based on occupancy of the enzyme by the drug. This dose was 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). Maintenance of BTK transcript and protein are governed by BCR pathway. We previously demonstrated a decline in BTK protein levels after one cycle of ibrutinib and hypothesized that the ibrutinib dose could be lowered as levels of its target, BTK, declined. To test this postulate, a pilot clinical trial was designed to systematically and preemptively reduce ibrutinib dosing within the same patient. Following an initial cycle of standard dose of 420 mg/d (3 capsules/d), the dose was reduced to 280 mg/d in cycle two and then to 140 mg/d in cycle three. Plasma and intracellular levels of ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy on average >95% of BTK protein. In concert, downstream signaling inhibition such as phospho-BTK was maintained with 140 mg/d ibrutinib in cycle three. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar over the three cycles. This data demonstrates that following one cycle of ibrutinib, the dose can be reduced without losing biological activity, however clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate ibrutinib combination approaches.