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A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia

Lisa S. Chen, Prithviraj Bose, Nichole D. Cruz, Yongying Jiang, Qi Wu, Philip A. Thompson, Shuju Feng, Michael H. Kroll, Wei Qiao, Xuelin Huang, Nitin Jain, William G. Wierda, Michael J. Keating and Varsha Gandhi

Key points

  • A pilot trial evaluated step-wise reduction of ibrutinib dose in patients with CLL from 420 to 280 to 140 mg/d over three 28-day cycles

  • BTK occupancy, signaling and biomarker data show that lower dose of ibrutinib after 1 full dose cycle is enough for biological activity

Abstract

Ibrutinib is highly efficacious and used at 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in BTK protein levels in CLL cells after 1 cycle of ibrutinib, suggesting that ibrutinib dose could be lowered after the first cycle without loss of biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce ibrutinib dosing within the same patient with CLL over three 28-day cycles. Following an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2 and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and nine completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of ibrutinib were compared. 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, BTK downstream signaling inhibition was maintained with 140 mg/d ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223) protein levels across 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar over the 3 cycles. These PK/PD data demonstrate that following one cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations.

  • Submitted June 28, 2018.
  • Accepted September 18, 2018.