Pilot Study Supports Lower Dose of Ibrutinib in Chronic Lymphocytic Leukemia

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In patients with chronic lymphocytic leukemia, a lower ibrutinib dose appears to confer sufficient biological activity, but further study is needed.
In patients with chronic lymphocytic leukemia, a lower ibrutinib dose appears to confer sufficient biological activity, but further study is needed.

A pilot study showed that in patients with chronic lymphocytic leukemia (CLL), the dose of ibrutinib can be lowered after 1 full cycle without compromising biological activity (ClinicalTrials.org Identifier: NCT02801578).1 A lower ibrutinib dose could reduce drug costs and toxicity as well, noted the study authors. The findings were published online September 25, 2018, in Blood.

The study enrolled 11 patients with CLL to receive three 28-day treatment cycles with ibrutinib. For cycle 1, patients received standard ibrutinib dosing of 420 mg once daily. Ibrutinib dosing was lowered in a step-wise fashion to 280 mg once daily for cycle 2 and 140 mg once daily for cycle 3. Nine patients completed all treatment cycles.

Blood was collected at 16 time points to evaluate plasma and intracellular pharmacokinetics (PK), Bruton's tyrosine kinase (BTK) occupancy, and pharmacodynamic (PD) response across the 3 treatment cycles.

The researchers found that plasma and intracellular levels of ibrutinib varied by dosing. Yet, an analysis of BTK occupancy showed that even at cycle 3, more than 95% of BTK protein was occupied on average; further, BTK downstream signaling inhibition was maintained. Reductions in phospho-BTK (Tyr223) protein levels as well as plasma chemokine CCL3 and CCL4 levels (which are biomarkers of response) were similar across all the treatment cycles.

“These PK/PD data demonstrate that following 1 cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity,” the study authors wrote.

The investigators advocated for further investigation of the findings, writing, “A larger, more comprehensive study with clinical end points including formal response assessments as well as PK/PD investigations, and lymph node biopsies in consenting patients, is planned, and is needed before ibrutinib dose reduction after 1 cycle at 420 mg/d can be considered the standard of care for patients with CLL.”

Reference

  1. Chen LS, Bose P, Cruz ND, et al. A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia [published online September 25, 2018]. Blood. doi: 10.1182/blood-2018-06-860593

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