Outcomes of Reduced Frequency Dosing of Ibrutinib in Chronic Lymphocytic Leukemia Patients Following Complete or Partial Remission: A Pilot Study

Abstract

Background Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has shown to be a superior choice in the treatment of chronic lymphocytic leukemia (CLL) and a simple, oral alternative to other chemoimmunotherapies. The standard dose is 420 mg daily; however, its irreversible binding mechanism allows adequate target blockade at much lower doses due to prolonged effect. Dose reductions or interruptions are often used in clinical practice to limit its distinct side effects, including diarrhea, bleeding and atrial fibrillation and emerging evidence exists that these do not hinder efficacy. Using a retrospective clinical audit of a single-center outpatient hematology clinic, we aimed to examine outcomes and toxicities of a reduced frequency dose regimen of ibrutinib in patients beyond the confines of a clinical trial. Methods A small pilot study was conducted on 16 voluntary CLL patients that had achieved partial or complete remission on standard dose ibrutinib and were considering cessation due to side effects. Patients were consented and prescribed a 420 mg thrice weekly regimen and side effects and outcomes were recorded on routine review. A retrospective clinical audit from 2015 to 2018 was then conducted to compare pilot participants to patients that had remained on standard dosing and results from the extended follow-up of the landmark RESONATE trial. Results None of the 16 patients in the pilot relapsed or died during the study period equating to a 100% progression free and overall survival. There was resolution or reduction in all side effects reported following switchover; however, the study was too small to establish a statistical relationship. Conclusion This is the first study to demonstrate use of a thrice weekly regimen to reduce ibrutinib-related toxicities whilst preserving safety and efficacy in patients following complete or partial remission on standard dose therapy. Higher powered, prospective studies are required to establish positive health and financial implications in the elderly and vulnerable CLL demographic.

Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

“…An ibrutinib dosage of 2.5 mg/kg QD was found to result in >95% Btk occupancy in PBMC, but higher doses (420 mg and 560 mg QD for CLL and MCL, respectively, corresponding to 6 mg/kg and 8 mg/kg QD for a person of 70 kg) were selected for treatment, also based on the safety and tolerability the drug [ 75 ]. Recent retrospective and pilot studies show comparable outcomes in patients with CLL on reduced dose (280 mg QD, 140 mg QD) or reduced frequency dosing of ibrutinib [ 135 , 136 , 137 , 138 , 139 ]. In one study even the lowest dose (140 mg/d) was sufficient to occupy >95% of Btk in PBMC [ 136 ].…”