Ibrutinib dose modifications in the management of CLL

Abstract

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) in 2014. Ibrutinib is often used to treat patients who are younger than the patients originally included in theclinical trials have additional unfavorable prognostic factors and suffer from additional comorbidities excluded from the original phase III trials. Our objective was to examine current clinical practices and their impact in this expanded population of CLL patients who often require adjustments in the standard prescribed dose and schedule of therapy. Materials and methods: An extensive review of the medical literature was conducted to establish the consensus on ibrutinib dose modifications in patients with CLL. Twenty-nine studies were reviewed including fourteen clinical trials and fifteen "real-world practice"studies. Results: The average discontinuation rate was similar between clinical trials and "real-world practice"studies though the reasons for discontinuation differed. CLL progression was a more common reason for discontinuation in clinical trial studies while toxicity was a more common reason for discontinuation in "real-world practice"studies. Some studies have suggested worse outcomes in patients requiring dose reductions in ibrutinib while others have shown no change in treatment efficacy in patients requiring dose reductions due to concomitant CYP medications or increased immunosuppression post-transplant. Conclusion: The impact of ibrutinib dose modifications on clinical outcome remains unclear. Patients on concomitant CYP3A inhibitors should be prescribed a lower dose than the standard 420 mg daily, in order to maintain comparable pharmacologic properties. Further research is required to establish definitive clinical practice guidelines.