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.

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

“…Novel agents, including inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the antiapoptotic protein BCL-2 (venetoclax), are superior compared to conventional chemoimmunotherapy (CIT) regimens. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) and allogeneic stem cell transplant (allo-SCT) are available for high-risk patients [3][4][5][6][7][8][9]. New challenges emerge when patients relapse on novel agents, and optimal sequencing strategies have not been established.…”

Current and future treatment strategies in chronic lymphocytic leukemia

“…While ibrutinib is generally well-tolerated, treatment discontinuations or interruptions due to toxicity may limit the efficacy of ibrutinib in patients receiving continuous oral therapy. A recent review reported that discontinuation rates for ibrutinib were similar between clinical trials and real-world practice (32% vs 34%, respectively), though the reasons for discontinuation differed [ 33 ]. One large-scale, real-world study reported that 41% of patients discontinued ibrutinib and that ibrutinib toxicity was the main reason for these discontinuations [ 34 ].…”

Treatment strategies for a rapidly evolving landscape in chronic lymphocytic leukemia management

“…Real‐world data show that intolerance is the most frequent reason for discontinuation or interruption of ibrutinib 41,54,55 . Dose reductions and temporary breaks are common and often required 41,55,56 .…”

“…Younger, fit patients may have a lower incidence of discontinuation or interruption due to AEs, as observed in E1912 12,40 . Strategies to minimize ibrutinib intolerance and maximize efficacy are needed 41,54,56 …”