Real-World Outcomes of Patients Treated with Single-Agent Ibrutinib for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): A Systematic Review and Meta-Analysis

BACKGROUND: Ibrutinib improves progression-free survival (PFS) compared to chemo-immunotherapy in both previously untreated and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; hereafter, CLL) patients. Adverse events, such as atrial fibrillation, bleeding and fungal infections, are the leading cause of drug discontinuation. Observational studies of real-world patients suggest that the rate of ibrutinib-related adverse events is higher in practice than in clinical trials. Dose reductions and drug discontinuations are more common, which may affect outcomes, although evidence has been conflicting.

OBJECTIVES: The objective of this study is to systematically review and synthesize real-world toxicity and tolerability of CLL patients on ibrutinib.

METHODS: Prospective and retrospective cohort studies and case series of patients with CLL treated with single agent ibrutinib as first or subsequent line treatment outside of clinical trials were retrieved from the Pubmed, Embase, and CENTRAL databases. Studies were critically appraised using Joanna-Briggs Institute checklists. Meta-analyses of studies deemed of moderate to high quality were done if the risk of heterogeneity was low.

RESULTS: We screened 4458 titles and abstracts and moved 251 records to full-text review. 25 full-text studies were included in the qualitative analysis. Most studies were of low to moderate quality. Rates of any bleeding ranged from 5.4 to 54.1 events/100 persons-year. Rates of severe bleeding ranged from 0 to 6.4 events/100 persons-year. Rate of infection was 9.2 to 49.8 infections/100 persons-year. Rate of atrial fibrillation varied from 2.5 to 26.0 events/100 persons-year. Pooled estimate of risk of atrial fibrillation per 100 person-years was 7.0 (95% CI 5.8, 8.2) by meta-analysis of moderate quality studies. Rate of dose reductions varied from 15.1 to 26.8 events/100 person-years, and dose reductions did not affect outcomes. The rate of drug discontinuation varied from 6.4 to 55.2 events/100 person-years. The most common cause for drug discontinuation was adverse events.

CONCLUSION: The risk of atrial fibrillation is higher in the real-world than reported from clinical trials. There was a large range of prevalence of other bleeding and infection. These adverse events were the leading cause of dose reduction and drug discontinuation. This study has many limitations arising from heterogeneity of patient characteristics and outcomes ascertainment. This highlights the need for standardized post-marketing studies of new drugs and for inclusive criteria for inclusion into randomized controlled trials.