Long-term, real-world data support the efficacy and safety of ibrutinib/ibrutinib in CLL

Final results from the EVIdeNCE study support ibrutinib as a valuable treatment option for patients with chronic lymphocytic leukemia (CLL). EVIdeNCE data from real-world practice confirms ibrutinib's previously demonstrated efficacy and safety in clinical trials involving patients with CLL. Cardiovascular disease did not affect patient clinical outcomes. EVIdeNCE is the largest prospective Italian study designed to recruit CLL patients receiving ibrutinib monotherapy across multiple lines of therapy in a real-world clinical setting.

In this trial, investigators enrolled309 patients with CLL who received single-agent ibrutinib at first-line (1L; n=118), 2L (n=127), and ≥3L (n=64). Of note, a proportion of patients had comorbidities, especially cardiovascular disease (33.3%). Among 266 patients tested for adverse genetic profiles, 69.6% had unmutated IGHV and 50.0% had 17p deletions or TP53 mutations. The majority of patients (63.1%) were male, and 60.2% were 70 years or older.

Across the entire cohort, 2-year retention rate was 70.2% (1L: 75.4%; 2L: 70.1%; ≥3L: 609%). The 2-year progression-free survival rate and overall survival rate were 85.4% and 91.7% respectively for 1L, 80.0% and 86.2% for 2L, and 70.1% and 80.0% for ≥3L. The high rate of CLL patients remaining on ibrutinib at 2 years is consistent with data from previous clinical trials and real-world retrospective studies.

However, differences in patients' baseline clinical and biological characteristics, number of previous treatments, years of treatment, patient management, and heterogeneity in the follow-up period may contribute to variability. For example, in one study, a group of patients in France (97% of whom had relapsed or refractory disease) had a discontinuation rate of 15% with a median follow-up of 3 months, compared with 65% with a median follow-up of 25 months.

In their study, patients who received ibrutinib in the first line had higher 2-year retention rates than those who received it later. Because patients who received ibrutinib as advanced line therapy after prior chemoimmunotherapy were at higher risk for refractory CLL, adverse events, and cytopenias, there is another potential strategic component to improving patient compliance and duration of ibrutinib treatment: emotional support. They cited the real-world, multicenter German REALITY study, in which researchers reported that patients with high uptake had higher rates of compliance and retention compared with patients with low uptake.

Median follow-upAfter 23.9 months, 29.8% of EVIdeNCE patients discontinued ibrutinib (1L: 24.6%; 2L: 29.9%; ≥3L: 39.1%), mainly due to adverse events/toxicity (AE; 14.2%). In the 1L and ≥3L cohorts of EVIdeNCE, the most common AE leading to discontinuation was infection, while in the 2L cohort, cardiac events were the most common cause.

The trial's AE pattern was consistent with the AE characteristics recorded in early clinical studies of ibrutinib, mainly infection, bleeding, fatigue, neutropenia and diarrhea. The prevalence of atrial fibrillation in patients was 8% and increased with each line of therapy: 1L, 6.8%; 2L, 8.7%; and ≥3L, 9.4%.

These findings, combined with its safety profile and the potential for dose reduction and flexibility associated with ibrutinib, suggest that the novel ibrutinib and venetoclax combination has a favorable benefit-risk profile.