Long-Term, Real-World Data Support Ibrutinib Efficacy, Safety in CLL

EVIdeNCE study data, from real-world practice, confirm the efficacy and safety that ibrutinib previously demonstrated in clinical trials involving patients with CLL, according to the study authors.

Final results of the EVIdeNCE study strongly support ibrutinib (Imbruvica; AbbVie/Pharmacyclics) as a valuable treatment option for patients with chronic lymphocytic leukemia (CLL). The EVIdeNCE data, from real-world practice, confirm the efficacy and safety that ibrutinib previously demonstrated in clinical trials involving patients with CLL, according to the study authors.

Cardiovascular conditions did not impact patients’ clinical outcomes, they noted. EVIdeNCE was the largest prospective investigation in Italy to enroll patients with CLL who received ibrutinib monotherapy across multiple lines of treatment in real-world clinical settings. These results were published in Cancers.

The investigators enrolled 309 patients with CLL who received single-agent ibrutinib in first line (1L; n = 118), 2L (n = 127), and ≥3L (n = 64) in this prospective trial. Notably, a prevalence of patients had comorbidities, especially cardiovascular disorders (33.3%). Among the 266 patients tested for unfavorable genetic features, 69.6% had unmutated IGHV and 50.0% had either 17p deletion or a TP53 mutation. Most patients (63.1%) were male and 60.2% were 70 years or older.

In the whole cohort, the 2-year retention rate was 70.2% (1L: 75.4%; 2L: 70.1%; ≥3L: 60.9%).

Chronic lymphocytic leukemia | Image credit: jarun011 -

Chronic lymphocytic leukemia | Image credit: jarun011 -

The 2-year progression-free survival and overall survival rates were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L.

The high rate of patients with CLL remaining on ibrutinib at 2 years is in line with data from previous clinical trials and real-world retrospective studies, noted the authors.

However, “differences in the baseline clinical and biological characteristics of patients, number of prior treatments, years of treatment, patient management, and heterogeneity in the follow-up periods may contribute to…variation,” they said. For instance, the discontinuation rate in a French cohort of patients, 97% of whom had relapsed or refractory disease, was 15% with a median follow-up of 3 months, whereas that rate was 65% over a median follow-up of 25 months in a study involving US Medicare beneficiaries.

It wasn’t surprising, they noted, that the 2-year retention rate in their study was higher in patients receiving ibrutinib in the front line compared with those receiving it in later lines, given the higher risk of refractory CLL, adverse events (AEs), and cytopenia in patients who receive ibrutinib as advanced-line therapy after prior chemoimmunotherapy,

The authors suggested another potential strategical component of improving patient compliance and duration of ibrutinib treatment: emotive support. They cited the real-world multicentric German REALITY study, whose investigators“reported higher adherence and retention rates in patients with high, compared with those with low, acceptance” of their CLL.

After a median follow-up of 23.9 months, 29.8% of patients in EVIdeNCE discontinued ibrutinib (1L: 24.6%; 2L: 29.9%; ≥3L: 39.1%), primarily due to AEs/toxicity (14.2%). In EVIdeNCE’s 1L and ≥3L cohorts, the most common AE leading to discontinuation was infection, while in the 2L population, cardiac events were most frequently to blame.

The trial’s AE pattern aligned with the AE profile documented in earlier clinical studies of ibrutinib, the authors noted, with infections, bleeding issues, fatigue, neutropenia, and diarrhea predominating. The prevalence of atrial fibrillation among patients was 8%, and it increased with each treatment line: 1L, 6.8%; 2L, 8.7%; and ≥3L, 9.4%.

These study results suggest, they concluded, that when providers have more expertise and familiarity with the management of ibrutinib-related AEs, long-term outcomes of patients with CLL improve.

“Furthermore, the reassuring safety profile and the possibility of dose reduction and flexibility associated with ibrutinib suggest a favorable benefit–risk profile for the novel ibrutinib–venetoclax combination,” they wrote.


Mauro FR, Scalzulli PR, Scarfó L, et al. Real-world outcome of treatment with single-agent ibrutinib in Italian patients with chronic lymphocytic leukemia: final results of the EVIdeNCE study. Cancers. 2024;16(6):1228. doi:10.3390/cancers16061228. 

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