Single-Agent Ibrutinib Improves Survival and Prolongs Time to Next Treatment in Early-Stage CLL

In the double-blind, randomized CLL12 trial, patients with treatment-naïve, early-stage chronic lymphocytic leukemia (CLL) who received single-agent ibrutinib had longer event-free survival (EFS), progression-free survival (PFS), and time to next treatment (TTNT), compared with those who received placebo. The results from this study were presented as a late-breaking abstract by Petra Langerbeins, PhD, of the University of Cologne, at the 24th Congress of the European Hematology Association.

“The majority of patients with CLL are diagnosed at an early stage, where observation is the standard of care,” Dr. Langerbeins said, adding that there has been no proven benefit with chemotherapy or chemoimmunotherapy in this subgroup of patients. “With this trial, we aimed to ask if early-stage patients with increased risk of progression would benefit from an early intervention with ibrutinib.”

The CLL12 trial enrolled 363 patients with previously untreated, asymptomatic CLL. Most patients (n=273) had intermediate-risk disease. Participants were then randomized to receive either:

  • ibrutinib 420 mg once daily (n=182)
  • placebo (n=181)

The median treatment duration in each group was 21 cycles (range = 1-57) and 18 cycles (range = 1-57), respectively.

At a median of 31 months, the EFS (primary endpoint) was not reached in the ibrutinib group and was 47.8 months in the placebo group (hazard ratio [HR] = 0.25; 95% CI 0.14-0.43; p<0.0001). Median PFS also was not reached in the ibrutinib group, compared with 14.8 months in the placebo group (HR=0.18; 95% CI 0.12-0.27; p value not provided).

Ibrutinib treatment was associated with longer TTNT, as well (HR=0.21; 95% CI 0.11-0.39; p<0.0001). The most commonly prescribed subsequent treatment was
chemoimmunotherapy or an ibrutinib-based regimen, Dr. Langerbeins added. However, she noted that ibrutinib-treated patients who had very high-risk disease did not have
consistent EFS, PFS, and TTNT improvements, compared with participants with lower-risk disease.

Regarding the safety profile of ibrutinib, Dr. Langerbeins reported that, “surprisingly, adverse events [AEs] of any grade did not significantly differ between both arms,” occurring in 82.2% of ibrutinib-treated patients and in 84.8% of patients receiving placebo. AEs led to treatment interruption in 41.6% of ibrutinib-treated patients and 21.3% of placebo-treated patients (p value for comparison not reported); these were most often arrhythmias and bleeding events.

While more patients in the ibrutinib group experienced grade ≥3 AEs (43.2% vs. 38.8%), the difference was not statistically significant. As expected, rates of AEs of clinical interest associated with ibrutinib occurred more frequently in the ibrutinib group than the placebo group:

  • overall AEs of interest: 57.3% vs. 39.9% (p=0.001)
  • bleeding: 27.6% vs. 9.6% (p=0.0)
  • atrial fibrillation: 17.8% vs. 7.3% (p=0.003)
  • hypertensive disorders: 9.7% 3.9% vs. 3.9% (p=0.04)

At the time of study presentation, four patients (2.2%) in the ibrutinib group and five patients (2.8%) in the placebo group died because of a fatal AE, although none of the fatal AEs were considered related to treatment.

Although these results demonstrate a survival benefit with single-agent ibrutinib for patients with early-stage CLL, Dr. Langerbeins said that further survival data are needed to confirm the benefit of this approach, noting a limitation of this analysis.

The authors report relationships with Janssen, which sponsored this trial.


Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage chronic lymphocytic leukemia (CLL): primary endpoint results of the phase 3 double-blind randomized CLL12 trial. Abstract #LB2602. Presented at the 24th European Hematology Association Annual Congress, June 16, 2019; Amsterdam, The Netherlands.