Ibrutinib improved event-free survival (EFS) when compared with placebo in patients with early-stage, asymptomatic chronic lymphocytic leukemia (CLL), according to phase 3 trial results published in Blood.

However, because overall survival (OS) data from this trial are pending, researchers concluded that they cannot recommend ibrutinib over a “watch and wait” approach at this time.

The researchers compared ibrutinib with placebo in the phase 3 CLL12 trial (ClinicalTrials.gov Identifier: NCT02863718). The trial enrolled patients with asymptomatic, treatment-naïve, Binet stage A CLL who had an increased risk of progression.

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The patients were randomly assigned to receive ibrutinib (182 patients) or placebo (181 patients) at a dose of 420 mg daily. Baseline characteristics were well-balanced between the treatment arms. Overall, the median age was 64 years (range, 36-85 years), 60.2% of patients had mutated IGHV, 3.6% had del(17p), and 7.4% had TP53 mutations.

The median treatment duration was 18.4 months in the ibrutinib arm and 16.3 months in the placebo arm. The median observation time was 31 months.

Safety Results

There were no significant differences in the incidence and severity of adverse events (AEs) between the treatment arms. The most common grade 3 or higher AEs in the ibrutinib arm were atrial fibrillation (6.3%), pneumonia (4.4%), and rash (3.2%).

Bleeding events of any grade occurred in 33.5% of patients on ibrutinib and 14.8% of those on placebo. To reduce the risk of bleeding events, the study protocol was amended by prohibiting the use of direct factor Xa inhibitors and educating physicians on CYP3A4 drug-drug interactions.

Any-grade cardiac arrhythmias were reported in 21.5% of patients in the ibrutinib arm and 7.7% in the placebo arm. There were 4 fatal AEs in the ibrutinib arm and 5 in the placebo arm.

Efficacy Results

The trial met its primary endpoint — a significant improvement in EFS with ibrutinib. The drug also improved progression-free survival (PFS) and time to next treatment.

The median EFS was not reached in the ibrutinib arm and was 47.8 months in the placebo arm (hazard ratio [HR], 0.25; 95% CI, 0.14-0.43; P <.0001). The 3-year EFS rate was 87.3% and 60.4%, respectively.

The median PFS was not reached in the ibrutinib arm and was 14.8 months in the placebo arm (HR, 0.18; 95% CI, 0.12-0.27; P <.0001). The 3-year PFS rate was 80.9% and 28.5%, respectively.

At 36 months, the percentage of patients who had not gone on to another CLL treatment was 91.3% in the ibrutinib arm and 67.5% in the placebo arm (HR, 0.21; 95% CI, 0.11-0.39; P <.0001).

An OS analysis could not be performed due to an insufficient number of events, but the trial is ongoing.

Although the primary endpoint was met, the researchers concluded that a lack of demonstrated OS benefit means there is not enough evidence to support changing the current recommendation of a “watch and wait” strategy for patients with asymptomatic, early-stage CLL.

“Modifications of this observational approach require evidence of a significant survival advantage in the ibrutinib arm,” the researchers wrote.

Disclosures: This research was supported by Janssen-Cilag. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Langerbeins P, Zhang C, Robrecht S, et al. The CLL12 trial: Ibrutinib versus placebo in treatment-naïve, early stage chronic lymphocytic leukemia. Blood. Published online November 10, 2021. doi:10.1182/blood.2021010845