Ibrutinib Significantly Prolongs PFS in Early-Stage CLL

Ibrutinib monotherapy significantly improved event- and progression-free survival compared with placebo in treatment-naïve patients with early-stage, asymptomatic chronic lymphocytic leukemia.

Petra Langerbeins, MD

Ibrutinib (Imbruvica) monotherapy significantly improved event- and progression-free survival compared with placebo in treatment-naïve patients with early-stage, asymptomatic chronic lymphocytic leukemia (CLL), according to results from the phase III CLL12 study presented at the 2019 European Hematology Association (EHA) Congress.1

Median event-free survival (EFS) was not reached (NR) in the ibrutinib arm compared to 47.8 months in the placebo group (HR, 0.25; 95% CI, 0.14-0.43; P <.0001). Median progression-free survival (PFS) was also NR with ibrutinib versus 14.8 months with placebo (HR, 0.18; 95% CI, 0.12-0.27; P <.0001). The time to next treatment (TTNT) was longer in the ibrutinib arm versus the placebo arm (HR, 0.21; 95% CI, 0.11-0.39; P <.0001). The median observation time was 31 months.

“So far, treatment of asymptomatic, early-stage CLL patients has not been proven beneficial; ibrutinib is a Bruton tyrosine kinase inhibitor with impressive clinical efficacy in advanced or relapsed CLL that has not been tested in treatment-naïve, early-stage CLL,” explained Petra Langerbeins MD, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Köln, Germany. Therefore, Langerbeins and the German CLL Study Group were prompted to conduct the double-blind, randomized, placebo-controlled, phase III CLL12 trial evaluating whether ibrutinib prolonged EFS in patients with early-stage CLL and increased risk of progression, as defined using a score system newly developed by this group.2

The trial enrolled treatment-naïve, asymptomatic Binet A patients with intermediate, high, or very high risk of progression. Of these, 182 were randomly assigned to receive ibrutinib at 420 mg per day and 181 were randomized to placebo. The median patient age in both cohorts was 64 years, and approximately 89% of patients were ECOG PS 0. In the ibrutinib and placebo arms, 75.8% and 82.9% of patients, respectively, had thymidine kinase >10 U/L, and fewer than 10% of patients in either arm had mutated TP53 or 17p deletions. In the ibrutinib and placebo arms, 11.5% and 10.5% of patients, respectively, had 11q deletions.

The primary endpoint was EFS and secondary endpoints included PFS and TTNT. The endpoints were defined as the time from randomization until occurrence of active disease according to iwCLL guidelines, new CLL treatment, or death (EFS); progression/death (PFS); or until the date of initiation of subsequent treatment for CLL (TTNT). The 152 patients with low-risk disease were not included in the primary endpoint analysis.

Langerbeins noted that EFS, PFS, and TTNT improvement were consistent across all risk groups analyzed, except in the very high risk group where there were just 8 patients.

The safety evaluation included 185 patients on ibrutinib and 178 patients on placebo. “There were no differences in most adverse events with ibrutinib compared to placebo,” she said.

The incidence of any grade adverse events (AEs) was 82.2% versus 84.8% with ibrutinib and placebo, respectively. AEs leading to treatment interruption occurred in 41.6% versus 21.3% of patients, respectively. The most commonly reported AEs in the respective cohorts leading to interruption included arrhythmias (18 vs 0 patients), bleeding (8 vs 1 patients), diarrhea (4 vs 3 patients), and neoplasia (4 vs 3 patients).

AEs of clinical interest were mostly grade 1/2 and occurred significantly more frequently with ibrutinib; AEs of clinical interest occurred in 57.3% and 39.9% of patients, respectively (P = .001). AEs grade ≥3 in the respectieve ibrutinib and placebo arms included diarrhea (31.4% vs 24.7%), bleeding (27.6% vs 9.6%), atrial fibrillation (17.8% vs 7.3%), and hypertensive disorders (9.7% vs 3.9%). Overall, 126 serious AEs were reported that included infections (11.4% vs 11.8%), neoplasms (5.9% vs 10.7%), and cardiac disorders (8.6% versus 6.7%) in patients on ibrutinib and placebo, respectively.

Treatment discontinuation was reported for 34.1% versus 45.9% of ibrutinib versus placebo patients, respectively; the primary cause of discontinuation was disease progression in 2 and 45 patients, respectively. Adverse events (53 patients) were the primary cause of discontinuation in the ibrutinib arm.

Six deaths on study occurred in the ibrutinib arm and 5 deaths occurred in the placebo arm “The results of this study allow us to conclude that ibrutinib significantly improves EFS, PFS, and TTNT in asymptomatic patients with treatment-naïve early stage CLL when compared to placebo,” commented Langerbeins.


  1. 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. Presented at 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2602.
  2. Pflug N, Bahlo J, Shanafelt TD et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124(1):49-62. doi: 10.1182/blood-2014-02-556399.