Highlights from

EHA 2019

European Hematology Association

Amsterdam 13-16 June 2019

Exciting survival data for ibrutinib vs placebo in treatment-naïve, early-stage CLL

Patients with early-stage, asymptomatic, newly diagnosed chronic lymphocytic leukaemia (CLL) showed improved survival outcomes with ibrutinib monotherapy compared with placebo, according to results from phase 3 CLL12 study presented by Dr Petra Langerbeins (University of Cologne, Germany).

“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,” Dr Langerbeins explained. To address this gap, Dr Langerbeins and the German CLL Study Group conducted the double-blind, randomised, placebo-controlled, phase 3 CLL12 trial evaluating whether ibrutinib prolonged event-free survival (EFS; primary endpoint) in patients with early-stage CLL and increased risk of progression, as defined using a score system newly developed by this group.

Median EFS was not reached in the ibrutinib arm compared with 47.8 months in the placebo group (HR 0.25; 95% CI 0.14-0.43; P<0.0001). Median progression-free survival (PFS) was also not reached with ibrutinib vs 14.8 months with placebo (HR 0.18; 95% CI 0.12-0.27; P<0.0001). The time to next treatment was longer in the ibrutinib arm vs the placebo arm (HR 0.21; 95% CI 0.11-0.39; P<0.0001), with a median observation time of 31 months.

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 randomised 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 time to next treatment. The 152 patients with low-risk disease were not included in the primary endpoint analysis. Dr Langerbeins noted that EFS, PFS, and TTNT improvement were consistent across all risk groups analysed, 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 and noted no differences in most adverse events for ibrutinib compared with placebo. The incidence of any grade adverse events (AEs) was 82.2% vs 84.8% with ibrutinib and placebo, respectively. AEs leading to treatment interruption occurred in 41.6% vs 21.3% of patients, respectively. The most commonly reported AEs in the respective cohorts leading to interruption included cardiac arrhythmias (18 vs 0 patients), bleeding (8 vs 1 patients), diarrhoea (4 vs 3 patients), and neoplasia (4 vs 3 patients). Treatment discontinuation was reported for 34.1% of ibrutinib vs 45.9% of placebo patients, respectively; the primary cause of discontinuation was disease progression in 2 and 45 patients, respectively. AEs were the primary cause of discontinuation in the ibrutinib arm (n=53).

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 time to next treatment in asymptomatic patients with treatment-naïve early stage CLL when compared with placebo,” concluded Dr Langerbeins.

  1. Langerbeins P, et al. Abstract LB2602, 24th Congress of the EHA, 13-16 June 2019, Amsterdam, the Netherlands.

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