Ibrutinib versus placebo in patients with asymptomatic, treatment‐naïve early stage chronic lymphocytic leukemia (cll): final results of the cll12 trial

Introduction: We present the final analysis of the phase 3, double-blind, placebo-controlled CLL12 trial evaluating ibrutinib in patients with early stage CLL at increased risk of progression defined by a comprehensive score (NCT02863718). Methods: We randomly assigned patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. Patients with low risk CLL were allocated to the watch and wait group (W&W; n = 152). The final analysis evaluated event-free survival (EFS; defined as time to symptomatic progression, CLL treatment or death), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). Results: At a median observation time of 69.3 months the overall response rate was 72.5% in the ibrutinib group. PFS, EFS and TTNT were not reached in the ibrutinib group as compared to 14 months (p < 0.001; HR 0.174, 95% CI 0.122–0.246), 51.6 months (p < 0.001; HR 0.276, 95% CI 0.188–0.407), and 68.5 months (p < 0.001; HR 0.244, 95% CI 0.156–0.380) in the placebo group. A total of 29 (15.9%), 79 (43.6%), and 25 (16.4%) subsequent treatment lines were administered in the ibrutinib, placebo and W&W group, respectively. The median overall survival was not reached in neither treatment group (p = 0.562, HR 0.791, 95% CI 0.358–1.748) with 12 (6.6%) deaths in the ibrutinib and 14 (7.7%) deaths in the placebo group. The estimated survival rate at 5 years for patients treated with ibrutinib and placebo was 93.3% and 93.6%, respectively. A total of 6 (3.9%) deaths occurred in the W&W group with median survival from CLL diagnosis not reached, as compared to 258 months for the placebo and not reached for the ibrutinib group. Causes of death were progressive disease (1x ibrutinib), Richter Transformation (3x placebo), treatment-related adverse event (1x ibrutinib, subdural hematoma), infection (2x ibrutinib, 1x placebo, 1x W&W), concomitant disease (4x ibrutinib, 5x placebo, 4x W&W), and other (4x ibrutinib, 5x placebo, 1x W&W). Adverse events were documented in 99.4% of ibrutinib and placebo treated patients, with 71.8% and 66.1% of patients experiencing CTC grade 3–5 events, respectively. More bleeding events (36.5% vs. 14.9%), cardiac arrhythmias (22.4% vs. 9.5%), other cardiac events (17.6% vs. 15.5%), diarrhoea (40.6% vs. 28.6%), and hypertensive disorders (19.4% vs. 8.3%) occurred in ibrutinib as compared to placebo-treated patients. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Janssen Keyword: molecular targeted therapies Conflicts of interests pertinent to the abstract P. Langerbeins Consultant or advisory role: Janssen, AbbVie, AstraZeneca, Beigene, Roche Honoraria: Janssen, AbbVie, AstraZeneca, Beigene, Roche Research funding: Janssen P. Cramer Consultant or advisory role: AbbVie, Acerta, AstraZeneca Honoraria: AbbVie, AstraZeneca, Janssen, Roche Research funding: AbbVie, AstraZeneca, BeiGene, Gilead, Janssen, Novartis/ GSK, Roche Educational grants: AbbVie, AstraZeneca, Gilead, Janssen, Roche M. Fürstenau Honoraria: Abbvie Research funding: Abbvie, AstraZeneca, Beigene, Janssen, Roche O. Al-Sawaf Consultant or advisory role: AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Honoraria: AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Research funding: AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche A. Fink Honoraria: AstraZeneca Research funding: AstraZeneca and Celgene Educational grants: AbbVie K. Kreuzer Consultant or advisory role: Mundipharma, Roche, Janssen Honoraria: Mundipharma, Roche, Janssen Research funding: Mundipharma, Roche, Janssen E. Tausch Consultant or advisory role: Roche, Abbvie, Beigene and AstraZeneca Honoraria: Roche, Abbvie, Beigene and AstraZeneca Research funding: Roche, Abbvie and Gilead C. Schneider Consultant or advisory role: AstraZeneca und AbbVie Honoraria: AstraZeneca und AbbVie M. Reiser Consultant or advisory role: Jannsen-Cilag, Abbvie, Amgen, Roche, Novartis, Beigene Honoraria: Jannsen-Cilag, Abbvie, Amgen, Roche, Novartis, Beigene M. Hensel Consultant or advisory role: AbbVie, Janssen, Roche, Beigene Honoraria: AbbVie, Janssen, Roche Educational grants: AbbVie, Janssen, Roche H. Hebarth Consultant or advisory role: AbbVie, AstraZeneca, Beigene, Celgene, Janssen, and Roche Honoraria: AbbVie, AstraZeneca, Beigene, Celgene, Janssen, and Roche Educational grants: AbbVie, AstraZeneca, Beigene, Celgene, Janssen, and Roche C. Wendtner Consultant or advisory role: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene Honoraria: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene Research funding: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene Educational grants: Janssen-Cilag, Hoffmann-La Roche, GSK, Gilead, AbbVie, AstraZeneca, BeiGene K. Fischer Consultant or advisory role: AstraZeneca Honoraria: AbbVie, Roche S. Stilgenbauer Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Research funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis Educational grants: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis B. Eichhorst Consultant or advisory role: Janssen-Cilag, Roche, Abbvie, Beigene, Gilead, Novartis, Celgene, ArQule, AstraZeneca and Oxford Biomedica (UK) Honoraria: Janssen-Cilag, Roche, Abbvie, Beigene, Gilead, Novartis, Celgene, ArQule, AstraZeneca and Oxford Biomedica (UK) Research funding: Janssen-Cilag, Roche, Abbvie, Beigene and Gilead M. Hallek Consultant or advisory role: Roche, Gilead, Janssen, Bristol Myers Squibb, AbbVie, AstraZeneca Honoraria: AbbVie, Celgene, Gilead Sciences, Janssen, Mundipharma, Pharmacyclics, Roche Research funding: Roche, Gilead, Janssen, Bristol Myers Squibb, AbbVie, AstraZeneca.