Bruton tyrosine kinase inhibitor ibrutinib significantly improved event-free survival (EFS) in patients with early-stage chronic lymphocytic leukemia (CLL) and unfavorable prognostic factors, but the agent was associated with relevant cardiovascular (CV) toxicity, according to findings from the CLL12 trial published in Blood.
Data from the study, according to corresponding author Petra Langerbeins, PhD, of the University Hospital Cologne in Germany, also corroborate prior publications that have documented the CV toxicity of ibrutinib. This toxicity, Dr. Langerbeins added, may be reduced in this patient population by avoiding CYP3A4-interacting drugs and oral anticoagulants.
The current standard of care for early-stage asymptomatic CLL is a watch-and-wait observation approach until the manifestation of clinical signs of progressive bone marrow failure or leukemia-associated symptoms.
“The concept of watch and wait for asymptomatic CLL is based on several trials that have failed to improve outcome by early treatment intervention,” Dr. Langerbeins explained. “The CLL12 trial challenges this concept by a risk-stratified, targeted intervention and demonstrates efficacy of ibrutinib in patients with asymptomatic Binet stage A CLL and unfavorable prognostic factors.”
In the phase III CLL12 trial, Dr. Langerbeins and colleagues enrolled treatment-naïve patients with asymptomatic Binet stage A CLL who were at increased risk of progression. Risk of progression was determined by eight differently weighted factors, including age (>60 years), male sex, beta2-microglobulin 1.7-3.5 mg/L or >3.5 mg/L, Eastern Cooperative Oncology Group performance status >0, thymidine kinase >10 U/L, unmutated immunoglobulin heavy chain gene status, 11q deletion, and 17p deletion.
Patients were randomly assigned to receive either 420 mg/day of ibrutinib (n=182) or placebo (n=181). The primary endpoint was EFS. The investigators also assessed progression-free survival (PFS), subsequent treatment, and safety as secondary outcomes.
A total of 100 patients in the ibrutinib arm and 85 patients in the placebo group were still receiving treatment at data cutoff for the primary endpoint analysis. Approximately 35.7% of patients in the ibrutinib group and 45.9% of patients in the placebo arm discontinued their assigned therapy early, most commonly due to adverse events in the ibrutinib group (81.5%) and disease progression in the placebo arm (54.2%).
At the median follow-up period of 31 months, patients in the ibrutinib group showed a significant improvement in EFS compared with patients assigned to placebo (median, not reached vs. 47.8 months, respectively; hazard ratio [HR] = 0.25; 95% CI 0.14-0.43; p<0.0001). The three-year EFS rate was also higher in the ibrutinib group (87.3% vs. 60.4%). Due to a pending survival analysis, the investigators noted that the data were too immature to confirm an overall survival benefit with ibrutinib.
Median PFS was not reached in the ibrutinib arm and was 14.8 months in the placebo group (HR=0.18; 95% CI 0.12-0.27; p<0.0001). A greater proportion of patients in the placebo arm received subsequent therapy (26% vs. 6.6%).
Both treatment groups had similar incidence rates and severity of adverse events (AEs). Atrial fibrillation, pneumonia, and rash were the most common serious AEs (SAEs) in the ibrutinib group, while the most common SAEs in the placebo arm were basal cell carcinoma, pneumonia, and myocardial infarction.
Ibrutinib-associated risk for bleeding was observed in 33.5% of patients. The investigators were able to decrease this risk by eliminating oral anticoagulant use through a study protocol amendment and by educating clinicians on CYP3A4 drug-drug interactions.
Dr. Langerbeins noted that the distribution of AEs in the placebo group appeared to represent the typical health- and leukemia-related issues: most commonly pneumonia, basal cell carcinoma, and acute myocardial infarction.
“The results indicate that secondary complications may be triggered by a reduced immune surveillance in untreated CLL and point to a potential protective effect of ibrutinib preventing thromboembolic complications by decreasing glycoprotein VI collagen-mediated platelet activation, spreading, and aggregation,” she said.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Langerbeins P, Zhang C, Robrecht S, et al. The CLL12 trial: Ibrutinib versus placebo in treatment-naïve, early stage chronic lymphocytic leukemia [published online ahead of print, 2021 Nov 10]. Blood. doi: 10.1182/blood.2021010845.