Comparative neuropsychiatric outcomes of ibrutinib and acalabrutinib in patients with chronic lymphocytic leukemia: A propensity-matched real-world cohort study

Abstract Background: Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL). However, emerging evidence suggests that ibrutinib, a first-generation BTK inhibitor, may be associated with neuropsychiatric side effects. Second-generation agents like acalabrutinib exhibit greater selectivity, potentially offering a more favorable safety profile. This study aimed to compare the real-world incidence of neuropsychiatric disorders in CLL patients treated with ibrutinib versus acalabrutinib. Methods: Using the TriNetX US Collaborative Network, we identified adults with CLL who were prescribed either ibrutinib or acalabrutinib and had no prior mental or behavioral health disorders. Patients receiving ibrutinib (n=5,364) and acalabrutinib (n=2,174) were propensity score matched 1:1 based on demographics, cardiovascular and metabolic comorbidities, and BMI. The final matched cohorts (n=2,167 each) were analyzed for the development of anxiety, depression, dementia, bipolar disorder, and eating disorders following BTK inhibitor initiation. Risk ratios, odds ratios, and Kaplan–Meier survival analyses were conducted, excluding patients with pre-existing psychiatric diagnoses. Results: Patients receiving ibrutinib had a significantly higher risk of developing anxiety (OR 1.65, 95% CI 1.27–2.13), depression (OR 2.22, 95% CI 1.62–3.04), and dementia (OR 2.29, 95% CI 1.42–3.68) compared to those on acalabrutinib. The incidence of bipolar disorder was similar between groups (OR 1.00, 95% CI 0.42–2.41). There was no significant development of new eating disorders for comparison between the two groups. Kaplan Meier survival analyses revealed lower event free survival for anxiety and depression among ibrutinib users. Median follow up was longer in the ibrutinib group (median 1,236 vs 589 days), suggesting potential differences in the duration of exposure. Conclusion: Ibrutinib is associated with a higher incidence of neuropsychiatric complications, anxiety, depression and dementia, compared to acalabrutinib in patients with CLL. These findings highlight the importance of individualized risk assessment and longitudinal monitoring when selecting BTK inhibitors, especially in patients with significant personal or family history of neurocognitive or psychiatric disorders.