A Case of Severe Ibrutinib‐Induced Liver Injury and Successful Transition to Acalabrutinib

We read with great interest the recent article by Chodup et al. titled “Drug-Induced Liver Injury Associated With Emerging Cancer Therapies” published in Liver International [1]. The authors provided a comprehensive and timely review of the hepatotoxic potential of novel antineoplastic agents, including Bruton's tyrosine kinase (BTK) inhibitors. We commend their effort to synthesise management strategies for these complex clinical scenarios where the balance between oncologic efficacy and hepatic safety is precarious. In this context, we wish to report a case that reinforces the authors' observations regarding the idiosyncrasy of these reactions and expands on the feasibility of alternative therapeutic options. As noted in the review, ibrutinib is a cornerstone in the treatment of chronic lymphocytic leukaemia (CLL) [2], and while severe hepatotoxicity is rare, it presents a significant challenge. We present a case of a 67-year-old female with Stage II CLL who developed severe acute liver injury fulfilling Hy's Law criteria (hepatocellular injury with jaundice) associated with ibrutinib. Our case highlights a critical “washout” phenomenon that adds nuance to the monitoring strategies discussed by Chodup et al. [1]. The patient had been receiving ibrutinib therapy for 3 months. Crucially, anamnesis revealed that she had discontinued the medication without medical advice approximately 3 weeks prior to the onset of severe jaundice and fatigue. She was admitted to our department on August 22, 2025. The initial evaluation revealed severe acute hepatocellular injury. Alanine aminotransferase (ALT) peaked at 1372 U/L on admission, aspartate aminotransferase (AST) peaked at 1241 U/L on August 23, and total bilirubin reached a critical maximum of 24.87 mg/dL on August 25. In contrast, alkaline phosphatase (ALP) levels remained relatively low, measuring 142.5 U/L on presentation, peaking at 150 U/L on Day 2, and normalising by Day 6. Despite the severity of the hepatocellular injury, hepatic synthetic function remained relatively preserved; the International Normalised Ratio (INR) was 1.19 on presentation and peaked transiently to 1.27 on Day 3, followed by rapid normalisation. Concurrently, the white blood cell (WBC) count peaked at 89.55 × 109/L, reflecting the high leukaemic burden. Our diagnostic approach adhered strictly to the EASL Guidelines [3]. After excluding viral and autoimmune etiologies and establishing a “probable” causality score via RUCAM, a percutaneous liver biopsy was performed. Histopathology demonstrated interface hepatitis, ballooning degeneration, and prominent cholestasis with eosinophilic infiltration. This pattern suggested an immune-mediated mechanism [4], prompting the initiation of corticosteroid therapy. The patient responded favourably to the intervention. The temporal evolution of her laboratory parameters, highlighting the “washout” phenomenon and subsequent resolution, is summarised in Figure 1. Notably, during the washout period on October 8, 2025, the leukaemic burden significantly decreased (WBC 45.05 × 109/L), likely secondary to the lympholytic effect of the corticosteroids. Furthermore, Chodup et al. discussed the consideration of switching to alternative kinase inhibitors. Our case provides concrete clinical evidence supporting this approach even after life-threatening toxicity. Following the resolution of the hepatic injury, managed with corticosteroids, we successfully transitioned the patient to acalabrutinib, a highly selective second-generation BTK inhibitor. At the 3-month follow-up (December 12, 2025), the patient maintained complete remission of her CLL with no recurrence of hepatotoxicity (ALT 28.4 U/L). This experience supports the premise that severe, idiosyncratic hepatotoxicity to a first-generation BTK inhibitor like ibrutinib does not necessarily preclude the use of the entire drug class. We hope this report adds a valuable practical dimension to the excellent framework provided by Chodup et al. [1], encouraging clinicians to consider second-generation alternatives like acalabrutinib as a viable salvage strategy [5]. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.