Chronic Lymphocytic Leukemia: Evolving Management With New Data From EHA 2025 - Episode 11
Managing Adverse Effects in CLL—BTKi Toxicities in Focus
Panelists discuss how real-world data from retrospective studies show that second-generation Bruton tyrosine kinase inhibitors (BTKi) have lower rates of hypertension compared with ibrutinib, and surprisingly reveal that patients treated with venetoclax-obinutuzumab continue to experience serious infections requiring hospitalization at rates of approximately 10% even 12 to 36 months after completing fixed-duration therapy, which is higher than the 6% rate seen in patients on continuous BTKi therapy and challenges assumptions about infection risk resolution after treatment completion.
Managing Adverse Effects in CLL—BTKi Toxicities in Focus
Recent retrospective analysis of BTKi toxicity profiles provides important insights into cardiovascular safety differences between first- and second-generation agents. A large cohort study examining patients treated with various BTKi over the past 5 years revealed significant baseline cardiovascular risk factors, with approximately 50% of patients having preexisting hypertension across all treatment groups. The analysis focused on both worsening of existing hypertension and development of new-onset hypertension during BTKi therapy. Results demonstrated that second-generation BTKi, including acalabrutinib and zanubrutinib, showed lower frequencies of both hypertension worsening and new-onset hypertension compared with first-generation ibrutinib, although longer follow-up data are needed to fully assess the clinical significance of these differences.
Infectious complications represent another critical safety consideration that challenges assumptions about treatment-free intervals following fixed-duration therapy. A retrospective analysis comparing patients treated with venetoclax-obinutuzumab vs continuous BTKi therapy revealed unexpected findings about serious infection rates during and after treatment completion. Contrary to expectations that patients would have minimal infectious complications once off therapy, those who completed fixed-duration treatment continued to experience significant infectious complications requiring intravenous antibiotics and hospitalization for extended periods post treatment. At 12, 18, 24, and 36 months after therapy completion, infection rates remained elevated compared with patients on continuous therapy, with approximately 10% vs 6% serious infection rates, respectively.
The comparative analysis with patients with untreated chronic lymphocytic leukemia (CLL) provides valuable context for attributing adverse events to specific therapies vs underlying disease characteristics. Patients on continuous BTKi therapy demonstrated infection rates similar to those of patients with untreated CLL, suggesting that continuous therapy may not significantly increase baseline infection risk. This finding highlights the complexity of adverse event attribution in clinical trials, where infections occurring during treatment are often automatically attributed to therapy when they may represent natural disease progression or coincidental events. These data emphasize the importance of prospective long-term safety monitoring that extends well beyond treatment completion periods, particularly for fixed-duration approaches where patients may continue to experience treatment-related complications during supposed treatment-free intervals.
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