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Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
Posted: Monday, April 14, 2025
As CLL management continues to advance with novel therapies, clinicians must remain vigilant about drug-drug interactions and adjust treatment plans accordingly. Collaboration across specialties and ongoing research are essential for optimizing patient outcomes in this increasingly complex therapeutic landscape.
Chronic lymphocytic leukemia (CLL) remains the most common adult leukemia, with treatments now focused on continuous use of Bruton tyrosine kinase inhibitors (BTKis) like ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, or the time-limited application of Bcl-2 inhibitors such as venetoclax, reported Sofija Kozarac, from the Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, and colleagues.
These agents, either as monotherapy or in combination with CD20+ monoclonal antibodies, have significantly improved overall survival and progression-free survival among patients, including those with high-risk features. Clinical trials have demonstrated a 5-year progression-free survival exceeding 60% with ongoing improvements in overall survival for most patients.
However, managing adverse effects, including cardiotoxicity and infections, and addressing preexisting comorbidities is crucial. These factors can compromise treatment efficacy, overall survival, and progression-free survival, particularly when considering potential drug-drug interactions involving concomitant medications, noted Kozarac and colleagues.
Mechanisms of Drug-Drug Interactions
BTK and Bcl-2 inhibitors are metabolized primarily by cytochrome P450 (CYP) enzymes, especially CYP3A4. Concomitant use of CYP3A4 inducers or inhibitors can significantly affect drug exposure, potentially leading to reduced therapeutic efficacy or increased toxicity. P-glycoprotein and breast cancer resistance protein are also involved in drug distribution and elimination, complicating the pharmacokinetics of these treatments.
“Strong CYP3A4 inhibitors should be avoided during treatment with ibrutinib, acalabrutinib, and zanubrutinib. If a strong interacting medication is required for a short duration (up to 7 days), temporary discontinuation of ibrutinib and acalabrutinib may be necessary,” noted the study authors.
Examples of significant drug-drug interactions include:
Additionally, various CLL therapies can interact with anticoagulants, antimicrobial agents, antihypertensives, herbs, and antiarrhythmics, requiring thorough monitoring and management to avoid treatment complications.
Recommendations and Future Directions
Effective management of CLL in the context of comorbidities and concurrent medication use requires a multidisciplinary approach involving hematologists, cardiologists, and pharmacists. Ensuring regular monitoring, assessing drug-drug interactions, and making timely dose adjustments are critical for maintaining therapeutic efficacy while minimizing risks. Further studies are needed to improve understanding of CLL treatment management under complex clinical conditions.
Disclosures: The authors had no conflicts of interest to report.
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