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ASH 2020: Dr. Ian Flinn on Combination Zanubrutinib and Venetoclax for Treating Chronic Lymphocytic Leukemia (CLL)

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Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that revolutionized treatment of chronic lymphocytic leukemia (CLL), and it is now used as a first-line treatment. However, it can cause some undesirable side effects such as diarrhea, rash, bleeding, and atrial fibrillation. These side effects are likely due to off-target inhibition on other kinases in the body. Next-generation BTK inhibitors are designed to be more specific than ibrutinib, so that they hopefully cause fewer off-target side effects. 

At the annual meeting of the American Society of Hematology (ASH) 2020Steven Bloom, CLL Society’s Chairman of the Board and President, interviewed Dr. Ian Flinndirector of lymphoma research at Sarah Cannon Cancer Institute in Nashville, TN. They discussed the potential role of next-generation BTK inhibitor zanubrutinib in combination with venetoclax for treating CLL. 

Takeaways: 

  • Zanubrutinib is a next-generation BTK inhibitor that is currently approved for the treatment of mantle cell lymphoma. It is being tested in clinical trials for use in CLL. 
  • In a previous study comparing zanubrutinib to ibrutinib in patients with Waldenstrom macroglobulinemia, rates of atrial fibrillation were much lower in the zanubrutinib group as compared with the ibrutinib group (~2% vs 15%). 
  • Early clinical data suggested that zanubrutinib was active and well-tolerated in treatment-naïve CLL/SLL patients with deletion of chromosome 17p [del(17p)]. See our previous interview with Dr. Constantine Tam for more details. 
  • Because the safety profile of zanubrutinib is thought to be much cleaner than ibrutinib (large clinical trials in CLL are currently ongoing), it will likely make it easier to pair with other therapies. 
  • BTK inhibitors do a wonderful job of controlling CLL, but they do not get patients into complete remission. This means that you have to take them indefinitely to control the disease. 
  • Combining BTK inhibitors with venetoclax can get patients into deep remissions with undetectable minimal residual disease (uMRD). This allows patients to have a time-limited treatment that they can stop once they achieve uMRD. 
  • The combination of zanubrutinib and venetoclax is currently being tested in treatment-naïve CLL/SLL patients with del(17p) in an ongoing phase 3 clinical trial. 

 Conclusions: 

Next-generation BTK inhibitors such as zanubrutinib will hopefully provide the same benefits as ibrutinib but with fewer toxicities. Combining BTK inhibitors with venetoclax could provide patients with effective and time-limited treatment options. These types of combinations may also be helpful for high-risk patients with del(17p). We eagerly await the results of ongoing clinical trials with zanubrutinib. 

Please enjoy this interview with Dr. Flinn from the virtual ASH meeting which was held December 2020. 

You can read the actual ASH abstract here: Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma and del(17p): Arm D of the SEQUOIA (BGB-3111-304) Trial 

 Take care of yourself first. 

 Ann Liu, PhD