Brian T. Hill, MD, PhD
In the past 5 years, there has been a major shift in the treatment of patients with chronic lymphocytic leukemia (CLL), said Brian T. Hill, MD, PhD, with an abundance of novel agents and a diminished role for chemotherapy.
State of the Science Summit™ on Hematologic Malignancies, Hill, assistant professor, hematology and oncology, Cleveland Clinic, discussed some of the recent advances and regulatory decisions in the treatment of patients with CLL.
OncLive: What is the current state of CLL treatment?
In contrast to the old way of treating, which was chemotherapy and chemoimmunotherapy over and over again with diminishing results, we now have so many highly active and effective agents. It is getting challenging now for general oncologists to figure out how to select from these treatments and how to sequence them.
We also know that venetoclax (Venclexta) is highly active; with proper dose-escalation, it can be safely administered without any real risk for tumor lysis syndrome. Recent data in a head-to-head trial against bendamustine—this was the MURANO trial—showed strong advantage for venetoclax in patients with advanced disease. Chemotherapy's days are dwindling. If it is going to be used, it should only be used once. You should think about moving to the targeted agents.
What are your thoughts on the recent duvelisib approval?
The data on duvelisib are not overwhelming. The response rates in the registration trial are keeping in line with what we would think about for the other PI3K inhibitor, idelalisib (Zydelig). The toxicity profile looks pretty similar in terms of diarrhea and pneumonitis. It is not a drug that represents a major breakthrough in the treatment of CLL. In particular, we do not have any data showing whether this agent is even tolerable for those who cannot tolerate idelalisib.
Are there any situations where you would choose a PI3K inhibitor versus a BTK inhibitor?
PI3K inhibitors are active. Despite their slight toxicity issues, they still have some role in CLL. If the patient has major bleeding risk or cytopenia, then BTK inhibitors become less attractive. It is difficult to put PI3K inhibitors above venetoclax. More time will tell—for those patients who have had venetoclax and are ready for another line of therapy—if PI3K inhibitors can be slotted into that spot.
Are there any strategies for patients who become resistant to BTK inhibitors?
The main resistance to BTK inhibitors is from mutations in BTK itself or other signaling pathways. There are assays and ways to assess from this. If you have those mutations, you're likely to relapse quickly and become resistant to the ibrutinib therapy. There are some noncovalent BTK inhibitors in development. Right now, the standard approach to patients who are resistant to BTK inhibition is venetoclax.
Is there anything else you would like to add about venetoclax?
Venetoclax is so well tolerated and active, that we know we are getting deeper remissions than with ibrutinib or acalabrutinib. These responses seem to be even better when you partner venetoclax with monoclonal antibodies, such as anti-CD20. Going forward, the interesting thing about venetoclax is that you might be able to discontinue therapy after 2 years if you are in complete remission. This is something we do not have with BTK inhibitors.
Verastem Oncology receives FDA approval of COPIKTRA (duvelisib) capsules. Published September 24, 2018. https://bit.ly/2NDQm80. Accessed September 24, 2018.
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