CLL Paradigm Rapidly Evolving With Novel Agents

Emmanuel S. Antonarakis, MD, associate professor of oncology and urology at Johns Hopkins Medicine

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.

The most recent agent to enter the landscape is duvelisib (Copiktra), which received FDA approval in September 2018 for the treatment of patients with relapsed or refractory CLL/small lymphocytic lymphoma or relapsed/refractory follicular lymphoma.

The CLL/SLL approval was based on results from the phase III DUO trial, in which duvelisib demonstrated a 60% reduction in death or progression compared with ofatumumab (Arzerra). However, Hill said that the data with the PI3K inhibitor have not yet been groundbreaking.

OncLive: What is the current state of CLL treatment?

In an interview during the 2018 OncLive^® 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.Hill: 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.

There is probably still a role for chemotherapy in patients with the right comorbidities and molecular profile. This is still a very active treatment. BTK inhibitors remain the go-to agent for relapsed disease, and we are now seeing these being used in the frontline setting. Beyond BTK inhibitors, we know ibrutinib has some challenges, so there is now the potential to use acalabrutinib in that setting.

What are your thoughts on the recent duvelisib approval?

Are there any situations where you would choose a PI3K inhibitor versus a BTK inhibitor?

Are there any strategies for patients who become resistant to BTK inhibitors?

Is there anything else you would like to add about venetoclax?

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. 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. 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. 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. 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.