Expert Discusses Ongoing Advances in CLL

Farrukh T. Awan, MD

Over the past several years, there have been several key developments in the treatment landscape for patients with chronic lymphocytic leukemia (CLL), particularly with the approvals of novel agents such as ibrutinib (Imbruvica) and venetoclax (Venclexta), according to Farrukh Awan, MD.

These agents are now being explored in combination regimens. For example, the combination of venetoclax and rituximab (Rituxan) significantly improved progression-free survival compared with rituximab plus bendamustine (Treanda) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to findings from the phase III MURANO study (NCT02005471).

OncLive: Can you provide an overview of your presentation on CLL?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Awan, an associate professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center, discussed novel agents and combinations in CLL, as well as the critical importance of FISH and IGHV testing for patient selection in this population.Awan: There has been a lot of excitement in the field of CLL in the last few years. I spoke about patient selection and what kinds of tests we need to do, especially with regards to fluorescence in situ hybridization (FISH) testing and the IGHV mutational analysis. Those tests are still underutilized, so we want to make sure that there is awareness about them. Those tests should be done on a regular basis in every patient, not just at the time of diagnosis or the time of deciding the initial therapy, but also at the time of subsequent therapies if needed.

I also discussed chemoimmunotherapy and some of the more recent data about durable remissions, what kind of patients are expected to have those responses, and the issues associated with them. We talked about the new kinase inhibitors and novel targeted therapies, which have made a huge improvement in the outcomes of our patients with CLL, primarily with the approvals of ibrutinib and venetoclax. We spoke about idelalisib (Zydelig) and anti-CD20 monoclonal antibodies, specifically obinutuzumab (Gazyva).

Can you discuss the emergence of venetoclax and potential combinations with this agent?

There are many things that are happening in the field right now. We have to make sense of how we utilize those drugs in the right settings for the best outcomes.Venetoclax by itself causes some issues with tumor lysis, which delayed its development. But once those issues were resolved, we know how to safely use that drug and have found that it is effective. In fact, it has been approved now for relapsed patients with 17p deletion.

On its own, venetoclax is very effective and important since it causes deep remissions. That hasn't been seen before outside of chemoimmunotherapy, so we're very excited about venetoclax by itself. People are trying different strategies to improve the outcomes of venetoclax so patients can have deeper responses and stay in remission longer.

There has been a lot of promise shown with ibrutinib. What are the next steps with this agent?

For that reason, one of the combinations that have been tested is the venetoclax/rituximab combination. It is too early to say how that research will pan out, but what we know so far is that the combination is safe, well tolerated, and effective. Determining how durable the remissions are and how patients will do long-term remains to be seen. These are all promising advances in trying to enhance the outcomes for our patients. One issue [with ibrutinib] that is unresolved is that we don’t know how long a patient should continue to receive it. There are many studies which are utilizing ibrutinib in combination with other drugs with a defined endpoint.

In a combination study, patients will be treated for a certain number of months and then treatment stops to determine how the patients will do. That hasn't been done in regards to single-agent ibrutinib. Those are exciting studies, some of which will be published soon. Then, the other issue with ibrutinib is also the management of adverse events (AEs); that is a big problem. Our understanding is getting better and our ability to manage those patients effectively is also improving.

If we understand the AEs—for example, the bleeding issues—we can manage them more aggressively and allow the patients to stay on the drug for longer.

Regarding combinations with ibrutinib, that approach has been proven to be effective and very promising. However, it hasn't been shown that the combination of ibrutinib is better than ibrutinib alone. That is the biggest criticism we have with ibrutinib combinations. Having said that, trials have already been completed that have compared ibrutinib with ibrutinib combinations. Specifically, there is the ALLIANCE trial in elderly patients in the frontline setting comparing ibrutinib with ibrutinib plus rituximab and chemoimmunotherapy.

That trial has been completed and we are awaiting the results about whether ibrutinib by itself is enough or whether it needs to be combined with other agents. It appears that you may not be able to stop ibrutinib without adding another agent, or patients might just relapse quickly once you stop it because they are not deep [enough] remissions.

Can you discuss the recent data you mentioned with chemoimmunotherapy?

What are the takeaways from your talk and from this meeting as a whole?

That is why there is a lot of potential to further improve the outstanding activity that is seen with ibrutinib.With regards to chemoimmunotherapy, the HELIOS trial combined ibrutinib with bendamustine and rituximab and has shown promise. That is an option for some of our patients. However, we don't know if that is better than ibrutinib by itself. In CLL, the most critical thing that I would like to stress is the underutilization of FISH and IGHV testing. We've seen that testing is essential—not just to prognosticate our patients and give them a true picture of how we expect the disease to behave, but also in selecting the right therapy. This cannot be stressed enough. We also know from our market data that it isn't being done universally, which is an area we can improve upon.

Regarding the entire [State of the Science Summit^TM], many of the tumors that are seen in the community setting are malignancies of solid organs. Hematologic malignancies make up a small group of patients. However, it is important to discuss hematologic malignancies since there are so many advancements and developments in each of these tumors, which would be difficult to keep up with if you're not seeing them on a regular basis. You see patients with breast cancer, colon cancer, and lung cancer more frequently than you would see patients with CLL. That is why it is important to have events like these that would revise or review some of the treatments for patients.

It will be very important to have these meetings cover the developments and advancements in hematologic malignancies. Hopefully, physicians can improve their practices based on meetings like this.