First-Line therapy for Chronic Lymphocytic Leukemia - Episode 3

CLL: The Rapidly Evolving Treatment Landscape


Susan M. O’Brien, MD: There are other Bruton tyrosine kinase inhibitors in clinical trials for CLL. At this time, there’s acalabrutinib (Calquence), and there’s zanubrutinib (BGB-311). Gilead also has a drug that’s being looked at. None of them are actually approved for the treatment of CLL yet. The only one that has an approval at all is acalabrutinib, which has been approved for mantle cell lymphoma. There are no other BCL-2 inhibitors close on the horizon, as there are with the BTK inhibitors, but there are other drugs being looked at, including MCL1 inhibitors. This is important because there are some early data to suggest that one of the mechanisms of resistance to venetoclax may be upregulation of MCL1.

In addition to new BTK inhibitors—in terms of the ones that we know about from acalabrutinib to zanubrutinib, etc—there are other PI3K inhibitors coming out. Duvelisib is a drug that will likely be available for the treatment of CLL sometime this year, based on a positive randomized trial versus ofatumumab (Arzerra). There are some others, such as umbralisib (TGR-1202), that are also in registration trials. There is a lot of interest in combining these cell receptor inhibitors of different families—combining some of the PI3K inhibitors with venetoclax, the BCL-2 inhibitor. I think we will see more and more combination therapies moving forward.

I think what is going to happen in the long run in the treatment of CLL is that we’re moving toward small molecule combinations, either with or without antibody. These combinations are very exciting because early data suggest high response rates and high levels of MRD negativity. The other exciting point about this, and what may change treatment compared with what we do now with small molecules, is that the ability to have a high rate of MRD negativity may allow finite therapy. In other words, we may be able to discontinue those patients from treatment, and that’s very exciting, as opposed to telling a patient that they’re going to be on a therapy for life.

One of the challenges of having all these novel agents is how to sequence them, and we’re still learning. Right now, we sequence them based on what’s approved for what indication, etc, and what works when the other drug doesn’t work, but we will be able to learn a lot more about this moving forward. Don’t forget that ibrutinib was approved probably only about 4 years ago. In the interim, we’ve had idelalisib (Zydelig), we’ve had venetoclax, and we may have duvelisib this year. The landscape is changing so rapidly that we’re really learning on our feet; and I think sequencing is going to be important moving forward.

Transcript Edited for Clarity