We have very good speakers and some really interesting topics at this year’s CLL session. The session opens with Dr. Lydia Scarfò’s presentation on next-generation sequencing (NGS) and what to do when additional abnormalities are found at diagnosis.
A lot of centers, particularly academic ones, are now using NGS to detect molecular abnormalities that are relevant to CLL. Of course, the most important example is TP53. Deletions or mutations in TP53 carry a poor prognosis and can influence treatment decisions.
However, when running NGS, we often get more data than anticipated including other abnormalities that show up with some frequency. The question is what is their relevance to CLL?
Sometimes those mutations are what we would consider myeloid abnormalities. That raises even more complicated questions. Do they matter for CLL management, or are they incidental? That is a big black box right now, and I am particularly interested in this talk for my own education.
But this is often something we will see in practice. A patient will ask, “What does it mean that I also have a RAS mutation?” and then the clinician is in the uncomfortable position of having to say, “I don’t know.” Unless we gather data and analyze it, we cannot give clear answers to our patients.
To my knowledge, there is no published dataset yet that looks at how these additional mutations influence outcomes in CLL. These mutations may or may not matter, and that is what makes this such an important topic. The takeaway may simply be that yes, this happens, and we need to further investigate it.
The session will also feature a debate on a timely topic in CLL, which I think will be fun. Drs. Jeff Sharman and Gianluca Gaidano will debate the two dominant options for sequencing therapy after covalent BTK inhibitor failure.
Historically, when patients progressed on covalent BTK inhibitors, we knew that you could not move from one to another. So, if a patient had progression on ibrutinib, acalabrutinib, or zanubrutinib, that was the end of that drug class. You could switch from one covalent BTK inhibitor to another if the issue was intolerance. Sometimes a patient has a side effect on one that they do not experience on another. That is a well-established strategy, and in those cases, you can continue using covalent BTK inhibitors. But if the problem is true progression, then a class switch is necessary.
Until recently, our only option after covalent BTK failure was venetoclax, which is a very effective drug. It works well even in patients who have failed covalent BTK inhibitors. Now, though, we have a second option, which is pirtobrutinib. This is the first and currently only noncovalent BTK inhibitor approved for CLL. It is active in patients who are resistant to covalent BTK inhibitors, which gives us a new decision point.
Dr. Sharman is going to argue in favor of switching to pirtobrutinib. There is another drug in development, nemtabrutinib, but it is not approved by the US Food and Drug Administration. Right now, pirtobrutinib is the only available noncovalent BTK inhibitor.
Dr. Gaidano will argue in favor of going to a venetoclax-based regimen instead. Both approaches are valid, and I think you can make a case for either strategy. I am curious to see who makes the more convincing argument.
I am also looking forward to a presentation on new targets and emerging therapies from Dr. Meghan Thompson. This is a topic I think everyone will be interested in, particularly because of its relevance to what we are now calling double-refractory or double-exposed patients. These are patients who have already received both a BTK inhibitor and venetoclax. If they are truly refractory, treatment options become very limited.
There is some interesting data coming out on bispecific antibodies. These are not yet approved in CLL, but they are approved in lymphoma. Many physicians are already familiar with them and have used them. They seem to show promising activity in CLL as well.
We are also seeing clinical trials now exploring a new category of agents called BTK degraders. Rather than inhibiting the BTK protein, these drugs work by degrading it. What is especially interesting is that they appear to be effective even in the presence of BTK mutations.
As the number of double-exposed patients continues to grow, we are going to need new drugs and strategies to manage them, which is why I think this session will be especially relevant this year.
Other sessions of interest:
- Paula Cramer, MD, of the University of Cologne, will present strategies for improving outcomes with combination therapies, optimal sequencing, and the duration of MRD-guided treatment. Dr. Cramer will address whether MRD should be used to determine how long treatment should last, an active area of debate, especially as new trials explore time-limited regimens.
- Following the debate, Mazyar Shadman, MD, MPH, of Fred Hutchinson Cancer Center will present interesting clinical cases of CLL.
