Kerry Rogers, MD, Ohio State University, Columbus, Ohio, participated in a debate in which she argued against discontinuing Bruton’s tyrosine kinase (BTK) inhibitors among patients being treated for chronic lymphocytic leukemia (CLL).

“I think the major reasons to not stop a BTK inhibitor are that the mechanism predicts it works best over time [and] responses deepen over time. [Also], remissions after discontinuation are generally shorter and the best efficacy, we've seen to date with any therapy in CLL is really with continuous BTK inhibitors,” concluded Dr Rogers.

 This research was presented at the 2024 Annual Society of Hematologic Oncology (SOHO) meeting in Houston, Texas.

Transcript:

Hi, I am Kerry Rogers. I'm an associate professor in the division of hematology at the Ohio State University. I'm excited to talk a bit about something I [discussed] at the SOHO meeting. This is a debate style format that I was asked to participate in. The topic I was assigned was the question: Can BTK inhibitors be discontinued? I was given the “no” side of the argument, which was difficult because I think there's extremely valid points on both sides of this. I [was] look[ing] forward to what Dr. Ahn [had] to about the “yes” side. I think there's some great points there too.

I think this is an interesting question, that we as a field have been increasingly interested in over time. As most people know, covalent BTK inhibitors, which was the first-in-class ibrutinib, and now zanubrutinib and acalabrutinib that have a better cardiovascular safety profile are a standard initial therapy for CLL that's widely utilized.

The other standard initial therapy, at least in the United States, is venetoclax and obinutuzumab. That sets up for either a fixed-duration or a continuous treatment and leads to a lot of interest in [answering the question] can we change this continuous treatment, because we all know BTK inhibitors are highly convenient and highly effective, but one of the major drawbacks is that they're given long-term.

I also object a little bit to the question being, “Can BTK inhibitors be discontinued?” because we all know that we can do something, right? We can go back to using just chemotherapy for CLL. I think the better question is: Should we discontinue BTK inhibitors, or should BTK inhibitors be discontinued? And as I said, this is a debate, and I think Dr. Ahn's going to make some extremely good points about when we should discontinue BTK inhibitors.

I'm going to talk about some of the reasons that these really should be a continuous and not a discontinued therapy. One of the reasons goes back to the mechanism of these drugs. The way I like to describe it when I'm talking to patients is that this targeted agent, which inhibits a non-mutant protein, interferes with a pro-survival signal in the CLL cells and ligates, homing to tissues, lymph nodes, and bone marrow. So, you see again, the lymphocytosis in the blood—that's classic and it makes the cells behave less like CLL cells.

This is something that results in a dramatic and rapid clinical improvement, both with things like hemoglobin and platelets, but even faster cytokine symptoms resolve, or lymph nodes decrease. But it doesn't eliminate the CLL very quickly, so even though patients feel better, and some disease markers improve, you see that the lymphocytosis persists in the blood for a long time, and that's not actually adverse for progression-free survival (PFS) or the outcome of this therapy. The mechanism of this inhibiting a non-mutant protein in B-cell receptor signaling, blocking that per survival signal, results in a lot of therapeutic efficacies, but not this rapid cell killing that you see with certainly cytotoxic chemotherapies and with BCL2 inhibitors where you see a lot of rapid cell death.

This mechanism of interfering with some of these cell-signaling pathways that CLL cells rely on suggests that giving these over a long period of time is going to be necessary to get the benefit. You can see that this is true looking at the clinical data as well. The complete remission rate early into treatment or in the first year is low, but if you go out to 5 years, it's higher and you really don't see any responses with undetectable leukemia early in treatment. And you don't see that many, even many years into treatment either.

If you think about the type of responses we see and what the drug does, it predicts [that] it needs to be given for a long period of time. If you look at patients that discontinue BTK inhibitors, remissions are usually shorter. If you discontinue within the first couple years of treatment, you can expect only a couple years of remission. The longer you're on them, the more durable benefit you get from them.

We all have patients that say “My lymph nodes are better, I feel better. Can I stop this drug now?” If you discontinue a drug early in treatment, the disease comes back quickly. I think another reason that BTK inhibitors really shouldn't be discontinued is not only that responses deepen over time or the mechanism predicts that responses will take a long time to develop, but also you see when you stop them, remissions don't last very long or aren't durable after discontinuation, which is of course the opposite of what we see with cytotoxic agents like chemotherapies or venetoclax, the BCL-2 inhibitor.

One of the final points I want to make about this in my brief discussion of the reasons we shouldn't discontinue BTK inhibitors is that this is the most effective therapy that I've seen in CLL. The median progression-free survival with ibrutinib in a first-line setting, granted in the RESONATE 2 study, which did not include patients with TP53 disruption or deletion 17P, is 8.9 years. I've not seen a median progression-free survival that is that same duration with any other therapy, and that's for a continuous treatment with ibrutinib.

At our institution [OSU], we had a phase 2 study that patients are in follow-up for that was a little more than a year's duration of obinutuzumab, ibrutinib, and venetoclax together. In previously untreated patients, the median progression-free survival was 7.3 years. I think that if you do a study with a drug treatment that's fixed-duration that includes a covalent BTK inhibitor where you get high response rates and a reasonable rate of undetectable leukemia, you still don't see the same kind of progression-free survival that you get from a continuous BTK inhibitor therapy. I think that's one of the major reasons that these shouldn't be discontinued; If you give them continuously, you get the best therapeutic benefit that we have so far for CLL. Not that that will always be the case or there's not more work to be done—I just think that needs to be considered as a reason that you shouldn't stop a continuous BTK inhibitor.

I do think there's some valid arguments for why they should be stopped, especially when you're looking at something that's less effective in terms of progression-free survival like a BTK inhibitor, venetoclax combination therapy, looking at sequencing and repeating treatments, looking at concerns toward toxicity and developing resistance, which occur over time.

I think the major reasons to not stop a BTK inhibitor are that the mechanism predicts it works best over time [and] responses deepen over time. [Also], remissions after discontinuation are generally shorter, and the best efficacy, we've seen to date with any therapy in CLL is with continuous BTK inhibitors. I heard that they're going to poll the audience, and I look forward to hearing other people's opinions on this topic.

Source:

Rogers K. Debate: Can Therapy With BTKi Be Discontinued: NO. Presented at the 2024 Society of Hematologic Oncology meeting. Houston, Texas; September 4-7, 2024.