Duration of BTKi therapy correlates with time to next treatment in CLL | Kerry Rogers, MD | #ASH24

I'm, Kerry Rogers. I'm an associate professor in the division of hematology at the Ohio State University in Columbus, Ohio. I'm super pumped to be here at the American Society of Hematology meeting in San Diego, California. So this is a retrospective study we did at Ohio State. That was actually, led by one of our, physician trainees.

And the major question that we've had for some time for BTK inhibitors, is about what happens if you have to stop them due to side effects. So, BTK inhibitors, which is ibrutinib., acalabrutinib, and zanubrutinib, are designed to be taken kind of continuously until either they stop working, meaning the CLL comes back while people are still taking them, or they develop a side effect and have to stop taking them.

I think that in many cases when people stop due to side effects, the question is, do you have to pick another CLL treatment right away, or can you be in remission some time? And as a physician taking care of people with CLL, I see that if they have been on, you know, BTK inhibitor for many years and earned a good remission, if they have to stop due to a side effect or some other change in their health, that, like my perception was they did well for some time and didn't need a new treatment.

But if you stopped like a month in due to a side effects, you probably do. So we wanted to look at our experience at Ohio State, specifically the experience of the group of patients who had to stop a BTK inhibitor for what we call adverse events, which are side effects, and how long they stayed in remission after they stopped the treatment.

So we had over 600 patients that were included. The vast majority had received ibrutinib, with some receiving acalabrutinib. And that's really because of the time frame where we are looking at this data so with the newer agent zanubrutinib, we just don't have a lot of follow up on those patients, cause it was more recently approved, and we actually found about one out of five patients or 20% ish had to stop due to due to side effects with the medication.

So I think that's, that's actually it's really important to look at this when you're seeing that's a substantial number of people that had to stop taking these drugs due to side effects. There's a bunch of, information we provided in the report on kind of like who the patients were in terms of age and things like that.

But one of the messages we have is that for people that had to stop due to side effects, it was just under two years before they had to take the next treatment. So this really means that some people can get some time off treatment, even if they stopped due to side effects. However, we wanted to look at, kind of factors associated with a longer or shorter time to needing to start a new treatment and actually did an analysis of people that stopped during the first 24 months or two years of treatment, or people that stopped due to side effects after two years and found that, it was actually a shorter time to needing, a new treatment or having progression of the CLL for those that stopped during the first two years of a BTK inhibitor, it was a median, which is not exactly average, but you can think of it like average of about nine months, versus a median of like closer to two years or around two years for people that stopped after taking two years of a BTK inhibitor.

So I think this really suggests that people, right when they start treatment, if they have to stop due to side effects, should really be thinking, what am I going to do as my next treatment? But for people that are a couple years in or more specifically more than two years in, if they have to stop due to side effects, they can probably be thinking, hey, I can enjoy some time before I have to pick a new CLL treatment.

We did see that people that had taken more treatments in general for their CLL seem to have a shorter time to next treatment, and that makes sense. Usually people that have had more treatments, you know, have, you know, kind of a shorter time to next treatment or continue to need more treatment so that, that sort of logically made sense to us.

We had mostly ibrutinib treated patients, but some that got acalabrutinib. We did find that patients were are taking acalabrutinib were less likely to need to discontinue treatment. So it's only about 14% versus about one out of five with ibrutinib. We kind of expected that because we see fewer cardiovascular side effects with acalabrutinib. We did look at whether or not people stopped ibrutinib or acalabrutinib, if that made a difference for how long they were in remission.

And it did not. So that was not significant. And so it's likely that how long they took the drugs, rather than which drug they're taking is what made the difference there. The American Society of Hematology meeting is always really, a great place to hear about what's, coming in terms of new treatments for CLL. And this is where a lot of the big phase three clinical trials are presented, that are drug regimens that are likely to be approved for CLL.

For a long time, we've seen that ibrutinib and venetoclax in combination can be quite effective. And in fact, a kind of 15 cycle, which is around 15 months of treatment regimen that ibrutinib and venetoclax, is approved by the EMA in Europe, but is not approved in United States. And at this particular meeting, we're going to get results of a large, phase three clinical trial that randomized patients who needed first treatment, to a standard care arm of chemo immunotherapy, which is either FCR or BR.

Now in the United States, I don't really think chemo immunotherapy is a standard or recommended treatment. But that is the control arm here. And it was the physician enrolling the patient that got to pick which chemo immunotherapy they received. But it's most interesting is there are two investigational arms. One was acalabrutinib and Venetoclax. So it was a time limited or fixed duration treatment.

And then one was acalabrutinib and venetoclax with the addition of obinutuzumab, which is an anti CD20 monoclonal antibody. So this is the first trial where we're seeing comparison head to head. And a large number of patients of a BTK inhibitor Venetoclax so acalabrutinib and venetoclax here. You know, without or with the addition of an antibody, the studies major goal or the primary reason the study was done was not to compare, you know, acalabrutinib and venetoclax with or without the antibody.

But we are going to see that result. So far, what we've learned from the study that was reported in the abstract form is that both AV, which is acalabrutinib and Venetoclax and AVO which is acalabrutinib, venetoclax, and obinutuzumab, had a better progression free survival than the chemo immunotherapy, which is FCR or BR.

And progression free survival being better means that more of the patients who received investigational therapy, were alive and had their leukemia controlled than with chemo immunotherapy. So we're going to see the results of the study, coming up in a few days. I can't talk about them yet. So we'll see side effects, things like that in more detail.

But knowing that, the two investigational arms were more effective than chemo immunotherapy means that there's a possibility they'll be approved by the FDA or could be used in the United States. So I'm hoping that what we'll see is the first, BTK inhibitor, venetoclax. Venetoclax is a BCL two inhibitor. So BTK inhibitor, BCL two inhibitor, fixed duration regimen that will be approved as a standard of care in the United States.

If that is the case, this will be a third option, right along with continuous BTK inhibitors with or without obinutuzumab. Obinutuzumab and Venetoclax. And then we would have venetoclax and acalabrutinib. So I think that's really exciting. I do think the field still has some work to do to try to figure out what the benefit of adding obinutuzumab is.

So with acalabrutinib just giving continuously adding obinutuzumab for patients without deletion 17 P or a Tp53 mutation. And their CLL does improve progression free survival. So how long people are in remission or have the leukemia controlled. It looks like that might be the case. Adding obinutuzumab to acalabrutinib and venetoclax for a fixed duration.

However, there were more, you know, adverse events, with that. So higher rates of neutropenia, which is a neutrophil count, and it looks like there were more people that died or died from Covid 19 with the addition of obinutuzumab compared to acalabrutinib. And venetoclax. I don't know if that's, statistically significant, but more drugs always means more side effects.

I think having AB or acalabrutinib and venetoclax will be good, and I look forward to seeing more results before I decide if the antibody’s worth it and who that might be best for. Either way, I think more treatment options for people living with CLL is always better, so people can continue to get the right treatment for them.