Impact of Venetoclax Discontinuation or Modification on Survival Outcomes Among Patients With CLL

Anthony Mato, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, NY, highlights findings from a post-hoc analysis of the phase 3 MURANO trial, which explored the impact of venetoclax dose modification and early discontinuation on survival outcomes for patients with chronic lymphocytic leukemia (CLL).

Transcript:

Hi, my name is Anthony Mato from Memorial Sloan Kettering Cancer Center. I'm the director of the CLL program and I'm happy to be with you today to discuss this topic.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

There has been some work on BTK inhibitors specifically looking at lower doses, dose interruptions, early discontinuations and how that might impact progression-free and overall survival. But in the case of venetoclax, which is a time-limited therapy, there's really not a lot of information from the clinical trials looking at the impact of, for example, 12 months of therapy versus 24, or dose reductions, or dose interruptions and how they may impact patients. Since our goal is to treat patients for the full treatment duration as per the way these regimens were derived, we wanted to try to understand what the impact might be on survival outcomes if a patient has to stop short. That's the background, then the MURANO Trial was a randomized trial looking at venetoclax, rituximab, ven is given for 24 months versus bendamustine rituximab.

The schedule of ven-r is again, 24 months, overwhelmingly positive for progression free and overall survival, helping to change the standard of care in the relapse refractory setting. However, there were a sizeable minority of patients—72% completed the therapy, but certainly that sizable minority of 28% did not—and I wanted to try to understand whether or not stopping early in a drug that does induce a deep remission might impact progression-free survival, for example.

OLN: Please briefly discuss any significant findings from the study.

The most important finding was that, for the subset of patients who discontinued venetoclax for any reason—of course, disease progression would be excluded from that—that the progression free survival was inferior. And specifically, in the subset who came off due to an adverse event early—again, earlier than that 24 months—the PFS was inferior and the P value was highly significantly different. And the risk of developing an event like PFS OS event was reduced for every extra month of exposure to venetoclax patients got, impacting the PFS and the overall survival significantly. Really supporting the fact that, at least, in the relapse refractory setting, a goal of 24 months of therapy is the standard of care that we should be striving to achieve.

This also speaks to understanding what the adverse events that are occurring on the trial, and whether there are ways to improve management due to better supportive care. For example, an interruption due to an adverse event most commonly happened in the setting of neutropenia. That was the number one reason why there was an interruption or a dose reduction. Those really didn't impact PFS or OS, as long as the drug was resumed for patients. But to me, this really suggests that, for example, growth factor support should be strongly considered in venetoclax-based therapy, in order to maintain our ability to dose patients for an adequate duration of exposure. Reductions were noted in dose in 23% of patients, but again, dose reductions didn't impact outcomes either, as long as patients were getting to the goal of as close to 24 months as possible.

So, understanding what the adverse events are, understanding how to manage them, including growth factor support and dose reductions really can lead to a strategy where patients will get the adequate exposure to therapy, but at the same time, be done in a safe way to better mitigate the risk of having a progression event or a death event related to early discontinuation. That's largely the crux of our findings for this trial, and certainly excited that the sponsors were more amenable to sharing this data, letting us look at the soft underbelly of the study, so to speak, in terms of the weaknesses of the regimen to better understand how we can successfully deliver care to patients with this great therapy.

OLN: Were any of the outcomes particularly surprising?

No, I think it does make sense to me that you should try to treat for the appropriate duration. I guess what isn't known is what is the optimal exposure to venetoclax? And prior to this study, I might have questioned a little bit, like maybe we could get away with 12 months like we do in the frontline setting, but these results really do support [that] a longer exposure does result in a better survival outcome for patients.

OLN: What are the possible real-world applications of these findings in clinical practice?

Well, this is, of course, the ideal situation. This is the clinical trial. In reality, we don't really know what's going on with time-limited venetoclax-based therapies. We did do some early real-world studies, published 2 or 3 years ago for ven-based therapy, but those haven't been updated, and a lot of that was ven given as a continuous treatment, so to make the connection between the clinical trial results and the real world data has not yet been done with the time-limited frontline and relapse refractory approaches, and that's really what we need to do now.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what are/will be your next steps?

Oh yeah. We're always expanding our real-world data. I am focusing this year on ven-based therapy, so expect to hear more, hopefully later in the year.

Source:

Mato AR, Sharman JP, Biondo JML, et al. The impact of early discontinuation/dose modification of venetoclax on outcomes in patients with relapsed/refractory chronic lymphocytic leukemia: post-hoc analyses from the phase III MURANO study. Haematologica. 2022;107(1):134-142. doi: 10.3324/haematol.2020.266486.