A Rapid Shift in Treatment for Chronic Lymphocytic Leukemia - Episode 6

Obinutuzumab + Venetoclax for Frontline CLL


Nicole Lamanna, MD: We pretty much talked about BTK inhibitors in frontline therapy. Well, now we have the approval of venetoclax and obinutuzumab. Let’s talk about the CLL14 data and how that fit in. We’re talking about continued therapy, patients have done well long term on ibrutinib monotherapy from the original studies. Now venetoclax and obinutuzumab are approved frontline. How do you feel about that therapy?

Javier A. Pinilla-Ibarz, MD, PhD: I think we went from fixed-duration chemoimmunotherapy that, as we discussed, may be used still in the community. Although I think, as we discussed recently, BTK inhibitors are a pre-established standard of care. I think that the importance of the CLL14 studies is that they’re bringing back once again this limited duration of therapy that some patients may prefer over long-term therapy.

I think the data still are not mature enough, and I believe they have at least in the frontline, 1 year, and in the second line, around 2 years of therapy. I think it’s important to really emphasize that we still need to really see how those patients are going to evolve over time, how those patients are going to do after discontinued therapy, and which risk categories and risk stratification of patients will do better or worse will depend on this time-limited therapy.

As we first were discussing, we know that in the low-risk category—ibrutinib in the long run or BTK in general—they do fantastic if the follow-up up is really 5, 10, 7 years. However, we don’t have the same data with time-limited therapy or usually we can or cannot really think about extrapolate the famous MRD [minimal residual disease] negative. That is another concern that minimal residual disease negative is coming back to our clinic, and how we’re going to really use it in the standard practice is very unclear. I mean, the FDA has still not really defined.

Nicole Lamanna, MD: We’ll get to MRD. Dr Jan Burger, what about—do you use venetoclax or obinutuzumab up front in any of your patients? Those patients who we talked about who have cardiac risk factors, need frontline therapy. Does that come into your discussion if you go, “Oh, I want to avoid a BTK, because they have AF [atrial fibrillation] and on anticoagulation.”

Jan Burger, MD, PhD: Exactly the point that was made. I think that’s exactly that population. If there’s a patient we fear is not going to do well and somebody who had recent bleeding problems or who has a cardiac history, and we fear that BTK inhibitors would put that patient at some risk, then venetoclax is a good alternative. If we use it in the frontline, 1 of the key problems is if we do limited-duration treatment, patients will relapse from that and we don’t have a clear strategy what then to use next. The hope is those patients would probably respond to BTK inhibitors.

Nicole Lamanna, MD: We have some limited data that have emerged.

Jan Burger, MD, PhD: It’s very limited, and there was probably a reason why in the first place we didn’t use a BTK inhibitor. There are some problems with that. On the other hand, it’s a highly effective regimen and the issue is sometimes in high-risk patients, for example, we don’t know what is the best duration of treatment. The choice in the relapsed setting to go for 2 years, in the frontline setting in CLL14 to go for a year—that’s coming from the drawing board. And in high-risk patients, I would have some issues stopping treatment early because relapses are to be expected.

Javier A. Pinilla-Ibarz, MD, PhD: I want to add that you were mentioning the high-risk patient, but we have to really go back to this fit patients or even patients who have low risk as we discussed. They can do good with anything that we have. In my opinion, it may be an area that originally we were going to see how these data evolved. Limited-duration therapy was very successful in eliminating cells from the bone marrow. It may be a good opportunity for those patients in exchange for the classical chemoimmunotherapy that we have been discussing, right? Well, chemotherapy will eradicate the disease in terms of these deep MRDs and may really prolong PFS [progression-free survival].

I will advocate that maybe with more mature data, this population of patients may be better for this time-limited duration because they may potentially wait for long-term follow-up benefiting the most for these therapies running like a high-risk patient that we discussed. Most likely they will have a higher risk to relapse and sooner, or later they’re going to really require a second or third drug.

Richard R. Furman, MD: Just to follow up on that though, we very quickly went from continuous therapy to 2 years of venetoclax to 1 year of venetoclax as we moved up with really no data guiding that decision.

Nicole Lamanna, MD: Correct.

Richard R. Furman, MD: I think that everyone discusses how patients would prefer to have fixed duration of therapy, yes. If you were to ask me, I would rather be on therapy for 1 year than 2 years, but that’s with the caveat that both therapies are equal and we right now don’t have those data. It’s an important educational point that, yes, these are fixed-duration regimens, but we don’t know if we’re sacrificing anything. Ultimately, the hope is that when you do progress, you just go back on the same therapy or a different therapy. Then you do well, and we’ve avoided having our patients treated for that period of time. I mean, that’s the hope, and that’s certainly the goal, but it’s important to have an informed discussion with the patient.

Nicole Lamanna, MD: Would you guys like to see a study then? Knowing what many patients, particularly some of our younger ones, really want, once venetoclax and obinutuzumab got approved in frontline, a lot of patients had that sense of, “Oh, I want this time-limited duration.” Would you like to see a head-to-head trial of ibrutinib or acalabrutinib versus venetoclax or obinutuzumab? Another arm, how long—do we do 12 months, do we do 24 months? Farrukh?

Farrukh Awan, MD: Ideally we would love to see something like that, but we can have cross-trial comparisons from multiple trials and take the arms from those trials. I understand that that’s not the best way to do that, but if you look at the progression-free survival, at 2 years it is exactly the same for all 3 approaches in combination with an antibody and BTK inhibitors and the same for BCL2 combinations. It hasn’t really changed despite the MRD negativity being higher with venetoclax. I think long term might be different, but short term it appears to be very similar across trial comparison.

The other argument is that if my high-risk patients are dropping off and relapsing, maybe 12 months is not enough for those guys. One thing that’s happened recently that I recall practice changing is in those patients, at least in the untreated setting. We can talk about the relapsed setting later on, but in the untreated setting, I’m reluctant to just stop at 12 months in my high-risk patients.

Nicole Lamanna, MD: I was just about to ask you all that.

Farrukh Awan, MD: I would argue that even if they’re MRD negative, we sit down and feel more comfortable in stopping those groups of patients. The vast majority of my high-risk patients, I would not stop at 12 months.

Nicole Lamanna, MD: What do you feel for your high-risk? Let’s just talk about that for a moment.

Richard R. Furman, MD: I just want to add that the question is probably going to not be answered by a head-to-head study, just because that’s a very long, cued study that’s unlikely to really be worthwhile. I think we will be able to get the question answered by looking at a lot of phase II data. If a patient progresses after obinutuzumab-venetoclax, what happens when they get re-treated with venetoclax again? Those are data we will have 1 day, so I’m hoping that these important questions will be answered.

Currently, what I think is 1 of the most important questions about venetoclax is whether there really is a maximal time before you end up with no further benefit. The question becomes whether there really is anything to gain by continuing therapy beyond 2 years. We will hopefully have data within the next 6 months regarding that question, but I think right now in my patients, the data that are probably most guided are the mathematical data looking at doubling the time to MRD negativity. It might predict the time for maximal benefit.

For a lot of the patients, I do 2 years of therapy and then have the discussion, depending on how deep of a response that they’ve attained. I think the CAPTIVATE study will also be very helpful because it will also look at discontinuation of ibrutinib in addition to venetoclax and the reintroduction of ibrutinib plus or minus venetoclax. We’ll really address a lot of the questions related to discontinuous therapy.

Transcript Edited for Clarity