A session with experts Paolo Ghia, Susan O’Brien, Lydia Scarfo and Othman Al-Sawaf, who discuss the latest chronic lymphocytic leukemia (CLL) updates from EHA and ICML 2021.

Welcome to The CLL Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Paolo Ghia, Susan O’Brien, Lydia Scarfo and Othman Al-Sawaf, who discuss the latest chronic lymphocytic leukemia (CLL) updates from EHA and ICML 2021.

The topics of discussion include long-term data, second-generation BTKs and fixed-duration therapy. Additionally, in this insightful discussion, the experts highlight recent data from trials such as the RESONATE-2, CLL14, MURANO and ELEVATE-RR studies.

Long-term data

 

“The seven-year update showed that with a median follow-up of about six-and-a-half years, there was still no median progression-free survival, which is sort of astounding and, at that six-and-a-half-year mark, the progression-free survival was 61%.”

– Susan O’Brien

Second-generation BTKs

 

“In the analysis of the ELEVATE-RR study, acalabrutinib was shown to be associated with lower rate of atrial fibrillation and hypertension. These are two of the most frequent adverse events that have been previously associated with ibrutinib treatment. In terms of cardiovascular toxicity, actually, acalabrutinib seems to have a better profile in this setting”

– Lydia Scarfo

Fixed-duration therapy

 

“I was impressed in this study, especially the CAPTIVATE, but also in the GLOW with the durability of the responses. Regardless of achieving undetected MRD, still, the PFS curves and this disease-free survival curves are very flat.”

– Paolo Ghia

Watch the full session
Full Transcript

Paolo Ghia:

Welcome to everyone. Today, we are joining the VJHemOnc event where we are going to update you on all the news that we heard at EHA, ASCO, and ICML, so this long congress season in Spring 2021.

Paolo Ghia:

I’m happy Susan O’Brien from University of California Irvine, by Othman Al-Sawaf, a physician of the German CLL Study Group, and Lydia Scarfo from Università Vita-Salute San Raffaele in Milan. So, thank you for joining.

Paolo Ghia:

We can say that after, I will say, many months, finally, we saw very interesting results, very new results, and that are very promising also for our patients. I would say that we can start from the longest follow up that we ever seen in CLL with the novel therapy. I’m referring to the RESONATE-2 update. What do you think about it?

Susan O’Brien:

I thought that data was quite impressive. Just to remind the viewers, this was the original trial that led to the frontline approval for ibrutinib as a therapy in CLL, the first small molecule to get that approval. And that, of course, was the randomized trial versus chlorambucil. About two years ago, we had seen a five-year update that looked quite impressive at that time with no median progression-free survival in the ibrutinib arm and, now, we have the seven-year update. The seven-year update showed that with a median follow-up of about six-and-a-half years, there was still no median progression-free survival, which is sort of astounding and, at that six-and-a-half-year mark, the progression-free survival was 61%. So not only are these remissions very durable, but it’s quite impressive in the setting where we’re actually not talking about too many complete responses, and we’re certainly not really talking about MRD undetectability, and yet we have these incredibly durable remissions.

Susan O’Brien:

The other very impressive point is that, in marked contrast to chemotherapy regimens where we know with every chemoimmunotherapy regimen we have, one of the most important predictors of progression-free survival is the mutation status with the unmutated having a significantly shorter progression-free survival. In marked contrast to that on this trial with now seven years of follow up, there’s absolutely no difference in outcome between the mutated and the unmutated. This is a great treatment in general, but it’s a particularly great treatment for unmutated patients who, even if they got FCR upfront, the best chemoimmunotherapy that we have would not still be in remission for the most part six to seven years later. That’s for sure.

Paolo Ghia:

What also was impressive, and sometimes we forget about it, is that the quality and the depth of response, though you said that there is no undetectable MRD, most patients still have partial responses. But still, after seven years, we do see an increase in complete remissions also. Do you want to comment about that?

Susan O’Brien:

It’s still low number but, I have to say I doubt that anybody’s going back, say, at five years and doing bone marrows. It does make me wonder if the CR rate… now, it’s just really an extension study so that we can get this long-term data, that’s really just collecting progression survival, that kind of thing. I doubt people are going back and doing bone marrows on these people. It does make me wonder the CR rates roughly about a third. If, in fact, we did go back and do bone marrows on them, which is not going to happen, if many of those people that are now still in remission, six, seven years out, actually, aren’t in complete remission, so no way to know but it wouldn’t surprise me.

Paolo Ghia:

That’s an interesting point. But, indeed, it’s also an important message for our patient because maybe, one day, we might think of stopping finally, at least some patients, at least those with the best response. This is, of course, something that we should not do without data but this is something that should be explored in a study. Maybe those patients who we do we go back and do the bone marrow, and we really get a complete remission maybe we could randomize and see.

Susan O’Brien:

The other advantage of that is that if, at later times, they go on to progress off drug, it raises the question like we’re seeing in some of the other trials, could you go back and retreat if you stop? Would you actually potentially get more shelf life out of the drug if you did that rather than just continuing it to progression? Again, as you said, we have no data but it’s an interesting thought.

Paolo Ghia:

It’s an interesting question that, of course, would take many, many years before one could answer if we started the study today. But these are all interesting and important questions that actually refer me directly to Othman because these are the questions that the study that he led and presented again also at EHA are really asking, so about fixed duration, about stopping treatment, about retreatment and, in particular, I’m referring to the CLL14 study for which Othman presented the four year update a EHA and I was particularly impressed by the data on unmutated patient. Again, Othman, do you want to comment about it, please?

Othman Al-Sawaf:

Thanks, Paolo. So, we showed some new data from CLL14 with long and ongoing follow-up. Just as a reminder, the setup of CLL14 phase three randomized study for previously untreated CLL elderly patients with coexisting conditions, and the patients were randomized to either 12 cycles of venetoclax-obinutuzumab or 12 cycles of chlorambucil-obinutuzumab. Previously, we’ve seen a significant PFS advantage as can be expected for a venetoclax-obinutuzumab. And now with the longer follow-up, we are seeing that all patients being off treatment for at least three years in both arms, we can see that there is a sustained PFS benefit so the overall four-year PFS rate was 74% venetoclax-obinutuzumab compared with 35% with chlorambucil-obinutuzumab. As you just mentioned, Paolo, indeed, we do see that both groups, the mutated and the unmutated IGHV groups benefit more from the venetoclax than from the chlorambucil-obinutuzumab om terms of progression-free survival.

Othman Al-Sawaf:

But what we do see is, in contrast to what has been reported in RESONATE-2 that there is a difference in the outcome also for the unmutated IGHV group when treated with venetoclax-obinutuzumab although their median PFS has not been really reached now and although the numbers at-risk are very small at the four and five years, we do still see that they benefit substantially, so the median PFS would definitely be over 15 months in the unmutated IGHV group.

Othman Al-Sawaf:

I think what we clearly can see, however, is that IGHV is too prognostic for this group of patients. And therefore, I think we can still understand them as high-risk patients in that sense, also in the context of targeted agents because, in other clinical studies, like the iLLUMINATE study where ibrutinib was used in a patient population that was only somehow comparable to CLL14, so these were also elderly and more or less unfit patients were we also see that the unmutated IGHV group with ibrutinib falls poorer than the mutated IGHV group. I think at the end, clinically speaking, we can still consider the unmutated IGHV group as a risk group in terms of needing better treatment strategies in the future.

Paolo Ghia:

Maybe we will be discussing in few minutes about the combination between BTKis and BCL-2 inhibitors. But still, [inaudible] 50-month of PFS in the unmutated patient with only 12 months of treatment. That’s the important thing. It really allow us to think and dream about the possibility of retreating the patient, and especially because they relapse after several months. After several years, it’s very likely they will respond. Do you have already any data about this? Do you want to comment?

Othman Al-Sawaf:

We don’t have retreatment data after the frontline setting yet. We are starting, in a few months, phase two study that will recruit in several countries including several countries in Europe and the US, the so called [inaudible] study. In this study, patients who have received 12 cycles of venetoclax-obinutuzumab irrespective of the setting, so irrespective of whether in a study or outside, can be retreated with the same regimen with 12 cycles of venetoclax-obinutuzumab.

Othman Al-Sawaf:

We do have some very reassuring data regarding the genetics and the frequency of BCL-2 mutations after 12 cycles of venetoclax-obinutuzumab. These data were shown by [inaudible] also at EHA and ICML. We do see that in none of the relapses after venetoclax-obinutuzumab, there isn’t any case of even subclonal BCL-2 mutation in any patient that relapse of venetoclax-obinutuzumab, which suggests that the short treatment duration doesn’t really express enough pressure to allow for the selection of these kind of clones and which is quite reassuring for any kind of retreatment strategy. I think, potentially, this will be a very viable option. We’ve seen that also in the MURANO study last year at ASH where there are several cases who have been successfully treated, retreated with venetoclax after relapse in the relapse setting, so a setting that is potentially much more challenging than in the frontline setting.

Paolo Ghia:

From the MURANO, actually, we understood, of course as we expected, that the time of relapse will count. The closer to the end of the therapy, of course, the less likely he will respond. In your study, that one that you mentioned for the retreatment, did you put any cutoff or are you enrolling everyone failing VG in terms of time to recovery?

Othman Al-Sawaf:

No. We actually have very long discussions with it. In this study, which is also led by my colleague, Kirsten Fischer, and Matthew Davids in the US who was coordinating the study from the US perspective, we have very long discussions about this. Because all thresholds are, to a certain extent, arbitrary, similar to the era of chemoimunotherapy where, until today, there is no consensus on whether two or three years is considered an early relapse. Similarly, of course, with venetoclax-obinutuzumab, we have even less data but what we said is that the patient should have responded at least for one year after venetoclax-obinutuzumab. Practically speaking, we don’t have any real disease progressions in CLL14 after one year of treatment anyway. This is more of a formal cutoff. But what we said is that patients who relapse between one and two years that these would not be treated for just 12 cycles, but for 24 cycles of venetoclax, whereas the late relapses will be treated again with 12 cycles and fixed duration although we leave it a little bit up to the investigator at the end in case as well, for instance, in case of deletion 17p and so on, we know that many investigators would like to continue treatment, particularly in the MRD positive patients. So, we leave that option a little bit open in this Phase II setting.

Paolo Ghia:

That’s very interesting. You said that nobody really relapsed or progressed or needed therapy within one year after the end of therapy. What about the TP53 patient, those with TP53 aberration that we saw you confirm that indeed they are progressing a little bit earlier than the other patient?

Othman Al-Sawaf:

Indeed. We do see that TP53 is highly prognostic in terms of progression-free survival, also in the context of venetoclax-obinutuzumab. However, we do you see that the median PFS is still almost four years. Similar to what you suggested with the unmutated IGHV group, we clearly see that the outcome is poorer for these compared to TP53 unaberrated status but, still with a 12 cycle treatment, we are seeing this substantial median progression-free survival, which again, where we have the option of retreating the patients particularly again, if I may refer to [inaudible] analysis, we don’t see an expansion of the TP43 clone in patients who have TP53 aberrations which, again, suggests that somehow this short treatment duration is quite favorable in terms of the selection pressure that we induce by our treatment.

Paolo Ghia:

That’s very reassuring in terms of clonal evolution. The two studies that we mentioned, there were updates so we knew about them. It’s always reassuring to see long term data. But what has been really impressive this year is that we saw two head-to-head studies comparing the BTK inhibitors. We don’t have any more only one BTK inhibitor, ibrutinib; we have now the so-called second generation BTK inhibitors, acalabrutinib and zanubrutinib. Indeed both studies have been presented at EHA comparing acala in the ELEVATE-RR or zanubrutinib in the ALPINE study with the ibrutinib in head-to-head comparison.

Paolo Ghia:

Lydia, which one impressed you more? What are they about?

Lydia Scarfo:

I say they are both quite impressive though the follow-up in the ALPINE study is shortest. Probably, we have to wait longer to gain more solid conclusion. But in the ELEVATE-RR study, the second generation BTK inhibitor acalabrutinib was compared in a head-to-head comparison with ibrutinib in so called high-risk patients with CLL that the time of study design were defined based on the presence of 11q deletion or a 17p deletion. The study is based on a non-inferiority design. The first result is based on the fact that acalabrutinib is non-inferior to ibrutinib in terms of progression-free survival in this category of patients. But as we all know, in clinical practice, probably the most relevant issue in the management of patients with CLL on BTK inhibitor is the long-term management of adverse events. In this category of patients, of course, being the elderly patient with comorbidities, the cardiovascular adverse events of interest.

Lydia Scarfo:

In the analysis of the ELEVATE-RR study, acalabrutinib show to be associated with lower rate of atrial fibrillation and hypertension. These are two of the most frequent adverse events that have been previously associated with ibrutinib treatment. In terms at list of cardiovascular toxicity, actually, acalabrutinib seems to have a better profile in this setting. The same for the occurrence of atrial fibrillation was also confirmed in the ALPINE study comparing zanubrutinib that is also a second generation BTK inhibitor with ibrutinib in the relapsed/refractory setting. The population is not exactly the same in the sense that in ALPINE, they did not select for high risk cytogenetic, let’s say, but still the atrial fibrillation and among the other toxicity seems to be lower in the zanubrutinib arm.

Lydia Scarfo:

Actually in Europe, in Italy, in particular, we do not have yet experienced with these two drugs, acalabrutinib and zanubrutinib outside clinical trials. Probably in US, they have more experience especially with acalabrutinib they have used since long time.

Paolo Ghia:

I think Lydia wants to ask you a question, Sue. What is your experience here? Of course, you had access to acalabrutinib and also zanubrutinib. What is your experience? Do you see the same thing that we saw in the clinical studies? What do you think about the neutropenia, for example, which appears to be a side effect with zanubrutinib that is not so frequent with the other molecules?

Susan O’Brien:

I actually have no personal experience with zanubrutinib but I have pretty good experience with acalabrutinib. I can’t really comment from my own personal perspective on this.

Paolo Ghia:

Also, to remind the audience that zanubrutinib is approved for mantle cell lymphoma, not for CLL in the US. That’s the other reason why.

Susan O’Brien:

Right. So, the acalabrutinib, it’s interesting. As Lydia said, the incidence of hypertension and AFib appear to be less. But what I also find is that some of the side effects that are quite annoying to patients but never rise to the level of grade three or four, for the most part, are reduced with acalabrutinib, for example, mouth sores, cramps, which are quite common with acalabrutinib, cramps in the hands or cramps in the feet. Diarrhea, we already know about, arthralgias. I feel from my own personal experience that those are all less common with acalabrutinib. Again, they don’t rise to the level of SAEs but they’re very annoying to the patients and particularly if the patient thinks, “Oh, I’m going to be on this drug for many years, and I’m going to have to deal with this.” I think they’re less with acala.

Susan O’Brien:

The one side effect, of course, we know that is more frequent in particular to acalabrutinib is the headache. I don’t know, maybe you have an idea, Paolo, if there’s any explanation for what causes the headache with acala but I will say that it tends to be mild. It often responds to pretty much anything, caffeine, aspirin and acetaminophen, and it generally is very short lived. My experience within a few weeks, it’s gone. But it’s an interesting toxicity because one we’ve really seen with ibrutinib and were with zanubrutinib, and we know that both the second generation drugs have lower IC 50s to get some of the other off-target kinases that we feel are actually responsible for many of the side effects with ibrutinib as opposed to direct inhibition to BTK. I don’t know if anybody in the group is aware of any potential explanations for that headache, but doesn’t seem to be a major problem.

Paolo Ghia:

It’s not a major issue, I will say. Also in the study, the median of the resolution of the headache is three weeks, I think. Interestingly enough also with zanubrutinib, you do see a certain percentage of patient not so high as with acalabrutinib, but still some patients who have suffered from these headache, which is, as we said, the transient and mild, typically.

Lydia Scarfo:

If I may. Let’s say what is bothering me at this point is how do you select patients for acalabrutinib instead of ibrutinib. Are general cardiovascular comorbidities a key point to to favor one BTK inhibitor compared to the other?

Paolo Ghia:

Sue.

Susan O’Brien:

I think it could be, yes. When I talk to patients about the options, I do mention the decrease in the hypertension and AFib. But it’s also fair to point out that if the AFib rate with aggregate rate with ibrutinib is 10% to 14%, that means the vast majority of people that get treated with that drug are in fact not going to have AFib and do quite well.

Susan O’Brien:

When I talk to the patients, one of the things I mentioned in favor of acala is the cardiovascular toxicity. One of the things I mentioned in favor of ibrutinib is, a, the very long term follow-up. In fact, in the relapse setting, we had the recent publication of eight to nine years follow-up in relapse with no new late safety signals. I also mentioned that that’s the only drug that’s been compared to what I think most of us would consider more effective chemoimmunotherapy in a randomized trial. Right? That’s the only drug, ibrutinib, that’s been randomized against VR and FCR and, in both cases, showed significantly better progression-free survival where the randomization of acala and venetoclax-obinutuzumab have been against chlorambucil. That’s another point that I bring up. It may or may not be important to the patient, but that’s something that I do point out.

Paolo Ghia:

We can also say having so many drugs, we really have to play well our card. As you said, a minority of patient would develop atrial fibrillation, so one may start safely ibrutinib and maybe we can become spoiled, and the patient who will develop atrial fibrillation, you might shift to the other drug, and maybe we will resolve or will not occur again, so really trying to keep the patient the longest time possible on the same class of drugs before switching, for example, them to a BCL-2 inhibitor.

Paolo Ghia:

Othman, do you want to add anything? Do you have experience in the real world, let’s say, with acala in Germany?

Othman Al-Sawaf:

Not in the real world, only in clinical studies and for zanubrutinib also only in clinical sites, and they’re particularly in a little bit different setting in patients with Richter’s transformation. There, it seems to be quite although it’s difficult because patients with Richter’s transformation, of course, often have a different clinical profile, so to speak, in terms of their fitness and their symptoms and so on, they often, of course, have a much heavier symptom burden than your standard CLL patient. But I think it’s from my experience of very well tolerated that’s very similar to acalabrutinib rarely any real cardio specific toxicities, although we should also appreciate from the tables that we’ve seen at ASCO, EHA, and ICML that it seems to be that these are overall relative reductions of the risk. If you look at the rates of bleedings, they are significantly less frequent with acalabrutinib but they are still much higher than we would expect in chemo-treated patients. I think the rate of hemorrhages was around 35% in the ELEVATE-RR, so much less than, I think, the fee of 55% with ibrutinib but still I think this is clinically irrelevant. If you have a patient that is on, I don’t know, double platelet inhibition after a stent, also, I think acalabrutinib I’m still wouldn’t be the best option for the patient.

Othman Al-Sawaf:

In terms of atrial fibrillation, it’s a little bit difficult to say if you look at the data from the ELEVATE-TN study that were also shown at the summer congresses and an update. You do see it. If you look at the atrial fibrillation, right, it seems to be slightly higher than the chlorambucil-obinutuzumab arm. I think there’s still, somehow to a certain degree, a class effect of BTK inhibitors that hasn’t been completely overcome also with a second generation BTK inhibitors. For that matter, I think with zanubrutinib, it seems that the only toxicity that is statistically less frequent with zanubrutinib is the atrial fibrillation because the rate of leading events and hypertension and so on seem to be very comparable to ibrutinib. I think Sue put it perfectly in saying that the longest follow up that we have is for ibrutinib both in terms of efficacy and toxicity, and therefore, for patients that doesn’t really fall in any of these risk categories, I think, it’s still fair to start a patient with ibrutinib. For me, clinically, the more pressing factor that’s decides on what kind of treatment strategy to choose is probably more the question of fixed duration and continuous of high-risk or low-risk. These are probably more the factors that are still guiding the decision, at least, to me.

Paolo Ghia:

With that comment, then I’m happy to now introduce the topic of fixed duration but, again, with ibrutinib involved in the combination with BCL-2. That’s, again, the other piece of news that we all heard at ASCO, EHA, ICML, so the combination of fixed duration between ibrutinib and venetoclax, and this has been tested in two different studies, the phase two study for young patients with CLL, first line, of course, in the CAPTIVATE study, and the fixed duration portion of the CAPTIVATE, and also the elderly in a randomized phase three study comparing ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab.

Paolo Ghia:

Sue, do you want to start commenting on this and then we will go around the table because this is the future, I will say?

Susan O’Brien:

Sure. actually I’ll just point out the very first combination, then the only one that’s been published was actually done by MD Anderson. That was, at least for the first 15 months, the exact same design as CAPTIVATE, meaning it was a three month lead in with ibrutinib. And now we’re seeing with all of this small molecule combination trials, plus or minus antibody, this three-month or two-month lead in, of course, which is done to try and debulk the patient and reduce the risk for tumor lysis once the venetoclax starts.

Susan O’Brien:

What’s interesting is that the MD Anderson data and the CAPTIVATE data are basically identical, which is good, because they’re up until 12 months the exact same regimen, meaning three months lead in with ibrutinib, no antibody, and then 12 months of the combination, producing very high MRD undetectability rates up around high 70, 77%, and, of course, then potentially the opportunity to have fixed duration treatment. We saw with the CAPTIVATE the fixed duration cohort. We have previously seen the other cohort earlier in the trial, which was not fixed duration. In that cohort at 15 months, there’s a randomization based on whether they’re MRD positive or negative. But again, very comforting to know that in the fixed duration cohort who got exactly the same treatment as the prior cohort for the first 15 months, all the data across the three trials looks significant.

Susan O’Brien:

Interestingly in GLOW, it was not quite as impressive with lower rates of MRD undetectability. Now, you pointed out very correctly that the CAPTIVATE study… the MD Anderson study wasn’t limited by age, but the CAPTIVATE study were young patients because all of those patients had to be under the age of 70 which, for CLL, is actually quite young. In the GLOW study, it’s a bit different.

Susan O’Brien:

Do you think or I would welcome anybody’s comments, maybe Lydia could comment what she thinks, do we think that age could account for that if everybody’s getting the same therapy or in the GLOW trial we’re more people are stopping therapy or dose reducing. I’m not quite sure why age might account for the differences but I believe in the GLOW trial, the MRD undetectability was down in the 50s, so lower than CAPTIVATE, lower than the MD Anderson data. You have any thoughts on that, Lydia?

Lydia Scarfo:

Well, that’s actually a very good point. I’d say that, in general, in terms of tolerance, it seems that this combination is quite well-tolerated meaning that we are seeing the adverse events of ibrutinib and the adverse events of venetoclax, but not an exponential increase in the adverse events related to the combination. Probably, considering that the disease affects duration regimen and those intensity, let’s say, keeping the drug together for the right amount of time is crucial to obtain deep response and to stop safely treatment. I do not have in mind the details but my main hypothesis is that actually elderly patient could ever receive the lower dose of the combination drug and I’ve interrupted treatment earlier or discontinued at least one of the two drugs for tolerability issues. That could be an explanation.

Paolo Ghia:

Indeed, 25% around the patient did not complete the 15 cycles of treatment. But what I want also to comment is what I was impressed in this study, especially in the CAPTIVATE, but also in the GLOW is the durability of the responses. Regardless achieving undetected MRD, still, the PFS curves and this disease-free survival curves are very flat. This is something that, Othman, you also started showing in the CLL14. So maybe with venetoclax in the game, we are somehow modifying the natural history of the disease. We are somehow changing or modifying the clone, so that proliferate less or, I don’t know, expand less. It takes longer time, even if we don’t really bring it to a low level. Do you want to comment on that?

Othman Al-Sawaf:

Yeah. I think that’s a very fair point. Of course, it’s a little bit too early for both regimens, the obinutuzumab combination and the ibrutinib combination to say anything about that particularly because in the context of chemomonotherapy with FCR, the mutated IGHV status, we do actually also see overall survival differences and so on. Therefore, I think, it’s easier to say that we, by the addition of CD20 antibodies, have been able to change the history, so to speak, the natural history of the disease.

Othman Al-Sawaf:

Whether we are that far with venetoclax, I’m not sure yet. We have some signals that we discussed at the summer congresses in terms of clonal growth and so on that seems to be a little bit different between the BCL-2 targeted treatments and against the chemomonotherapy. How much this also happens in a combination of venetoclax and ibrutinib, we don’t know as of yet. But as you say, I think efficacy-wise, the time to event dates are very reassuring also from the GLOW study that this is also a very feasible treatment option for elderly and unfit patients.

Othman Al-Sawaf:

Of course, I think something that I found striking in the CAPTIVATE study was the relative, although the adverse events, as Lydia was just alluding, frequency was quite… or the serious adverse events and so on, were relatively rare and the treatment was well tolerated. What I noticed was the frequency of diarrhea in 60% of the cases in the CAPTIVATE study. They were all grade one and grade two. If based on the definitions of grade two with this, I think this would be roughly five or six bowel movements per day, which from a clinical perspective for the patient, is quite heavy. If you tell him this is only low grade, they will probably disagree with you. I think this might be actually an additive toxicity because we also see in CLL14 that the additional venetoclax to the obinutuzumab actually then starts the higher rates of frequency. We have diarrhea both with BCL-2 inhibitors and with BTK inhibitors, and therefore maybe this combination in this regard can be maybe challenging. But the GlOW study didn’t have such a high rate, and need to see, I think, longer follow up data to better understand this.

Paolo Ghia:

Now, for me, again, we are lucky to be in this period in which we have many options and, probably in the future, we will be picking the best for our patients. Maybe from what you said during this half hour, we are going to the conclusion, is that maybe for mutated patient, we can be happy with VG with a fixed duration treatment, very nice responses, prolonged responses. We can use monotherapy in the elderly patient, and they can continue for many years without really having to come to the hospital, get infused with anything. And maybe the IV will be the good option for unmutated patient, young patient who can tolerate it, but still have a fixed duration treatment. So we will see in the future.

Paolo Ghia:

But before closing, I want to give the word to Lydia, who presented the work that can be somehow compromized between all these continuous therapy, fixed duration, which combinations, how many drugs, and that’s the IMPROVE study to whom I’m referring. Lydia, do we want to, in 30 seconds, summarize your study?

Lydia Scarfo:

Yes, we presented actually an update of our study in the relapsed/refractory setting where we chose a different approach, meaning that we started in comparison to many other trials currently ongoing. We started treatment with venetoclax single agent because venetoclax alone is able to obtain undetectable minimal residual disease in quite relevant proportion of patients, and then added ibrutinib only in those who did not achieve undetectable minimal residual disease after 12 months of venetoclax monotherapy. By monitoring MRD status over treatment, we were then able to stop the combination of ibrutinib and venetoclax in more than 80% of cases because they reached the undetectable minimal residual disease status. I dare say we all agree that the one-size-fits-all approach can be improved, and we can design different types of studies. This is actually increasing the intensity of treatment by adding additional drugs only in patients who have disease that is whether a disease that is not responsive to monotherapy or less intensive treatment, let’s say.

Paolo Ghia:

Indeed, there are also those few patients who did not achieve undetectable MRD either way, they continue their ibrutinib as continuous therapy. So really identifying those who must continue indefinitely the therapy because they know that they will not reach any other response.

Paolo Ghia:

Thank you very much. The time passed by very fast as usual when you are enjoying. I thank you, again, for your insightful information, discussion, and opinion. Thank you for joining and thank you, the audience, for staying with us.

 

Disclosures

Paolo Ghia receives honoraria from AbbVie, AstraZeneca, ArQule/MSD; BeiGene, Celgene/Juno/BMS, Janssen, Lilly/Loxo, Roche and Research support from AbbVie, AstraZeneca, Gilead, Janssen, Sunesis.

Lydia Scarfò is on advisory boards for AbbVie, AstraZeneca, Janssen.

Othman Al-Sawaf received research support by AbbVie, BeiGene, Janssen, Roche; honoraria/fees by AbbVie, Adaptive, AstraZeneca, BeiGene, Gilead, Janssen, Roche.

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