Othman Al-Sawaf:
Hi, everyone. Thank you for your interest in this webinar. My name is Osman Al-Sawaf. I’m a hematologist and oncologist from the University Hospital of Cologne. And I’m joined today by two distinguished speakers, Dr. Lydia Scarfo, who would like to introduce herself.

Lydia Scarfo:
Hi, everyone. My name is Lydia Scarfo. I’m a hematologist based in Milano at St. Raffaele Hospital working in the Strategic Research Programme on CLL. And joined also by Alessandra Tedeschi.

Alessandra Tedeschi:
I am Alessandra Tedeschi. I work in Milano too. I am a hematologist working in a big general hospital in the Guarda Cancer Center.

Othman Al-Sawaf:
Wonderful. So we have the opportunity for the next 30 minutes or so to discuss a few of the current topics in chronic lymphocytic leukemia management, treatments and clinical studies and also, of course, clinical considerations around managing this disease. And maybe I can ask Lydia if you could maybe focus a little bit on first-line treatment of CLL and your thoughts. What keeps you busy in your clinic when it comes to first-line CLL therapy at the moment?

Lydia Scarfo:
Thank you so much. I believe this is actually a crucial question, meaning that first-line is a very relevant point in the disease trajectory. I would say that at my institution, we are strictly following the EHA-ESMO guidelines, still awaiting for the updated version that should be coming soon. But our, let’s say, first assessments are based on the biomarker profile of the disease. So we test for the presence of TP53 aberration by FISH and TP53 mutation and the immunoglobulin gene mutation status. And these, let’s say, stratify patients according to the disease risk, meaning that patients carrying TP53 aberration have the highest risk of developing, let’s say, very aggressive disease and are the ones in the guidelines suitable for continuous BTK inhibitor treatment, while those carrying unmutated immunoglobulin genes or mutated immunoglobulin genes, but without TP53 aberration, they are the best candidates for fixed duration regimen. And then we have to further stratify based on comorbidity, not exactly age, but let’s say fitness status. So it’s very difficult to define it. And of course, patient preference. And we have very effective treatment options that are based, of course, venetoclax-based regimen, either venetoclax combined with an anti-CD20 monoclonal antibodies. And we know that in first line, we can use obinutuzumab, that is a very effective treatment, or the combination of a covalent BTK inhibitors with venetoclax. And now in Europe, there are actually two regimens approved, one based on the administration of ibrutinib plus venetoclax and the other of Acalabrutinib plus Venetoclax. So we have plenty of choices, but we try to adapt based on the patient features.

Othman Al-Sawaf:
Very good. Thank you, Lydia. So moving then on, let’s say you have a patient that comes to you and has relapsed CLL after prior successful therapy of CLL for the first-line setting. How are your thoughts there, Alessandra,. How do you approach these situations?

Alessandra Tedeschi:
As Lydia said, the first line it’s very important and at the time of relapse, we are most focusing again on prognostic factors 17p deletion is always retested in every patient, as well as, of course, TP53 aberration. And everything depends on what the patient received in first line and in the type of, of course, relapse. If a patient relapsed after a covalent BTK inhibitor, now we have two choices, fixed duration treatment with venetoclax rituximab or we have the possibility to use PIRTO. I think that there is not possible to say which is the best choice in this moment based on the studies we have in our hands. Everything depends on the characteristics of patients. Again, patient preference. I wouldn’t jump from a fixed duration, from a continuous treatment to a fixed duration, and then again to a continuous treatment. So maybe in the more elderly patient, a covalent BTK inhibitor may be an option. In the younger, again, we think about a fixed duration treatment. Of course, we have patients relapsing after fixed duration treatment. And again, there is a problem. For example, in Italy, we can’t reuse venetoclax after venetoclax in first line, but we can use venetoclax after ibrutinib-venetoclax or acala venetoclax. So everything depends on the duration of the first response and, again, on the patient’s characteristics.

Othman Al-Sawaf:
Thanks, Alessandra, for this summary for the relapsed setting. So we’ve talked about, I think, a major consideration even regardless of TP53 and these clinical variables is the consideration around using a continuous therapy and a fixed duration therapy, which seems to be predominant both in the first line as well as in the relapsed setting because we have these two options. I mean, a few years ago, we would have thought about chemotherapy and where to place it and which subgroups and so on. But now, I think the main distinction is really around the continuous and fixed duration therapy in any setting of CLL therapy, interestingly. And obviously, there have been some study activities in this field. And all three of us have been participating in CLL 17 and working on that study for some time. I don’t know, maybe from Lydia’s perspective, can you discuss a little bit CLL17 and how this pertains to the continuous versus fixed duration points that we mentioned now?

Lydia Scarfo:
That’s a very difficult question. I mean, doing that on behalf of the principal investigator but of course it’s a great trial because I mean it’s the only one comparing treatment paradigms like the use of continuous BTK inhibitions versus two different types of fixed duration regimen venetoclax plus obinutuzumab or ibrutinib plus venetoclax. The study wanted to prove a non-inferiority in terms of progression-free survival, and Othman recently successfully presented the three-year follow-up that confirmed the non-inferiority of fixed duration regimen compared to the continuous treatment. So this is something very reassuring for us because we are progressively shifting from continuous treatment, that was the treatment paradigm when we used mainly continuous BTK inhibitors, covalent BTK inhibitors, to fixed duration regimen. And the study basically, let’s say my take home message, proved that this approach is very effective in several subgroups of patients. The only one for which I would say we need longer follow-up in order to better understand how to manage at best, is the subgroup including patients with TP53 aberration. Because there, the follow-up is probably still limited, still short. But it seems in this preliminary analysis that with continuous BTK inhibitor, we are still achieving longer progression-free survival. On the other side, what I want to point out is that we have very limited data, as also Alessandra mentioned, on the sequencing. So basically here we are focusing on PFS-1. But in the in the long run what would matter the most is probably the time to class failure meaning that we want for us it’s okay it’s even better if we can reuse the same mechanism of action several times allowing the patient to get treatment holidays instead of administering continuous treatment that in the end leads to treatment resistance. So I believe that the CLL-17 trial provided now evidence that we can use the fixed duration approach in the vast majority of our patients with CLL. And that’s actually where we wanted to go based on the preliminary data we had available. I don’t know if I summarise it well, if you want to point out further take on messages.

Othman-Al Sawaf:
Well, excellent. Thank you. That was a beautiful summary. So, yeah, I think, as you say, I think what we can take from these data at this point really is that for most patients with CLL, fixed-duration therapy in the first-line setting can be considered equally effective within the limitations of our current observation time. And maybe a subsequent question that also comes up a lot with CLL17, of course, is given that we have two fixed duration therapies that independently showed non-inferiority to continuous therapy. Many people, of course, asked them, well, which of the fixed duration therapies should we use? And I don’t know, Alessandra, do you have any thoughts on this between VO and VI or generally V with BTK inhibition?

Alessandra Tedeschi:
I believe that venetoclax-obinotuzumab, not only in the CLL-17 study, but also in the CLL-14 and CLL-13, gave a prolonged progression for survival and a very important prolonged time to next treatment. At the same time, what I’m slightly afraid of with Obinutuzumab infusions is the slightly higher rate of infections that has been also seen in the CLL-17 study. But we should say that the CLL-17 study suffered of the COVID period. So as all the studies that were conducted in that period, we have a slight excess of infections, but still from your infectious curve, we can see that infections are still present after the 12 months of fixed duration treatment. And this is something I would consider when starting a treatment for a patient. So the infectious history, maybe it’s important. It is important, of course, as Lydia said, the 17p deletion. I wouldn’t focus too much in the mutational status in this moment. I believe that both fixed duration treatment have prolonged progression free survival and time to next treatment. Maybe if you have both factors that have prognostic impact, such as bulky disease and unmuted status, there I would think about the combination of a covalent BTK inhibitor plus venetoclax.
Othman Al-Sawaf:
Right. And are there any other, beyond infections, any other variables that you use to distinguish between V plus CD20 antibody and BTK inhibitor?

Alessandra Tedeschi:
For us, it’s very important considering the type of population we have in our hospital. I said it’s a general hospital, so it’s also a referral center, but we have a lot of elderly patients, patients that need a lot of caregivers. So in that case, we would avoid too many infusional problems and too many access in hospital. So it’s there where I still find that there is a value of continuous BTK treatment because it’s more simple for the elderly patients, patients with comorbidities logistically out from Milano that comes from the mountains outside. In this case, we still think about continuous treatment. And just to avoid infusion problems in the more elderly, if they are fit to receive a covalent BTK inhibitor plus venetoclax, we use this combination.

Othman Al-Sawaf:
Right. And any other thoughts on this, Lydia? Do you stratify your patients maybe differently or similarly?

Lydia Scarfo:
No, I totally agree with Alessandra. I either say that probably on one side, when we use the covalent BTK inhibitors, we have to take into account that there is a higher risk of cardiac adverse events. So that’s something that I also take into account when defining the best treatment choice. On the other side, when we start with the combination of the covalent BTK inhibitor and venetoclax, you have three months or two months, it depends on the covalent BTK inhibitor of lead-in. And at that time, you greatly reduce the disease burden. So when the patients start venetoclax, the risk of developing TLS or requiring IV hydration or even hospitalization is very low because the disease burden is much lower. So I believe that in terms of convenience of administration, if you combine covalent BTK inhibitors and venetoclax, the hospital access is not that frequent because you, in the end, debulk the disease before starting the BCL2 inhibitor. And so there is less need of a regular check of blood test or IV hydration or hospital access because the disease burden is much lower at the time of Venetoclax initiation.

Othman Al-Sawaf:
Yeah. And then you mentioned interestingly that in the relapse situation in Italy, you cannot reuse Venetoclax. So this has, of course, then implications for your treatment sequencing quite substantially. So meaning that, let’s say, if you give, let’s say, venetoclax ibrutinib or venetoclax obinutuzumab, what would be then the typical second-line strategy?

16:14-16:19 overlapping chatter, edit out and start from Alessandra at 16:20

Alessandra Tedeschi:

The restriction is only for venetoclax obinutuzumab. In that case, we can’t reuse venetoclax. If you use a covalent BTK plus venetoclax, we can use venetoclax rituximab. So the restriction of venetoclax after venetoclax obinutuzumab, for me, it’s very important because in that case, we jump, I would say, a strategy because we can’t reuse obinutuzumab. So in front of a patient, we have to make this choice to use at least once obinutuzumab and that is only in first line with venetoclax. Otherwise, we can’t reuse obinutuzumab or venetoclax.

Othman Al-Sawaf:
Right. So, meaning if you give venetoclax BTK inhibitor, you would be still able to use a continuous BTK inhibitor, so to speak.

Alessandra Tedeschi:
Yes, and venetoclax rituximab.

Othman Al-Sawaf:
Ah, okay.

Alessandra Tedeschi:
But not if you use venetoclax rituximab in first line.

Othman Al-Sawaf:
Oh, interesting. Okay.

Lydia Scarfo:
We’re waiting for the day of the ReVenG study

Alessandra Tedeschi:
The ReVenG sudy you are trying to do. I hope you will arrive at the end because no patients relapse after venetoclax obinutuzumab, so it’s difficult to see results from the ReVenG study, but maybe will allow us one day to retreat patients with venetoclax after first-line venetoclax-obinutuzumab.

Othman Al-Sawaf:
All right, yeah, that’s a good point. So, as you mentioned, so ReVenG, the trial tests exactly in this patient population that they’ve received first-line VEN plus CD20 antibody, a retreatment with venetoclax-obinotuzumab. I think we are at almost 50 patients now, and the study is still open until this year. So until end of this year. So hopefully you’ll have a good data set to address this in particular in terms of the response and durability of the responses. Now, since we touched the topic around the relapsed therapy and maybe in general as an outlook, given that some, as Lydia said, some of the more definitive answers around TP53 and fixed duration therapy and so on probably will need longer observation time. But what else would you say are open questions and clinical trials and results that are needed to further optimize the treatment outcomes in CLL? Maybe, Lydia, what thoughts do you have on that?

Lydia Scarfo:
I mean, that’s a very important question. I dare say that in the setting of relapsed refractory CLL, there are several unmet needs. I would say that one is represented by patients who develop resistance to covalent BTK inhibitors as continuous treatment. And I believe that we don’t have yet a strategy that is able to achieve long-term responses in this setting. And on the other side, what I believe is not any more applicable to our current patient population is that with the data we have for the venetoclax plus rituximab combination, they are derived from the MURANO study that was conducted basically in a different era, it seems ages ago, because patients enrolled into the study were all previously exposed to chemoimmunotherapy and only few of them have received targeted agents like covalent BTK inhibitors. So I believe what’s very interesting now to study, and we need to collect additional data, is how to improve our fixed duration regimen in the relapsed/refractory setting. And I believe on one side, we can, let’s say, improve the efficacy of the combination of the BCL2 inhibitor and the anti-CD20 monoclonal antibodies. And you, Othman, are currently running a study where you are combining sonrotoclax with an anti-CD20, the obinutuzumab or rituximab, in order to study if you can achieve a better response this way, especially in patients we see nowadays in our outpatient clinic. And on the other side, data were recently press released about the combination of the non-covalent BTK inhibitor Pirtobrutinib with the combination with venetoclax and rituximab. And this was a Phase three study that was conducted by administering both treatment arms for a fixed duration of time, 24 months. The standard treatment is the combination of venetoclax plus rituximab, as we know it, according to the label. And the experimental arm adds to this combination, pirtobrutinib. And the press release just stated that there was a benefit in terms of progression-free survival. That was the primary endpoint of the study. But of course, we need to see the data in more detail in order to understand how relevant is the benefit and if and how we can introduce this strategy in our everyday clinical practice once and if approved.

Othman Al-Sawaf:
Any further thoughts on that, Alessandra? Any other things you think needs to be quite optimized?

Alessandra Tedeschi:
Coming back to the baseline treatment, I believe that the biggest problem we have in this moment now is to see if MRD-guided treatment is something that is the future of CLL treatment. We know that our fixed-duration treatment, how it is now, venetoclax-obinutuzumab and covalent BTKs plus venetoclax are based on studies in which treatment was given for one year. But we have seen from other studies, the MD Anderson study, I plus V, or the study of the United Kingdom group, that there is a value of MRD-directed treatment with a better, for sure, progression-free survival compared to the I plus V of one year. So if it will be this possible in clinical practice, we will have to standardize all the methods and so on. But I believe that the studies that are going now on MRD guided will provide us on the answer if it’s better and if it will be possible. Of course, we know that there is a different kinetics of MRD between mutated and unmuted patients. There is a lot to learn from these studies, the CLL-18 study with pirto-venetoclax. I know that there is an arm of fixed duration and an MRD-oriented arm. So we have a lot of answers in this topic. And maybe with an amelioration of the first line, we won’t need a second-line treatment. Who never knew?

Othman Al-Sawaf:
Excellent. Yeah, thank you. That’s a great thought at the end of our discussion. Optimizing first-line therapy in a way that maybe we don’t need to think so much about relapsed therapy, at least for most patients with CLL. And I think we are getting step by step closer to that. The fact that, yeah, so many trials are running already now for MRD-guided optimization of the treatment duration and so on means that maybe in a few years, we will indeed be able to further refine the treatments and the outcomes of patients with CLL, especially in the first line. So yeah, I think we’ve covered a lot of ground, especially for the first-line setting. We talked about the fixed and continuous treatment concepts, the MRD guidance concept at the end, the considerations around relapsed therapy that mirror some of the challenges from the first-time context so I’d like to thank Alessandra and Lydia for your excellent thoughts and discussion points you raised and thank you all for listening and your interest in this webinar. And I look forward to further data and further discussions in in upcoming webinars, thank you.

Lydia Scarfò:

Honoraria and Advisory Boards: AbbVie, AstraZeneca, BeiGene, Lilly, Johnson&Johnson

Data Monitoring Committee: Merck

Othman Al Sawaf:

Research Funding: AbbVie, BeOne, Genmab, Johnson&Johnson, Lilly, Roche-Genentech

Honoraria: AbbVie, Adaptive, Ascentage, AstraZeneca, BeOne, Genmab, Gilead, Hikma, Johnson&Johnson, Lilly, Roche

Alessandra Tedeschi: TBA