So, hi, this is Lydia Scarfo from San Rafaelle Hospital and University Vita salute San Rafaelle, Milano, Italy. Today with me is Othman Al-Sawaf from University of Cologne, Germany. And we’re very excited to be here at the EHA Congress in Frankfurt and want to discuss novel BTK innovators in the treatment of chronic lymphocytic leukemia. So Othman, let’s start by discussing about the current unmet clinical need in chronic lymphocytic leukemia.

Yeah. Thank you Lydia. I think there are still a lot of medical needs in CLL for sure, even though we had tremendous progress over the recent years, especially in terms of frontline management of CLL and also maybe the 2nd and 3rd relapse, we can manage not easily, but it is relatively straightforward. Nowadays, with in terms of our clinical routine, I think definitely one of the key challenges is certainly the double refractory setting, meaning patient’s who have relapsed and are really refractory to BTK inhibitors or covalent BTK inhibitors and BCL-2 inhibitors. So these are still small groups of patients. But I think they are nevertheless very relevant because the number is increasing over time since patients are now starting to relapse after prior successful therapies. So I think this is one of the key challenges where we need more research and more development of novel therapies. And then maybe also open questions as to how to manage patients best after they had limited exposure to therapies. I think this is another open question.

I totally agree with you. And I think that actually as you correctly pointed out double refractory patients are nowadays relevant unmet clinical need, especially because for these category of patients, we have very few standard, let’s call them standard treatment options. So based on our recent experience, I was very excited to see the results of the non-covalent BTK inhibitor that were recently presented. Don’t know if you have the chance to use in your patient population pirtobrutinib or other non-covalent BTK inhibitors. And if you want to share with us your impression on them. So at our center, we haven’t had any considerable experience with pirtobrutinib. As of yet, we just started participating in pirtobrutinib studies and we are also preparing a large Phase III study with other collaborators across Europe, including the Italian CLL group to test pirtobrutinib in the frontline setting as well in a certain way. But beyond that, I haven’t had any hands on experience with pirto. And I think nevertheless, the data that we are seeing now largely based on the Phase I BRUIN study, which is a very large Phase I study. But nevertheless, at the moment, more or less our exclusive data set for pirtobrutinib. And it has been quite encouraging in terms of especially the efficacy data that they have reported bearing in mind that they have one of the largest cohorts of double refractory patients in their studies. So that’s why I think it is very encouraging to see that they see efficacy and the progression free survival of more than 1-1.5 years in these double refractory patients. So, in your clinical practice, are you testing for BTK mutations? Because as we are all aware, a variable proportion of patient, but let’s say 60-80% of patient’s progressing on covalent BTK inhibitors are carrying BTK mutations in the CLL clone. So are you testing for it or do you think that in the next future we will use this test to guide treatment choice?

Yeah, I think certainly it is an interesting phenomenon that we see treatment specific mutations that patients acquire only when they have been exposed to certain agents. Nevertheless, I think the clinical implications at the moment are fairly limited. So therefore, it’s not really a part of our routine. We have a NGS panel that covers also BTK mutations and that we sometimes apply but not so much for clinical decision making. But more in terms of understanding how the disease has evolved. So it’s not part of our routine. And we don’t recommend also from our end when we get referrals to do this kind of test, because ultimately, if a patient has relapsed on continuous BTK inhibitor, then the clinical decision making is done irrespective of whether the patient has a mutation or not. Because if a patient, let’s say was on ibrutinib or acalabrutinib for four or five years, and then started developing increasing lymphocytosis, new lymph nodes and has clinical signs of progression. Whether or not the patient has a detectable mutation doesn’t change the fact that we can’t continue to treat with a covalent BTK inhibitor in that case, because the patient is refractory and therefore it is an interesting tool to consider the evolution. But at the moment in my view, it doesn’t have immediate clinical implications. I don’t know what the operating,

I totally agree with test only for research purposes actually in our clinical practice. But what I found reassuring from the novel non covalent BTK inhibitors is that they seem to work in both BTK mutated and unmutated patients. So this is something we can use even to identify the presence of the mutations in our patient population. So that that’s definitely something that is pointing out about the mechanism of resistance I would suggest especially because also with this novel non covalent BTK inhibitors and the updated results will be presented at this meeting BTK mutations have been identified inpatient progressing or non covalent BTK inhibitors. So probably BTK is still key in the disease resistance and biology and it still remains probably a suitable target for treatment once patients develop mutations.

Definitely, I think we see this even before the non-covalent inhibitors were introduced, that CLL cells, even when they have mutations remain addicted to BCR signaling, whether or not they have BTK mutation or not or whether whether or not they have been really have become refractory to BTK inhibition. I think what’s interesting. And as you mentioned, there are interesting data that are being presented also at this meeting that really show that the pattern of mutations is different after non covalent BTK inhibitor. So across all the covalent BTK inhibitors that we have with ibrutinib, acalabrutinib, zanubrutinib. But if we have a quite a robust data set nowadays, from various studies demonstrating the mutational pattern that we see. And the majority of these mutations are gatekeeper mutations that occur on or around the BTK inhibitor binding sites. And with the non covalent BTK inhibitors, there’s a new pattern and phenomenon that we see where we observed that patient’s or CLL cells acquire kinase (inaudible) mutations that ultimately would allow for covalent BTK inhibitors to still bind to BTK. But the kinase itself is more or less inactive and rather scaffolding proteins that are recruited around BTK become much more relevant in terms of maintaining the signaling, the downstream signaling. So I think therefore, these observations are very interesting because they also have implications towards sequencing of the treatment. I don’t know… What are your thoughts on the order of covalent, non-covalent inhibitors in future pathways?

That’s a great question actually because… nowadays, we have only data with non covalent BTK inhibitors after covalent BTK inhibitors. And we know that they work to the response duration, especially in, let’s say, heavily pretreated patients is not endless. I say because it’s one year and a half, almost two years, I’m still trying to understand what is the best sequencing. But I think one other key point is about tolerability of these novel agents because BTK inhibition is a key target. And I think it has demonstrated to be very effective in CLL but especially with the initial compounds, there were some tolerability issues with the novel generation. We we are improving on tolerability. I say, would you agree on that?

Definitely, I think especially based on the head to head data that we have for acala and zanubrutinib, if we seem to have at least for certain toxicities, relative risk reduction, that is quite significant in these studies. So things especially like atrial fibrillation and cardiac arrhythmia, something that is quite common with Ibrutinib and has been come quite common over the years. It’s something that is relatively less common with acala and zanubrutinib. So I think in that sense, the next generation inhibitors have a toxicity advantage. It will be interesting to see how the non covalent inhibitors whether they can replicate this. There is an ongoing head to head study again for pirtobrutinib against ibrutinib which will I assume show a somewhat similar pattern. But again, it comes down also a little bit to how much this translates to other toxicities that we see. So we’ve seen for instance, a distinct pattern between zanubrutinib even acalabrutinib when it comes to the incidence of bleeding events or hypertension, where we see less with acalabrutinib compared to ibrutinib. Whereas on zanubrutinib seems to have fairly similar incidences of hypertension and bleeding. So even within the next generation, because I think there’s a distinct profile for each of those compounds, it will be interesting to see how close a pirtobrutinib will be in this regard, the BRUIN data again, Phase I but large cohort is quite encouraging and that they have an extremely low incidence of atrial fibrillations, even though they have over 700 patients. On the other hand, they have a slightly younger patient population than what we have seen in ELEVATE TN. And for instance, in the Sequoia study for Zanu. So again, the key goal of the benchmark has to be really a proper prospective randomized study. It would be really certain about the incidence rates. Until then I think the next generation inhibitors are certainly at the moment, the treatment of choice when it comes to choosing between BTK inhibitors. And then the distinction between the different agents in the next generation is something that we’ll need to substantiate. I think in the next coming years.

Now, I’m curious, you mentioned we do not know how to treat patients who relapse after fixed duration regimens. Would you elaborate on that? How are you managing patients relapsing after let’s say venetoclax plus obinutuzumab in firstline. What are the key factors you are taking into account in order to decide the treatment choice? I think the obvious thing to do after a relapse is to switch to a different class of agents. So a patient has received venetoclax before let’s switch to BTK inhibitors if the patient is BTK inhibitor naive. So this is something of course stands to reason and it’s one certainly viable option to do. But I think the key that we have here or the the key opportunity that we have now that we have the ability to use limited duration treatment is to re-treat patient’s because we have we have seen in the relapse setting and also in the front line setting. Be it with venetoclax, obinutuzumab, but also with venetoclax plus ibrutinib that when patient’s relapse after a fixed duration, they are not refractory. So they, none of them have detectable BTK mutations or BCL2 mutations. So, biologically, at least it would make sense that they would still respond to re-exposure.

And so I think therefore, this is a new opportunity that we have to retreat the patient’s again with the same combination that we used before and also to give it in a limited duration way. And this is something that I think is now important to explore and especially to capture these precious patients that when they relapse after these long term effective regiments, that we try to put them into prospective randomized, into prospective studies. So this is what we are at the moment, what we’re doing. So we try to put patients who will relapse for instance, after VenO, to into our (inaudible) study where patient’s are then retreated again with the same regimen for one year. And to see ultimately, what’s the efficacy and feasibility of a fixed duration re treatment for for these patients?

totally agree. I think this is a great question we need to explore in the next future because I mean, of course, we would all go for fixed duration treatment because it’s better tolerated. But it seems that some disease features are actually associated with short lasting responses with fixed duration treatment. So I think we need to identify patient’s who would need an intensified treatment and those in whom we can deescalate treatment even shorten the duration of treatment as we define nowadays because they have a very responsive disease and don’t need to be exposed to prolonged treatment schemes. So I just say these are all relevant questions for the next future. Thank you so much for sharing your thoughts on this. Happy to enjoy the meeting.