Arnon Kater

Thank you very much for this invitation. I’m Arnon Kater from the Amsterdam University Medical Centers, and I’m very happy to also have here Paolo Ghia, the famous CLL doctor from Milan but also from Boston nowadays. We’re going to discuss the more and more difficult part of relapsed patients in CLL based on all the change we have seen in frontline disease. So let’s start maybe Paolo with the guidelines. We are slowly but surely, specifically in Europe, moving from continuous treatment in frontline to fixation treatments. How much does that affect your choice of the patients in relapse?

Paolo Ghia

Thank you, Arnon. I think that the first point that we had to make that is is true also in the relapsed/refractory setting is that there is no more space for immunochemotherapy if there is access to novel therapies. And that was already true in the previous version of the guidelines and it is definitely now very clear in the current guidelines. And in fact, the only option that we find is, as you mentioned, either continuous therapies or fixed duration treatment. In the relapsed/refractory setting, it is, of course, a little bit easier to decide what treatment to do because the patient already received a prior treatment. And therefore, your options are decreasing. And very likely, if the patient received a continuous treatment and the patient became resistant, then the obvious option remains the fixed duration treatment with the typical combination with venetoclax plus rituximab, because the continuous treatment is typically based on a BTK inhibitor. If the opposite happens, so if patient relapses after a fixed duration treatment in frontline, then there we have many more options that we may discuss in details later on, because indeed one could really retreat the patient with fixed duration treatment, though it really depends on the local regulation and the possibility of access of the retreatment with the fixed duration combination, or you have always, of course, the option of moving towards continuous treatment with the BTK inhibitor, for example.

Arnon Kater

And now I’m good to mention this, Because in most countries, I think you have the two regimens probably most effective for first-line patients, if you want to go for fixed duration, is ven plus ibrutinib, maybe soon acalabrutinib, and venetoclax plus obinutuzumab. And then in second line, if you want to go again for a finite treatment, the only option you have is venetoclax rituximab. Because of that landscape, is that for you a reason to choose maybe one or the other in the first line so you have more chance for longer remissions in second line? Do you think it’s it’s independent of your first line choice?

Paolo Ghia

That’s very true. It is also true that you can use the finite treatment with venetoclax rituximab in the second line regardless what you started with and so that is probably not really changing so much my attitude towards either one or the other. so I would decide to treat based on the, as explained by Dr Eichhorst, Shuh, and Scarfo in another filming in frontline you choose based on many other features that typically don’t consider so much what is going to happen in the second line because indeed either even if you start with I plus V or with venetoclax plus obinutuzumab then you can always decide to use venetoclax plus rituximab or you can instead decide to go for continuous treatment and that probably depends on how the patient responded in front line, how well tolerated venetoclax and the antibodies and so on and so forth. So you will learn much more during the first treatment so that you can probably adapt your choice in the second line.

Arnon Kater

Yeah and added to that, you, me, and ERIC had very much always emphasized that every line of treatment it deserves to do p53 del17p maybe also complex karyotype it’s still debating but with all the new targeted agents, how differently would you decide if a patient has a TP53 at relapse than if he doesn’t have it? How does that impact your decision?

Paolo Ghia

That is very true. Of course, again, the patients with p53 aberration that tend to increase in terms of frequency in the relapsed/refractory setting, at least after the immunochemotherapy, are definitely the patient on which we typically pay and put more attention. In general we all believe starting from the front line that continuous treatment is probably the best option or the one where we feel safer in terms of having control and keeping control maintaining control for a long time. It is also true that under continuous treatment with a patient with p53 when the patient’s relapse it is really becoming refractory to that treatment so you cannot re-utilize it anymore, typically BTK inhibitors. So you are either way then obliged to use a venetoclax based treatment and definitely a finite treatment with venetoclax plus rituximab. You can also use continuous venetoclax but still there is no really proof that there is an advantage compared to the fixed duration. And we also know that patients, based on the MURANO study, though that population was mainly pre-treated with, the vast majority were pre-treated with immunochemotherapy, we know in that particular population that at the relapse, when patients are treated with venetoclax rituximab, the patients who are relaxing earlier with a shorter progression-free survival are indeed those with aberrations in the p53 gene.

Arnon Kater

Yeah, very true. And do you think besides p53 maybe as relevant or more relevant could be that we put in guidelines that you also have to check for BTK mutations if you have continuous treatment, but maybe also after final treatment of BTK inhibitors, we say the evidence is too low, it’s still research, BTK mutations.

Paolo Ghia

No, in fact, thank you for the question. There will be soon a a new recommendation published by ERIC for the first time on the use of mutations in the context of targeted therapies. So not only BTK mutation, PLC gamma 2 mutation that can occur after treatment with BTK inhibitors, but also the BCL2 mutation that can occur after treatment with venetoclax. Definitely we do recommend not to perform the analysis because it’s not really adding much to the management of our patients because even if there is a mutation and there is still a clinical response we should continue the therapy and we definitely should not switch to another treatment, there is no proof, there is no data that that could be of any value for the patient. Also we have to keep in mind that a proportion of patients will relapse without developing mutations in BTK, PLC gamma 2 or BCL2. So the role of these mutations remain very still very elusive and in particular it doesn’t have any strong clinical implication at the moment

Arnon Kater

Yeah, so keep it more for research. You know, but we have to do it in trials.

Paolo Ghia

Definitely, we have to learn and also learn how this may be different depending on the inhibitor, how we can potentially in the future sequence the different inhibitor, but that really remains research.

Arnon Kater

There was also in the guidelines this distinction between if you relapse at a short remission duration or long remission duration, but that’s maybe also more chemoimmunotherapy related but you also said maybe fixed duration. What is the cutoff? It says 24 months, it had been 36 months, it had been longer even for some therapies.

Paolo Ghia

This is a $1 million question, meaning that indeed it could be 24 months, 36 months, there is really no strong data, if not in the setting of immunochemotherapy, showing what is the right time to consider someone refractory to the disease, even if the patient initially responded but then progressed. If it progresses in a shorter time, we still consider that as a refractory patient to the previous treatment. And that is something that we have still to understand in the era of limited treatment, or finite treatment, because again it is definitely true that it’s better to relapse later than earlier, of course, even after venetoclax plus obinutuzumab or ibrutinib plus venetoclax. But the 36 months is anyhow quite some time, meaning it would mean one year of treatment, for example, with venetoclax plus obinutuzumab, followed by two years before the relapse. And plus, we have also to consider that in CLL, you have also the time to next treatment. So we have another period, extra month, where the patient will not need yet treatment, though progressing. And knowing that all these drugs and all these combinations are very well tolerated, definitely much better than the chemoimmunotherapy, I always think that it doesn’t cost much to try again because maybe you gain another few months. You might say this is a failure but in the overall patient journey that’s still a success because we are postponing the passage the shift to another really different class of drugs. So we really exploit and optimize at maximum the use of that particular drug. So this is the general, it’s not written in the guideline, but it’s my personal interpretation. But the general feeling is really that it’s difficult to evaluate when it is too early, when it is too late. And probably it’s worth it to try and see.

Arnon Kater

Although you also have got data from Jennifer Woyach, for instance, that if you switch the drug that may be the clone that appeared also can disappear again. But it’s all good reasons.

Paolo Ghia

Again that is research. It’s a very attractive possibility but we don’t really know and I think in that case we would really be betting on each single patient which we probably don’t want because at the end are we then wasting somehow another line of treatment too early, so that’s also the concern of a patient. Because definitely a patient who relapses after the first treatment with the novel therapy is anyhow a more difficult patient to be treated in the future. That we know for a pre-existing condition or because of the effect of the therapy but it’s definitely much more difficult so we have really to be very careful in optimizing the use of any drugs that is left over.

Arnon Kater

Thank you for the bridge because that brings me not so much time anymore. We mostly discuss now first relapse but in my clinic and I’m very sure you see that too, you see more and more patients with at least double exposed and also actually more double refractory disease. For example, double refractory we define as both BTK exposed and refractory and venetoclax refractory, although as Paolo said it’s very difficult to have a good definition for that. But with those patients what is now your current treatment outside clinical trials what are you doing?

Paolo Ghia

Here in the current guidelines we were already somehow looking into the future because we added the non-covalent BTKi as a possibility of treatment, an option for patient progressing on a previous covalent BTKi. And actually there we made a small mistake because we didn’t list the non-covalent BTKi in patients who were relapsed/refractory who carry p53 mutation or the del17p. So it looks like we don’t advise to use the non-covalent BTKi, which is absolutely wrong because we know that the non-covalent BTKi, in particular pirtobrutinib, which is the first one that has been very recently approved also in the European community. It has already been approved in the US since a few months. So pirtobrutinib a non-covalent BTKi it works after failing or becoming refractory to covalent BTKi. So we know from the original study both the Phase I and the Phase III that it works also very effectively in the setting that you mentioned. So in patients with double refractory disease, so failing both the covalent BTKi, and venetoclax. And therefore, that is definitely the option for the patient who now will come to our hospital with the double refractory disease. But the approval, for example, in Europe, has been after the failure, only the failure of a covalent BTKi. So that is something that we will learn by doing, very likely, because, of course, we will be using now, very likely, pirtobrutinib earlier than what we were used in the past, based also on the Phase I study. So we were using it in a single refractory patient. So it would be interesting also to see how and for how long treatment with the venetoclax after two BTKis, which type of efficacy it will have.

Arnon Kater

And after that, or maybe if the patient is responding to pirtobrutinib, what would be the moment, if at all, you would consider patients when you are in the US for CAR-T, in Europe maybe for an allotransplant, if he or she is eligible of course. Would we do that during pirtobrutinib plateau or after, how do you see this?

Paolo Ghia

That is tough. So that is probably one of the reasons that one should keep in mind, thinking about the sequencing of the drug. So that is probably the setting, if I have a young patient, in particular maybe someone with p53 aberration, in a patient who were probably, I would exhaust the BTKi option first, so covalent and non-covalent. Because there we never or very rarely can reach a deep response, as we want to go to for allotransplant. And then we leave venetoclax as the last option, because with venetoclax, still in a proportion of patients, we will get very deep responses, so the best setting to do the allotransplant. So using venetoclax too early would mean also to anticipate earlier the allotransplant which remains in my mind always somehow not the last resort but definitely more advanced resort because we are talking anyhow about the young patient where we can definitely control disease for a few years and we don’t want to expose them to the risk of treatment-related deaths, as it can happen unfortunately with allotransplant.

Arnon Kater

Do you give CAR T-cells and to what patients then do you reserve them for?

Paolo Ghia

Even in the US, the use of CAR-T remains still a very limited option, meaning that in CLL, there are so many different drugs approved, and pirtobrutinib was already approved earlier in the US, that somehow CAR-T replaces somehow the space where in Europe we would do allotransplant. And due to the cost, and therefore also problem of access, depending on the insurance, so very often, probably the option of a clinical trial remains probably the most viable option for the specific patient.

Arnon Kater

Yeah. Very good. So I think we’ve covered most of the challenges that we have now, but also all the opportunities for relapsed/refractory patients. Do you have anything else that we didn’t cover Paolo?

Paolo Ghia

I think that we have to be optimistic because again talking now about allotransplant or CAR-T, I think that we have another generation of drugs that are coming to CLL in the relapsed/refractory setting in particular in the double refractory now probably in the triple refractory setting. I’m talking about the BTK degrader or the bispecifics, that as you well know they they showed really a high level of efficacy with again oral therapy like in the case of BTK degrader or anyhow just a small infusion or even subcutaneous for the bispecific, so much easier also in terms of management and logistics for the patient.

Arnon Kater

Yeah, completely agree. And how many years do you think before we don’t need to discuss relapsed/refractory anymore because we can cure them in the first line?

Paolo Ghia

Well, you have to ask our British friends. I don’t really know. I think that for many years we will still treat and retreat the patient. Most of our patients, in some probably we will reach a level at least of a functional cure, so they will have only one treatment in their life. But most patients we will probably keep on doing this treatment and retreatment. In particular, probably we will optimize even the length of the treatment in frontline which is not only to extend it searching for cure but to reduce it in order to maintain the response also for later lines.

Arnon Kater

I agree to really make CLL like a chronic disease or more chronic condition with some diseases that you have to treat and then long-term a good outcome. Yeah thank you very much.

Paolo Ghia

Thank you.

Paolo Ghia: Galapagos: Consultancy; Johnson&Johnson: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGen: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbvVie: Consultancy, Research Funding; Loxo@Lilly: Consultancy; MSD: Consultancy; Galapagos: Consultancy; Roche: Consultancy.

Arnon Kater: Roche/Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Steering Committee, Research Funding; LAVA: Membership on an entity’s Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee; BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee, Research Funding.