Barbara Eichhorst:

So welcome everyone. My name is Barbara Eichhorst, I’m a consultant at the University Hospital in Cologne in Germany and I’m also chairing the German CLL study group. And for this event by VJHemOnc, discussion on ESMO CLL guidelines. I’m here with my very nice and esteemed colleagues, Lydia Scarfo from San Raffaele in Milan, and CLL expert, as well as Professor Anna Schuh from the Oxford University in the UK. Thank you Lydia, thank you Anna for joining me here today. As you know, we had an update of the ESMO guidelines and certainly we will soon get a new update with what is all happening right now in CLL. But for the audience I would like to discuss with you today the frontline treatment recommendations according to the guidelines. And before we talk about treatment, I think we should wrap up first a little bit about diagnosis. So maybe Lydia, can you start and what about the diagnostic criteria for CLL and also maybe covering already what some patients are asking for evaluating their risk factors while they’re still on early stage CLL?

Lydia Scarfò:

Thank you so much Barbara, for the nice introduction and thank you for having me today. CLL as you are all aware of it, is the most frequent leukemia in the western world in the adults. And generally it’s diagnosed in asymptomatic patients. They perform blood tests for several different reasons. The general practitioner or other colleagues identify the presence of lymphocytosis and this requires of course further assessment. The good news is that CLL can be diagnosed based on the blood test, meaning that if the lymphocytes show a typical distinctive immunophenotype, we can already achieve the CLL diagnosis without any need of additional assessment like lymph node biopsy or bone marrow biopsy.

And it’s characterized generally by the presence of the expression of CD5, CD23, CD20 at low levels. And in the recent year other markers have been added including CD200. So generally, what I do in my practice, when I see for consultation a patient with lymphocytosis, I prescribe this flow cytometry assessment in order to confirm the CLL diagnosis. We have to take into account that in the diagnosis the number of circulating cells is also relevant, because we have a so-called preneoplastic condition, monoclonal B-cell lymphocytosis where the number of CLL cells is below 5,000 per microliter. What I generally do besides the physical exam, of course I’m checking for the complete blood cell count because we need to know if the patient is experiencing anemia or low platelet value. But generally at diagnosis these features are not present.

These are actually the only required assessment according to the staging system and the guidelines, so these are absolutely mandatory. Then probably the practice is different from US to Europe. I generally ask also for an abdominal ultrasound in order to check for the spleen sites and the presence of deep lymphadenopathies and as general testing, we are also checking for renal function and liver function. In terms of disease characterization, actually the biomarker profile is not required at diagnosis, and the guidelines suggest that we perform the biomarker profile characterization at the time of progression because at that time the information we obtain from the biomarker assessment are used to define the best treatment choice. Some prognostic scores are used, and so in some practices probably they are assessing immunoglobulin gene mutation status and TP53 aberrations at the time of diagnosis. But this is not required according to the guidelines and it is generally used only for prognostic purposes so that is something do not favor in my current practice.

Barbara Eichhorst:

Thank you very much Lydia. Anna, how do you perceive with prognostic factors and what do you recommend patients who may have been detected with a TP53 mutation but still being in early stage? And what are your considerations then for starting treatment in CLL?

Anna Schuh:

Yeah, thank you Barbara. Basically, largely we follow the same procedures as Lydia has just outlined. I should say though that in the UK, especially bigger centers will proceed with the immunoglobulin status analysis and get a diagnosis to establish the risk of progression. Because many people with these early stages of CLL actually if they are hyper mutated at the immunoglobulin locus because they’re not necessarily seen face-to-face in a specialist practice, but they’re being referred back into a telephone referral system of which they are increasingly, the bigger hospitals increasingly have those telephone services including also in Oxford.
So certainly the people with hyper mutated immunoglobulin locus with a mild lymphocytosis after diagnosis and no peripheral lymphadenopathy, they would be seen in these or not seen, followed up in those telephone clinics. So the TP53 analysis, however we really only do when patients are heading for treatment. If by chance we detect these mutations beforehand for whatever reason before the patients need treatment, the general consensus is that actually patients when they’re not exposed to cytotoxic agents, they don’t have a poorer prognosis, they don’t particularly progress faster than patients with TP53 mutations. So we basically, therefore only go on and look for these other prognostic markers when it actually comes to treatment. Because there’s predictive value.

Barbara Eichhorst:

Yeah. Thank you very much. And also that, so there have already been a couple of trials evaluating if early treatment may help in patients with higher risk factors. We have to say that even with early use of ibrutinib, a recent trial has not shown that there is a benefit that with respect to patients overall survival. Therefore, the [inaudible 00:07:47] wait in case patients have for whatever reasons been undergoing TP53 testing. I think in my experience it needs or it requires particularly a lot of communication with the patient that it’s really no reason to panic and to go ahead with the treatment early on.

Anna Schuh:
Yeah, that’s correct. So in routine clinical practice we definitely go with the iwCLL criteria for treatment initiation. And largely that means that patients have to have some form of symptoms or signs, progressive lymphadenopathy signs of bone marrow failure or very significant B symptoms.

Barbara Eichhorst:

Yeah. Thank you very much both for summarizing this topic. So when we move now to the ESMO guidelines with respect to frontline treatment, the guidelines differentiated different groups. First of all, patients should be looked at, what you both mentioned already, according to the IGHV stages, if they have a mutated good prognostic CLL unmutated more rapidly progressing or if they even have a TP53 mutation or deletion 17p. And then at least for the patients with mutated and unmutated IGHV stages, the guidelines differentiate between fit and unfit. Maybe before we speak about the specific recommendations, what do you think about still differentiating between fit and unfit patients or how would you define that in your clinical practice? Maybe Lydia, you want to start?

Lydia Scarfò:

In your defense because you were writing the guideline, I understood that this choice was also related with the eligibility criteria of the clinical trials because in the past years we had different trials based on the age and the fitness status of the patient. Then while at the time of chemotherapy, the cumulative index rating scale and the Charlson Index were adopted in order to differentiate the patient characteristic, also because the intensity of the chemotherapy was different according to the age and the comorbidity profile.

I think this is changing in the current therapeutic scenario. And more than age, what I generally assess and take into account when defining treatment choice is the comorbidity profile and in particular, the cardiovascular comorbidities, the renal function of course and the profile of the concomitant medication. Because this is something we should include in our assessment in order to identify the best suitable treatment. And also from a management perspective, we have to take into account the possibility of a care partner for a patient who can help because for some type of treatments the patient should come frequently to the clinic to have the lab test assessed or to receive infusion. So I do not think we have already available a comprehensive score that defines fitness nowadays, but there are different factors we are considering and that are relevant in defining the treatment choice.

Anna Schuh:

Yeah. I think I agree with that. I think what I would add to this also is that over the last decade or so, the preference of patients with respect to certain treatments, I think has sort of become more important. Whereas before, we had less choice and we had to look much harder and differentiate much harder with respect to toxicities and certain toxicities. Now we are in the fortunate situation that patients have a lot of choice and we can also give patients their choice for as long as we discuss the treatment options with them and the pros and the cons. So as you have already pointed out, some people might not want to come for infusion therapy and spend a lot of time in hospital, other patients don’t want to be on continuous therapy and be reminded that they have a disease every day when they’re taking the tablet. So I think these are very important points as well to realize and to discuss with patients.

Barbara Eichhorst:

Yeah, I agree. Actually, also our national guidelines, they do not consider any more fitness as a relevant factor for the choice of treatment, rather what you mentioned already, the type of comorbidities patients are currently having considering that. Well, the reason to be honest, why we still had for the ESMO guidelines age or fitness as cutoff is that in some countries in Europe, FCR treatment is still being used, and as we all had the experience, this treatment is not very well tolerated in elderly patients or patients with comorbidity, which is inducing even significant mortality. And therefore maybe Anna, you want to start with the every favor risk group of patients with a mutated IGHV status and the recommendations here for the fit unfit or what do you think we shouldn’t differentiate here anymore between fit and unfit younger and elderly patients?

Anna Schuh:

Yeah, no, I mean I wouldn’t differentiate. Obviously we are in the UK where, like I already said, in a fortunate position that we don’t have to give fixed duration the chemotherapy to anybody anymore. I think the arguments in favor of FCR were this very small group of hyper mutated patients where you can see that their overall survival and progression-free survival was excellent. I mean basically two thirds of them have achieving functional cure with immunotherapy. But of course, that’s a very small proportion of people because you have to be hyper mutated and then on top of that you also have to be fit enough to tolerate FCR treatment. So now we’ve moved on from there and I think a fixed duration of venetoclax-obinutuzumab in that population is also a very good choice. That’s probably what we would advise if it’s not a fixed duration, venetoclax-ibrutinib of course.

Lydia Scarfò:

I agree. I totally agree. If I may, I think that the subgroup of patients with mutated immunoglobulin genes has a very biologically favorable disease. So it’s very difficult to do a mistake in this patient population unless you use chemoimmunotherapy. Because except for FCR that Anna mentioned was restricted to a very small proportion of patients with CLL, the other chemotherapy combination were doing much worse compared to novel targeted agents in terms of long-term disease control.

So here I see the category where concomitant medications, comorbidities play the most relevant role, meaning that as Anna mentioned, in the elderly population, you would like to avoid probably the cardiovascular adverse event profile of the combination of ibrutinib plus venetoclax and you start by considering the combination of venetoclax plus obinutuzumab, that was indeed designed for elderly patients in the beginning. Now they have also data in the young fit population, but first trial was exploring the use of this combination in the elderly and fit patients. But for example, if the patient has logistic issue and doesn’t want to come to the site and is fine with continuous treatment, I think we can also decide to use a continuous treatment if the preference taking into account pros and cons is in favor of this treatment scheme.

Barbara Eichhorst:

Yeah, thank you very much. But as you both pointed out, due to the very fair prognosis, time limited treatment would be here, the preference, since we assume that patients have a medium progression-free survival probably beyond seven or eight years in the medium when they hit this very favorable prognostic subtype, particularly with the younger patients. And therefore the guidelines say you can use the continuous treatment with the BTKI inhibitors, but certainly with respect to disease control and also time of treatment, the time limited options would be preferred because if we have the guidelines decided that when we think the different treatment options may be equal, time limited treatment in order to have patients off treatment, also in order to save money with respect to treatment costs in comparison to continuous treatment was then the preferred treatment option in patients.

Maybe just a comment because so far we suspect to the double oral combinations, ibrutinib-venetoclax is so far the only approved combination we know today. We have also data for acalabrutinib-venetoclax, which is not yet approved. And therefore maybe Anna you want to comment on in which case you wouldn’t use ibrutinib-venetoclax when you will prefer time limited treatment.

Anna Schuh:

Yeah, I mean as you know, the duration of venetoclax and ibrutinib treatment in the UK ideally would be MRD directed. Now that is not approved. So for the time being it’s a 15 months regimen. So it’s quite a short exposure of ibrutinib. However, we’ve also shown in the flair study that there is an excess of sudden cardiac death and other cardiovascular complications with ibrutinib in the continuous arms at least. And so there is that worry of especially giving this combination to older people with cardiovascular comorbidities. And so therefore, switching to, not switching, but basically starting venetoclax-acalabrutinib provided it’s approved, is an attractive thought.

Barbara Eichhorst:

Thank you. Lydia?

Lydia Scarfò:

Yes, I totally agree with what Anna said. As you mentioned the guidelines, I really like that they are favoring time limited treatment, not only for correct management of resources, but also because from a biological standpoint patients progressing on continuous treatment are generally experiencing a more aggressive disease. And by definition, if the patient is progressing on a treatment, you cannot use similar agents or the same agent to rescue at the time of progression. So the greatest advantage I see with time limited treatment is that we can reduce of course, the adverse event burden by limiting the treatment duration. But also, potentially setting regulatory constraints apart, we can reuse the same regimen or similar combination in order to achieve again, disease control.

I agree with what Anna said in terms of cardiovascular toxicity, probably in elderly comorbid population, especially those with an impaired performance status, those very relevant cardiovascular diseases like some patients enrolled into the GLOW study. I would avoid the potential toxicity of ibrutinib, but we still have to understand if the acalabrutinib plus venetoclax is a feasible combination in this patient population because the amplify enrolled actually fit young and older patients. But I’d say it’s available, it’s something we can consider based also on the disease biology.

Barbara Eichhorst:

Yeah, thank you very much. So when we think about time limited treatment, they’re still recommended in unmutated IGHV stages. So we have learned already from chemoimmunotherapies though they’re also effective in this group, but we see the relapses coming much earlier even when patients have undetectable MRD. So Lydia for a young and fit patient discussing with him when his CLL has an unmutated IGHV stages, how would you then discuss the time limited treatment with respect to maybe earlier relapse than in patients with good prognostic profile of the CLL versus continuous treatment?

Lydia Scarfò:

Of course, as you mentioned, this is a very important discussion. I would also take into account that progression in clinical trials does not necessarily mean need for additional treatment, meaning that generally what we see in several recent trials is that upon progression patients do not require treatment for additional time. So this is also relevant in the clinical practice. Then I am quite reassured, so it’s a small patient population from the results of the CAPTIVATE study where they had a re-treatment cohort. So patients who progressed earlier after stopping treatment because the follow-up was still short were re-treated with ibrutinib or the combination of ibrutinib plus venetoclax if they relapsed later on more than 24 months and the majority of patients achieved again, disease control.

So we are generally thinking in terms of progression-free survival for first line treatment, but then probably we should start thinking about progression survival before losing efficacy of a specific class of drug. So it’s something that combines actually PFS-1 and PFS-2 because if then you re-treat the patient with the same regimen and achieve again disease control, this is still relevant and you have allowed a treatment free period in between.

Barbara Eichhorst:

Yeah, thank you Anna. In the FLAIR trial, as you mentioned already, you used ibrutinib-venetoclax MRD-driven with a median duration of treatment of 27 months. So extended treatment, but the results are really impressive and in fact these results were also leading to the update of the ESMO guidelines because, so as you mentioned, so it’s not approved yet in clinical routine, but they’re so impressive that therefore ibrutinib-venetoclax would be here the first choice in particular for the group of patients with unmutated IGHV status. Maybe can you comment from your experience from the clinical trial, and is there an option you can use the extended treatment on an MRD basis? What are your thoughts on that?

Anna Schuh:

Yes, I mean basically it’s the median time on treatment like the 27 months, but then it’s also important to look at what actually the spread was, right? So some people go into undetectable MRD very fast and other people it takes them much longer. And when you’re taking those kind of outliers, the best responders and the poor responders, that’s actually I think about 30%, 40% of people overall. And it helps you to understand how important personalization is and how MRD can help you with personalization of the duration of treatment. If you want to achieve optimal results, yes, you can achieve very good results going a fixed time point, but you can achieve much better results, even better if you are personalizing.

That’s really where I think why I think MRD directed treatment duration would be, especially for the unmutated patients, would be a good thing. Of course, we also know that they have become MRD detectable more quickly because of the kinetics of the disease, and so their treatment-free survival after treatment will be shorter, but I think it’s still a good thing that we are allowing them to be off treatment for some time before then restarting treatment and hopefully at some point in a molecular relapse. Of course, at the moment we are looking at static study, looking not at molecular treatment, re-treatment not driven by molecular relapse, but by an increase in lymphocytosis.

So it’s a slightly different scenario. But I do think that it’s a very good treatment approach for those patients. I do think also that there are subsets in particular the patients with TP53 mutated disease or other very high risk CLL will probably actually benefit from continuous therapy rather than these treatment interruptions. So I think in future, research has to focus on identifying those molecular signatures that pinpoint in this unmutated group of patients pinpoint to the ones who will benefit from continuous therapy versus exploration therapy.

Lydia Scarfò:

If I may, I totally agree with what Anna just mentioned, and on the other side, I think that the relevance of MRD, I’m totally in favor of MRD driven approach in treatment duration and intensification might be different according to the type of treatment and the biomarker profile, meaning that for patients with mutated immunoglobulin genes, it might be that we do not need to reach undetectable MRD because they have a milder disease with a lower replicative rate, so it takes a long time anyhow to experience the progression of the disease while with patients who are unmutated immunoglobulin genes, I think the achievement of MRD is adding a lot to long-term disease control.

Anna Schuh:

Yeah, I think I totally agree with you Lydia. The problem with MRD is that it’s not an independent readout, it depends on the type of treatment, whether it’s monoclonal antibodies, there’s a compartment effect, there’s so many different variables and that’s really the downside. So we do need those types of studies like the FLARE study where we are assessing the role of MRD with each treatment. It’s not something that you can generalize, unfortunately.

Lydia Scarfò:

I agree. And we also need, I mean probably to standardize the assessment, if it’s becoming something we base our clinical decision on in order to be sure that the results we get from the lab are performed and are reliable.

Anna Schuh:

Yeah, totally agree.

Barbara Eichhorst:

Yeah, thank you both. So maybe adding a little bit on the, when we look at the order of recommendations in the guidelines, there is not only the preference of time limited over continuous in general for the already said reasons, there’s also a little bit of a differentiation between the different covalent BTK inhibitors, which are so far approved in particular with respect to ibrutinib already mentioned versus the so-called second generation BTK inhibitors, acalabrutinib and zanubrutinib. Maybe Lydia, you want to start and talk a little bit about the background, why there is a small differentiation here between the choice of different BTKis?

Lydia Scarfò:

Sure. I think we gained evidences in the last few years that the mechanism, I mean the inhibition of the BTK is a key target and is very effective. We can improve in terms of selectivity and reduce the adverse event burden. So in the last years, the switch from the prescription of ibrutinib single agent where I feel that the continuous BTK inhibition is important to second generation covalent BTK inhibitors. And these actually even in first line, so the evidence we gathered derived from studies conducted in the relapse refractory setting on one side, the ELEVATE-RR trial and on the other side the ALPINE trial where acalabrutinib and zanubrutinib were compared with ibrutinib. And for acalabrutinib, the design was a non-inferiority design, but the acalabrutinib was not inferior to ibrutinib, and showed a better tolerability profile including a lower rate of bleeding events, atrial fibrillation, hypertension. So this is something that is very relevant in the everyday management of the patients. On the other side, in the ALPINE trial, though the design was quite different, zanubrutinib proved to be superior to ibrutinib in terms of overall response rate, that is the primary endpoint of the study, and progression-free survival with a much lower rate of atrial fibrillation in these patient populations. So they say that where we feel that continuous BTKi treatment is appropriate, nowadays the choice of second generation covalent BTK inhibitors is my favorite one.

Barbara Eichhorst:

Yeah. Thank you very much. Maybe coming to the last group, Anna, you addressed already, TP53 mutated or elided patients, patients in whom first choice of treatment would indeed be continuous treatment. Your thoughts on that?

Anna Schuh:

Yeah, I think, as I said, I think for this group of people we have seen that the progression-free survival with fixed duration therapy is a little bit disappointing compared to the other two groups. So here I would advise continuous therapy and then ideally, as Lydia has already said, with a second generation BTKi starting in acalabrutinib zanubrutinib, I don’t think we have the data really to say one is better than the other. There’s been over the years some cross trial comparisons and attempts to use clever statistics. I don’t really think that these are sufficient evidence to decide one is better than the other.

Barbara Eichhorst:

Maybe one last comment on adding obinutuzumab to acalabrutinib. It is approved and the Phase III trial has shown a small but significant difference on overall survival only in comparison to the chemoimmunotherapy arm with chlorambucil plus obinutuzumab. The guidelines give the chance you could add that, and which patients would you add obinutuzumab to acalabrutinib?

Anna Schuh:

Thanks for reminding me. It’s not paid for in the UK, so we can’t actually give it outside the private setting. The trial was not designed to detect the difference between the two acalabrutinib arms, but of course when you look at the curves it looks pretty convincing that there might be a difference. I have to say I probably would, number one, I would always give choice to the patient because obinutuzumab is a weekly infusion and it is, you have to come to hospital and it’s not completely side effect free, to say the least. So I would have explained this clearly to the patient. I think secondly, possibly patients where I would think some degree of MRD would be a good thing. So younger patients fit patients. That would be my guess with the combination. But as I said, in the UK we can’t really give it.

Lydia Scarfò:

We discussed with a couple of patients here in Italy because as in UK it’s not reimbursed. We were discussing in a specific biomarker profile setting, like young, as Anna mentioned, patients carrying unmutated immunoglobulin genes, so without TP53 aberration because based on the curve it seems that this is the subgroup benefiting the most from the addition of obinutuzumab. The only issue at the present is that this does not lead to a treatment interruption, meaning that even though you improve the long-term disease control, patients are still continuing on acalabrutinib based on the trial design. So also from a patient’s perspective, it isn’t so appealing to, it’s very difficult to grasp the concept of deepening the response, but then continuing with a continuous BTKi even though you improved the disease control. So we didn’t use it yet in our current clinical practice.

Barbara Eichhorst:

Yeah, thank you. So it’s reimbursed in Germany, but I have to admit, I also rarely use it, sometimes in patients who may have autoimmune cytopenia, for example, in order to get them faster into remission. But yeah, as you said, there are significant side effects and you anyhow have to do a continuous treatment. Okay, so I think we covered all aspects with respect to the frontline treatment of CLL according to the ESMO guidelines. I hope this discussion was useful for everyone who was listening to that. As mentioned, we will write an update this year and so therefore maybe there’s a chance to catch up next year again. Thank you very much for listening to that discussion, and thank you very much again, Lydia and Anna for the excellent discussion and your contributions. Thank you.

Anna Schuh:

Thank you.

Lydia Scarfò:

Thank you.

Lydia Scarfò: Honoraria and Advisory Boards: AbbVie, AstraZeneca, BeiGene, Lilly, Johnson&Johnson; Data Monitoring Committee: Merck

Anna Schuh: Honoraria: Beigene, AbbVie; Research funding: AstraZeneca, Janssen; Advisory boards: Janssen, BeiGene; DMC: Genmab; Other: In-kind contributions from Oxford Nanopore Technologies; Founder of SERENOx